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284 publications mentioning hsa-mir-142 (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-142. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 323
Some of the miR-142-3p mutants acquire novel target regulatory functions vis-à-vis the ZEB1 or ZEB2 transcriptional repressors while some lose their ability to downregulate the known targets RAC1 and ADCY9. [score:9]
To show that the mutation in the miR-142-3p-m1 indeed affect the expression level of their mRNA targets, polyclonal rabbit antibodies against the ZEB2 protein were generated using a bacterially expressed GST-ZEB2 fusion protein as previously described [41]. [score:8]
In our previous study on miRNA expression in DLBCL, we found that both miR-142-3p and-5p were expressed at comparable levels (1.1% and 0.8%, respectively, of the total miRNA count) and they may therefore be of equal importance for the regulation of cellular targets [24]. [score:8]
In contrast to the regulation of the mouse p300 gene/mRNA by miR-142-5p, we were not able to demonstrate a downregulation of human p300 by miR-142-5p, neither by testing the 3′ UTR nor by expression of miR-142 in human cells. [score:7]
Seed-sequence mutations of miR-142-3p result in downregulation of ZEB2 protein expression. [score:7]
In addition, the putative tumor suppressor nasopharyngeal carcinoma -associated gene 6 (NGX6), when expressed in colon carcinoma cell lines, induced the expression of miR-142-3p, whereas miR-146a, which is known to be induced via NFkb by the EBV oncogene LMP1 [57], was reduced by NGX6 [58]. [score:7]
It is thus conceivable that at the seed-sequence mutations in miR-142-3p result in a release of RAC1 suppression with a subsequent block in apoptosis, for instance via binding to BCL-2. It is thus conceivable that some of the mutations described in this communication contribute to the induction of DLBCL via a loss of RAC1 inhibition by the mutated miR-142-3p. [score:7]
The two mutants m1 and m2 which show a “gain of function” vis-à-vis the ZEB1 and ZEB2 3′ UTRs also lose their ability to downregulate a second known target of miR-142-3p, the ADCY9 3′ UTR. [score:6]
Because there are no confirmed human miR-142-5p targets, it was not possible to test whether the larger product (or the other mutants affecting the mature miR-142-5p) was still able to regulate a potential target. [score:6]
We also analyzed the expression levels of the cloned miR-142 genes and found no obvious change in the expression of either miR-142-3p or-5p in the various clones (Fig. 6). [score:5]
MiR-142-3p is downregulated in acute myeloid leukemia [24] and inhibits migration and invasion of hepatocellular carcinoma lines [25]. [score:5]
We therefore asked whether the mutation in the seed sequence of miR-142-3p-m1 or -m2 had an influence on the downregulation of RAC1 by this miRNA. [score:5]
As shown in Figures 4A and S5, the vector expressing miR-142-3p-wt did not change the levels of ZEB2 in 293T cells, whereas the expression of the mutant m1 clearly led to a reduction of about 40% in the amount of endogenous ZEB2. [score:5]
When assayed with the various expression vectors, we found that miR-142-3p-wt downregulated the luciferase activity by about 35% (P = 2.4 exp 7), while both -m1 and -m2 had lost their ability to influence the RAC1 3′ UTR (P = 0.23 and P = 0.133, respectively) (Fig. 5A). [score:5]
The mutation in the seed sequence of miR-142-3p as identified by us generated three novel potential binding sites on the 3′ UTR of the mRNA coding for the transcriptional repressor ZEB2 (SIP1), which is, on one hand, involved in the switch of EBV latent to lytic replication [31], but also plays a role in cancer biology by regulating E-cadherin expression and the ensuing epithelial-to-mesenchymal transition (EMT) [32]. [score:5]
In a previous study, we found no change in the expression levels of both miR-142-5p and-3p when we compared EBV -positive versus EBV -negative cases of DLBCL where both miR-142-5p and-3p were expressed at about equal ratios [24]. [score:4]
However, all lymphomas harboring mutations in miR-142 showed expression of IRF4/Mum1 including those of GCB subtype by IHC (Table S1). [score:4]
Figure 3 Downregulation of the ZEB1 3′ UTR by miR-142-3p-m1 but not m2. [score:4]
Figure 4 Downregulation of the ZEB2 protein by miR-142-3p mutant m1. [score:4]
Downregulation of the ZEB2 protein by miR-142-3p mutant m1. [score:4]
In that study, we found that various cellular miRNAs were up- or downregulated at least twofold due to EBV infection, but no significant change in the levels of miR-142-3p or-5p was observed [23]. [score:4]
Point mutations in the seed sequence of miR-142-3p generate novel target sites in the ZEB1 and ZEB2 3′ UTRs. [score:4]
It might be possible that both miR-142-3p and-5p are involved in the regulation of pathways that eventually converge at (a) final target(s). [score:4]
Since no targets are known for miR-142-5p, we can only speculate about the consequences of the mutations affecting miR-142-5p. [score:4]
Conversely, we were able to demonstrate that the mutations in the seed sequence of miR-142-3p destroyed the ability of the miRNA to inhibit the RAC1 mRNA. [score:4]
We have also found a downregulation of miR-142-3p in EBV -positive nasal NK/T-cell lymphoma [52]. [score:4]
Figure 2 Downregulation of the ZEB2 3′ UTR by miR-142-3p mutant m1. [score:4]
Furthermore, we found that both mutants also lost their potential to downregulate the ADCY9 3′ UTR, while miR-142-3p-wt clearly had an effect toward this 3′ UTR (P = 0.000021 for miR-142-3p-wt, P = 0.027 for -m1, and P = 0.28 for -m2) (Fig. 5B). [score:4]
The mutations in m5 and m6 affected the mature miR-142-3p, and mutations in -m7 and -m10 were present in the mature miR-142-5p, but outside the seed sequence. [score:3]
On the other hand, miR-142 might have a tumor-suppressive role in B cells, and the loss of function could then contribute to the induction of DLBCL. [score:3]
We could clearly demonstrate the downregulation of the ZEB2 mRNA by the miR-142-3p mutant m1 (Fig. 1) both in the reporter assays using the ZEB2 3′ UTR (Fig. 2) and on the ZEB2 protein level (Fig. 3). [score:3]
Figure 6 Expression of miR-142 mutants. [score:3]
This is in contrast to recently published data which identified the 3′ UTR of the mouse p300 gene as a target for miR-142-5p [30]. [score:3]
In addition, it is unclear whether this aberrant miRNA still contained the complete sequence present in miR-142-5p or whether, for instance, the 5′ nucleotides essential for target recognition were absent. [score:3]
We then tested the expression level of ZEB2 in 293T cells transfected with empty vector, the pSG5-miR-142-wt vector, and pSG5-miR-142-3p-m1. [score:3]
The mutations were at different sites within the miR-142 precursor; apparently, this patient suffered two individual mutations. [score:3]
A comparison of the miR-142-5p levels in Burkitt's lymphoma versus DLBCL showed that primary Burkitt's lymphoma expresses significantly less miR-142-5p than primary DLBCL [56]. [score:3]
Of those, the mutant designated m9 had two base changes flanking miR-142-5p, and m10 had three mutations (two flanking and one mutation in the mature miR-142-5p outside the seed sequence). [score:3]
Sharma et al. had previously shown that the mouse p300 gene is a target for miR-142-5p. [score:3]
Figure 7The human p300 mRNA is not a target for miR-142-5p. [score:3]
We did not observe mutations in other miRNAs, which indicates that the mutations are specific for miR-142. [score:3]
Therefore, the impact of the miR-142 mutants on ZEB1 expression was not pursued further. [score:3]
A reduced inhibition of ADCY9 by the mutated miR-142-3p would result in increased cAMP levels. [score:3]
Likewise, it is important to identify targets for miR-142-5p. [score:3]
Finally, when we assayed some of the miR-142-5p mutants on the human p300 3′ UTR, we did not find a downregulation by either the wild-type or the mutant miRNAs. [score:3]
We therefore tested the 3′ UTR of the human p300 gene (accession number NM_001429) for its responsiveness to miR-142-5p-wt and of the mutants m1 (mutation in the miR-142-3p), m3 (mutation in the miR-142-5p seed sequence), and the incorrectly processed 5p mutant m9. [score:3]
Recently, the mRNAs coding for the small GTP -binding protein RAC1 and the adenylate cyclase 9 protein (ADCY9) were shown to be targets for miR-142-3p [25, 26]. [score:3]
It was previously shown that the 3′ UTR of the mRNAs for the small GTP -binding protein RAC1 as well as the ADCY9 represents targets for miR-142-3p [18, 26]. [score:3]
The various miR-142-3p,-5p, or precursor mutants were expressed in HEK 293T cells. [score:3]
MicroRNA expression using RNA mimics was done by transfecting 0.75 nmol per 10 [6] cells miR-142-3p-wt, miR-142-3p-m1, or miR-142-3p-m2 (Applied Biosystems/Ambion, Darmstadt, Germany). [score:3]
Robbiani et al. reported a reciprocal translocation in mature B-cell leukemia involving the miR-142 gene locus and the c-myc gene in transgenic, p53 -deficient mice overexpressing AID [19]. [score:3]
RAC1 was shown to be a target of miR-142-3p in hepatocellular carcinoma cells [26]. [score:3]
Furthermore, reduced levels of miR-29a and miR-142-3p are shown to promote growth of acute myeloid leukemia cells, while overexpression leads to a differentiation of myeloid cells with reduced growth properties [50]. [score:3]
To ascertain that the miR-142-5p and the other mutants were processed correctly, we carried out a analysis comparing the transiently expressed miR-142-5p-wt, -m1, -m3, and -m9 along with RNA from U2932 DLBCL cells [24]. [score:3]
As shown in Figure 7A, the p300 3′ UTR was not responsive to either the miR-142-wt or any of the mutants, while the RAC1 3′ UTR assayed in parallel was clearly downregulated by miR-142-wt. [score:3]
Figure 5 MiR-142-3p mutants m1 and m2 lose their potential to downregulate the RAC1 and ADCY9 3′ UTRs. [score:3]
Recently, the mouse p300 gene was identified as a target for murine miR-142-5p [30]. [score:3]
Human p300 is not a target for miR-142-5p. [score:3]
We had access to normal tissue in four cases that featured a mutation in miR-142 (patients with mutants m3, m7, m9, and m10/11). [score:2]
However, as the mutations occurred both in the mature miR-142-5p and-3p form, we assume that the observed gain of function for miR-142-3p on the ZEB1 or ZEB2 3′ UTR was a fortuitous event. [score:2]
Mutations in miR-142 affect correct processing. [score:2]
Here, we show that 11 of 56 DLBCLs suffered mutations in the gene-encoding miR-142 affecting either miR-142-5p, miR-142-3p, or the 87 nt precursor encompassing both miRNAs. [score:2]
We again hypothesize that the miR-142 mutations will most likely result in a loss rather than a gain of function. [score:2]
As described by Wu et al. [26], miR-142-3p appears to be a negative regulator of cell growth. [score:2]
However, we detected a mutation affecting the seed region of miR-142-3p, which generated a potential novel binding site in the 3′ UTR of the ZEB1 mRNA and three potential novel binding sites in the 3′ UTR of the ZEB2 mRNA. [score:2]
miR-142 mutations found in 56 DLBCLs. [score:2]
At least in some cases of DLBCL, the mutations in miR-142-3p/5p might also influence the tumor cell growth via reduced differentiation. [score:2]
In both cases, the translocation affected the levels of c-myc transcript, whereas point mutations in the miR-142 locus were not reported. [score:2]
In the controls (DNA of 20 healthy blood donors and of 10 benign tonsils), no mutation affecting miR-142 was detected (data not shown). [score:2]
The nature of the genes that are regulated by miR-142 in DLBCL is unknown and needs to be elucidated. [score:2]
Mutations in the seed sequence of miR-142-3p result in a loss of responsiveness of the RAC1 and the ADCY9 3′ UTRs. [score:2]
At present, we favor the idea that the mutations within either miR-142-3p or-5p result in a loss of function, which might result in a growth stimulation in DLBCL. [score:2]
The same holds true for the different miR-142 mutations found. [score:2]
The expression of miR-142-3p m1 and m2 (A and C) or-5p (B) was assayed byting using the indicated probes. [score:2]
In addition, the sequences of the miRNAs obtained from the miRNA profiling data of 10 cases each of prostate carcinoma and normal prostate tissue that were previously obtained [35] also showed no mutation in the mature miR-142-3p or-5p (J. Szczyrba, pers. [score:2]
Thus, the occurrence of the miR-142 mutations cannot be correlated to a certain DLBCL subtype. [score:2]
Mutations affecting miR-142 are found in 20% of DLBCL analyzed. [score:2]
Two point mutations each affected the seed sequences of miR-142-5p (mutants designated -m3 and -m4 in Fig. 1) or-3p (mutants designated -m1 and -m2 in Fig. 1). [score:2]
As none of the C-residues in the miR-142 mutants described in the present paper confers to the WRCY (tryptophan-arginine-cysteine-tyrosine) motif used by AID, we assume that the mutations were not caused by AID but by another mechanism active in DLBCL. [score:2]
We thus analyzed a total of 56 cases of DLBCL for the presence of mutations affecting miR-142 and also assayed the regulation of the above-mentioned 3′ UTRs vis-à-vis the mutant miRNA. [score:2]
In one of the cases, we noted a mutation from T to C at position 8 in the seed sequence of miR-142-3p that was confirmed by DNA sequencing of the original tumor specimen. [score:2]
However, as depicted in Figure 1, we found single mutations within the 87 nt long precursor sequence for miR-142 in 11 (19.64%) of 56 cases of DLBCL. [score:2]
Figure 1 Mutations of miR-142 found in DLBCL. [score:2]
Of the 11 lymphomas with miR-142 mutation, five were of ABC and six of GCB type as determined by immunohistochemistry (IHC) [36]. [score:2]
Of those, four single point mutations were present in the mature miR-142-5p or-3p. [score:2]
None of the miR-142 constructs had an effect on the empty pMIR reporter vector (Fig. 2A, left panel). [score:1]
Lv et al. have shown that miR-142-3p plays an oncogenic role in T-lineage acute lymphoblastic leukemia (T-ALL) [51]. [score:1]
org/) employing the mutated seed sequence of miR-142-3p-m1 shown in Figure 1 indicated that the 3′ UTR of the ZEB2 mRNA contained three potential novel binding sites for m1. [score:1]
HEK 293T cells were transfected with empty pSG5 vector, pSG5-miR-142-3p-wt or the m1 mutant as indicated. [score:1]
The mature human and the mouse miR-142-5p are identical. [score:1]
The correct processing to miR-142-3p was previously demonstrated [42]. [score:1]
Further experiments will be necessary to analyze the function of miR-142-3p and-5p for lymphoma cell growth. [score:1]
Because ZEB2 plays a role in tumorigenesis [32], we wanted to see whether miR-142 was mutated in a larger number of DLBCL cases. [score:1]
As shown in Figure S4, miR-142-5p-wt and m1 migrated to the same position as the endogenous miR-142-5p from the U2932 cells. [score:1]
The mutant m9 showed correct processing to the mature miR-142-3p but exhibited a somewhat larger “mature” miR-142-5p. [score:1]
In the case of miR-142-5p-m9, we observed aberrant processing of the miRNA which led to the generation of a larger final product. [score:1]
As already shown in Figure 6, m3 was not recognized using the probe for miR-142-5p-wt, and the m9 mutant again migrated to a higher position. [score:1]
The sequence of the wild-type (WT)miR-142 precursor is shown on top, sequences of the mature miR-142-5p and-3p are underlined with the seed sequences shown in boldface. [score:1]
As shown in Figure 6, all mutants with the exception of m9 were properly processed to the mature miR-142-5p or-3p. [score:1]
Features of the tumours with mutations in miR-142 (OS: overall survival; BA: break-apart assay; cell of origin: determined according to Ref. [score:1]
For the mutations of the binding sites of the miR-142-3p mutants in the 3′ UTR of ZEB2, the sites 1–3 as shown in Figure S1 were sequentially mutated as described [34] using the primer pairs ZEB2 mut1 5′-ACT CTA CTT ATG TAT AGA TCT AAA CTT TAA AAA AC-3′ and ZEB2 mut1rev 5′-GTT TTT TAA AGT TT A GAT CTA TAC ATA AGT AGA GT-3′; ZEB2 mut2 5′-TTT AAT TGC TCG AGA TCT AAT GCA TCA GTA TTA-3′ and ZEB2 mut2rev 5′-TAA TAC TGA TGC ATT AGA TCT CGA GCA CAT TAA A-3′; ZEB2 mut3 5′-CAT TTT AAA AAG GTG CCC G AG ATC TCA TAC ATC AG-3′ and ZEB2 mut3rev 5′-CTG ATG TAT G AG ATC TCG GGC ACC TTT TTA AAA G-3′. [score:1]
The DLBCL cell line U2932 was transfected with RNA mimics using the miR-142-3p-wt or a scrambled RNA mimic (“NC”) as controls as indicated (C). [score:1]
For the amplification of the miR-142 gene with the proof-reading Phusion DNA polymerase (New England Biolabs, Frankfurt/M. [score:1]
We could also demonstrate an effect of the mutants miR-142-3p-m1 and -m2 on the 3′ UTR of the ZEB1 mRNA. [score:1]
We initially observed no or low signals for miR-142-m3-5p, m7-5p, and m10-5p. [score:1]
Thus, miR-142 can be added to the growing number of genes that are mutated in DLBCL. [score:1]
analysis of the miR-142-mutants -m3, -m4, -5, and m10. [score:1]
A corresponding translocation in human aggressive B-cell leukemia involving the miR-142 locus (there called the bcl3 gene) and c-myc was described earlier [20]. [score:1]
The seed sequence is indicated by bold letters, the binding region for miR-142-5p by a bar. [score:1]
As shown in Figure 6, the miR-142-5p-wt probe did not yield a signal for m3 or m7. [score:1]
The alignment of the predicted and known binding sites for miR-142-5p in the human and the mouse p300 3′ UTRs, respectively, are shown in Figure 7C. [score:1]
We then analyzed the EBV -negative U2932-DLBCL cell line for the influence of miR-142-3p-wt or the -m1 mutant. [score:1]
Zhnag et al. have shown that high levels of miR-375 and low levels of miR-142-5p are a predictor for the outcome of gastric carcinoma [49]. [score:1]
Comparison of transiently transfected miR-142-5p mutants with endogenous miR-142-5p. [score:1]
HEK 293T cells (A) were transfected with empty pSG5 vector, pSG5-miR-142-3p-wt, or the m1 mutant as indicated. [score:1]
The luciferase reporter analysis shown in Figure 2A, right panel, demonstrated that m1 but not the miR-142-3p wild-type nor the miR-142-3p-m3 mutant had a significant effect on the reporter. [score:1]
Schematic representation of the potential binding sites for miR-142-m1 and miR-142-m2 in the ZEB1 and ZEB2 3′ UTRs in the luciferase reporter constructs. [score:1]
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[+] score: 300
Previously we identified SIRT1 as a direct target of miR-142; SIRT1 is downregulated in cell lines and neurons overexpressing miR-142 [8] and is known to induce MAOA expression [23]. [score:11]
This regulation of MAOA expression and activity by miR-142 is mediated indirectly through repression of the direct miR-142-5p target, SIRT1, that otherwise induces MAOA expression. [score:10]
This effect of miR-142 on MAOA expression level is mediated by downregulation of the direct miR-142-5p target SIRT1. [score:9]
Although miR-142 expressing cells had lower MAOA expression and activity, miR-142 cannot target MAOA directly as there are no miR-142 recognition elements in the MAOA 3′UTR. [score:8]
We report that chronic overexpression of miR-142 in a neuronal cell line leads to downregulation of expression and activity of the neurotransmitter-metabolizing enzyme monoamine oxidase (MAO) type A. Decrease in MAOA protein level was also confirmed in primary human neurons that were transduced with miR-142. [score:8]
Upregulation of miR-142 may contribute to such changes in dopaminergic neurotransmission in the disease by lowering MAOA expression and activity. [score:8]
Since miR-142 expression leads to decreased levels of SIRT1 [8], and SIRT1 can act on the MAOA promoter to upregulate its expression [23], we hypothesized that introduction of additional SIRT1 would increase the level of MAOA. [score:8]
We isolated mitochondria from miR-142 and miR -null clones to enrich for the MAOs, and tested each for MAO enzyme activity, using the specific inhibitors, clorgyline to inhibit MAOA activity and pargyline to inhibit MAOB activity. [score:7]
Among the miRs that were found to be differentially expressed in the disease condition compared to uninfected control samples, miR-142 was upregulated both in the frontal cortex white matter in humans [7], as well as in the caudate nucleus and hippocampus in monkeys and caudate nucleus in humans [6]. [score:7]
Downregulation of SIRT1 by miR-142 therefore leads to the reduction in MAOA expression and activity, and may contribute to the changes in catecholaminergic neurotransmission in HAND. [score:6]
Upregulation of neuronal miR-142 expression was also reported following peripheral nerve crush [17] and cocaine treatment [18]. [score:6]
In HIVE/SIVE, miR-142 expression is upregulated in neurons. [score:6]
Decrease in SIRT1 levels due to upregulation of miR-142 could therefore explain this decrease in MAOA expression and activity. [score:6]
miR-142 downregulates MAOA protein expression and enzyme activity in BE(2)M17 cells. [score:6]
miR-142 downregulates MAOA protein expression in human neurons. [score:6]
Summary of microarray and qRT-PCR analyses comparing differences in gene expression between stable BE(2)M17 clones expressing miR-142 and miR -null. [score:5]
Overexpression of SIRT1 restores MAOA protein levels in miR-142 -overexpressing BE(2)M17 clones. [score:5]
Therefore regulation of MAOA by miR-142 must be mediated by a direct miR-142 target. [score:5]
Stable overexpression of miR-142 in BE(2)M17 cells reduces MAOA mRNA expression level. [score:5]
In conclusion, we found that chronic increase in neuronal miR-142 expression leads to decrease in MAOA expression and activity. [score:5]
Further investigation is therefore required to elucidate the functional effect of upregulation of miR-142 and downregulation of MAOA in microglia/macrophages in SIVE. [score:5]
The expression of eight genes was altered between the miR-142- and miR -null -expressing clones using these criteria. [score:5]
To identify miR-142-regulated genes relevant to neuronal pathophysiology, we created stable clones of BE(2)M17 neuroblastoma cells expressing miR-142 or the control plasmid, denoted miR -null. [score:4]
In a previous study we showed that in the brain, miR-142 is upregulated within neurons and macrophage/microglia nodules in SIVE [8]. [score:4]
The goal of the present study was to identify neuronal genes affected by chronic miR-142 upregulation and that may contribute to the neuronal pathology in HAND. [score:4]
In HIVE/SIVE both strands of miR-142 are upregulated [6], [7]. [score:4]
However, very little is known about downstream effects of chronic miR-142 upregulation in neuronal cells. [score:4]
Schematic representation of downstream effects of miR-142 upregulation in neurons. [score:4]
In order to investigate the downstream effects of such increase in neuronal miR-142 expression we compared gene expression of stable BE(2)M17 clones expressing miR-142 to clones that were transduced with miR -null. [score:4]
While as expected the Western blot analysis showed that SIRT1 protein level was lower (fold change  = -2.3, p<0.05, n = 3) in the miR-142 expressing clone compared to the miR -null clone, in both clones increased expression of the SIRT1 protein level following the transfections led to an increase in MAOA protein level (miR -null clone 1A, fold change  = 1.7, p<0.01, n = 3; miR-142 clone 6B, fold change  = 1.8, p<0.05, n = 3) (Figure 3A, B). [score:4]
We also identified the NAD -dependent deacetylase Sirtuin1 (SIRT1) as a direct target for miR-142-5p, one of the two functional mature forms of miR-142 [8]. [score:4]
Genes downregulated in the miR-142 clones with a p-value <0.001 were validated by qRT-PCR, which was performed using TaqMan 96-well array (Applied Biosystems, CA, USA) with GAPDH, HPRT1 and GUSB as endogenous controls. [score:4]
In addition to neurons, upregulation of miR-142 was also observed in myeloid cells in the SIVE brain [8]. [score:4]
Upregulation of miR-142 may therefore contribute to changes in dopaminergic neurotransmission reported in HAND. [score:4]
Preparation of stable BE(2)M17 clones expressing miR-142 and miR -null. [score:3]
0079579.g004 Figure 4 Normally, uninfected neurons have minimal miR-142 expression. [score:3]
Chronic overexpression of miR-142 led to decrease in MAOA mRNA and protein levels, as well as a reduction in the enzyme activity. [score:3]
However, in brain sections from rhesus macaques with SIVE, co-localization studies with cell type markers showed that in addition to myeloid cells, miR-142 is expressed both in neurons as well [8]. [score:3]
Overexpression of miR-142 in primary human neurons leads to decrease in MAOA protein levels. [score:3]
We found that miR-142 over -expression in neuronal cell lines and neurons results in lower MAOA mRNA and protein levels, as well as enzyme activity. [score:3]
The FUGW vector was digested with PacI and NheI to generate sticky ends corresponding to that of the pre-miR-142 fragment from the mutated pEP-miR-142 expression vector. [score:3]
Mitochondria were isolated from miR-142 and miR -null expressing BE(2)M17 clones using mitochondria isolation kit for cultured cells (MitoSciences, OR, USA). [score:3]
Normally, uninfected neurons have minimal miR-142 expression. [score:3]
Lentivirus expressing miR-142 was prepared as described previously [25]. [score:3]
In this context, in vitro miR-142 has been shown to target the transcripts of key neuronal genes encoding the D1 dopamine receptor (DRD1) [19] and the Clock-partner aryl hydrocarbon receptor nuclear translocator-like (ARNTL or BMAL1) [20]- [22], both of which play important roles in neuronal function. [score:3]
One of the two mature strands of this miR, miR-142-5p, binds to the 3′UTR of SIRT1 mRNA and prevents its translation. [score:3]
Overexpression of miR-142-3p and-5p in the stable BE(2)M17 clones was confirmed by performing qRT-PCR for the respective mature miRs. [score:3]
miR-142 -overexpressing clones have lower MAOA protein levels and enzyme activity. [score:3]
In addition to SIVE, miR-142 expression in neurons has been reported following nerve crush injury [17] and cocaine treatment [18]. [score:3]
We therefore transfected one of the miR-142 (clone 6B) and one of the miR -null clones (clone 1A) with a SIRT1 expression plasmid (lacking the 3′-UTR with the miR-142 recognition site). [score:3]
qRT-PCR revealed that all except one, that was not detectable, were decreased in the miR-142 expressing cells. [score:3]
Preparation of miR-142 expressing lentivirus and transduction of primary human neurons. [score:3]
Expression levels of miR-142-3p and-5p were confirmed by performing qRT-PCR. [score:3]
Western blot analysis was performed with whole cell lysates from three stable BE(2)M17 clones expressing miR-142 (clones 6B, 6C and 6G) and three miR -null clones (1A, 2A, 2B). [score:3]
Therefore, we postulate that miR-142 decreases MAOA expression by reducing SIRT1 protein level. [score:3]
Cells that express high levels of miR-142 in SIVE have lower SIRT1 protein levels [8]. [score:3]
They were then transduced with either a miR-142 expressing lentivirus or a control GFP lentivirus. [score:3]
These studies, like most with miRs, were conducted after transient overexpression of miR-142. [score:3]
RNA was extracted from three independent miR-142 clones and three miR -null clones, and microarray analysis was performed to determine the differences in gene expression. [score:3]
The BE(2)M17 cell line was chosen because it does not express any endogenous miR-142. [score:3]
SIRT1 is also a validated target for miR-142-5p [8]. [score:3]
Three independent miR-142 and miR -null clones were picked and miR-142 expression was confirmed by qRT-PCR using TaqMan microRNA assay (Applied Biosystems, CA, USA) for miR-142-3p and-5p, and U6 snRNA as endogenous control. [score:2]
In addition to reduction in MAOA mRNA level, MAOA protein level was 3.5 fold lower in the miR-142 -expressing clones compared to the miR -null clones (Figure 1 A, B). [score:2]
MiR-142 is known to be expressed in the cells of the hematopoietic lineage [13]. [score:2]
First, the BamH1 restriction site present upstream of the pre-miR-142 sequence in the pEP-miR-142 expression vector was mutated to a PacI restriction site using the following PCR primers. [score:2]
MiR-142 has been extensively studied in the hematopoietic cell lineage, where it regulates differentiation of T lymphocytes and myeloid cells [13]– [16]. [score:1]
MiR-142 has two functionally active mature strands, miR-142-3p and-5p. [score:1]
Quantification of Western blots from 5 human neuron donors revealed a significant decrease in MAOA level after miR-142 transduction (fold change -1.9, p<. [score:1]
FUGW without precursor miR-142 insert was used as control. [score:1]
Human neurons grown in vitro for 11 days were transduced with either miR-142 or GFP lentivirus. [score:1]
Forward: 5′-tcgattaattaaccttggggggat-3′ Reverse: 5′-tcgagctagcggagg-3′ The PCR product was run on a 1% agarose gel and was extracted from the band corresponding to the length of pre-miR-142 fragment (approximately 300 base pairs) using QIAquick gel extraction kit (Qiagen, Valencia, CA). [score:1]
0079579.g002 Figure 2 Human neurons grown in vitro for 11 days were transduced with either miR-142 or GFP lentivirus. [score:1]
Several colonies were picked and screened for the pre-miR-142 sequence using double digestion with PacI and NheI followed by separation and visualization on 1% agarose gel. [score:1]
The pre-miR-142 fragment was then ligated to the FUGW vector using T4 DNA ligase (Invitrogen, Carlsbad, CA). [score:1]
HEK293T cells were transfected with miR-142-FUGW, Δ8.9 and vesicular stomatitis virus G protein using XtremeGene HP transfection reagent (Roche Applied Science, IN, USA) according to manufacturer's protocol. [score:1]
Primary human neurons were grown in vitro for 11 days and transduced with miR-142 or control lentivirus at a concentration of 5×10 [6] lentiviral particles/mL. [score:1]
BE(2)M17 neuroblastoma cells were transfected either with pEP-miR-142 or a pEP-miR -null plasmid (Cell Biolabs, CA, USA) using Neuromag transfection reagent (Oz Biosciences, France) according to manufacturer's protocol. [score:1]
The MAOA 3′UTR does not have any binding sites for either miR-142-3p or-5p. [score:1]
Forward: 5′-tcgattaattaaccttggggggat-3′ Reverse: 5′-tcgagctagcggagg-3′ The PCR product was run on a 1% agarose gel and was extracted from the band corresponding to the length of pre-miR-142 fragment (approximately 300 base pairs) using QIAquick gel extraction kit (Qiagen, Valencia, CA). [score:1]
0079579.g003 Figure 3 (A) Representative Western blot for SIRT1 and MAOA in BE(2)M17 clones 1A (miR -null) and 6B (miR-142). [score:1]
DNA from colonies that were positive for pre-miR-142 sequence was sent to the UNMC DNA sequencing core facility to confirm the presence of pre-miR-142 sequence. [score:1]
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The HIF-1α level in cells was downregulated by manual overexpression of miR-142, which also brought down the protein expression of vimentin and VEGF-C while promoting the protein expression of E-cad under hypoxic microenvironments, suggesting that miR-142 could inhibit the hypoxic microenvironment -induced epithelial-mesenchymal transition (EMT). [score:12]
Overexpression of miR-142 could down-regulate the protein level of HIF-1α, while knockdown of miR-142 could up-regulate the expression of HIF-1α. [score:12]
Results froms revealed that over -expression of miR-142 inhibited the replication of the PANC-1 and SW1990 cell lines while down-regulation of miR-142 promoted the proliferation of the PANC-1 and SW1990 cell lines (Fig.  1D,E). [score:8]
Since the effect of certain miRNAs on carcinogenesis depends on their downstream targets (Chen et al., 2015; Profumo et al., 2015), TargetScan, miRanda and miRWalk online tools were used to predict the candidate targets of miR-142. [score:7]
PANC-1 and SW1990 cell lines were transfected with miR-142 mimics or miR-142 inhibitor to achieve miR-142 overexpression or inhibition, respectively, and the transfection efficiency was verified using real-time PCR (Fig.  1C). [score:7]
The protein expression of HIF-1α was then determined in response to miR-142 overexpression or inhibition. [score:7]
The hypoxia treatment induced cells’ proliferation, and invasion could be inhibited by miR-142 overexpression or HIF-1α inhibition. [score:7]
In the hypoxic microenvironment, HIF-1α was up-regulated while miR-142 was down-regulated. [score:7]
Table 1. Relative expression levels of HIF-1α and miR-142 according to clinicopathological parameters Abnormalities in miRNAs’ expression are observed almost in all fields of malignant biology, such as cell replication, apoptosis, invasion and/or metastasis, and they may serve as either tumor inhibitors or promoters (Hwang and Men dell, 2007). [score:7]
The expression levels of five candidate targets, ASH-1L, HIF-1α, HMGA1, HMGB1, TCF7, were determined in response to miR-142 overexpression in PANC-1 and SW1990 cells (Fig.  2A). [score:7]
Among five candidates, HIF-1α was shown to be the most significantly down-regulated by miR-142 overexpression. [score:6]
In summary, it was identified that through targeting HIF-1α, pancreatic cancer cell proliferation and invasion are inhibited by miR-142; through regulation of E-cad, vimentin and VEGF-C. The miR-142/HIF-1α axis established in the present study may be essential in modulating pancreatic cancer cell growth and invasion, and may serve as a new medical portal for pancreatic cancer treatment in the future. [score:6]
In our study, the real-time PCR results indicated that miR-142's expressional level was obviously down-regulated both in pancreatic cancer tissues and cell lines. [score:6]
miR-142 inhibits the expression of HIF-1α via directly binding to HIF-1α 3′ UTR. [score:6]
To clarify the molecular mechanism of how miR-142 inhibits the growth of pancreatic cancer cell, the TargetScan (http://www. [score:5]
Moreover, in surgical pancreatic cancer samples, the expressional level of HIF-1α significantly increased, and inversely correlated with miR-142 expression. [score:5]
Overexpression of miR-142 decreases protein expression of HIF-1α. [score:5]
Intervention of miR-142 expression was conducted by transfection with miR-142 mimics or miR-142 inhibitor (Genepharma, Shanghai, China) with the help of Lipofectamine 2000 (Invitrogen). [score:5]
Manual enhanced expression of miR-142 significantly inhibited the proliferation and invasion of pancreatic cancer cells. [score:5]
miR-142 expression is negatively correlated with HIF-1α expression in pancreatic cancer tissues. [score:5]
Moreover,s (Fig.  1F,G) showed that cell invasion ability was significantly inhibited by ectopic expression of miR-142 in PANC-1 and SW1990 cells. [score:5]
To validate the correlation between miR-142/HIF-1α axis and the pathological stage in pancreatic cancer, 42 pancreatic cancer cases were analyzed, and the relative expression levels of HIF-1α and miR-142 according to clinicopathological parameters were exhibited in Table 1. As exhibited, the expression of HIF-1α (P=0.016) and miR-142 (P=0.038) was positively or negatively correlated with the stage of pancreatic cancer, respectively, and miR-142 was negatively correlated with lymphatic metastasis (P=0.043). [score:5]
The above results expressed that miR-142 could potentially be tumor-suppressive in pancreatic cancer. [score:5]
After either HIF-1α knockdown or miR-142 overexpression, the effect of hypoxia on the above factors could be partly restored, thus regulating the cell proliferation and invasion (Fig.  4F). [score:5]
Table 1. Relative expression levels of HIF-1α and miR-142 according to clinicopathological parameters To quantify the expressional level of miR-142 in pancreatic cancer tissues and cell lines, SYBR green quantitative PCR analysis was performed. [score:5]
These data suggested that miR-142 inhibits the expression of HIF-1α in pancreatic cancer cells. [score:5]
The TargetScan, miRanda and miRWalk online tools were used to predict potential targets of miR-142. [score:5]
Song et al. (2009) indicated that cell proliferation in both colorectal carcinoma and osteogenic sarcoma cell lines was inhibited by overexpression of miR-142. [score:5]
The proliferation and invasion of SW1990 cells in response to miR-142 overexpression or HIF-1α knockdown in hypoxia (1% O [2]) treatment or normoxia (20% O [2]) condition was then monitored using MTT ands (Fig.  4D,E). [score:4]
The luciferase reporter assay confirmed the inhibitive effect on the translation of miR-142's putative binding in the HIF-1α 3′UTR region in SW1990 cells. [score:4]
miR-142 is largely downregulated in both pancreatic cancer tissues and cell lines and hinders the proliferation and invasion of pancreatic cancer cells. [score:4]
In this study, we demonstrated that the expression of miR-142 could be significantly suppressed in pancreatic cancer specimens and cell lines compared to their adjacent tissues and normal pancreatic cells. [score:4]
Fig. 1. miR-142 is largely downregulated in both pancreatic cancer tissues and cell lines and hinders the proliferation and invasion of PANC-1 and SW1990 cells. [score:4]
Moreover, expression of epithelial-mesenchymal transition (EMT) markers, Vimentin, VEGF-C and E-cad, was altered under hypoxia conditions and regulated by miR-142/HIF-1α. [score:4]
Moreover, the promotive effect of hypoxia on cancer cell proliferation and invasion could be partly restored after either miR-142 overexpression or HIF-1α knockdown. [score:4]
In this research, it was confirmed that miR-142, known as tumor-suppressive miRNA, had a regulatory relationship with an oncogene, HIF-1α. [score:4]
With the help of bioinformatics analysis, hypoxia-inducible factor 1 (HIF-1α) was identified to be a direct target of miR-142, and a luciferase reporter experiment confirmed this discovery. [score:4]
To further confirm whether the miR-142/HIF-1α axis was involved in the regulation of pancreatic cancer cell proliferation and invasion under hypoxia treatment, the cell proliferation and invasion was monitored under hypoxia conditions, as well as the expression alternation of invasion-related factors. [score:4]
MiR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1. [score:4]
Fig. 3. MiR-142 expression is negatively correlated with HIF-1α expression in pancreatic cancer tissues. [score:4]
After seeding into a 24-well plate, SW1990 cells were cultured overnight, then co -transfected with the wild-type/mutated HIF-1α 3′ UTR luciferase reporter vector and pRL-TK plasmids, or transfected with miR-142 mimics/miR-142 inhibitor. [score:3]
These results indicate that miR-142 appeared to be tumor-suppressive in pancreatic cancer cell lines in vitro. [score:3]
These findings suggest that miR-142 could play a tumor-inhibitive role in the above cancers; however, as far as we know, its potential functional mechanisms remain uncertain and need further exploration in pancreatic cancer. [score:3]
In addition, 42 pancreatic cancer cases were analyzed, and the expression of HIF-1α and miR-142 was correlated with the stage of pancreatic cancer, and miR-142 was correlated with lymphatic metastasis. [score:3]
Hairpin-it TM miRNAs qPCR kit (Genepharma, Shanghai, China) was used to detected the mature miR-142 expressional levels in cells. [score:3]
The miR-142 mimic/inhibitor and wt-HIF-1α vector were co -transfected into the SW1990 cell line. [score:3]
We confirmed that miR-142 inhibited pancreatic cancer cell proliferation and invasion, partly by choosing HIF-1α as its binding site. [score:3]
In this study, we chose miR-142 as the research aim because of its potential suppressive function in human malignancies. [score:3]
Results showed that hypoxia could significantly promote SW1990 cell proliferation and invasion compared with that of the normoxia condition, while the promotive effect of hypoxia on SW1990 cell proliferation and invasion could be partly restored by miR-142 overexpression and HIF-1α knockdown (Fig.  4D,E). [score:3]
de/apps/zmf/mirwalk2/) online tools were used to predict potential targets of miR-142. [score:3]
Downregulation of plasma MiR-142-3p and MiR-26a-5p in patients With colorectal carcinoma. [score:3]
By comparison, when the miR-142 inhibitor silenced endogenous miR-142, the cell invasion (Fig.  1F,G) was enhanced. [score:3]
SW1990 cells were co -transfected with wt-HIF-1α/mut-HIF-1α and miR-142 mimics or miR-142 inhibitor. [score:3]
An inverse correlation was observed between miR-142 and HIF-1α expression levels (Fig.  3D). [score:3]
Growth and invasion of PANC-1 and SW1990 cells were attenuated by overexpression of miR-142 in vitro. [score:3]
To quantify the expressional level of miR-142 in pancreatic cancer tissues and cell lines, SYBR green quantitative PCR analysis was performed. [score:3]
Above all, these findings provided insights on the functional mechanism of miR-142, suggesting that the miR-142/HIF-1α axis may interfere with the proliferative and invasive properties of pancreatic cancer cells, and indicated that miR-142 could be a potential therapeutic target for pancreatic cancer. [score:3]
By using Wilcoxon's paired test, we compared the expression of miR-142 in pancreatic cancer surgical biopsy tissues and the adjacent normal tissues of them. [score:2]
As exhibited by western blot assays, increased miR-142 level in PANC-1 and SW1990 cell lines significantly repressed HIF-1α protein expression, and knockdown of miR-142 increased the protein level of HIF-1α as compared with negative control (NC) (Fig.  2B). [score:2]
Conversely, knocking down of miR-142 might accelerate cell growth and invasion. [score:2]
Compared to control cells, in miR-142 mimic transfected cells the HIF-1α 3′ UTR's luciferase activity was significantly reduced, while it was increased in miR-142 inhibitor transfected cells (Fig.  2C). [score:2]
miR-142/ HIF-1α axis regulates hypoxia -induced cell proliferation and invasion. [score:2]
Besides, compared with normal cell line HPC-Y5, the miR-142 expression level was significantly lower in all four human pancreatic cancer cell lines, PANC-1, SW1990, Hup and CFPAC-1 (Fig.  1B). [score:2]
Taken together, miR-142/HIF-1α axis regulates hypoxia -induced cell proliferation and invasion of pancreatic cancer. [score:2]
Propofol exerts anti-hepatocellular carcinoma by microvesicle -mediated transfer of miR-142-3p from macrophage to cancer cells. [score:1]
SW1990 cells or miR-142 mimics or si-HIF1-α transfected cells were seeded into 6-well plates or Transwell upper inserts, cultured in hypoxia chamber in a humidified atmosphere with 94% N [2], 5% CO [2] and 1% O [2] for 24 h then change to normoxia for additional 24 h for real-time PCR, western blot analysis and. [score:1]
Taken together, miR-142/HIF-1α axis was correlated with the pathological stage of pancreatic cancer, and miR-142 was correlated with lymphatic metastasis of pancreatic cancer. [score:1]
The correlations between miR-142/HIF-1α axis and the pathological stage of pancreatic cancer. [score:1]
We chose to focus on miR-142 because it is closely related to many different malignancies, such as osteosarcoma (Zheng et al., 2015), colorectal carcinoma (Ghanbari et al., 2015) and liver cancer (Zhang et al., 2014). [score:1]
Given the key role of HIF-1α in the regulation of genes associated with angiogenesis, tumor resistance, invasion and metastasis under hypoxia conditions (Kim et al., 2015; Li et al., 2009a; Park et al., 2010), further experiments were arranged to investigate how miR-142/HIF-1α axis regulates tumor biological function in hypoxic microenvironment in pancreatic cancer. [score:1]
These findings bring about novel knowledge of miR-142's character and functional mechanism regarding the pathobiology of pancreatic cancer. [score:1]
Besides, the miR-142 -mediated repression of HIF-1α 3′ UTR luciferase reporter activity could be abolished by mutating the putative miR-142 binding sequence in the HIF-1α 3′ UTR (Fig.  2C). [score:1]
Nevertheless, so far, miR-142's role in pancreatic cancer tumorigenesis and the detailed functional mechanisms of how miR-142 performs remain uncertain. [score:1]
Inversely, the expression of miR-142 was repressed in hypoxia (1% O [2]) treatment compared to that in the normoxia (20% O [2]) condition, as exhibited by real-time PCR assays (Fig.  4B). [score:1]
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The result from this study reveals that CXCL12 could down-regulate the expression of miR-142-3p in human CD4 [+] T cells, which indicates that CXCL12 may act as an up-stream regulator for the expression miR-142-3p in CD4 [+] T cells under ASO condition. [score:9]
To up-regulate the expression miR-142-3p in CD4 [+] T cells, lentivirus expressing miR-142-3p (Lv-miR-142-3p) was used. [score:8]
The down-regulation of miR-142-3p could increase the migration of CD4 [+] T cells into the vascular walls by regulation of actin cytoskeleton via its target genes, RAC1 and ROCK2. [score:7]
Thus, the down-regulated miR-142-3p in CD4 [+] T cells under ASO condition could increase the migration of CD4 [+] T cells by regulation of actin cytoskeleton via its target genes, RAC1 and ROCK2. [score:7]
To identify the direct target genes of miR-142-3p that are related to cell migration, we first performed the bioinformatics analysis and found that RAC1, ROCK2 and WASL could be its potential target genes. [score:6]
As shown in Figure 1C, the expression of miR-142-3p in human CD4 [+] T cells was significantly down-regulated by CXCL12-stimulation (Figure 1C). [score:6]
2. Down-regulation of miR-142-3p in Human CD4 [+] T cells from Patients with ASOThe expression of miR-142-3p in CD4 [+] cells (Purity>97%) was determined by qRT-PCR and in situ hybridization. [score:6]
As miR-142-3p is down-regulated in CD4 [+] T cells from ASO, lentivirus expressing miR-142-3p is constructed and used to determine its biological role. [score:6]
The result shows that up-regulation of miR-142-3p in CD4 [+] T cells could inhibit their migration into aortas or spleens from circulating blood. [score:6]
The relative expression level of miR-142-3p was assessed by qRT-PCR, and an up-regulation of miR-142-3p was seen in Lv-miR-142-3p group (Figure 2C). [score:6]
The decreased miR-142-3p is able to increase the expression of its target genes, RAC1 and ROCK2. [score:5]
In additional other up-stream regulators and their detailed molecular mechanisms responsible for the down-regulation miR-142-3p in CD4 [+] T cells need to be identified in future studies. [score:5]
The results demonstrated that miR-142-3p might inhibit the actin polymerization and polarization through its target genes in CD4 [+] T cells. [score:5]
In contrast, miR-142-3p has a strong inhibitory effect on the expression of RAC1 and ROCK2 at both mRNA and protein levels. [score:5]
Genes related with migration were analyzed by bioinformatics and the potential target genes of miR-142-3p were screened by Targetscan, Miranda, Mirbase, Pic Tar, RNA 22 and PITA, which were further selected according to their positive predictive values. [score:5]
Compared with that from healthy donors, the expression of miR-142-3p in CD4 [+] cells from patients with ASO was significantly down-regulated as determined by the qRT-PCR (Figure 1A). [score:5]
We thus hypothesized that the regulatory effect of miR-142-3p on CD4 [+] T cell migration may be mediated by regulation of actin cytoskeleton via its target genes, RAC1, and ROCK2. [score:5]
The results have revealed that the miR-142-3p expression is down-regulated by 70% in CD4 [+] T cells from patients with ASO compared with that in cells from the healthy donors. [score:5]
CXCL12 inhibits the expression of miR-142-3p in CD4 [+] T cells. [score:5]
Then, each psiCHECK-2 construct along with control vector (vector), miR-142-3p mimics, miR-142-3p inhibitor, mimics control or inhibitor control was transfected into HEK293T cells. [score:5]
2. Down-regulation of miR-142-3p in Human CD4 [+] T cells from Patients with ASO. [score:4]
A hypothesis of the increased migration of CD4 [+] T cells by the down-regulation of miR-142-3p in ASO. [score:4]
In the current study, the down-regulation of miR-142-3p in CD4 [+] T cells from ASO patients is verified by qRT-PCR and is further confirmed by the in situ hybridization. [score:4]
The results demonstrated that both RAC1 and ROCK2 were down-regulated by miR-142-3p at both mRNA (Figure 4A) and protein (Figure 4B) levels. [score:4]
In summary, the current study has identified that miR-142-3p in CD4 [+] T cells is significantly down-regulated in patients with ASO, at least in part, by inflammatory chemokines such as CXCL12 (Figure 6). [score:4]
Taken together, RAC1 and ROCK2 were direct target genes of miR-142-3p. [score:4]
4. Up-regulation of miR-142-3p via Lentivirus -mediated Gene Transfer. [score:4]
Up to date, the mechanisms related to the down-regulation of miR-142-3p in CD4 [+] T cells under the ASO condition are still unknown. [score:4]
MiR-142-3p has recently been identified as a down-regulated miRNA in CD4 [+] T cells in patients with systemic lupus erythematosus, which is associated with the over-activation of CD4 [+] T cells [3]. [score:4]
The down-regulation of miR-142-3p in CD4 [+] cells from patients with ASO was further confirmed by analysis of fluorescence intensity via in situ hybridization (Figure 1B). [score:4]
Taken together, the results indicate that RAC1 and ROCK2 are two direct target genes of miR-142-3p in CD4 [+] T cells. [score:4]
Up-regulation of miR-142-3p by lentivirus -mediated gene transfer. [score:4]
0095514.g006 Figure 6A hypothesis of the increased migration of CD4 [+] T cells by the down-regulation of miR-142-3p in ASO. [score:4]
To test the potential target genes of miR-142-3p that are related to its biological effect on CD4 [+] T cell migration, we first performed the bioinformatics analysis of the genes that are related to the regulation of actin cytoskeleton and have the miR-142-3p binding sites in their 3′UTRs. [score:4]
Indeed, our result by actin staining has revealed the attenuation of actin polymerization and polarization in cells after up-regulation of miR-142-3p. [score:4]
However, the detailed molecular mechanisms that are responsible for CXCL12 -mediated downregulation of miR-142-3p in human CD4 [+] T cells are still unclear. [score:4]
Our results show that in the presence of the RAC1 or ROCK2 3′UTR, miR-142-3p mimics significantly decrease the luciferase activity, while miR-142-3p inhibitor show an opposite result. [score:3]
The expression of miR-142-3p in CD4 [+] cells (Purity>97%) was determined by qRT-PCR and in situ hybridization. [score:3]
After stimulation with CXCL12, cells transfected with Lv-NC showed a normal pattern of actin polymerization and polarization (Figure 5A), while an inhibitory result was shown in Lv-miR-142-3p group (Figure 5B). [score:3]
In contrast, no effect of miR-142-3p on the expression of WASL was found. [score:3]
The results showed that in the presence of the RAC1 or ROCK2 3′UTR, miR-142-3p mimics significantly decreased relative luciferase activity while miR-142-3p inhibitor showed an opposite effect (Figure 4C). [score:3]
of the miRNA array in our laboratory have identified that miR-142-3p is down-regulated in patients with ASO compared with that in healthy donors. [score:3]
The current study has identified, for the first time, that miR-142-3p has a strong inhibitory effect on human CD4 [+] T cell migration in cultured system in vitro. [score:3]
7. Actin Cytoskeleton Regulation of miR-142-3p in Human CD4 [+] T cells RAC1 and ROCK2 are two known regulatory genes of actin cytoskeleton. [score:3]
6. Target Gene Identification of miR-142-3p. [score:3]
3. CXCL12-stimulation Decreases the Expression of miR-142-3p. [score:3]
The inhibitory effect of miR-142-3p on cancer cell migration is also demonstrated in hepatocellular carcinoma cells in a recent report [18]. [score:3]
To verify the inhibitory effect of miR-142-3p on CD4 [+] T cell migration in vivo, we have performed the animal trafficking experiment in vivo by using fluorescent labeled mouse CD4 [+] T cells. [score:3]
5. Target Prediction of miR-142-3p. [score:3]
Thus, WASL is not a target gene of miR-142-3p in CD4 [+] T cells. [score:3]
The expression of miR-142-3p in human CD4 [+] cells. [score:3]
As shown in Figure 3A, a significant decrease in migration toward CXCL12 (decrease in chemotaxis index) was identified in CD4 [+] T cells overexpressing miR-142-3p induced by Lv-miR-142-3p. [score:3]
Target gene identification of miR-142-3p. [score:3]
However, miR-142-3p has no effect on the expression of WASL. [score:3]
In addition, the expression of miR-142-3p after transfection is significant increased as determined by qRT-PCR. [score:3]
The results of animal trafficking experiment were summarized in Table 7. These results indicated that miR-142-3p had an inhibitory role in migration of CD4 [+] T cells both in vitro and in vivo. [score:3]
0095514.g001 Figure 1The expression of miR-142-3p in human CD4 [+] cells. [score:3]
Sequences of primers used for dual luciferase assay were summarized in Table 4. Each psiCHECK-2 construct along with vector, miR-142-3p mimics, miR-142-3p inhibitor, mimics control or inhibitor control (RIBOBIO) was transfected into HEK293T cells. [score:3]
Although in this study, we have focused on the RAC1 and ROCK2, other target genes of miR-142-3p that are related cell migration should be tested in future studies to determine whether they are related to miR-142-3p -mediated effect on CD4 [+] T cell migration. [score:3]
At 3 hours after stimulation, the expression of miR-142-3p returned to the basal level. [score:3]
After transfection with Lv-miR-142-3p or control virus (Lv-NC), both mRNAs and proteins in human CD4 [+] T cells were collected to evaluate the expression levels of these predicated target genes. [score:3]
If miR-142-3p -mediated effect on CD4 [+] T cell migration is through its target genes, RAC1 and ROCK2, the actin cytoskeleton should be affected. [score:3]
When the binding sequence in RAC1 or ROCK2 3′UTR was mutated, the regulatory effect of miR-142-3p on luciferase activity was abrogated (Figure 4D). [score:2]
When the binding sequences in RAC1 or ROCK2 3′UTR are mutated, the regulatory effect of miR-142-3p on luciferase activity is abrogated. [score:2]
0095514.g004 Figure 4(A) After transfection with Lv-miR-142-3p, mRNAs of RAC1 and ROCK2 were down regulated, while there was no statistically difference shown in WASL in human CD4 [+] T cells, detected by qRT-PCR. [score:2]
ASO, patients with ASO; Control, healthy donors; n = 8; **P<0.01 compared with the control in A and 0 time point in C. (A) The expression of miR-142-3p in CD4 [+] cells from patients with ASO (n = 8) and from healthy donors (n = 8), detected by qRT-PCR. [score:2]
The followed several reports have also revealed that miR-142-3p may play important roles in the regulation of activation and proliferation of CD4 [+] cells [3]– [5]. [score:2]
Actin cytoskeleton regulation of miR-142-3p in human CD4 [+] T cells. [score:2]
7. Actin Cytoskeleton Regulation of miR-142-3p in Human CD4 [+] T cells. [score:2]
0095514.g005 Figure 5Actin cytoskeleton regulation of miR-142-3p in human CD4 [+] T cells. [score:2]
Moreover, the binding and inhibitory effect of miR-142-3p on RAC1 and ROCK2 is further verified by the luciferase assay. [score:2]
MiR-142-3p may provide a novel molecular mechanism involved in CD4 [+] T cell migration and may represent a novel targets for preventing and treating ASO. [score:2]
Sequences of primers used for lentivirus construction were listed in Table 3. CD4 [+] T cells were transfected with either negative control lentiviral vector (Lv-NC) or lentiviral vector expressing miR-142-3p (Lv-miR-142-3p) at a multiplicity of infection of 1×10 [7] transfecting units per ml in the presence of polybrene (8 µg/ml) [8]. [score:2]
The effect of miR-142-3p on the migration of CD4 [+] T cells. [score:1]
The 3′UTR sequence of RAC1 or ROCK2 containing the putative binding sites of miR-142-3p were cloned into psiCHECK-2 vector. [score:1]
Blue fluorescent represented nuclear and red fluorescent represented miR-142-3p. [score:1]
5. The Effect of miR-142-3p on the Migration of CD4 [+] T cells. [score:1]
After lentivirus transfection, cells in Lv-miR-142-3p or Lv-control (Lv-NC) -treated groups were injected into ApoE [−/−] C57BL/6 mice. [score:1]
ASO, patients with ASO; Control, healthy donors; n = 8; **P<0.01 compared with the control in A and 0 time point in C. To test whether or not the stimulation of chemokine could affect the expression of miR-142-3p in CD4 [+] cells, CXCL12 stimulation assay was performed. [score:1]
To test this hypothesis, the effect of miR-142-3p on actin cytoskeleton in human CD4 [+] T cells was determined by actin staining. [score:1]
Forty-eight hours later, the ratio of CD4 [+] T cells in Lv-miR142-3p group was significantly lower than that in Lv-NC group in either aorta (Figure 3B) or spleen (Figure 3C), while the ratio of cells remaining in blood was higher in Lv-miR-142-3p group (Figure 3D). [score:1]
0095514.g003 Figure 3The effect of miR-142-3p on the migration of CD4 [+] T cells. [score:1]
Although the migration of CD4 [+] T cells from blood to vascular walls and within the vascular walls are prerequisite for CD4 [+] T cells to achieve its immune injury in arteries, no study has been performed to test the potential role of miR-142-3p in CD4 [+] T cell migration. [score:1]
Aorta(%) Spleen(%) Blood(%) Lv-NC group (n = 3) 2.3±0.4 3.5±0.5 8.8±1.2 Lv-miR-142-3p group (n = 3) 1.1±0.2** 2.0±0.3** 13.4±2.1** Ratio is presented as mean±SD. [score:1]
After 0, 1, 2 and 3 hours’ culture, total RNAs of cells were extracted to evaluate the expression of miR-142-3p by qRT-PCR. [score:1]
The current study is thus designed to determine the potential role of miR-142-3p in CD4 [+] T cell migration and the mechanisms involved. [score:1]
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5
[+] score: 257
Since DNA methylation has been found to be both upregulated 30– 33 and downregulated 34– 36; in a number of cancer types including PDAC, we reasoned that dysregulated methylation may be responsible for the observed changes in miR-142-3p expression. [score:10]
Error bars represent the standard deviation Low miR-142-3p expression and high DNMT1 expression correlate with poor survival in human cancersThe data we present here identify a novel mechanism by which mutant p53 [R172H] is able to decrease expression of miR-142-3p in a mouse mo del of PDAC, through genomic hypermethylation due to increased expression of DNMT1. [score:9]
Statistical significance is represented as * p < 0.05 The miR-142 genomic locus is hypermethylated in mutant p53 [R172H] -expressing primary cell linesAs direct depletion of Dnmt1 and a methylation-inhibiting drug were both shown to induce miR-142-3p expression, direct analysis of CpG dinucleotides in the miR-142 genomic locus was carried out. [score:9]
Statistical significance is represented as * p < 0.05 and *** p < 0.005. c A representative western blot showing the expression of Dnmt1, Pten, p53 and β -actin in the primary cell lines As we observed an inverse correlation between miR-142-3p and Dnmt1 expression, we asked if inhibiting DNA methylation had an impact on miR-142-3p expression levels. [score:9]
Murine primary pancreatic tumour tissues and primary cell lines, as well as ectopic expression of human mutant p53 [R175H] in TP53 null cells, all showed that miR-142-3p is downregulated in mutant p53 [R172H] or p53 [R175H] -expressing PDAC. [score:8]
Statistical significance is represented as * p < 0.05 As direct depletion of Dnmt1 and a methylation-inhibiting drug were both shown to induce miR-142-3p expression, direct analysis of CpG dinucleotides in the miR-142 genomic locus was carried out. [score:7]
These findings are very much in line with our data which show that Dnmt1 inhibition increases miR-142-3p expression and that increasing miR-142-3p expression reduces the invasive potential of tumour cells. [score:7]
As 5-aza-DC is a functional inhibitor of all members of the DNMT family [38], we asked if specific inhibition of Dnmt1 was also able to affect miR-142-3p expression. [score:7]
This suggests that miR-142-3p and miR-340-5p expression is directly affected by mutant p53 [R172H] expression. [score:6]
RT-qPCR validation confirmed that the expression of miR-142-3p and miR-340-5p does not differ between the two control conditions (Kras p53 [flox] and Kras Pten [flox]), but both miRNAs are significantly downregulated in the Kras p53 [R172H] tissues (Fig.   1c). [score:6]
A recent study found that miR-142-3p is downregulated in human PDAC when compared to paired adjacent normal tissue and in pancreatic cancer cell lines, and showed that hypoxia-inducible factor (HIF1α) is a direct target of miR-142-3p in PDAC [29]. [score:6]
As there is no wild-type p53 expressed in these cells for the mutant p53 [R175H] to act upon in a dominant -negative manner, this strongly suggests that miR-142-3p is being downregulated due to the gain-of-function activity of this mutant. [score:6]
These results taken together with our findings identify both direct and downstream secondary targets by which miR-142-3p functions in human patients and link its expression to invasion and metastasis. [score:6]
Ectopic expression of mutant p53 [R175H] led to a downregulation of miR-142-3p, which confirmed our results for the mouse protein. [score:6]
Dnmt1 is dysregulated by mutant p53 [R172H] in PDACOur investigations of the PDAC mo dels did not uncover any global changes in mature miRNA expression, so we focused on regulatory mechanisms pertaining to the specific dysregulation of miR-142-3p expression. [score:6]
Zhang Y Lui Y Xu X Upregulation of miR-142-3p improves drug sensitivity of acute myelogenous leukemia through reducing P-glycoprotein and repressing autophagy by targeting HMGB1Transl. [score:6]
RT-qPCR of the cells lines showed that expression of miR-142-3p follows the profile observed in the tissue samples, with no difference between the control conditions (Kras p53 [flox] and Kras p53 [R172H]) and a significant downregulation in the mutant Kras p53 [R172H] cells (Fig.   2b). [score:6]
Previous findings of the impact of miR-142-3p on tumour progression along with the data presented in this study, linking mutant p53 [R172H] and DNMT1 expression, suggest that DNMT1 may be a potential therapeutic target in PDAC. [score:5]
A two-tailed Mann–Whitney U-test was used to assess for statistically significant differences between the two bisulphite sequencing groups Overexpression of miR-142-3p inhibits p53 [R172H] -driven invasion in vitroGiven that mutant p53 [R172H] has been shown to drive invasion and metastasis in PDAC [6], we investigated the impact of overexpression of miR-142-3p on cell invasion. [score:5]
Error bars represent the standard deviation The data we present here identify a novel mechanism by which mutant p53 [R172H] is able to decrease expression of miR-142-3p in a mouse mo del of PDAC, through genomic hypermethylation due to increased expression of DNMT1. [score:5]
Here we show that mutant p53 [R172H] inhibits expression of miR-142-3p, a microRNA known to drive invasion and metastasis in PDAC [29]. [score:5]
Additionally, two recent studies have shown that increasing miR-142-3p expression in acute myelogenous leukaemia [41] and non-small cell lung cancer [42] improves chemosensitivity by decreasing autophagy due to translational repression of HMGB1. [score:5]
All data sets which show a statistically significant correlation are reported, all of which show a correlation between high DNMT1 expression and poor patient survival a The data set in the YM500v3 database shows a clear correlation between low miR-142-3p expression and poor survival in human PDAC. [score:5]
Statistical significance is represented as * p < 0.05 Our investigations of the PDAC mo dels did not uncover any global changes in mature miRNA expression, so we focused on regulatory mechanisms pertaining to the specific dysregulation of miR-142-3p expression. [score:5]
miR-142-3p overexpression inhibits mutant p53 -driven invasion in vitro. [score:5]
The data presented in this study identifies a potential new mechanism by which mutant p53 [R172H] is able to affect gene expression in a gain-of-function manner, through increased expression of DNMT1 which in turn leads to hypermethylation of miR-142-3p and perhaps other genes. [score:5]
Low miR-142-3p expression and high DNMT1 expression correlate with poor survival in human cancers. [score:5]
Overexpression of miR-142-3p inhibits p53 [R172H] -driven invasion in vitro. [score:5]
MiR-142-3p expression can be rescued by inhibition of methylation. [score:4]
However, the previously published data does not connect dysregulation of miR-142-3p to gain-of-function mutations in TP53 nor does it identify a mechanism by which miR-142-3p is dysregulated. [score:4]
Mackenzie TN Triptolide induces the expression of miR-142-3p: a negative regulator of heat shock protein 70 and pancreatic cancer cell proliferationMol. [score:4]
Chen Y Zhou X Qiao J Bao A MiR-142-3p overexpression increases chemo-sensitivity of NSCLC by inhibiting HMGB1 -mediated autophagyCell Physiol. [score:4]
Statistical significance is represented as * p < 0.05. c The average change in miR-142-3p expression in cells transfected with the miR-142-3p expression vector compared to cells transfected with empty vector. [score:4]
Therefore, we wished to determine whether miR-142-3p or DNMT1 expression correlates with human patient survival. [score:3]
The YM500v3 database was interrogated to see how miR-142-3p expression correlated with human patient survival. [score:3]
a The data set in the YM500v3 database shows a clear correlation between low miR-142-3p expression and poor survival in human PDAC. [score:3]
Meanwhile, low expression of miR-142-3p correlated with an increased incidence in lymphatic metastasis. [score:3]
As in the case of 5-aza-DC treatment, expression of miR-142-3p was significantly increased following depletion of Dnmt1 in the Kras p53 [R172H] cell line (Fig.   5a, b). [score:3]
Conditions with overexpression of miR-142-3p included a preceding day, where cells were transfected with either an empty vector or one containing the miR-142 primary microRNA sequence. [score:3]
Kras p53 [flox] (n = 2), Kras p53 [R172H] + empty vector (n = 4) and Kras p53 [R172H] + miR-142 expression vector (n = 4) mouse primary PDAC cells were analysed for their invasive potential. [score:3]
In addition, these data show that the human orthologue of the TP53 mutant is also able to affect the expression of miR-142-3p. [score:3]
Statistical significance is represented as * p < 0.05, ** p < 0.01 and *** p < 0.005 Table 1 ▓▓▓▓ microRNA FDR FC Pten [flox] vs p53 [R172H] FC p53 [flox] vs p53 [R172H] mmu-miR-142-3p 0.015912686 −3.7405517 −4.579501 mmu-miR-30c-2-3p 0.046220515 −15.577352 −10.701015 mmu-miR-340-5p 0.03768438 −1.9938585 −2.1791608 mmu-miR-378b 0.04617887 −2.1360645 −1.9538167 This analysis provides information about miRNA expression changes in the physiological context of the primary tumour environment in mouse mo dels. [score:3]
Statistical significance is represented as * p < 0.05, ** p < 0.01 and *** p < 0.005 Table 1 ▓▓▓▓ microRNA FDR FC Pten [flox] vs p53 [R172H] FC p53 [flox] vs p53 [R172H] mmu-miR-142-3p 0.015912686 −3.7405517 −4.579501 mmu-miR-30c-2-3p 0.046220515 −15.577352 −10.701015 mmu-miR-340-5p 0.03768438 −1.9938585 −2.1791608 mmu-miR-378b 0.04617887 −2.1360645 −1.9538167This analysis provides information about miRNA expression changes in the physiological context of the primary tumour environment in mouse mo dels. [score:3]
This revealed a strong correlation between poor survival and low miR-142-3p expression in human PDAC (Fig.   8a). [score:3]
The miR-142 genomic locus is hypermethylated in mutant p53 [R172H] -expressing primary cell lines. [score:3]
Importantly, overexpression of miR-142-3p in the Kras p53 [R172H] cells leads to a significant reduction in the invasive potential of these cells in vitro (Fig.   7a–c). [score:3]
A two-sample, two-tailed, paired t-test was used to compare the average percentage of invasion between biological repeats (n = 4) for Kras p53 [R172H] + empty vector and Kras p53 [R172H] + miR-142-3p expression vector. [score:3]
Importantly, we show that both DNMT1 and miR-142-3p expression correlate with patient survival, which may provide opportunities for therapeutic intervention. [score:3]
Methyl primer Express software (Applied Biosystems) was used to interrogate a sequence of DNA 700 bp both up and downstream of the miR-142 precursor sequence. [score:2]
Lu Y MiR-142 modulates human pancreatic cancer proliferation and invasion by targeting hypoxia-inducible factor 1 (HIF-1α) in the tumor microenvironmentsBiol. [score:2]
A CpG island which overlaps the miR-142 genomic locus was identified using Methyl Primer Express software (Applied Biosystems, Waltham, MA, USA) (Fig.   6). [score:2]
The other miRNAs under investigation showed mild to no change in expression following Dnmt1 depletion, demonstrating selectivity for miR-142-3p. [score:1]
Fig. 8Low miR-142-3p and high DNMT1 correlate with a poor prognosis in human PDAC. [score:1]
Treatment of the Kras p53 [R172H] cell line for 24 h with 1 μM of 5-aza-DC led to a significant induction of miR-142-3p while having no effect on the expression of other miRNAs investigated in this study (Fig.   4). [score:1]
Using the definition of a CpG island as a sequence with a CpG observed/expected ratio >0.6, a 590 bp CpG island was observed overlapping the miR-142-3p precursor sequence. [score:1]
Low miR-142-3p and high DNMT1 correlate with a poor prognosis in human PDAC. [score:1]
A total of four miRNAs, miR-142-3p, miR-30c-2-3p, miR-340-5p and miR-378b, were found to be dysregulated in the Kras p53 [R172H] tissues compared to both the Kras p53 [flox] and Kras Pten [flox] tissues. [score:1]
Triptolide has been shown to be efficacious in treatment of PDAC through induction of miR-142-3p [56]. [score:1]
A two-tailed Mann–Whitney U-test was used to assess for statistically significant differences between the two bisulphite sequencing groups Given that mutant p53 [R172H] has been shown to drive invasion and metastasis in PDAC [6], we investigated the impact of overexpression of miR-142-3p on cell invasion. [score:1]
It is possible that the same mechanism is inducing Dnmt1 transcription in this PDAC mo del, leading to subsequent hypermethylation of miR-142-3p. [score:1]
Transfected cells not used for the invasion assay were used to quantify the degree of miR-142-3p overexpression using Taqman assays. [score:1]
We show that this occurs through a DNMT1 -dependent mechanism leading to increased genomic methylation around the miR-142-3p genomic locus. [score:1]
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6
[+] score: 238
The potential targets of mir-142-3p and-5p were predicted using the TargetScan and PicTar algorithms, and the targets predicted by both algorithms were listed in Additional file 4. The conserved E-box (CACGTG) in the upstream regulatory sequence of mir-142 was analyzed using DNAman, and the conservation track was obtained from the UCSC genome browser (http://genome. [score:8]
These results showed that mir-142-3p could regulate the expression of Bmal1 by directly targeting its 3’UTR. [score:7]
The over -expression (in 293ET and NIH3T3 cells) and knockdown (in U87MG cells) of mir-142-3p reduced and up-regulated the Bmal1/BMAL1 mRNA and protein levels, respectively. [score:7]
Here in this study, we found that mir-142-3p directly targeted Bmal1 and its expression was regulated by CLOCK/BMAL1 heterodimers. [score:7]
The expression levels of mir-142-3p in control NIH3T3 (mir-NC) and 293ET (pcDNA3.1) cells were normalized against that in mir-142-3p/mir-142-pcDNA3.1 -transfected cells which were set at 1. Note that, because the mir142-3p expression was low in control 293ET cells (pcDNA3.1) and was increased more than 1000-fold when cells were transfected with mir-142-pcDNA3.1, the relative expression level of mir-142-3p in control group (pcDNA3.1) was very low. [score:7]
Mir-142-3p is a Bmal1 -targeting miRNABy computational prediction using three algorithmic methods (TargetScan, PicTar and MicroCosm), we found two miRNAs that putatively target Bmal1 (Figure 1A). [score:7]
Taken together, CLOCK/BMAL1 heterodimers can bind to the E-box in the upstream regulatory sequence and activate the expression of mir-142; one product of mir-142, mir-142-3p, can act as a negative regulator of Bmal1 by targeting its 3’ UTR. [score:7]
To confirm that mir-142-3p can regulate the expression of Bmal1, mir-142-3p was over-expressed in the NIH3T3 and 293ET cells or knocked down in U87MG cells, and the mRNA and protein levels of human BMAL1 and mouse Bmal1 were determined. [score:7]
By over -expression of mir-142-3p in NIH3T3 cells, we showed mir-142-3p can regulate the expression of Bmal1. [score:6]
Although mir-142-3p has been reported to be a potential Bmal1 -targeting miRNA based on a luciferase reporter assay [17], the present report is the first confirmation that mir-142-3p can directly regulate the expression of Bmal1 both in mouse and human cells. [score:6]
The over -expression of mir-142-3p led to reductions in the levels of both Bmal1 (BMAL1) mRNA and protein in NIH3T3 (Figure 2B) and 293ET cells (Figure 2C), and knocking down mir-142-3p with antagomirs increased the expression of BMAL1 mRNA and protein in U87MG cells (Figure 2D). [score:6]
Moreover, the simultaneous ectopic expression of Clock and Bmal1 (but not Clock or Bmal1 alone) significantly induced the expression of mir-142-3p in NIH3T3 cells (Figure 5D). [score:5]
We also found that over -expression of mir-142 could significantly reduce the luciferase reporter RNA levels (Additional file 1B), suggesting that mir-142 was able to accelerate target mRNA degradation. [score:5]
The mir-142-pcDNA3.1 and mir-448-pcDNA3.1 expression plasmids were first transfected into 293ET cells and the expressions of mature miRNAs were verified by quantitative RT-PCR (Additional file 1A). [score:5]
Moreover, the expression level of mir-142-3p oscillated in serum-shocked NIH3T3 cells and the results of ChIP and luciferase reporter assays suggested that the expression of mir-142-3p was directly controlled by CLOCK/BMAL1 heterodimers in NIH3T3 cells. [score:5]
In our concise mo del, CLOCK/BMAL1 heterodimers enhance the transcription of mir-142, the product of which, in turn, inhibits the expression of Bmal1. [score:5]
The luciferase activity of (M1 + M2) was still decreased by about 30% with mir-142 over -expression, which may be ascribed to the background of luciferase reporter experiments for that mir-142 over -expression also led to an approximately 25% reduction of luciferase activity of the empty reporter vector (LUC) (Figure 1E). [score:5]
Mir-142-3p regulates the Bmal1 mRNA and protein levelsTo investigate the regulatory effect of mir-142-3p on the expression of endogenous Bmal1, we detected the expression level of mir-142-3p and Bmal1 protein level in six cell lines (NIH3T3, 293ET, MCF-7, U87MG, T98G and U251) generally used in our laboratory. [score:5]
In this study, we found that mir-142-3p directly targeted the 3’UTR of human BMAL1 and mouse Bmal1. [score:4]
However, a further study on the effects of knocking down mir-142-3p in appropriate murine cell mo dels (with high level of mir-142-3p) will help to confirm the relationship between mir-142-3p and its target at the physiological conditions. [score:4]
To investigate the regulatory effect of mir-142-3p on the expression of endogenous Bmal1, we detected the expression level of mir-142-3p and Bmal1 protein level in six cell lines (NIH3T3, 293ET, MCF-7, U87MG, T98G and U251) generally used in our laboratory. [score:4]
We have identified mir-142-3p as a potential regulator of Bmal1; therefore, it is of interest to explore the possibility that if this Bmal1 -targeting miRNA is under circadian control. [score:4]
The other product of mir-142, mir-142-5p, was also predicted to target numerous genes, the most interesting one of which is Clock, the other master regulator of the molecular clock (Additional file 4). [score:4]
Our study demonstrates that mir-142-3p can directly target the 3’UTR of Bmal1. [score:4]
In luciferase reporter assays, mutating each of the two mir-142-3p binding sites significantly reduced the repression effect of mir-142 over -expression on luciferase activity, and double mutations (M1 + M2) showed greater effect than single mutation (M1 or M2) (Figure 1E). [score:4]
Our study demonstrates that mir-142-3p can directly target the 3’UTR of Bmal1. [score:4]
In this study, we showed that the clock-controlled mir-142-3p can directly target its circadian activator, Bmal1. [score:4]
Besides the conserved canonical E-box, there is an unconserved non-canonical E’-box in the upstream regulatory sequence of mir-142 gene which might contribute to the induction of luciferase activity of P142-MT-LUC by co -expression of Clock and Bmal1 (Additional file 2). [score:4]
The 293ET cells were transfected with the mir-142 expression plasmid (mir-142-pcDNA3.1) or control vector (pcDNA3.1) (C). [score:3]
Predicting the targets of mir-142-3p and mir-142-5p. [score:3]
In addition, the expression of mir-142-3p is controlled by CLOCK/BMAL1 heterodimers, suggesting a potential negative feedback loop consisting of the miRNAs and the core clock genes. [score:3]
Other genes were also predicted to be targets of mir-142-3p (Additional file 4), and two of them (foxo1 and Nr3c1) are involved in the circadian clock [22, 23]. [score:3]
Click here for file Predicting the targets of mir-142-3p and mir-142-5p. [score:3]
In a synchronized NIH3T3 cell mo del, we found that the level of mir-142-3p oscillated rhythmically, with the peak levels (24 h and 48 h) phase lagging the crests (4 h and 28 h) of Bmal1 mRNA (Figure 3), suggesting the expression of mir-142-3p might be under circadian control. [score:3]
And then the expression patterns of Bmal1 mRNA and mir-142-3p were determined by quantitative RT-PCR (mean ± SD, n = 3). [score:3]
The expression level of mir-142-3p and BMAL1 mRNA in U87MG cells were determined by quantitative RT-PCR (mean ± SD, n = 3) and normalized against controls set at 1. All of the western blotting results were quantified from the pixel values in grayscales (mean ± SD, n = 3) and normalized against controls set at 1. Inserts are the representative western blotting results. [score:3]
Recently, a report showed that mir-494 and mir-142-3p, two circulating miRNAs, can target the Bmal1 3’ UTR in mice [17]. [score:3]
In contrast, NIH3T3, 293ET, MCF-7, T98G and U251 cells with low mir-142-3p levels expressed high levels of Bmal1 protein (Figure 2A). [score:3]
In addition to Bmal1, mir-142-3p was reported to target several genes, including ADCY9, whose product controls cAMP levels [21]. [score:3]
Figure 3 The expression of mir-142-3p oscillates in serum shocked NIH3T3 cells. [score:3]
The over -expression of mir-142-3p in NIH3T3 and 293ET cells was first verified, and then the Bmal1/ BMAL1 mRNA and protein levels were detected by quantitative RT-PCR (mean ± SD, n = 3) and western blotting, respectively. [score:3]
Figure 1 mir-142-3p can target Bmal1 3’UTR. [score:3]
The results confirmed that the over -expression of Clock and Bmal1 enhanced the transcription of mir-142. [score:3]
Over -expression of mir-142 but not mir-448 significantly repressed the activity of the Bmal1/ BMAL1 3’UTR-luciferase reporter (Figure 1B). [score:3]
Figure 5 CLOCK/BMAL1 heterodimers activate the expression of mir-142. [score:3]
Mir-142-3p is a Bmal1 -targeting miRNA. [score:3]
Even though we showed that mir-142 is transcriptionally controlled by CLOCK/BMAL1 heterodimers only in a mouse fibroblast cell line (NIH3T3), the E-box in the upstream regulatory sequence of mir-142 gene is perfectly conserved among mammals (Figure 4B). [score:2]
In our study, we identified mir-142-3p as a regulator of Bmal1 both in human and mouse cells. [score:2]
Click here for file There is an unconserved non-canonical E-box (E’-box) in the upstream regulatory sequence of mir-142 gene. [score:2]
Mir-142 expression is under clock control. [score:2]
There is an unconserved non-canonical E-box (E’-box) in the upstream regulatory sequence of mir-142 gene. [score:2]
Further studies are needed to confirm these prediction results and to uncover the regulatory role of the mir-142 gene in the circadian clock. [score:2]
The upstream regulatory sequence of mir-142 together with pre-mir-142 was inserted upstream of the luciferase reporter gene. [score:2]
Figure 2 mir-142-3p regulates the Bmal1 mRNA and protein levels. [score:2]
Figure 4 The upstream regulatory sequence of mir-142 gene contains a CLOCK -binding E-box. [score:2]
The top sketch modified from the miRBase shows that the pre-mir-142 can produce two mature miRNAs, mir-142-3p and-5p. [score:1]
Indeed, the results confirmed that mir-142-3p but not mir-142-5p repressed the Bmal1/ BMAL1 3’UTR-luciferase reporter activity (Figure 1C, bottom). [score:1]
Interestingly, by analyzing the 5’ flank sequence of the mir-142 gene we found a conserved canonical E-box (CACGTG) (Figure 4A). [score:1]
mir-142 reduces the mRNA level of reporter genes. [score:1]
For further study, a 1.6 kb upstream regulatory sequence of mir-142 gene containing the E-box together with pre-mir-142 was then used for a luciferase reporter assay (Figure 5A). [score:1]
The sequence of the synthetic mir-142-3p antagomirs is 5’-UCCAUAAAGUAGGAAACACUACA-3’. [score:1]
mir-142-3p: 5’-UGUAGUGUUUCCUACUUUAUGGA-3’; mir-142-5p: 5’-CAUAAAGUAGAAAGCACUACU-3’. [score:1]
The sequences of the synthetic mir-142-3p and mir-142-5p mimics are as follows. [score:1]
As there are two mir-142-3p binding sites in the 3’ UTR of Bmal1, we mutated one or both of them to determine which site was functional, even though the first binding site (position1-7) is poorly conserved among mammals (Figure 1D). [score:1]
Briefly, the NIH3T3 cells untreated or transfected with synthetic mir-142-3p mimics or control miRNA mimics were maintained in normal DMEM until the cells reached confluence. [score:1]
For the mutagenesis experiment, the mir-142-3p binding site was replaced with a random sequence by bridge PCR. [score:1]
Click here for file mir-142 reduces the mRNA level of reporter genes. [score:1]
Mir-142-3p regulates the Bmal1 mRNA and protein levels. [score:1]
293ET cells were co -transfected with luciferase reporter plasmids and mir-142 or mir-448 expression plasmids or control vector, and the normalized firefly luciferase activity was measured (mean ± SD, n = 3). [score:1]
Due to the low transfection efficiency of plasmids, the NIH3T3 cells were transfected with synthetic mir-142-3p mimics (mir-142-3p) or control mimics (mir-NC) (B). [score:1]
The schematic representation of the binding sites for mir-142-3p and mir-448 in the 3’ UTR of Bmal1 is shown on the bottom. [score:1]
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[+] score: 231
Of the differentially expressed genes following anti-miR-142-5p treatment listed in Table 5, and S1 and S2 Tables, only a few were found to be known direct targets of miR-142-5p according to the TargetScan prediction database. [score:8]
Of the selected upregulated genes in S1 and S2 Tables, several genes are predicted to be directly regulated by miR-142-5p (targetscan. [score:8]
Genes that were differentially expressed upon miR-142-5p inhibition (Table 5) largely reflected a directional change towards a gene expression profile more similar to non-colitic mice (Table 5, Fig 7). [score:8]
Genome-wide expression analyses were also performed in order to detect candidate target genes of miR-142-5p, of which inhibition resulted in most effective amelioration of colitis. [score:7]
[34] Upregulation could thus result in an anti-inflammatory immune response in the gut and therefore, during colitis, blocking the miR-142-5p -mediated Cyp2c55 regulation might prove crucial to decreasing disease severity. [score:7]
By studying tissue mRNA expression after miRNA silencing, both in vivo target genes and pathways targeted by miR-142-5p have been determined. [score:7]
Treatment with anti-miR-142-5p prevented wasting disease and ameliorates disease severity of transfer-colitic mice, and modulated downstream targets of the IL10RA pathway, corresponding with IL10RA activation. [score:7]
Differentially expressed genes are likely to be either directly or indirectly regulated by miR-142-5p. [score:6]
Three of the genes directly regulated by IL10RA are in the top-20 genes upregulated upon anti-miR-142-5p treatment: MEP1A, ALDOP, and DPEP1. [score:6]
Taken together, in vivo blocking of miR-142-5p results in the up- or downregulation of candidate target genes in the colon. [score:6]
While the CD4+CD45RO+ [hi] transfer colitis mo del showed a gene expression profile concordant with inhibition of IL10RA, treatment with anti-miR-142-5p was concordant with induction of IL10RA and reduction in colitis. [score:5]
A selection of genes, based on highest fold change after anti-miR-142-5p treatment with potential relation to inflammatory intestinal disorders or gut physiology, is shown in Table 5 (second and third column, respectively) and Fig 7. Of this table, Cyp2c55 and MAL (MyD88 adaptor-like) are the only genes predicted to be directly regulated by miR-142-5p (targetscan. [score:5]
Inhibition of these candidate miRNAs showed that miR-142-5p is the most effective in reducing colitis, and could potentially be a new target in the treatment of IBD. [score:5]
Anti-miR-142-5p reduced colitis and related wasting disease when administered in the T-cell transfer mo del, reflected in reduced weight loss and a lower disease activity index (DAI). [score:5]
Moreover, by genome-wide expression analyses, we found downstream activation of the anti-inflammatory IL10RA pathway, including three genes also found in the top-20 candidate target genes of miR-142-5p. [score:5]
Each miRNA has the potential to repress the expression of many different genes, and the observed phenotype of the mice receiving anti-miR-142-5p can be the result of interplay of multiple repressed targets. [score:5]
By analyzing the top-250 differently expressed genes, we found that the most significant predicted upstream regulator that affects a similar gene set as anti-miR-142-5p treatment is IL10RA. [score:4]
The gene that is most upregulated following anti-miR-142-5p treatment (Table 5) is Cyp2c55. [score:4]
[3]In order to identify putative direct upstream regulators following induction of colitis (experiment #1) or after anti-miR-142-5p treatment in colitic mice (experiment #4), IPA Upstream Regulator Analysis was used. [score:4]
Based on these results, antagomirs were created against the top-4 upregulated miRNAs in this colitis-transfer mo del (miR-142-5p, miR-146b, miR-203, and miR-223; experiment #2). [score:4]
S1 Table Overview of most significantly upregulated genes in the colon after anti-miR142-5p treatment versus scrambled LNA treatment in CD45RB transfer colitic mice. [score:4]
[3] In order to identify putative direct upstream regulators following induction of colitis (experiment #1) or after anti-miR-142-5p treatment in colitic mice (experiment #4), IPA Upstream Regulator Analysis was used. [score:4]
Thus, mice treated with anti-miR-142-5p revealed a directional change towards a gene expression profile similar to non-colitic mice. [score:4]
S2 Table Overview of most significantly downregulated genes in the colon after anti-miR142-5p treatment versus scrambled LNA treatment in CD45RB transfer colitic mice. [score:4]
Top 20 downregulated genes in anti-miR142-5p treated mice. [score:4]
Among them are three genes that are found in the top-20 significantly upregulated genes after anti-miR-142-5p treatment (S1 Table): MEP1A, DPEP1 and ALDOB. [score:4]
Reversal of expression profile toward a healthy state after anti-miR-142-5p treatment. [score:3]
This suggests that IL10RA is a key target of anti-miR-142-5p treatment and plays an important role in the improvement of intestinal inflammation. [score:3]
The strongest disease marker influenced by anti-miR-142-5p treatment was body weight loss: even more so than the reduction in histological inflammation. [score:3]
[32] Several other genes were also affected by anti-miR-142-5p treatment, meaning that they are possibly indirectly regulated by miR-142-5p. [score:3]
Furthermore, when assessing the DAI, mice treated with anti-miR-142-5p exhibit hardly any active disease (Fig 3B). [score:3]
Differential expression between transfer-colitic and control mice at each of the three time points and between anti-miR-142-5p and scrambled anti-miR treated mice, respectively, was assessed via an empirical Bayes moderated t-test. [score:3]
[26] MiR-223, miR-146a and miR-142-5p were among miRNAs expressed in colon biopsies and saliva shown to differentiate CD from UC. [score:3]
Disease parameters in anti-miR-142-5p -treated mice. [score:3]
To find candidate target genes of miR-142-5p, we treated transfer-colitic SCID mice with anti-miR-142-5p or the scrambled anti-miR for 5 days daily, after establishing 5% weight loss (experiment #4). [score:3]
0185097.g005 Fig 5 Disease parameters in RAG1-/- mice treated with anti-miR-142-5p. [score:3]
Disease parameters in RAG1-/- mice treated with anti-miR-142-5p. [score:3]
In experiment #1, the anti-inflammatory IL10RAis predicted to be inhibited in colitic mice (IPA activation Z-score -4.600; p = 5.45E-28) while in experiment #4 anti-miR-142-5p treatment in colitic mice is predicted to result in activation of IL10RA (IPA activation Z-score 2.828, p = 4.45E-11). [score:3]
[32]Several other genes were also affected by anti-miR-142-5p treatment, meaning that they are possibly indirectly regulated by miR-142-5p. [score:3]
Gene targets of miR-142-5p. [score:3]
Identifying candidate target genes of anti-miR-142-5p treatment. [score:3]
anti-miR-142-5p X To assess colonic mRNA expression profiles following blocking of miR-142-5p in transfer-colitic mice. [score:3]
Blocking miR-142-5p reduced colitis and prevented wasting disease, possibly by activation of the IL10RA pathway. [score:3]
[25]In IL-10 knockout mice, another experimental animal mo del of Th1 -mediated IBD, five out of the 11 miRNAs described in our current study (miR-223, miR-142-5p, miR-142-3p, miR-21 and miR-146a) were significantly elevated in severely inflamed colon. [score:2]
When comparing anti-miR-142-5p -treated to scrambled -treated transfer-colitic mice, we see an opposite relationship: IL10RA is predicted to be activated as an upstream regulator of genes affected by anti-miR-142-5p treatment. [score:2]
Several miRNAs were induced in the colon during colitis development, most significantly miR-223, miR-142-5p, miR-146B and miR-203. [score:2]
[25] In IL-10 knockout mice, another experimental animal mo del of Th1 -mediated IBD, five out of the 11 miRNAs described in our current study (miR-223, miR-142-5p, miR-142-3p, miR-21 and miR-146a) were significantly elevated in severely inflamed colon. [score:2]
[27] In miR-142 -deficient mice, this miRNA was identified as a specific regulator for CD4 [+] dendritic cell homeostasis and was demonstrated to cause a defect in priming of CD4 [+] T cells. [score:2]
To learn more about possible pathways involved in this beneficial effect, we isolated RNA from the colon of untreated mice and mice treated with anti-miR-142-5p. [score:1]
Validation of treatment results of anti-miR-142-5p. [score:1]
0185097.g004 Fig 4 (A) Non-colitic mouse (B) Scrambled -treated mouse (C) Anti-miR-142-5p -treated mouse. [score:1]
In conclusion, CD4+CD45RB [hi]-transfer colitis induces miR-142-5p. [score:1]
Silencing miR-142-5p. [score:1]
no cell transfer vehicle/PBS scrambled anti-miR-203 anti-miR-142-5p anti-miR-146banti-miR-223 X X XTo assess clinical impact of blocking selected miRNAs in transfer-colitic mice. [score:1]
[38] Colitic mice treated with anti-miR-142-5p seemed healthy and groomed, unlike the general unhealthy appearance of mice treated with other compounds. [score:1]
Volcano plot of genes affected by colitis and anti-miR-142-5p treatment. [score:1]
In experiment #4 we aimed to study the effect in the colon on a transcriptional level of blocking miR-142-5p. [score:1]
Volcano plot for the comparison of LNA anti-miR-142-5p treated mice versus scrambled LNA controls. [score:1]
In addition, anti-miR-142-5p treatment lowered colonic inflammation (p = 0.034, Fig 5D) and resulted in a significantly lower DAI (p = 0.016, Fig 5E). [score:1]
Other genes affected by therapeutic blocking of miR-142-5p as listed in S1 and S2 Tables that could also interfere with cross-talk interactions that NF-κB is a part of, are Nr5a2,[43] Cftr,[44] TNFRSF11b,[45] Adora1 (adenosine A1 receptor)[46] and PLAT. [score:1]
[47] In conclusion, in our mo del of blocking miR-142-5p in transfer-colitic mice, it is possible that systemic effects of the treatment are responsible for maintaining a healthy body weight, possibly by preventing immune -mediated cachexia. [score:1]
One mouse in the scrambled and one mouse in the anti-miR-142-5p group had to be humanely euthanized before antagomir treatment, as they reached the humane endpoint. [score:1]
[28] Silencing of miR-142-5p resulted in less weight reduction, a better survival and a reduced DAI score in our colitic mice, although histological inflammation seemed less pronounced in SCID than in RAG1-/- mice. [score:1]
receiving PBS or the scrambled LNA anti-miRNA showed most weight loss (Fig 3A), while the anti-miR-142-5p -treated and non-colitic mice showed least weight loss. [score:1]
When comparing the colon weight after sacrifice, we see a trend to lower colon-to-body-weight ratio in the anti-miR-142-5p -treated group (p = 0.058, Fig 5C). [score:1]
anti-miR-142-5p X X X To validate the clinical impact of blocking miR-142-5p in transfer-colitic mice from a different background and gender. [score:1]
In this experiment we also observed a clear effect of blocking miR-142-5p on the development of colitis as antagomir -treated mice demonstrated enhanced survival (Fig 5A) and less body weight loss (Fig 5B) compared to the scrambled -treated mice. [score:1]
Again we clearly observed the healthy appearance of the anti-miR-142-5p -treated mice. [score:1]
Interesting to note is that, while inflammation has not fully disappeared in anti-miR-142-5p treated mice, the body weight curve is similar to that of healthy animals (Fig 3A). [score:1]
Scrambled -treated mice showed apparent histological inflammation (Fig 6A), with crypt elongation, abscesses and immune cell infiltrates, while anti-miR-142-5p -treated mice display healthier intestinal mucosa (Fig 6B). [score:1]
It is however important to note that the DAI consists of three separate scores: while the weight loss was reduced to the level of healthy mice, there was no difference in stool score between anti-miR-142-5p and other treatments (S1 Fig). [score:1]
0185097.g007 Fig 7Volcano plot for the comparison of LNA anti-miR-142-5p treated mice versus scrambled LNA controls. [score:1]
The body weight curve of anti-miR-142-5p -treated mice is similar to the control mice that have not received any cell transfer, i. e. without induced colitis. [score:1]
In experiment #3, the antagomir showing the largest reduction in colitis, anti-miR-142-5p, was administered in male mice from a RAG1-/- background until death or sacrifice, using the scrambled antagomir as a control. [score:1]
Despite that anti-miR-142-5p seemed to result in strongest amelioration of colitis, no significant differences were found when comparing antagomir -treated mice to scrambled LNA antagomir -treated mice. [score:1]
By microscopically scoring all H&E-stained intestines of mice for granulocytes and mononuclear cells, we can estimate that, on a scale from 0 (no presence of cells) to 3 (extensive presence of cells), there were less granulocytes (1,75 in scrambled -treated mice, 1,25 in anti-miR-142-5p -treated mice) and less mononuclear cells (2,8 in scrambled -treated mice, 2,0 in anti-miR-142-5p -treated mice) present. [score:1]
Mice treated with anti-miR-142-5p show an improved survival. [score:1]
We also see that these cells have not infiltrated as deeply into the different layers of the colon; while we see both granulocytes and mononuclear cells within the muscular layer and serosa of the scrambled -treated mice, these cells are limited to the mucosa, submucosa and in one case also the muscular layer of the intestine of anti-miR-142-5p -treated mice. [score:1]
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[+] score: 228
Other miRNAs from this paper: hsa-mir-22
In the present study, we found that the expression of miR-142 was significantly down-regulated in cervical cancer tissues and cells, and miR-142 mimics up-regulated the expression of miR-142, and then miR-142 promoted cancer cell proliferation and invasion. [score:11]
Next, our team demonstrated HMGB1 gene as a direct target of miR-142 in cervical cancer cells, and verified that the inhibitory effect of miR-142 on cervical cancer cells was mediated by the regulation of expression of HMGB1. [score:9]
These findings suggested that miR-142 acts as a tumor-suppressing gene in the development of cervical cancer by directly targeting HMGB1, which will lay a new foundation for the target therapy of cervical cancer patients. [score:9]
We further identified that miR-142 targeted at HMGB1 and suppressed their expression at translation level in CC cells. [score:9]
Taken together with previous results, this study presents supplementary evidence that overexpression of miR-142 could suppress proliferation and invasion of CC cells by targeting 3′-UTRs of HMGB1. [score:7]
The dual luciferase assay strongly identified that HMGB1 gene was a direct target of miR-142, and HMGB1 could attenuate miR-142 -mediated inhibitory effects on the proliferation and invasion of cervical cancer cells as well as the expression of HMGB1 protein. [score:7]
To further out the potential molecular mechanisms underlying miR-142 -induced inhibition of cervical cancer biology, we used the bioinformatic tools to predict potential target genes of miR-142 using the free TargetScan. [score:7]
What is more, the 3′-UTR of HMGB1 was verified as a target gene of miR-142, and miR-142 inhibited the expression of HMGB1. [score:7]
In the present study, our team identified that the expression of HMGB1 was decreased due to enhanced expression of miR-142 in cervical cancer cells, and we demonstrated an inverse association between the miR-142 expression and HMGB1 mRNA by detecting cervical cancer tissues. [score:7]
The previous reports revealed that low expression of miR-142 was found in some cancer tissues, and the expression of miR-142 was significantly related to pathological indicators of cancer patients, and was involved in tumor biology by inhibition of related genes. [score:7]
To elucidate the important role of miR-142 in the development of cervical cancer, the expression of miR- 142 was obviously highly expressed in 30 cases of cervical cancer and adjacent non-tumor cervical samples in view of the results of qRT-PCR. [score:6]
In conclusion, our present study identified miR-142 as a tumor suppressor in the progression of cervical cancer, including cell growth, invasiveness and apoptosis via its direct target HMGB1. [score:6]
To validate our hypothesis, our team firstly conducted a dual luciferase assay and identified that miR-142 overexpression obviously inhibited the luciferase activity of wt-3′UTR of HMGB1, however miR- 142 overexpression did not affect the luciferase activity of mut-3′UTR of HMGB1 in both cervical cancer cells (Figure 3B). [score:6]
For example, overexpression of miR-142 affected prostate cancer cell growth via targeting its androgen receptor. [score:5]
HMGB1 over -expression attenuates the suppressive effect of miR-142 on cell proliferation. [score:5]
HMGB1 over -expression attenuates the suppressive effect of miR-142 on cell apoptosis and invasion. [score:5]
analysis identified that ectopic HMGB1 expression reverse its inhibition by miR-142 in some degree (Figure 4A). [score:5]
We found that miR-142 expression was negatively correlated with the expression of HMGB1 based on the results from 30 cases of tumor tissues (R2 = − 0.851, p < 0.001) (Figure 3D). [score:5]
The study demonstrates a potential molecular mechanism underlying the inhibitory effect of miR-142 on cervical cancer, and indicates that miR-142 might act as a potential prognostic biomarker and therapeutic target in cervical cancer patients. [score:5]
Ectopic miR-142 expression inhibits cell proliferation, invasion and induces cell apoptosis of cervical cancer cells. [score:5]
In recent years, some studies have demonstrated that miR-142 could be recommended as a tumor suppressor in gastric carcinoma, breast carcinoma, and lung cancer [11– 15], indicating that miR-142 might act as a powerful and useful therapy target for the treatment of cancer patients. [score:5]
In this work, our team identified that low expression of miR-142 can be found in a majority of cervical cancer tissues, and the potential mechanisms may be attributed to deregulation of generation of miR-142. [score:4]
HMGB1 is a direct target of miR-142 in cervical cancer. [score:4]
These findings indeed suggested that the role of miR-142 in cervical cancer cells is based on its regulation of HMGB1 expression. [score:4]
To elucidate the impact of miR-142 on the progression and development of cervical cancer, our team made a miR-142 overexpression vector. [score:4]
Furthermore, analyses results from proliferation and invasion assays indicated that the overexpression of HMGB1 dramatically restored cell proliferation and invasion inhibited by miR-142 in SiHa and HeLa cells (Figures 4 and 5). [score:4]
All things considered, our data indicates that altered miR-142 expression is a common event in patients of cervical cancer, and altered miR-142 expression may be implicated into malignancy of cervical cancer. [score:4]
Ectopic miR-142 expression affects cell proliferation and invasion in cervical cancer cells. [score:3]
In recent years, it has been reported that miR-142 and HMGB1 is involved in the progression of tumors by binding to their target genes [16– 20]. [score:3]
All in all, our data suggests that HMGB1 might become a potential target of miR-142. [score:3]
We found that miR-142 suppressed proliferation and invasion of cancer cells both in vitro. [score:3]
To characterize the biological role of miR-142 in targeting HMGB1 gene, miR-142 mimics or miR-NC were individually co -transfected into SiHa and HeLa cells with HMGB1 over -expression or negative control. [score:3]
Relative expression of miR-142 in cervical cancer tissues and cell lines as well as its correlation with overall survival of cervical cancer patients. [score:3]
In addition, over- expressed HMGB1 also had a similar opposite effect on SiHa and HeLa cell apoptosis mediated by miR-142 (Figure 5). [score:3]
Using cell apoptosis analysis, we found that ectopic miR-142 expression induced the apoptosis of SiHa and HeLa cells (Figure 2A–2B). [score:3]
Thus, miR-142 should become a promising novel target due to its diagnostic and prognostic value for cervical cancer. [score:3]
Figure 4(A) analysis of HMGB1 protein expression in cervical cancer cells with miR-NC or miR-142 transfected with either pcDNA3.1 or pcDNA3.1-HMGB1, GAPDH was used as a loading control. [score:3]
Importantly, our correlation analysis identified that low miR-142 expression had no significant association with clinical features, like age, grade. [score:3]
HMGB1 is a direct target of MiR-142 in cervical cancer cell lines. [score:3]
These phenomena indicate that miR-142- HMGB1 pathway may be a potential therapy target in the treatment of cervical cancer. [score:3]
The cervical cancer cell lines SiHa and HeLa were identified to over-express miR-142 or miR-NC (negative control). [score:3]
According to bioinformatics calculation, our team found that HMGB1 can act as a direct target of miR-142 (Figure 3A). [score:2]
Transwell cell invasion assay revealed that ectopic expression of miR-142 markedly repressed the invasion capacity of SiHa and HeLa cells (Figure 2C–2D). [score:2]
Figure 1(A) MiR-142 expression was measured by qPCR and normalized to U6 expression in 30 paired cervical cancer tissues, * P < 0.001, Student's T-test. [score:2]
As for dual luciferase activity assay, the 3′UTR target site could be amplified using PCR system, and then the luciferase reporter constructs were also amplified by PCR, which is the HMGB1 3′UTR and carried a putative miR-142 -binding site. [score:2]
As illustrated in Figure 2, compared with miR-NC, the over -expression of miR-142 significantly affected the growth capacity of SiHa and HeLa cells in a time -dependent fashion. [score:2]
The results revealed that a panel of cervical cancer cell lines all exhibited the lower expression level of miR-142 compared with human non-tumor keratinocyte line HaCaT (P < 0.01, Figure 1B). [score:2]
Cells were transfected with the reporter constructs and then transfected with miR-142 or control miRNAs using lipofectamine 2000 (Life Technologies, USA). [score:1]
Subsequently, our team investigated the impact of miR-142 on transcription and expression of HMGB1 gene. [score:1]
However, little is reported about the biological mechanisms of miR-142 in cervical cancer. [score:1]
MiR-142 mimics (sense: 5′-UAGCAGCACAUCAU GGUUUACA-3′, antisense: 5′-UAAACAUGAUGUG CUGCUGUU-3′), control miRNAs (10nmol/l), HMGB1 plasmids and control vector were all obtained from Ambion (Ambion, USA). [score:1]
HMGB1 is implicated in miR-142 -induced cell proliferation, invasiveness and apoptosis of cervical cancer cells. [score:1]
Up to now, miR-142 has been studied in some cancers, and exerts an obvious anti-tumor effect on tumor proliferation, just consistent with blocking of related genes [18]. [score:1]
Figure 3(A) miR-142 binding sites is located in the 3′-UTR of HMGB1 mRNA. [score:1]
Consistent with these findings, our team further measured the expression status of miR-142 in cervical cancer cells Caski, SiHa, HeLa, and human non-tumor keratinocyte line HaCaT by way of qRT-PCR. [score:1]
Cell proliferation was detected in SiHa (A) and HeLa (B) cells that were transfected with miR-142 mimics or mi-NC. [score:1]
Unfortunately, we did not find a significant relationship between miR-142 expression and other clinical characteristics including age, grade, and BMI (all P > 0.05). [score:1]
In view of these results, our team made a hypothesis that HMGB1 gene might be implicated in biological processes of miR-142 in the progressions of cervical cancer. [score:1]
Figure 2Cell proliferation was detected in SiHa (A) and HeLa (B) cells that were transfected with miR-142 mimics or mi-NC. [score:1]
[1 to 20 of 59 sentences]
9
[+] score: 210
Other miRNAs from this paper: hsa-mir-17, mmu-mir-142a, mmu-mir-17, mmu-mir-142b
Taken together, these results suggest that miR-142-3p is suppressed by DNA methylation in fibroblasts but that the downregulation of miR-142-3p during EB formation might be regulated by a different mechanism. [score:7]
This study revealed that miR-142-3p is expressed in undifferentiated iPS cells, but not in fibroblasts, and DNA methylation might play a pivotal role in suppressing miR-142-3p expression in fibroblasts. [score:7]
The expression of as-miR-142-3p did not affect the expression of Fgf5 or Gata4, although as-miR-17 enhanced expression of Fgf5, as expected (Figures 1(g) and 1(h)). [score:7]
Data revealed that as-miR-142-3p, but not as-miR-17, suppressed the expression of T brachyury, which is expressed specifically in cells of the mesodermal lineage [22] (Figure 1(i)). [score:7]
We observed that Klf4 upregulated luciferase activity but that Klf4 did not enhance the expression of endogenous miR-142-3p in 3T3 cells. [score:6]
TGF- βR1 and TGF- βR2 were both predicted to be targets of miR-142-3p [31], and TGF- βR1 was identified as a direct target in non-small-cell lung cancer [32]. [score:6]
The expression of miR-142-3p was upregulated by 5-aza-dC treatment (Figures 2(a) and 2(b)). [score:6]
In the current study, 5-aza-dC did not enhance the expression of miR-142-3p in mouse P1 thymocytes, supporting the hypothesis that DNA methylation is not a major mechanism that regulates the expression of miR-142-3p in hematopoietic cells. [score:6]
miR-142-3p was reported to be upregulated in the human melanoma cell line WM1552C after treatment with 5-aza-dC [27], suggesting that the expression of miR-142-3p was attenuated by DNA methylation not only in fibroblasts, but also in melanocyte lineage cells. [score:6]
The expression of miR-142-3p might be desilenced by the suppression of DNA demethylation and stimulated by other genes that play roles in the late phase of reprogramming. [score:5]
We also examined the effects of 5-aza-dC on miR-142-3p in EBs and found that 10  μM 5-aza-dC rather suppressed the expression (Figure 2(f)). [score:5]
Our data suggest roles for the methylation of CpG motifs in the 5′ genomic region of miR-142-3p in suppressing its expression in fibroblasts. [score:5]
We then analyzed the effects of overexpressing these transcription factors on the expression of endogenous miR-142-3p in 3T3 cells, but no effects were observed (Figure 3(i)). [score:5]
The expression of miR-142-3p is suppressed by DNA methylation of its CpG motifs in the 5′ genomic region in fibroblasts. [score:5]
miR-142-3p was expressed at a high level in undifferentiated iPS cells, whereas fibroblasts such as 3T3, mouse embryonic fibroblasts (MEFs), and tail-tip fibroblasts (TTF) expressed only very low levels (Figure 1(a)). [score:5]
We hypothesized that miR-142-3p expression is regulated epigenetically by DNA methylation in iPS cells and fibroblasts. [score:4]
To further elucidate the role of CpG sites and DNA methylation in regulating the expression of miR-142-3p, we analyzed the methylation status of the CpG sites identified in the region up to 700 bp upstream of the pre-miR-142-5p core region (Supplementary Figure 2) using bisulfite conversion. [score:4]
Although no similarity was found in the mouse and human upstream genomic regions (~2000 nt) of miR-142-3p, miR-142 expression is regulated by CpG methylation in both species. [score:4]
The expression of miR-142-3p in hematopoietic cells is regulated by various transcription factors that also play important roles in hematopoiesis [17, 18]. [score:4]
Levels of miR-142-3p were upregulated slightly by 10  μM of 5-aza-dC, but to a much lesser extent than observed in fibroblasts (Figure 2(g)). [score:4]
In hematopoietic cells, specifically, Spi1, Cebpb, Runx1, and LMO2 have all been reported to regulate miR-142 expression [17, 18]. [score:4]
5-Aza-2′-deoxycytidine Treatment Upregulates miR-142-3p in Fibroblasts. [score:4]
Luciferase analysis of the isolated genomic region of miR-142-3p supports the idea that the expression of miR-142-3p in cells including fibroblasts and iPS is regulated, at least partially, by DNA methylation. [score:4]
However, these transcription factors are mostly hematopoietic cell-specific, suggesting that the expression of miR-142 in undifferentiated iPS cells involves regulation of other factors. [score:4]
The identification of miR-142-3p target genes in the TGF- β and Wnt signaling pathways further supports the hypothesis that miR-142-3p is involved in the regulation of iPS cell physiology. [score:4]
To assess the transcriptional regulation of miR-142-3p expression, we examined its 5′ genomic sequence and identified 25 CpG motifs in a region covering ~1000 base pairs (bp) upstream of the miR-142-5p core sequence (Supplementary Figure 2). [score:4]
In addition, the expression of human miR-142 was recently reported to be regulated by the methylation of a CpG in its enhancer region in mesenchymal cells [8]. [score:4]
In contrast, the levels of miR-17 were rather reduced but not significantly by 5-aza-dC (Figure 2(c)), whereas the expression of neither miR-142-3p nor miR-17 was changed significantly by 5-aza-dC in undifferentiated iPS cells (Figures 2(d) and 2(e)). [score:3]
Supplemental Fig. 1: miR142-5p was strongly expressed in all the examined mouse iPS cell lines when cells keep immature state. [score:3]
We next constructed an expression plasmid encoding antisense miR-142-3p (as-miR-142-3p) and enhanced green fluorescent protein (EGFP; Figure 1(b)). [score:3]
Therefore, we hypothesize that a molecular environment related to reprogramming, which 3T3 cells lack, might be required for miR-142-3p expression. [score:3]
We previously characterized the expression pattern of miRNAs in mouse and human iPS and ES cells using miRNA arrays and found that miR-142-3p, but not miR-142-5p, was expressed at high levels in iPS cells (see Supplementary Figure 1 available online at http://dx. [score:3]
Morphology of colonies of iPS cell was indistinguishable between control and as-miR-142-3p expressing samples (Figure 1(f)). [score:3]
MEFs and 3T3 cells were treated for 3 days with 5 or 10  μM of 5-aza-2′-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor (Dnmt), and the levels of miR-142-3p were assessed using real-time qPCR. [score:3]
Therefore, the combination of these transcription factors in a wider genomic region might cooperate for the full induction of miR-142-3p expression. [score:3]
CpGs were also hypomethylated in day 5 EBs (Figure 3(g)), even though the expression of miR-142-3p was much lower than in undifferentiated iPS cells (Figure 1(a)). [score:3]
The population of Ki67 -positive cells was slightly, but significantly, lower in as-miR-142-3p -expressing iPS cells (Figure 1(d)). [score:3]
We first confirmed the expression pattern of miR-142-3p using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). [score:3]
The effect of expressing as-miR-142-3p on endogenous miR-142-3p was then examined and confirmed in mouse iPS cells (Figure 1(c)). [score:3]
We also examined the effects of 5-aza-dC for miR-142-3p expression in thymocytes. [score:3]
miR-142-3p, which is highly expressed in iPS cells but not in fibroblasts, plays roles in the proliferation and differentiation of iPS cells. [score:3]
Plasmids containing antisense sequences of mature miR-142-3p or miR-17 expression plasmid were constructed as follows: double strand DNA, which encode antisense of mature miR-142-3p or miR-17, was inserted downstream of U6 promoter using BamHI and EcoRI sites of pMX retrovirus vector containing EGFP after 5′ LTR (Figure 1(b)). [score:3]
When iPS cells were differentiated by formation of embryoid bodies (EBs), the expression of miR-142-3p fell to very low levels on day 2 but then increased on the following days (Figure 1(a)). [score:3]
We then counted the number of alkaline phosphatase- (ALP-) positive iPS colonies, and significantly fewer ALP -positive cells were found within the as-miR-142-3p -expressing iPS colonies (Figure 1(e)). [score:3]
miR-142 is highly conserved among vertebrates [8] and has been implicated in cardiac cell fate determination [9], osteoblast differentiation [10], and vascular development [11]. [score:2]
More recently, a report indicated that the miR-142-3p -mediated regulation of Wnt signaling could modulate the proliferation of mesenchymal progenitors [34]. [score:2]
Proximal CpGs in the miR-142-3p Genomic Region Regulate Transcriptional Activity. [score:2]
iPS cells were transfected with as-miR-142-3p/EGFP, purified according to their expression of EGFP, and then subjected to an EB formation assay. [score:2]
In cancer, miR-142-3p was identified at the breakpoint of a MYC translocation in B-cell leukemia [12] and was mutated in 20% of diffuse large B-cell lymphomas [13]. [score:1]
We then analyzed the roles of miRNA-142-3p on the ability of iPS cells to differentiate. [score:1]
Furthermore, miR-142-3p might also play roles in the mesodermal differentiation of iPS cells. [score:1]
We identified several potential binding sites for c-Myc and Sox2 in the genomic region up to 1 kb from the miR-142 mature sequence using the Genomatix Software Suite (http://www. [score:1]
In this study, we examined the roles of miR-142-3p in iPS cells and found that miR-142-3p might be involved in the proliferation of iPS cells and in maintaining their immaturity. [score:1]
CpG Methylation in the 5′ Genomic Region of miR-142-3p. [score:1]
The sequence of pre-miR-142 is highly conserved among vertebrates [8]. [score:1]
Specifically, as-miR-142-3p/EGFP was transfected into undifferentiated iPS to analyze the role of miR-142-3p in the proliferation and maintenance of immaturity in iPS cells. [score:1]
Roles of Pluripotency-Related Transcription Factors in miR-142-3p Gene Activation. [score:1]
Characterization of miR-142-3p Expression in iPS Cells, Embryoid Bodies, and Fibroblasts. [score:1]
Functional Analyses of miR-142-3p in iPS Cell Physiology. [score:1]
A plasmid without insertion of antisense miR-142-3p was used as a control for all experiments. [score:1]
Supplemental Fig. 2: Region covering 1 kb of 5' upstream genomic region of miR142 contains number of CpG sites. [score:1]
Regions covering up to 700 bp upstream of the miR-142 seed sequence were amplified and were cloned into pGEM-T Easy Vector (Invitrogen). [score:1]
miR-142 was first identified in hematopoietic cells [4], where it plays various roles in differentiation and functions during hemopoiesis [5– 7]. [score:1]
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The miRNAs that were differentially expressed between non-tumor gastric mucosae and MALT lymphoma lesions are listed in Table 2. The miRNA expression profile revealed that a hematopoietic-specific miRNA, miR-142 [23], [24], and an oncogenic miRNA, miR-155 [12], [25], were overexpressed in MALT lymphoma lesions, relative to the levels of expression in the corresponding non-tumor mucosae. [score:9]
miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their targetIdentification of miRNA target genes is essential for determining miRNA function. [score:7]
These findings suggest that TP53INP1 is a common target of miR-142-5p and miR-155 and is suppressed by overexpression of both miR-142-5p and miR-155 in gastric MALT lymphoma lesions. [score:7]
In agreement with these findings, our results showed that TP53INP1 was suppressed by both miR-142-5p and miR-155, possibly leading to inhibition of apoptosis and acceleration of MALT lymphoma cell proliferation. [score:5]
0047396.g004 Figure 4 miR-142-5p and miR-155 suppress TP53INP1 as their target. [score:5]
miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their target. [score:5]
miR-142-5p and miR-155 suppress TP53INP1 as their target. [score:5]
Overexpression of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphomaTo further confirm the molecular pathogenesis of gastric MALT lymphoma, we examined the expression levels of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphoma. [score:5]
The distinct connection between aberrant expression of miR-142-5p and miR-155 and the progression of MALT lymphoma suggests that miRNAs could be potential therapeutic targets. [score:5]
The expression data for patients #14 and #16 with gastric MALT lymphoma who achieved CR after H. pylori eradication therapy showed that the levels of miR-142-5p and miR-155 expression were significantly reduced after eradication (Figure 2B, p<0.05 and p<0.05, respectively). [score:5]
Overexpression of miR-142-5p and miR-155 is presumed to play a critical role in the initiation and progression of gastric MALT lymphoma, suggesting that these miRNAs may be potentially useful as therapeutic targets and novel biomarkers for gastric MALT lymphomas. [score:5]
These findings suggest that overexpression of miR-142-5p and miR-155 concomitant with suppression of TP53INP1 reflect the increased proliferation of MALT lymphoma cells. [score:5]
To confirm the target specificity of miR-142-5p and miR-155 for TP53INP1, we performed a luciferase reporter assay using a vector containing the putative TP53INP1 3′ UTR target sites downstream of the luciferase reporter gene, which was transfected into AGS cells. [score:4]
These findings are consistent with our results, and in the present study we focused on miR-142 and miR-155, because miR-142 is the most up-regulated miRNA and miR-155 plays a critical role in the pathogenesis of B-cell lymphoma. [score:4]
Overexpression of miR-142-5p and miR-155 in gastric MALT lymphomaTo identify miRNAs that play critical roles in the development of gastric MALT lymphoma, we performed miRNA microarray analysis using RNAs obtained from three gastric MALT lymphomas and three matched samples of non-tumor gastric mucosa. [score:4]
Quantitative RT-PCR analyses showed that the levels of expression of miR-142-5p and miR-155 were significantly higher in H. heilmannii-infected C57BL/6 mice (p<0.05 and p<0.05, respectively), being similar to the results for human gastric MALT lymphomas (Figure 3B). [score:3]
The levels of miR-142-5p and miR-155 expression in MALT lymphoma lesions which confers resistance to H. pylori eradication were significantly higher than those in lesions lacking the API2-MALT1 fusion gene, which exhibited CR after H. pylori eradication (p<0.0001 and p<0.005, respectively). [score:3]
The expression levels of miR-142-5p and miR-155 were significantly lower after H. pylori eradication. [score:3]
Inhibition of miR-142-5p and miR-155 might be a novel approach for the prevention and treatment of gastric MALT lymphoma. [score:3]
The levels of miR-142-5p and miR-155 expression in gastric MALT lymphoma lesions were significantly increased relative to the corresponding non-tumor gastric mucosae (p<0.05 and p<0.05, respectively). [score:3]
These patients showed increased expression levels of miR-142-5p and miR-155 (Figure 1). [score:3]
Overexpression of miR-142-5p and miR-155 in gastric MALT lymphoma. [score:3]
A recent study has shown that chemically engineered oligonucleotides, termed ‘antagomirs,’ can work as specific inhibitors of endogenous miRNAs in mice [35], and might be potentially applicable to silence miR-142-5p and miR-155 for the treatment of gastric MALT lymphomas that are resistant to H. pylori eradication therapy. [score:3]
0047396.g001 Figure 1Expression levels of miR-142-5p and miR-155 and responses to H. pylori eradication therapy in gastric MALT lymphoma cases. [score:3]
Expression levels of miR-142-5p and miR-155 and responses to H. pylori eradication therapy in gastric MALT lymphoma cases. [score:3]
The levels of miR-142-5p and miR-155 expression normalized to the level of U6 RNA were significantly increased in H. heilmannii-infected C57BL/6 mice. [score:3]
To further confirm the molecular pathogenesis of gastric MALT lymphoma, we examined the expression levels of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphoma. [score:3]
The base pairing between miR-142-5p and miR-155 and the wild-type (WT) or mutant (MUT) target sites in the 3′ UTR of TP53INP1 mRNA is shown in Figure 4A. [score:3]
Expression levels of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphoma. [score:3]
These cases showed increased expression of miR-142-5p and miR-155. [score:3]
As shown in Figure 1, the expression levels of miR-142-5p and miR-155 in the gastric MALT lymphoma lesions were significantly higher than those in the corresponding non-tumor gastric mucosae (p<0.05 and p<0.05, respectively). [score:3]
The levels of miR-142-5p and miR-155 expression were associated with the clinical course of gastric MALT lymphoma, including the response to H. pylori eradication. [score:3]
0047396.g002 Figure 2Expression levels of miR-142-5p and miR-155 in gastric MALT lymphoma cases before and after H. pylori eradication therapy. [score:3]
Therefore, we focused on TP53INP1 as a common target of miR-142-5p and miR-155. [score:3]
The base pairings between miR-142-5p and miR-155 and their putative target sites in the 3′ UTR of TP53INP1 mRNA are shown. [score:3]
Overexpression of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphoma. [score:3]
0047396.g003 Figure 3Expression levels of miR-142-5p and miR-155 in an animal mo del of gastric MALT lymphoma. [score:3]
As shown in Figure 1, the levels of expression of miR-142-5p and miR-155 in MALT lymphoma lesions that were resistant to H. pylori eradication were significantly higher than in cases showing complete remission (CR) after H. pylori eradication (p<0.0001 and p<0.005, respectively). [score:3]
The levels of miR-142-5p and miR-155 expression were evaluated using quantitative RT-PCR and normalized to the expression of U6 RNA. [score:3]
The expression levels of miR-142-5p and miR-155 showed no significant differences. [score:3]
Expression levels of miR-142-5p and miR-155 in gastric MALT lymphoma cases before and after H. pylori eradication therapy. [score:3]
On the other hand, in patient #1 with gastric MALT lymphoma harboring the API2-MALT1 fusion gene that was resistant to H. pylori eradication, there was no significant difference in the expression levels of miR-142-5p and miR-155 (Figure 2B). [score:3]
As shown in Fig. 4A, ‘seed’ matches between the 5′ end of the miRNAs and the 3′ UTR of TP53INP1 were stronger in miR-155 than in miR-142, suggesting that miR-155 may have a more profound effect on suppression of TP53INP1. [score:3]
These findings indicate that the levels of miR-142-5p and miR-155 expression have potential applicability as novel biomarkers of gastric MALT lymphoma. [score:3]
Levels of miRNA expression were analyzed using quantitative RT-PCR and the TaqMan microRNA assay for miR-142-5p and miR-155 (Applied Biosystems, Foster City, CA), in accordance with the manufacturer's instructions. [score:2]
To validate the microarray data, we performed quantitative RT-PCR for miR-142-5p and miR-155 in 20 cases of gastric MALT lymphoma. [score:1]
org), revealed that both miR-142-5p and miR-155 are able to bind to the 3′ UTR of the mRNA of the proapoptotic gene TP53INP1 (Tumor Protein P53 Inducible Nuclear Protein 1). [score:1]
The miR-142-5p and miR-155 precursor molecules and negative control precursor miRNAs were purchased from Ambion. [score:1]
In addition, we investigated the correlation between the levels of miR-142-5p and miR-155 expression and the clinical courses of gastric MALT lymphoma cases. [score:1]
miR-142-5p and miR-155 as novel biomarkers of gastric MALT lymphomaThe patients with gastric MALT lymphoma were divided into two groups according to their response to H. pylori eradication therapy (Table 1). [score:1]
Further studies involving more patients are warranted to explore the clinical use of miR-142-5p and miR-155 for diagnosis and treatment of gastric MALT lymphoma. [score:1]
miR-142, miR-155 and miR-223 have been reported to be hematopoiesis-specific miRNAs [24]. [score:1]
The luciferase activities of the AGS cells transfected with the TP53INP1-WT construct were significantly lower after transfection of miR-142-5p and miR-155, whereas those transfected with the TP53INP1-MUT construct or the pGL3 control vector (empty vector) showed no significant differences. [score:1]
The luciferase activities of the AGS cells transfected with the TP53INP1-WT construct were significantly lower after transfection with miR-142-5p and miR-155 (p<0.05 and p<0.005, respectively), whereas those of cells transfected with the TP53INP1-MUT construct and the pGL3 control vector (empty vector) showed no significant differences (Figure 4B). [score:1]
miR-142-5p and miR-155 as novel biomarkers of gastric MALT lymphoma. [score:1]
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In the case for ADCY9, miR-142-3p was reported to target this gene, resulting in the regulation of cAMP that is crucial to the suppressive effect enforced by in CD4(+) CD25(−) regulatory T cells during the resolution of the inflammatory response (Huang et al., 2009). [score:7]
Given its involvement during early events of phagocytosis (McGee et al., 2001; Caron et al., 2006; Park and Cox, 2009; Dart et al., 2012), and the strong prediction for it being a gene target for miR-142-3p (Tables 1 and 3), we asked whether this miRNA may target the 3′-UTR mRNAs Wasl (mRNA for N-Wasp). [score:5]
Moreover, miR-142-3p expression is associated to normal myeloid leukocyte differentiation (Careccia et al., 2009), and among its bona fide gene targets in the immune system, include the pro-inflammatory cytokine IL-6 that plays an essential role in protective and pathological immune responses (Sun et al., 2011). [score:5]
Bold entries represent actin binding proteins potential targets of miR-142-3p Table 3 Molecular functions go term enrichment analysis of predicted gene targets of mmu-miR-142-3p. [score:5]
Indeed, the control of these two gene targets indicates miR-142-3p can influence both arms of the immune system, and that aberrant expression of this miRNA (e. g., due to a microbial hijacking strategy), could then result in a defective inflammation response that is counter-productive to host fitness. [score:5]
Bold entries represent actin binding proteins potential targets of miR-142-3p Table 3 Molecular functions go term enrichment analysis of predicted gene targets of mmu-miR-142-3p. [score:5]
Finally, while miR-142-5p is generated along with miR-142-3p after maturation of the pre-miR-142 (Wu et al., 2009), it ultimately failed to target the mRNA sequence for Cdc42ep4 mRNA 3′-UTR, a Rho GTPase that regulates signaling pathways controlling diverse cellular functions including endocytosis (Data not shown). [score:4]
The expression of miR-142-3p was first reported to be exclusive to cells of the hematopoietic system, with aberrant dys-regulation in T-cell and B-cell leukemia (Bellon et al., 2009). [score:4]
Targeting of microRNA-142-3p in dendritic cells regulates endotoxin -induced mortality. [score:4]
In the case of IL-6, the high expression of miR-142-3p in murine and human dendritic cells was demonstrated to be essential to regulate the biosynthesis of this cytokine and prevent endotoxin -induced mortality (Sun et al., 2011). [score:4]
Collectively, we demonstrate that: (1) mycobacteria infection of Mφs results in a short-lived induction of miR-142-3p, and in the case of Mtb, accompanied by a partial decrease of N-Wasp protein levels (2) N-Wasp mRNA (Wasl) is a direct target for miR-142-3p, (3) miR-142-3p leads to a significant decrease of intracellular mycobacteria intake by Mφs, and (4) the siRNA -mediated inactivation of N-Wasp in human Mφs affects the initial rate of phagocytosis of Mtb. [score:4]
To assess this, we again employed the use of either “mimics” or “inhibitors” of miR-142-3p activity. [score:3]
Altogether, this demonstrates that Wasl is indeed a target of miR-142-3p. [score:3]
Unlike the treatment with mimics, Mφs transfected with inhibitors of miR-142-3p and subsequently challenged with these mycobacterial strains showed no significant change in the protein levels of N-Wasp, implying that a compensatory effect was occuring (Data not shown). [score:3]
As shown in Figure 1B, we observed at 1 hpi a slight, but significant induction miR-142-3p expression that was, however, short-lived: it returned to basal levels at 4 hpi. [score:3]
Our previous results confirmed that miR-142-3p targets the mRNA sequence of N-Wasp, suggesting it may influence the level of N-Wasp protein, and consequently, the phagocytosis process. [score:3]
Expression of miR-142-3p is induced in murine Mφs upon mycobacteria infection. [score:3]
1 macrophages treated with miR-142-3p mimics (A) or miR-142-3p inhibitors (B), and challenged with M. tuberculosis (MOI 10) for 4 h. Blue (DAPI), green (H37Rv-eGFP), and Light red/orange (Rhodamine-Phalloidin). [score:3]
Human Mφs were exposed to latex beads (to induce a “sterile” phagocytosis process), or challenge with either M. smegmatis or Mtb, and the miR-142-3p expression was quantified by qPCR analysis. [score:3]
The third contribution of this study is the suggestion that a novel but general strategy in the context of mycobacteria infection is the role of miRNAs in modulating mycobacterial uptake by phagocytic cells, revealed by the partial and temporal inhibition of N-Wasp activity via miR-142-3p. [score:3]
1 macrophages treated with miR-142-3p mimics (A) or miR-142-3p inhibitors (B), and challenged with M. smegmatis (MOI 10) for 4 h. Arrows indicate phagocytic cups. [score:3]
Figure 2 N-Wasp is a target of miR-142-3p. [score:3]
Bona fide targets for miR-142-3p include RAC1, CD133, IL-6, and ADCY9 (Huang et al., 2009; Bissels et al., 2011; Sun et al., 2011; Wu et al., 2011). [score:3]
As shown in Figure 2A, the relative luciferase activity is lower in the pair miR-142-3p/Wasl relative to the control, indicating that the miR-142-3p targets the Wasl mRNA 3′-UTR with high probability (P < 0.01). [score:3]
Figure 5 Expression of miR-142-3p and N-Wasp levels in infected human primary macrophages. [score:3]
Our results indicate that while Mtb infection of human Mφs specifically induces the expression of miR-142-3p, challenge with M. smegmatis or exposure to latex beads failed to do so (Figure 5A, left). [score:3]
Our findings in the murine mo del suggest that Mtb induces the timely expression of miR-142-3p in order to down-modulate the function of N-Wasp protein, and therefore, modulate the uptake by phagocytic cells. [score:3]
As shown in Figure 2B, Mtb significantly induced the expression levels for miR-142-3p at 1 hpi similar to that obtained with M. smegmatis challenge. [score:3]
MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells. [score:3]
This analysis showed that ABPs and cytoskeletal -binding proteins are indeed strongly enriched as potential targets of the miR-142-3p (Table 3). [score:3]
The miR-142-3p mimics and inhibitors (Dharmacon, Lafayette, CO, USA) were used for transient transfection in gain or loss-of-function experiments, respectively. [score:3]
Yet, similar to the pattern obtained during infection with M. smegmatis, the induction caused by Mtb was short-lived, as the expression levels for miR-142-3p drops considerably at 4 hpi and remains low at 24 hpi (Figure 2B). [score:3]
1 Mφs infected with M. smegmatis was slightly lower in the qPCR analysis compared to those obtained from the microarray data, they supported the notion that miR-142-3p is up-regulated at the earliest stage of infection. [score:3]
We employed the use of either “mimics” of miR-142-3p to imitate and increase its behavior (gain-of-function), or “inhibitors” to nullify its activity (loss-of-function), as described in Materials and Methods. [score:3]
In order to test this hypothesis, we first verified whether the pathogenic Mtb strain H37Rv was capable of modulating the miR-142-3p expression as M. smegmatis. [score:3]
The miR-142-3p is predicted to target two mRNAs encoding for ABPs, cofilin2 (Cfl2) and Wiskott-Aldrich Syndrome-Like (human) (N-Wasp), which are involved during the early events of phagocytosis (McGee et al., 2001; Caron et al., 2006; Park and Cox, 2009; Dart et al., 2012). [score:3]
Mtb induces miR-142-3p expression while decreasing that of N-WASP in human primary Mφs. [score:3]
In this manner, Mφs were transfected with mimics or inhibitors of miR-142-3p and subsequently challenged with either M. smegmatis or Mtb for 1 h. Whole cell extracts were then prepared for western blot analyses. [score:3]
miR-142-3p restricts cAMP production in CD4+CD25− T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. [score:3]
The modulation of miR-142-3p expression partially influences the amount of N-WASP protein. [score:3]
The mRNA for N-WASP is targeted by miR-142-3p. [score:3]
The second major contribution of this study is identification of miR-142-3p as a key candidate involved in the regulation of actin dynamics required in phagocytosis. [score:2]
org) with the potential to regulate ABP activity, we therefore ruled out that miR-142-5p can influence the early events of phagocytosis in concert with miR-142-3p. [score:2]
Therefore, if miR-142-3p plays a role in regulating N-Wasp activity, then it is only early on during the interaction with mycobacteria, such as the phagocytosis process. [score:2]
MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. [score:2]
Next, to examine whether miR-142-3p is able to regulate N-Wasp expression in Mφs, we conducted gain-of-function and loss-of-function experiments in order to measure N-Wasp protein levels during mycobacterial infection. [score:2]
The reduction of N-Wasp expression by the treatment mimicking miR-142-3p of Mφs infected with either mycobacterial strain, prompted us to investigate for a possible role for this miRNA in controlling the early stages of phagocytosis. [score:1]
Beyond the identification of miR-142-3p as a key candidate, and its implications (discussed below), there are 9 miRNAs (i. e., miR: 29, 93, 101, 181, 207, 329, 451, 574, and 684) in our list that are reported to be similarly modulated in multiple mycobacterial infection contexts (Fu et al., 2011; Ma et al., 2011; Sharbati et al., 2011; Wang et al., 2011; Yi et al., 2012). [score:1]
We performed a time course of infection (1, 4, and 24 hpi) with either strains and measured the miR-142-3p expression by qPCR analysis. [score:1]
miR-142-3p activity correlates with a reduction of the amount of internalized mycobacteria per Mφ. [score:1]
A representative blot from three independent experiments is shown with the densitometry quantification: quantification of the relative levels of N-Wasp in infected macrophages, treated with either mimics of miR-142-3p or scramble ([*] P ≤ 0.01; [**] P ≤ 0.001). [score:1]
Identification of the specificity of miR-142-3p to the 3′-UTR mRNA of N-WASP. [score:1]
The transfection efficiency achieved was approximately 90%, as evaluated by confocal microscopy using a miR-142-3p inhibitor labeled with Alexa 594 fluorochrome (Exiqon, Vedbaek, Denmark). [score:1]
In primary human Mφs, however, only the challenge with virulent Mtb resulted in rapid high levels of miR-142-3p over background, peaking at 4 h and declining thereafter. [score:1]
We argue that the miRNA list provided in this report have potential roles in these activities, all in some way relying on the host cell cytoskeleton, as evidenced by the role of miR-142-3p in partially controlling N-Wasp in activity in the process of phagocytosis. [score:1]
The induction of miR-142-3p as detected by our microarray analysis was confirmed by qPCR analysis with both non-virulent and virulent mycobacterial strains. [score:1]
1 macrophages transfected with mimics of miR-142-3p or not, and that of internalized mycobacteria (MOI 10) after a 1-h challenge. [score:1]
Next, we measured whether the difference in miR-142-3p expression obtained from the challenge with either mycobacterial strain at 1 hpi is sustained throughout infection. [score:1]
Based on these criteria, the miR-142-3p was selected as the best candidate for further study. [score:1]
Right: relative expression of miR-142-3p in human macrophages infected with M. smegmatis or M. tuberculosis as the indicated time points, as measured by EXIQON (DK) microRNA qPCR services. [score:1]
Given the Mtb is the etiological agent of TB in humans, and that human Mφs are the primary replication site for this obligate intracellular pathogen, we used primary human monocyte-derived Mφs in order to investigate whether the expression of miR-142-3p leads to a subsequent reduction of N-Wasp and alter the rates of phagocytosis. [score:1]
Altogether, these results suggest that the modulation of N-Wasp function via miR-142-3p might contribute to the phagocytosis process of Mtb in human cells. [score:1]
All things considered, our findings strongly suggest that effective modulation of N-Wasp activity via miR-142-3p can influence the rate of bacterial intake by Mφs, and to our knowledge, this is the first description of a microbial strategy employing the use of miRNAs to regulate actin -mediated events leading to phagolysosome biogenesis. [score:1]
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In-silico Prediction of Target miRNAs against Human Nrf2 and Experimental Validation of Nrf2 Downregulation by Forced Expression of miR144, miR153, miR27a and miR142-5pNrf2, an essential transcription factor for regulating both basal and inducible expression of diverse cytoprotective genes [26], [27] has been recently demonstrated to be regulated by miR144 and miR28 in non-neuronal mo dels [22], [23]. [score:12]
Individual overexpression of miR144, miR153, miR27a and miR142-5p directly target Nrf2 3′ UTR and downregulate expression of Nrf2 transcript. [score:11]
In-silico Prediction of Target miRNAs against Human Nrf2 and Experimental Validation of Nrf2 Downregulation by Forced Expression of miR144, miR153, miR27a and miR142-5p. [score:8]
Overexpression of miR144, miR153, miR27a and miR142-5p downregulates Nrf2 protein expression in SH-SY5Y cells. [score:8]
In general, these miRs (miR144, miR153, miR27a, miR142-5p) when individually present can regulate numerous targets/pathways and the effect of particularly targeting Nrf2 may vary from moderate to high depending on the cellular/stressor setting. [score:6]
miR144, miR153, miR27a and miR142-5p abrogates the interaction and binding of corresponding miRs to human Nrf2 3′ UTR, thus indicating Nrf2 as a direct regulatory target of these miRs. [score:5]
In each case, mutation of miR144 (or) miR153 (or) miR27a (or) miR142-5p binding sites on Nrf2 3′ UTR failed to downregulate the luciferase activity as opposed to those observed in WT type reporter construct (Fig. 5B –5E; compare lane 3 vs lane 4). [score:5]
Overexpression of miR144, miR153, miR27a and miR142-5p reduces GCLC and GSR expression affecting GSH/GSSG ratio and cellular ROS levels. [score:5]
To validate whether the computationally predicted miRNAs could target Nrf2 in neuronal system, we chose human neuroblastoma SH-SY5Y, a neuronal-like subline of SK-N-SH cells and overexpressed with each of these miRs (miR144, miR153, miR27a and miR142-5p) individually. [score:5]
Nrf2 transactivation and ARE -driven NQO1 gene expression were reduced by overexpression of different miRs, miR144, miR153, miR27a and miR142-5p. [score:5]
In-silico based identification of Nrf2 dependent molecular pathway and complex network of disease processes that could be regulated at the intersection of miR144, miR153, miR27a and miR142-5p. [score:4]
miR153, miR27a, miR142-5p and miR144 in regulating Nrf2 expression in SH-SY5Y neuronal cells. [score:4]
0051111.g007 Figure 7 In-silico based identification of Nrf2 dependent molecular pathway and complex network of disease processes that could be regulated at the intersection of miR144, miR153, miR27a and miR142-5p. [score:4]
Mutating miR144, miR153, miR27a and miR142-5p binding sites in Nrf2 3′ UTR confirms Nrf2 as a direct target of miR144/153/27a/142-5p. [score:4]
Nrf2 is a Direct Target of miR144, miR153, miR27a and miR142-5p. [score:4]
To further confirm that Nrf2 3′ UTR regulation by miR144, miR153, miR27a, miR142-5p indeed impact the expression of Nrf2 mRNA, we determined the levels of Nrf2 message in SH-SY5Y cells transfected with and without the aforementioned miRs using quantitative real time PCR for Nrf2. [score:4]
Thus, to test whether the forced expression of selected individual miRNA candidates (miR144, miR153, miR27a and miR142-5p) have any repressing effect on Nrf2 3′ UTR, we used a reporter construct that was cloned with 428 bp of human Nrf2 3′ UTR downstream of luciferase gene. [score:3]
While all the other target genes which are at the intersection of 4 miRs are represented by independent colored lines (miR144-brown; miR153-red; miR27a-black; miR142-5p-purple). [score:3]
As one to many miR:target relationships are likely, we next analyzed the possible strong candidates including Nrf2 that could be mapped at the intersecting points of miR144, miR153, miR27a and miR142-5p using “mirDIP (microRNA: Data Integration Portal)”. [score:3]
The results show that individual overexpression of miR144, miR153, miR142-5p effected a ∼42% repression and a maximal repression by about ∼68% was shown by miR27a (Fig. 2A). [score:3]
Results were analyzed and expressed as natural logarithm (ln) of relative quantity of miR144 and miR142-5p, normalized to U6 snRNA from a calibrator sample (scramble control miR) [42], [43]. [score:3]
It is to be noted that DIANA-mirPath analysis populated NFE2L2 as the principal gene at the intersection of miR144, miR153, miR27a, miR142-5p with a highest –ln(p-value) of 20.79 that is mapped to involve in Prion disease by KEGG pathway (Fig. 7B). [score:3]
According to our prediction analysis using TargetScan, we observed evolutionarily conserved binding sites for miR27a, miR142-5p, miR153 between 62–68, 83–90, 98–105 respectively in the human Nrf2 3′ UTR (Fig. 1B). [score:3]
Luciferase reporter constructs containing mutation of miR153, miR27a and miR142-5p target sites of Nrf2 3′ UTR were generated using partial overlapping primer based PCR according to Zheng et al. [25]. [score:3]
Thus, future studies should assess the relative timing and involvement of various closely linked events such as translation repression, mRNA deadenylation and decay in miR144/miR153/miR27a/miR142-5p induced silencing of Nrf2. [score:3]
Figure S5 Effect of 10 nM each of combination of miR144, miR153, miR27a and miR142-5p on Nrf2 protein expression. [score:3]
The results of Fig. S5 and S6 suggests that in a given cellular context, when these candidate miRs: miR144, miR153, miR27a and miR142-5p co-exist even at low levels, each would bind to Nrf2 via multiple, distinct binding sites and may perhaps increase the robustness and likelihood of targeting Nrf2 and its associated functions. [score:3]
Construction of miR-disease Network (MDN) with Respect to miR144/miR153/miR27a/miR142-5p. [score:3]
Overall, this data suggests that Nrf2 is translationally repressed by miR144, miR153, miR27a, miR142-5p in a specific manner. [score:3]
Thus our study is the first to demonstrate that Nrf2 protein could be subjected to translation repression by miR144/miR153/miR27a/miR142-5p in a Keap1 independent manner in neuronal cellular system. [score:3]
Thus, in view of preserving redox potential that is key to a normal cellular physiology, our results suggest that Nrf2 dependent redox homeostasis could be controlled in this neuronal system by regulation of levels of the following miRs: miR144/miR153/miR27a/miR142-5p. [score:2]
Totally 28 genes were computed to be at the intersection of 4 different miRs (hsa-miR144/hsa-miR153/hsa-miR27a/hsa-miR142-5p). [score:1]
Figure S6 Integration analysis of multiple miRNAs (miR144/miR153/miR27a/miR142-5p) to various human pathways by DIANA mirPath. [score:1]
miRNA precursors for hsa-miR144, hsa-miR153, hsa-miR27a, hsa-miR142-5p, hsa-miR21, scramble control miR, siPort™ Amine NeoFX and mirVana miRNA isolation kit were purchased from Ambion (Austin, TX). [score:1]
miR144/miR153/miR27a/miR142-5p Mediated Repression of Nrf2 is Keap1-independent. [score:1]
Endogenous level of miR144 and miR142-5p in SH-SY-5Y cells were observed to be negligible. [score:1]
Based on these criteria, we narrowed down to a list of 4 different miRs (hsa-miR27a, hsa-miR153, hsa-miR142-5p including the already reported hsa-miR144) (Fig. 1A). [score:1]
SH-SY5Y cells were transfected with either 40 nM of scramble miRNA or combination of miRs (10 nM each of miR144, miR153, miR27a, miR142-5p) for 48 h. (A) Nrf2 immunoblotting was performed in whole cell protein lysates with anti-GAPDH serving as loading control. [score:1]
miR144, miR153, miR27a and miR142-5p Represses Nrf2 3′ UTR and Endogenous Nrf2 mRNA. [score:1]
Transfection of miR144 and miR142-5p duplex increased the endogenous level of these miRs by log (2) 3.4 fold and 5.2 fold respectively (Fig. S1A; S1D). [score:1]
The schematic representation of binding sites and the individual mutants for miR144 (site-1 & site-2), miR153, miR27a and miR142-5p in the human Nrf2 3′ UTR was shown in Fig. 5A and the successful incorporation of mutagenized bases was confirmed by sequencing of the individual mutant constructs. [score:1]
[1 to 20 of 41 sentences]
13
[+] score: 146
As miRNAs regulate the expression of mRNAs by binding to the sequence-specific target sites on mRNAs, we intersected these selected genes with the predicted target list of miR-142-5p from TargetScan database (Agarwal et al., 2015). [score:10]
miR-142-5p Suppression Inhibits the Loss of PSD-95 in SH-SY5Y Neuronal Cells Treated with Aβ [42]Given the increase in miR-142-5p expression during the pathogenesis of AD, we hypothesized that miR-142-5p suppression may alleviate the AD phenotype. [score:9]
We used the predicted target lists from TargetScan database [3] to identify the target mRNAs of miR-142-5p (Agarwal et al., 2015). [score:7]
We filtered these genes based on the existence of conserved target sites of miR-142-5p using predicted target list from TargetScan database (Agarwal et al., 2015). [score:7]
One possibility is that the suppression of miR-142-5p target genes may have decreased the expression of PSD-95. [score:7]
Pretreatment with miR-142-5p inhibitor attenuated the decrease of PSD-95 mRNA expression after treatment with Aβ [42]. [score:5]
Although the decrease in PSD-95 expression after Aβ [42] treatment was compromised through the inhibition of miR-142-5p, the underlying mechanism is still unclear. [score:5]
One of the key experiments is to test whether the inhibition of miR-142-5p expression in the brain of animal AD mo del could restore the loss of PSD-95 and subsequently prevent neuronal loss and memory decline. [score:5]
Thus, miR-142-5p may affect PSD-95 indirectly by regulating the expression of other neuron-related genes. [score:5]
As the expression of miR-142-5p is greatly increased in Aβ [42] -treated cells (Figure 1), we selected mRNAs that exhibited decreased expression under same condition, using the microarray data for Aβ [42] -treated SH-SY5Y cells (GSE23000; Gatta et al., 2011). [score:5]
miR-142-5p Suppression Inhibits the Loss of PSD-95 in SH-SY5Y Neuronal Cells Treated with Aβ [42]. [score:5]
Because miR-142-5p expression is highly increased by Aβ [42] treatment, we selected only the mRNAs with decreased expression following Aβ [42] treatment. [score:5]
Given the increase in miR-142-5p expression during the pathogenesis of AD, we hypothesized that miR-142-5p suppression may alleviate the AD phenotype. [score:5]
This suggests that PSD-95 would be regulated by miR-142-5p indirectly. [score:3]
Synthetic miR-142-5p and control inhibitor were purchased from Ambion (Ambion, Austin, TX, USA). [score:3]
We pretreated differentiated SH-SY5Y cells with miR-142-5p inhibitor, followed by treatment with Aβ [42] (Figure 2A and Supplementary Figure S2). [score:3]
Among the target genes of miR-142-5p from (A), those genes with neuronal process-related GO terms in (B) were chosen. [score:3]
When we searched a possible binding site of miR-142-5p in the 3′-UTR of PSD-95, no site was identified from several target search algorithms (data not shown). [score:3]
As abnormal synaptic process is an important factor in cognitive dysfunction, our results suggest that miR-142-5p may be a potential target in AD for the improvement in synaptic signaling. [score:3]
Quantitative analysis of miR-32-5p, miR-142-5p, miR-455-3p and miR-1249-3p expression was performed with reverse transcription polymerase chain reaction (RT-PCR) using the TaqMan MicroRNA Reverse Transcription kit (Applied Biosystems, Waltham, MA, USA) and 10 ng of total RNA. [score:3]
We found that miR-142-5p suppression prevents the reduction of PSD-95 level in Aβ [42] -treated SH-SY5Y neuronal cells. [score:3]
However, pretreatment of SH-SY5Y cells with miR-142-5p inhibitor compromised the reduction in PSD-95 after Aβ [42] treatment. [score:3]
GO analysis for the decreased gene group with no target site for miR-142-5p (2919 genes) showed no neuron-related term among the top 10 enriched terms (data not shown). [score:3]
There need to be additional studies to use miR-142-5p as a therapeutic target of AD. [score:3]
Target Analysis of miR-142-5p and Its Functional Implication. [score:3]
The result indicates high PSD-95 signal for cells pretreated with miR-142-5p inhibitor. [score:3]
These mRNAs were intersected with the list of predicted target genes of miR-142-5p. [score:3]
The mRNA level of PSD-95 increased in Aβ [42] -treated SH-SY5Y cells subjected to miR-142-5p inhibitor pretreatment. [score:3]
Taken together, our results show that the inhibition of miR-142-5p prevented the Aβ [42] -induced loss of PSD-95 in SH-SY5Y cells. [score:3]
This analysis suggests that miR-142-5p plays a specific role in neuronal process during AD progression by targeting neuron-related genes. [score:3]
Figure 3Target analysis of miR-142-5p and its functional implication. [score:3]
In addition, bioinformatics analysis revealed the regulation of genes associated with neuronal maintenance and synaptic plasticity by miR-142-5p. [score:2]
Thus, the establishment of a proper method to manipulate the level of miR-142-5p would be important to verify the role of this miRNA in the regulation of synaptic plasticity and to alleviate the pathogenesis of AD. [score:2]
Supporting this, there is no sequence motif (ACUUUAU) in the 3′-UTR of PSD-95 which is complementary to the seed sequence of miR-142-5p (AUAAAGU). [score:1]
Our study shows that miR-142-5p plays a role in neuronal process. [score:1]
We selected miR-142-5p as the final candidate involved in the pathogenesis of AD. [score:1]
Figure 2Cellular analysis to identify the role of miR-142-5p in Aβ [42] -treated SH-SY5Y cells. [score:1]
The effect of miR-142-5p inhibition in Aβ [42] -treated SH-SY5Y cells was investigated with the evaluation of PSD-95 expression. [score:1]
This necessitates further studies to gain insight in the detail mechanism of the effect of miR-142-5p during the pathogenesis of AD. [score:1]
To identify target genes of miR-142-5p, we used the microarray data and measured global mRNA level changes after treatment of SH-SY5Y cells with Aβ [42] (Gatta et al., 2011). [score:1]
Thus, we shortlisted four miRNAs—miR-32-5p, miR-142-5p, miR-455-3p and miR-1249-3p. [score:1]
[1 to 20 of 41 sentences]
14
[+] score: 130
Other miRNAs from this paper: mmu-mir-142a, mmu-mir-142b
To verify whether TGF-β2 was the target of miR-142-5p, an inhibitor and a mimic of miR-142-5p were transfected into macrophages, and the effects were observed on TGF-β2 protein and mRNA expression levels. [score:7]
do) target-gene prediction software was used to predict the target gene of miR-142-5p, and TGF-β2 was predicted to be the most probable target gene. [score:7]
To investigate the effects of miR-142-5p on the rate of apoptosis of human macrophages, the cells were divided into seven groups: Control, control + ox-LDL, miR-142-5p inhibitor transfection + ox-LDL, TGF-β2 inhibitor transfection + miR-142-5p inhibitor + ox-LDL, miR-142-5p mimic transfection, TGF-β2 inhibitor + ox-LDL, N. C + ox-LDL. [score:7]
Expression levels of miR-142-5p are upregulated in human macrophages treated with ox-LDL. [score:6]
Expression levels of miR-142-5p are upregulated in the atherosclerotic plaques of mice. [score:6]
The present study demonstrated that miR-142-5p expression was upregulated in atherosclerotic plaques obtained from apoE−/− mice. [score:6]
In the present study, an atherosclerotic plaque apoE−/− mouse mo del was generated and the expression levels of miR-142-5p were upregulated in the atherosclerotic plaques of the apoE−/− mice. [score:6]
To verify whether TGF-β2 was a target gene, a miR-142-5p inhibitor and mimic were transfected into macrophages. [score:5]
A database -based target gene prediction software predicted that TGF-β2 was the most probable target gene of miR-142-5p. [score:5]
To study TGF-β2 expression levels in the macrophages, the cells were divided into five groups: Control, control + ox-LDL, miR-142-5p inhibitor transfection + ox-LDL, miR-142-5p mimic transfection, and negative control (NC) + ox-LDL. [score:5]
The expression levels of miR-142-5p in the human macrophages treated with ox-LDL were upregulated, as compared with the control macrophages (P<0.05). [score:5]
The expression levels of TGF-β2 were higher in the cells transfected with the miR-142-5p inhibitor and treated with ox-LDL, as compared with the cells undergoing ox-LDL treatment alone (P<0.05; Fig. 4), and were the lowest when the cells were transfected with the miR-142-5p mimic (P<0.05). [score:4]
In addition, miR-142-5p was shown to be associated with the apoptosis of macrophages, through the regulation of its predicted target gene, TGF-β2. [score:4]
In the present study, significant miR-142-5p expression was detected in macrophages, but not endothelial or smooth muscle cells. [score:3]
In conclusion, miR-142-5p was shown to be involved in atherosclerosis in mice, and TGF-β2 was identified as its target. [score:3]
MiR-142-5p is a member of the miR-142 miRNA family which have known roles in cancer, immune diseases and embryonic stem cells (12, 13). [score:3]
MiR-142-5p is a member of the miR-142 family, which is involved in the pathogenesis of various diseases (13, 32, 33). [score:3]
The present study also aimed to identify miR-142-5p target genes, and its effects on apoptosis in macrophages. [score:3]
Previous research into miR-142-5p has mainly focused on its associations with tumors, immune diseases and stem cells (32); however, its role in atherosclerosis remains unknown. [score:3]
The suspension was then added to the cells and incubated for 6 h, the medium was then replaced and the cells were cultured for a further 48 h. To study the miR-142-5p expression levels, the cells were divided into two treatment groups: Control and oxidized low-density lipoprotein treated (ox-LDL; 90 μl, 50 mg/ml, for 24 h). [score:3]
MiR-142-5p was shown to regulate macrophage apoptosis by targeting TGF-β2. [score:3]
However, the expression of miR-142-5p in atherosclerotic plaque and its roles in atherosclerosis are currently unclear. [score:3]
In the present study, the expression levels of miR-142-5p were detected in murine atherosclerotic plaques and human macrophages. [score:3]
The liposome suspension was then added to the mir-142-5p inhibitor liquid and incubated at room temperature for 15 min. [score:3]
Gene microarray analysis for miR-142-5p expression. [score:3]
The results verified that TGF-β2 was the likely target gene of miR-142-5p. [score:3]
,) of mir-142-5p inhibitor (Shanghai GenePharma Co. [score:3]
These results suggest that TGF-β2 may be a target gene of miR-142-5p. [score:3]
TGF-β2 is predicted to be a target gene of miR-142-5p. [score:3]
The following primer sequences were used: TGF-β2 forward, 5′-ACAAAATAGACATGCCGCCC-3′, and reverse, 5′-GATGGCATCAAGGTACCCACAG-3′; Hsa-miR-142-5p forward, 5′-AACTCCAGCTGGTCCTTAG-3′, and reverse, 5′-TCTTGAACCCTCATCCTGT-3′; Hsa-miR-142-5p inhibitor were, 5′-AGUAGUGCUUUCUACUUUAUG-3′; Hsa-miR-142-5p mimic forward, 5′-CAUAAAGUAGAAAGCACUACU-3′, and reverse, 5′-UAGUGCUUUCUACUUUAUGUU-3′. [score:2]
The expression levels of miR-142-5p were 6.84-fold higher in the mice with stable plaques, and was 2.69-fold higher in the mice with vulnerable plaques, as compared with the controls (Fig. 1). [score:2]
The expression levels of miR-142-5p, in the atherosclerotic plaques, were determined using a miRNA microarray assay with rat miRNA array probes (Kangchen Bio-tech Inc. [score:2]
In the present study, miR-142-5p was shown to be associated with the apoptosis of macrophages by negatively regulating TGF-β2. [score:2]
The present study determined that apoptosis of macrophages could be affected by miR-142-5p. [score:1]
[1 to 20 of 34 sentences]
15
[+] score: 127
Other miRNAs from this paper: hsa-mir-34a, hsa-mir-223, hsa-mir-4732
PKC stimulates RANKL expression in osteoblasts/stromal cells and PKC inhibitors reduce OC differentiation and function 15. miR-142-3p expression is significantly downregulated over the first 3 days of monocyte-to-OC differentiation with diminished expression maintained from day 3 through to day 12. [score:12]
These two molecules are also predicted targets of miR-142-3p and future work will provide insight into the contribution of miR-142-3p targeting of PKCα relative to its targeting of components downstream of PKCα signaling. [score:7]
miR-142-3p mediated down-regulation of PKCα expression contributes to reduced OC survival. [score:6]
The relative direct and indirect contributions of miR-142-3p target regulation on the observed phenotype will be interrogated. [score:6]
Overexpression of miR-142-3p inhibited cell-to-cell contact, clustering and fusion events, a property that we believe is attributed to reduced PKCα -mediated rearrangements of the microtubule and actin networks; however, this does not provide a rationale for the induction of cell death that we observed. [score:5]
OC cultures overexpressing miR-142-3p displayed greatly reduced clustering and fusion events relative to untreated, control mimic, or miR-142-3p inhibitor, at day 4 of culture. [score:5]
Overexpression of miR-142-3p inhibits monocyte to OC differentiation. [score:5]
The functional significance of miR-142-3p expression during osteoclastogenesis was assessed using transient transfection methods to introduce miR-142-3p mimic, inhibitor, or control mimic (miRNA mimic possessing no interaction with any human 3′ UTR) to differentiating cultures. [score:5]
Inhibition of macrophage and DC conversion to OC with miR-142-3p overexpression. [score:5]
This is consistent with our previously reported effects of miR-142-3p overexpression/knock-down during monocyte-to-macrophage differentiation, in which we described no significant alteration of cell viability in the presence of M-CSF, GM-CSF, or GM-CSF plus IL-4 signaling 12. [score:4]
Here we show miR-142-3p to be a negative regulator of both de novo and ‘second-hand’ osteoclastogenesis, and postulate that such an effect is likely to be more efficacious (with regards to therapy) than a single-pathway approach to targeted modulation. [score:4]
1, NFI-A and M-CSFR circuitry, including c-Fos and CREB 14, and while miR-142-3p is not predicted to target any of these, we show that miR-142-3p similarly regulates osteoclastogenesis. [score:4]
We have previously reported miR-142-3p expression to be similarly decreased during monocyte-to-DC differentiation. [score:3]
Expression of miR-142-3p over time for OC (left) and macrophage (right) is presented in Fig. 2C. [score:3]
Cells were transfected at day 2 with miR-142-3p mimic, inhibitor, or control mimic. [score:3]
miRNAs identified as differentially expressed during osteoclastogenesis included novel miRNAs such as miR-142-3p, as well miRNAs known to be involved in osteoclastogenesis- for example miR-223. [score:3]
Filled black squares represent miR-142-3p mimic transfected cells, filled grey squares represent miR-142-3p inhibitor transfected cells, and empty circles represent control mimic transfected cells. [score:3]
Phenotype and PKCα expression in osteoclast cultures transfected with miR-142-3p mimic or PKCα siRNA. [score:3]
Previously, we reported an inverse correlation of miR-142-3p with PKCα mRNA levels and confirmed PKCα as a novel target of miR-142-3p 11. [score:3]
miR-142-3p expression prevents the generation of OC from macrophage and DC. [score:3]
There was a trend for greater clustering, fusion and higher average number of nuclei per cell in miR-142 inhibitor transfected cells, but this was not statistically significant (data not shown). [score:3]
Day 7 cultures were left untransfected or transfected with miR-142-3p mimic, miR-142-3p inhibitor, or control mimic. [score:3]
Increased cell death of osteoclast precursors by overexpression of miR-142-3p. [score:3]
Macrophage and DC were transfected at day 7 with miR-142-3p mimic, miR-142-3p inhibitor, or control mimic, and culture conditions were substituted for OC-differentiating conditions. [score:3]
By day 9, OC cultures overexpressing miR-142-3p contained far fewer cells and displayed a reduced number of multi-nucleated cells (Fig. 3A, bottom). [score:3]
Day 2 differentiating OC were transfected with miR-142-3p mimic, inhibitor, or control mimic and PKCα protein and mRNA levels were assessed on day 6 and day 4, respectively. [score:3]
Cultures were left untreated or transfected with miR-142-3p mimic, miR-142-3p inhibitor, or control mimic at day 2. (A) Brightfield images of differentiating osteoclasts (M-CSF and sRANKL) were taken at day 4 (top) and images of cells stained with Hoescht (nuclei; blue) and MitoTracker (mitochondria, red) were taken at day 9 (bottom). [score:3]
At day 11, cultures combining transfection with control mimic or miR-142-3p inhibitor and OC-differentiating conditions displayed increased size, and in the case of MΦ to OC conversion, the presence of giant cells (highlighted by white arrows) (Fig. 5A). [score:3]
While we have demonstrated the direct effect on PKCα by miR-142-3p, it is likely that other interactions may contribute to our findings. [score:2]
Furthermore, while the fact that increased miR-142-3p expression correlates with increased cell death may be considered a weakness, we believe this must be tempered by the observation that it is RANKL -dependent. [score:2]
Expression profiles of miR-223, miR-34a-5p and miR-142-3p were examined by miScript PCR assays and SYBR Green Master Mix (both from Qiagen). [score:2]
The identification of previously reported miRNAs, such as miR-223, provides further support both for their role in osteoclastogenesis, and for the validity of the novel miRNAs identified, such as miR-142-3p. [score:1]
Our bioinformatic analysis has also revealed several potential interactions of miR-142-3p with BCL2 family members, including BCL2 and BCL2L1, as well as signaling molecules upstream of the PKCα pathway, such as phospho-inositide 3 kinase (PI-3K). [score:1]
Cultures transfected with miR-142-3p mimic displayed reduced PKCα at the level of mRNA and protein (Fig. 4A,B, respectively). [score:1]
Also, miR-142-3p mimic transfected macrophages or DCs were not adversely affected when exposed to M-CSF in the absence of sRANKL. [score:1]
In contrast, cultures combining transfection with miR-142-3p mimic and OC-differentiating conditions displayed very few cells (Fig. 5A). [score:1]
[1 to 20 of 36 sentences]
16
[+] score: 122
Rather, we show that formaldehyde is associated with the increased expression of miR-125b and the decreased expression of miR-142-3p, and decreased or increased expression of their respective target genes. [score:9]
Figure 2RT-PCR shows the altered expression of (A) apoptosis signaling-related genes predicted to be targeted by miR-125b, and (B) ILK signaling-related genes predicted to be targeted by miR-142-3p. [score:7]
Because miR-142-3p was decreased in expression by 6 ppm formaldehyde, we anticipated its potential targets to show increased expression. [score:7]
To confirm formaldehyde -induced miRNA expression changes, we performed RT-PCR using two miRNAs identified as the most increased in expression (miR-125b and miR-152) and the two miRNAs identified as the most decreased in expression (miR-145 and miR-142-3p) after 6 ppm formaldehyde exposure. [score:7]
Because miR-142-3p was decreased in expression, it was anticipated that its potential targets would have increased expression after formaldehyde exposure. [score:7]
It is important to note that these results do not demonstrate that miR-125b directly decreases the expression of BAK1, CASP2, MAP2K7, and MCL1 upon exposure to formaldehyde, nor that miR-142-3p directly increases the expression of ITGB8. [score:7]
This finding suggests that a) miR-142-3p may not influence RICTOR under the tested conditions, b) miR-142-3p may influence RICTOR protein levels by blocking RICTOR translation, or c) other mechanisms besides miRNA regulation may influence RICTOR expression. [score:6]
ILK-related miR-142-3p targets are altered in expression. [score:5]
Specifically, the two miRNAs most increased in expression (miR-125b and miR-152) and the two miRNAs most decreased in expression (miR-145 and miR-142-3p) in response to 6 ppm formaldehyde were validated using this alternative method. [score:5]
The two ILK signaling–related mRNA molecules predicted to be targeted by miR-142-3p were tested at the gene expression level using RT-PCR. [score:5]
Far fewer genes were identified for miR-142-3p, where 13 genes were predicted to be targeted by miR-142-3p, and thereby increased at the expression level. [score:5]
All apoptosis -associated genes (n = 4) predicted to be regulated by formaldehyde-responsive miR-125b, and all integrin-linked kinase (ILK) -associated genes (n = 2) predicted to be regulated by formaldehyde-responsive miR-142-3p, were tested at the gene expression level using RT-PCR. [score:5]
To understand genomic changes regulated via miRNAs that formaldehyde inhalation exposure may initiate, we computationally predicted mRNA targets of miR-125b and miR-142-3p. [score:4]
Systems-level analysis of the transcriptional targets predicted to be regulated by formaldehyde-responsive miR-125b and miR-142-3p revealed the highest enrichment between genes involved in apoptosis signaling and miR-125b. [score:4]
In comparison, only 13 genes were predicted to be targeted by miR-142-3p (see, Table S2). [score:3]
We focused our systems -based analysis on miR-125b and miR-142-3p because these miRNAs showed the highest increase and decrease in expression, respectively, upon exposure to 6 ppm formaldehyde through microarray analysis and were confirmed using RT-PCR analysis. [score:3]
Transcriptional targets of miR-125b and miR-142-3p were predicted. [score:3]
For this analysis, the predicted mRNA targets of miR-125b and miR-142-3p were overlaid onto a global interaction network. [score:3]
Pathway analysis of the predicted targets of miR-142-3p revealed an enrichment for ILK signaling. [score:3]
Similar confirmation was observed for miR-145 and miR-142-3p, where expression levels were significantly (p < 0.05) decreased following 6 ppm formaldehyde exposure (Figure 1). [score:3]
Three canonical pathways were identified as significantly overrepresented within the predicted targets of miR-142-3p [see, Table S3 (http://dx. [score:3]
ILK signaling is associated with miR-142-3p predicted targets. [score:3]
More specifically, miR-142-3p, miR-145, miR-152, miR-203, miR-26b, and miR-29a have all been shown to have altered expression levels in nasopharyngeal cancer tissue in comparison to noncancerous tissue (Chen et al. 2009; Li et al. 2011; Sengupta et al. 2008; Wong et al. 2012). [score:3]
These two miRNAs were selected because they showed the largest increase (miR-125b) or decrease (miR-142-3p) in expression after 6 ppm formaldehyde exposure. [score:3]
Predicting targets of miR-125b and miR-142-3p. [score:3]
Pathways with enrichment p-values < 0.05 were considered significantly enriched with the predicted targets of miR-125b or miR-142-3p. [score:2]
In order to evaluate the effects of formaldehyde inhalation exposure at the systems level, molecular targets of miR-125b and miR-142-3p were computationally predicted and analyzed for pathway enrichment. [score:1]
12* 6.7 × 10–5 0.055 miR-142-3p 12366 –4.12* 1.1 × 10–6 0.009 –2.92* 1.6 × 10–6 0.011 miR-29a 13448 –3.24 2.5 × 10–4 0.188 –3.15* 2.6 × 10–4 0.099 miR-145 15649 –3.15* 3.0 × 10–5 0.098 –3.56* 2.6 × 10–5 0.036 miR-142-3p 14658 –2.81 3.1 × 10–4 0.188 –5.01* 1.8 × 10–4 0.075 FC, fold change. [score:1]
Interestingly, the three miRNAs that were significantly decreased in response to 2 ppm formaldehyde (i. e., miR-142-3p, miR-145, and miR-203) were also significantly decreased in response to 6 ppm formaldehyde. [score:1]
To further assess the potential effects of formaldehyde exposure at the systems level, enriched canonical signaling pathways were evaluated for the 13 predicted targets of miR-142-3p. [score:1]
[1 to 20 of 30 sentences]
17
[+] score: 105
While M. tuberculosis and Mycobacterium smegmatis upregulate miR-142-3p leading to N-wasp downregulation and reduced phagocytosis (inhibition of M1 phenotype), M. bovis downregulates the same miRNA consequently activating NF-κB (M1 phenotype) (45, 127). [score:12]
Increased miR-142-5p expression resulted in decreased SOCS1 expression, while a decrease in miR-130a-5p expression resulted in increased PPARγ expression. [score:9]
In our own study of three miRNAs (miR-24, miR-30b, and miR-142-3p) whose expression were downregulated during MΦ differentiation and in response to LPS, and whose inhibitory potential are comparable, we have not observed synergy in their action (14). [score:8]
Mirroring their in vitro results, analysis of MΦ miR-142-5p and miR-130a-5p expression in tissue samples from patients with liver cirrhosis or idiopathic pulmonary fibrosis revealed the same pattern of miRNA-target expression. [score:7]
While the effect of miR-142-3p appears to be mediated, at least in part, through its direct targeting of PKCα, neither miR-24 nor miR-30b directly targets PKCα. [score:7]
While M. tuberculosis and Mycobacterium smegmatis upregulate miR-142-3p and suppress M1 phenotype, Mycobacterium bovis infection leads to repression of miR-142-3p and, hence, increased NF-κB signaling through derepression of IRAK1. [score:6]
We have reported that miR-142-3p, in addition to suppressing the generation and activation of M1 MΦs, also inhibits their conversion into OC (69). [score:5]
Our own work on miR-142-3p has revealed an inhibitory mechanism for this miRNA, which, in addition to the suppression of TLR4/2 mediated signaling, involves the accumulation of at the MΦ cell surface. [score:5]
We have previously reported that enforced expression of miR-24, miR-30b, or miR-142-3p in activated MΦs inhibits their production of(p40) (11, 13). [score:5]
The production of by MΦs is also inhibited by miR-142-3p (11, 13); however, unlike, this is not associated with sequestration at the cell surface. [score:3]
Their enforced expression inhibits NF-κB activation and cytokine production in mature MΦs(11– 13)Su et al. investigated the miRNA profiles of alternatively activated MΦs and identified miR-142-5p and miR-130a-3p as important contributors to the pro-fibrogenic MΦ program (78). [score:3]
For example, we have extensively characterized the inhibitory effects of miR-24, miR-30b, and miR-142-3p expression on myeloid inflammatory cell viz. [score:3]
These miRNAs, which include miR-26a and miR-142-3p, are pro-apoptotic as their targets include anti-apoptotic genes, for example, members of the BCL2 family (11). [score:3]
Their enforced expression inhibits NF-κB activation and cytokine production in mature MΦs(11– 13) Su et al. investigated the miRNA profiles of alternatively activated MΦs and identified miR-142-5p and miR-130a-3p as important contributors to the pro-fibrogenic MΦ program (78). [score:3]
Here, miR-142-3p expression in MΦs was shown to decline with age and this contributed to increased production. [score:3]
By using mouse mo dels of fibrosis, they were also able to demonstrate therapeutic efficacy via the introduction of miR-142-5p inhibitor and miR-130a-3p mimic. [score:3]
An in vivo study by Xu et al. (115) showed that overexpression of miR-142-3p in M2 MΦ induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset. [score:3]
Which is to say that the enforced expression of all three had no greater effect than that conferred by the most potent of the three (miR-142-3p). [score:3]
We have previously described miR-24, miR-30b, and miR-142-3p -mediated regulation of MΦ phagocytosis (13, 71). [score:2]
This convergence/divergence is mirrored by our studies on miR-24, miR-30b and miR-142-3p mediated cytokine regulation. [score:2]
This is also an area where convergent miRNA regulation appears to exist, as these same studies identified a very similar phenotype for miR-24 and miR-30b to that of miR-142-3p. [score:2]
This phenotype arises from the known role for miR-142-3p in regulating cytoskeletal rearrangement (14, 52). [score:2]
Interestingly, a recent publication in murine MΦs identified miR-142-3p as a regulator of the pro-inflammatory cytokine response to Mycobacterium bovis (45). [score:2]
Human and murine miR-24 and miR-142-3p possess 100% sequence homology, while miR-30b differs in 2 of its nucleotides. [score:1]
Taken together, our studies on miR-24, miR-30b, and miR-142-3p may provide a route toward novel therapies aimed at treating chronic inflammatory disorders. [score:1]
2015.4301 115 Xu S Wei J Wang F Kong LY Ling XY Nduom E Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma. [score:1]
Our studies on miR-142-3p have revealed human–murine functional homology in the context of bacterial -induced pro-inflammatory cytokine production (11, 13). [score:1]
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[+] score: 88
Overexpression of miR-142-3p in human CD133+HUCB-MNC cells can not only inhibit the expression of CD133 but also can inhibit the proliferation in vitro, arrest cell cycle progression, and promote apoptosis. [score:9]
The reagents for hsa-miR-142-3p inhibition were: hsa-miR-142-3p inhibitor (micrOFF™ hsa-miR-142-3p inhibitor, Standard, 5nmol, miR20000434-1-5), and negative control inhibitor (neg. [score:9]
The proportion of S phase cells decreased in the miRNA-142-3p mimic group compared with mimic control group at 6 Gy radiation dose (10 nM, 15.759% ± 1.096% vs 20.187% ± 1.002%, p < 0.01; 20 nM, 12.273% ± 1.030% vs 20.187% ± 1.002%, p < 0.001; 50 nM, 8.502% ± 1.382% vs 20.187% ± 1.002%, p < 0.001), and miRNA-142-3p inhibitor upregulated the proportion of S phase cells compared with inhibitor control group (20 nM, 25.967% ± 1.812% vs 21.987% ± 2.539%, p < 0.05; 50 nM, 30.757% ± 3.025% vs 21.987% ± 2.539%, p < 0.01; 100 nM, 36.595% ± 3.974% vs 21.987% ± 2.539%, p < 0.001) (Fig.   6E,F). [score:6]
MiRNA prediction tools included: miRanda [34], RNA22 [35], TargetScan [36], and MiRWalk [37] Combined with CD133 molecular regulation and human umbilical cord blood mononuclear cell s expressed miRNA two aspects of information, the final confirmation of the following 12 miRNA [19]: hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-200c-3p, hsa-miR-4423-5p, hsa-miR-335-3p, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-22-3p, hsa-miR-30a-5p, hsa-miR-30e-5p, hsa-miR-377-3p and hsa-miR-4739 (Supplementary Table  2). [score:6]
And transfection of miR-142-3p inhibitors in CD133+HUCB-MNC cells increased CD133 expression (20 nM, 1.779 ± 0.164 vs 0.992 ± 0.216, p < 0.05; 50 nM, 2.662 ± 0.213 vs 0.992 ± 0.216, p < 0.01; 100 nM, 3.661 ± 0.351 vs 0.992 ± 0.216, p < 0.001) (Fig.   5C,E). [score:5]
Moreover miR-142-3p directly targets CD133 to regulate its ability to confer cancer and stem cell-like features in HCC [21]. [score:5]
Wei-Wei Shen et al. reported that miR-142-3p functioned as a tumor suppressor by targeting CD133, ABCG2, and Lgr5 in colon cancer cells [17]. [score:5]
Transfection of miR-142-3p mimics in CD133+HUCB- MNC cells downregulated CD133 expression compared with the mimic control both in mRNA (10 nM, 0.672 ± 0.136 vs 0.979 ± 0.152, p < 0.01; 20 nM, 0.233 ± 0.082 vs 0.979 ± 0.152, p < 0.001; 50 nM, 0.155 ± 0.059 vs 0.979 ± 0.152, p < 0.001) and protein levels (Fig.   5B,D). [score:5]
Therefore, miR-142-3p acted on 3’UTR of CD133 mRNA to inhibit CD133 expression. [score:5]
Combined with CD133 molecular regulation and human umbilical cord blood mononuclear cells expressed miRNA two aspects of information, the final confirmation of the following 12 miRNA [19]: hsa-miR-29a-3p (Fig.   4A), hsa-miR-29b-3p (Fig.   4B), hsa-miR-200c-3p (Fig.   4C), hsa-miR-4423-5p (Fig.   4D), hsa-miR-335-3p (Fig.   4E), hsa-miR-142-5p (Fig.   4G), hsa-miR-22-3p (Fig.   4H), hsa-miR-30a-5p (Fig.   4I), hsa-miR-30e-5p (Fig.   4J), hsa-miR-377-3p (Fig.   4K) and hsa-miR-4739 (Fig.   4L) showed no difference between CD133+HUCB-MNC cells and CD133−HUCB-MNC cells. [score:4]
MiR-142-3p acted on 3′UTR of CD133 mRNA to inhibit CD133 expression. [score:4]
As showed in Fig.   6C,D, the proportion of apoptosis increased in the miRNA-142-3p mimic group compared with mimic control group (10 nM, 44.819% ± 3.572% vs 35.897% ± 4.880%, p < 0.01; 20 nM, 49.160% ± 8.047% vs 35.897% ± 4.880%, p < 0.01; 50 nM, 62.032% ± 9.634% vs 35.897% ± 4.880%, p < 0.001), while miRNA-142-3p inhibitor reduced the proportion of apoptosis compared with inhibitor control group (20 nM, 28.629% ± 3.572% vs 37.745% ± 3.094%, p < 0.01; 50 nM, 25.117% ± 4.496% vs 37.745% ± 3.094%, p < 0.01; 100 nM, 19.091% ± 4.371% vs 37.745% ± 3.094%, p < 0.001). [score:3]
MiRNA-142-3p mimic reduced CD133+HUCB-MNC cells’ proliferation rate compared with the mimic control group (10 nM, 0.580 ± 0.077 vs 0.747 ± 0.083, p < 0.05; 20 nM, 0.313 ± 0.085 vs 0.747 ± 0.083, p < 0.001; 50 nM, 0.172 ± 0.049 vs 0.747 ± 0.083, p < 0.001) (Fig.   6A), while miRNA-142-3p inhibitor increased the proliferation rate compared with the inhibitor control group (20 nM, 0.912 ± 0.038 vs 0.725 ± 0.107, p < 0.05; 50 nM, 1.126 ± 0.049 vs 0.725 ± 0.107, p < 0.01; 100 nM, 1.311 ± 0.059 vs 0.725 ± 0.107, p < 0.001) (Fig.   6B). [score:3]
To explore the effect of miRNA-142-3p on radiosensitivity in CD133+HUCB-MNC cells, both miRNA-142-3p mimic and miRNA-142-3p inhibitor were used to detect the effects on cell proliferation, cell apoptosis, cell cycle, AKT and ERK protein and mRNA levels after the 6 Gy radiation. [score:3]
And the miRNA-142-3p inhibitor showed opposite effects on the p-AKT and p-ERK (T202/Y204) levels. [score:3]
6 Gy radiation decreased miR-142-3p expression both in CD133 positive and CD133 negative cells (0.180 ± 0.087 vs 0.547 ± 0.067, p < 0.01) (Fig.   4F). [score:3]
Therapeutic delivery of miR142-3p in ATRT cells suggested effective reduction in its lethality by repressing tumor growth, inhibiting invasion, enhancing radiosensitivity, and prolonging survival time in orthotropic-transplanted immunocompromised mice [29]. [score:3]
Identification of the markers under the control of miRNA-142-3p and their regulation in CD133+HUCB-MNC cells may help develop efficient targeted treatments, improved diagnostic methods, and better prognostic evaluation. [score:2]
In this study, we identified miR-142-3p as a key modulator of CD133+ HUCB-MNC cells through pathways involving CD133, AKT and ERK pathways. [score:1]
CD133+HUCB-MNC cells were seeded into 12-well plates, and the vector (CD133-wt) was trasnfected into CD133+HUCB-MNC cells with hsa-miR-142-3p mimic (micrON™ hsa-miR-142-3p mimic, Standard, 5nmol, miR10000434-1-5) or negative control mimic (neg. [score:1]
miRNA-142-3p mimic increased radiosensitivity in CD133+HUCB-MNC cells. [score:1]
Genomic DNA was extracted from the blood, and the 3′UTR of CD133 containing miR-142-3p binding site was amplified. [score:1]
We further explored the effect of miRNA-142-3p on cell apoptosis after 6 Gy radiation exposures. [score:1]
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[+] score: 87
The predicted candidate miRNA targets expressed in immunological tissues (i. e. 201 genes for miR-21; 287 genes for miR-142-3p; 515 genes for miR-26a; and 580 genes for miR-29a) were then analyzed for overlapping target groups. [score:7]
Expression of miR-21 (triangles), miR-26a (squares), miR-29a (circles), miR-142-3p (diamonds), and miR-155 (hexagons) was compared between IFNγ -expressing T [H]1 (open symbols, n = 11) and IL-17 -expressing T [H]17 clones (black symbols, n = 9) of healthy donors prior to (A) and after in vitro activation (B). [score:6]
Predicted miR-21, miR-26a, miR29a, and miR-142-3p targets from the miRGen Internet platform were determined for expression in immunological tissues using Unigene Internet database (for details see ). [score:5]
Consistent pattern of differentially expressed miR-21, miR-26a, miR-29a, and miR-142-3p suggested a role of these candidates in T-cell immunity during tuberculosis disease and recovery. [score:5]
Ongoing studies aim at validating additional common targets of miRNA candidates to claryfy the role of miR-21, miR-26a, miR-29a, and miR-142-3p expression in tuberculosis. [score:5]
Median expression levels and standard deviations of all determined miRNAs are shown in Table 1. Four miRNAs, namely miR-21, miR-26a, miR-29a, and miR-142-3p, were differentially expressed between tuberculosis patients and LTBI (P = 0.035, P = 0.005, P = 0.008, and P = 0.002, respectively), whereas no differences were detected between LTBI and PPDneg (Table 1 and Figure 1A). [score:5]
Although the expression of miRNAs was heterogeneous between individuals, we detected markedly lower expression of miR-26a (P<0.01), miR-29a (P<0.01), and miR-142-3p (P<0.05) in children with tuberculosis as compared to children with LTBI (Figure 2A). [score:4]
In addition, the level of differentially expressed miRNAs of tuberculosis patients and controls correlated significantly and therefore, common regulation for miR21, miR-26a, miR-29a, and miR-142 was likely. [score:4]
0061609.g006 Figure 6(A) A Venn diagram indicates the overlap of target genes for miR-21, miR-26a, miR-29a and miR-142-3p. [score:3]
The present study provided evidence for a role of miR-21, miR-26a, miR-29a, and miR-142-3p in the immune response against human tuberculosis, a chronic infectious disease. [score:3]
Expression of miR-21 (triangles), miR-26a (squares), miR-29a (circles), and miR-142-3p (diamonds) in whole blood is shown for children with tuberculosis (TB, black symbols), healthy latently M. tuberculosis children (LTBI, grey symbols), and PPD negative contacts (PPD [neg], open symbols) (A) as well as for children with tuberculosis under therapy and recovery (B). [score:3]
Target genes and overlaps for miR-21, miR-26a, miR-29a and miR-142-3p. [score:3]
Analyses of miRNA candidates in whole blood of children with tuberculosis and contacts verified lower miR-26, miR-29a, and miR-142-3p expression in children with tuberculosis. [score:3]
Notably, miR-21, miR-26a, miR-29a, and miR-142-3p expression levels were comparable between children with tuberculosis and PPDneg children. [score:3]
0061609.g002 Figure 2Expression of miR-21 (triangles), miR-26a (squares), miR-29a (circles), and miR-142-3p (diamonds) in whole blood is shown for children with tuberculosis (TB, black symbols), healthy latently M. tuberculosis children (LTBI, grey symbols), and PPD negative contacts (PPD [neg], open symbols) (A) as well as for children with tuberculosis under therapy and recovery (B). [score:3]
Expression of miR-21, miR-26a, miR-29a and miR-142-3p after in vitro Re-stimulation of Naïve T Cells. [score:3]
Expression of miR-21, miR-26a, miR-29a and miR-142-3p in Human T [H]1 and T [H]17 Clones. [score:3]
Expression of miR-21 (triangles), miR-26a (squares), miR-29a (circles), and miR-142-3p (diamonds) in CD4 [+] T cells from tuberculosis patients (TB) (black symbols, n = 6), LTBI (grey symbols, n = 7), and PPD negative healthy controls (PPDneg) (open symbols, n = 3). [score:3]
MiR-29a and miR-142-3p showed only moderate expression differences with miR-142-3p being slightly decreased (Figure 3). [score:3]
The expression of miR-21, miR-26a, miR-29a, and miR-142-3p was homogeneous within the study groups and already moderate numbers of tuberculosis patients, LTBI, and PPDneg were sufficient to detect significant differences. [score:3]
Expression of miR-21, miR-26a, miR-29a and miR-142-3p in Human T [H]1 and T [H]17 ClonesIFNγ-secreting T [H]1 cells are crucial for protective immunity against M. tuberculosis infection [27]– [29]. [score:3]
Notably the level of differentially expressed miRNAs correlated markedly in T cells from individual donors (miR-21/miR-26a, P = 0.001; miR-21/miR-29a, P = 0.002; miR-21/miR-142-3p P = 0.001; miR-26a/miR-29a P<0.0001; miR-26a/miR-142-3p P<0.0001; miR-29a/miR-142-3p P<0.0001) (data not shown). [score:3]
It remains elusive whether miR-142-3p is also regulated by c-myc. [score:2]
No differences were detected for miR-21, miR-26a, miR-142-3p and miR-155 upon activation (Figure 4B). [score:1]
This rendered a common cause of decreased miR-21, miR-26a, miR-29a, and miR-142-3p of CD4 [+] T cells from tuberculosis patients likely. [score:1]
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[+] score: 86
Similarly, miR-142-3p was upregulated in human T-leukemic cell lines and primary T-leukemic cells isolated from T-cell acute lymphoblastic leukemia (T-ALL) patients and its expression levels correlated with prognosis 49. [score:6]
Interestingly, increased expression of PD-L1 has been reported in chronic lymphocytic leukemia (CLL) suggesting a possible association of miR-142-3p and PD-L1 expression 50. [score:5]
Overexpression of miR-24, miR-30b, and miR-142-3p suppress type I cytokines by DCs. [score:5]
Enforced expression of miR-24, miR-30b, and miR-142-3p in untreated MΦ significantly induced (~1.5–2 fold) CD86 expression (Fig. 5a,b). [score:5]
Marked induction (~2–4.5 fold) in PD-L1 expression was observed in miR-24, miR-30b, and miR-142-3p overexpressing cells compared to control mimic (Fig. 5a). [score:4]
These findings indicate that aberrant miR-142-3p and PD-L1 levels can suppress both innate and adaptive immune responses. [score:3]
Time kinetics of antigen uptake and processing in MΦ and DC overexpressing miR-24, miR-30b, and miR-142-3p. [score:3]
Impaired T-cell proliferation by MΦ and DC overexpressing miR-24, miR-30b and miR-142-3p. [score:3]
MΦ and DC overexpressing miR-24, miR-30b, and miR-142-3p exhibit impaired antigen processing. [score:3]
Our results show induced PD-L1 expression in miR-142-3p -transfected cells. [score:3]
In our previous study we showed that enforced expression of miR-142-3p in myeloid inflammatory cells results in defective phagocytosis as well as reduced secretion of proinflammatory cytokines 20. [score:3]
PD-L1 surface expression is induced in miR-24, miR-30b, and miR-142-3p transfected MΦ and DC. [score:3]
In this study we demonstrate an inhibitory effect of miR-24, miR-30b, and miR-142-3p on the uptake as well as processing of Ova by APCs. [score:3]
However, CD86 expression was significantly elevated only in miR-142-3p transfected MΦ treated with Ova while Ova treated or untreated DC transfected with miR-30b showed significant changes (Fig. 5a,b). [score:3]
MiR-24, miR-30b, and miR-142-3p mimics or inhibitors were purchased from Qiagen (Gaithersburg, MD, USA). [score:3]
MΦ and DCs overexpressing miR-24, miR-30b, and miR-142-3p are defective in antigen processing. [score:3]
Flow cytometric analysis showed antigen processing was reduced to approximately 22%, 38% and 40% in DC overexpressing miR-24, miR-30b and miR-142-3p, respectively (Fig. 1g–j). [score:3]
Time kinetics of antigen uptake and processing in miR-24, miR-30b, and miR-142-3p overexpressing APCs. [score:3]
miR-24, miR-30b, and miR-142-3p induce PD-L1 expression in APCs. [score:3]
Taken together, these results show that Th1 activation -associated cytokine profiles are suppressed in DC transfected with miR-24, miR-30b, and miR-142-3p. [score:3]
To examine the specific impact of miRNA mimics, we also used miR-142-3p inhibitor. [score:3]
Compared to control mimic, no significant differences were noted in the presence of miR-24, miR-30b or miR-142-3p inhibitor (Fig. 1e). [score:2]
MΦ transfected with miR-24, miR-30b and miR-142-3p mimics show reduced green signal compared to control mimics (Fig. 1a) suggesting impaired antigen processing upon enforced expression of the miRNA mimics. [score:2]
Overall, our results highlight novel mechanistic insights through which miR-24, miR-30b and miR-142-3p can regulate activation of adaptive immune responses guided by APCs. [score:2]
miR-24, miR-30b, and miR-142-3p impair Ova specific T-cell proliferation. [score:1]
We therefore examined the impact of miR-24, miR-30b and miR-142-3p on antigen processing by MΦ and DC. [score:1]
How to cite this article: Naqvi, A. R. et al. miR-24, miR-30b and miR-142-3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. [score:1]
MiRNA transfected cells, more specifically miR-142-3p, were also less efficient in clearing the antigen as reflected by the absence of population devoid of Ova (both Texas Red and BODIPY labelled Add; ‘see black arrows in Fig. 1, lower panels’. [score:1]
Impaired T-cell activation and proliferation by miR-24, miR-30b, and miR-142-3p transfected APCs. [score:1]
In MΦ, Mycobacteria tuberculosis (M. tb) infection induces high levels of miR-142-3p and impairs phagocytosis of pathogen 56. [score:1]
We next examined the impact of PD-L1 blocking on T cell proliferation by miR-24, miR-30b, and miR-142-3p. [score:1]
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[+] score: 85
MiR-27b mimic, miR-142 mimic, miR-206 mimic, miR-21 mimic, miR-130a mimic, mimic negative control, miR-27b inhibitor, miR-142 inhibitor, miR-206 inhibitor, miR-21 inhibitor, miR-130a inhibitor, and inhibitor negative control were obtained from RiboBio (Guangzhou, China). [score:13]
These results suggest that miR-142 could independently inhibit CYP3A4 and CYP3A5 expression and that miR-27b could inhibit CYP3A4 expression (Fig. 5a,b). [score:9]
Together, these data indicate that the effect of miR-142 on CYP3A activity occurs through inhibition of CYP3A4 and CYP3A5 transcription, and that the inhibition does not occur by directly targeting CYP3A4 and CYP3A5 mRNA, but rather by an indirect pathway. [score:9]
To validate whether miR-27b, miR-206, miR-21, and miR-130a regulate CYP3A4 and miR-27b and miR-142 regulate CYP3A5 by directly targeting binding sites, wild-type and mutant versions of CYP3A4 3′-UTR and CYP3A5 3′-UTR were constructed and cloned downstream of a luciferase reporter gene. [score:6]
Our results indicated that CYP3A activity could be repressed by miR-27b and miR-206 via translational regulation and by miR-142 through transcriptional inhibition of CYP3A4 and CYP3A5. [score:6]
The expression levels of four related miRNAs, namely, miR-27b, miR-21, miR-130a, and miR-142, were significantly negatively associated with CYP3A4 mRNA expression level. [score:5]
Data from the in vitro mo del showed that miR-142 could inhibit CYP3A4 and CYP3A5 gene expression as well as CYP3A activity. [score:5]
Three miRNAs predicted to target the CYP3A5 sequence, namely, miR-21, miR-130a, and miR-142, were marginally negatively associated with CYP3A5 mRNA level in 55 human liver tissues. [score:3]
Specifically, miR-27b, miR103, miR107 were previously reported to play key roles in regulating CYP3A and CYP2C 20 33, while miR-142 and miR-491 were reported to play key roles in regulating phase II enzymes, namely UGT1A1 and UGT1A3 34 35. [score:3]
The CYP3A5 mRNA level was significantly decreased by mimics of miR-27b, miR-142, miR-206 and miR-21, but increased by inhibitor of miR-142. [score:3]
However, only miR-142 was identified to be an independent contributor to variability of CYP3A4 and CYP3A5 mRNA expression. [score:3]
Multivariate linear regression analysis showed that the presence of cancer, CYP3A4*1G polymorphism, and miR-142 were independent factors influencing the variability of CYP3A4 mRNA expression with the mo del R [2] = 0.29. [score:3]
These results show that miR-27b and miR-142 do not target the predicted CYP3A5 MRE. [score:3]
To investigate the effects of miR-27b, miR-206, miR-21, miR-130a and miR-142 on regulation of CYP3A activity, 75 nM mimic or 100 nM inhibitor of miRNA or control was transfected into human primary hepatocytes using Lipofectamine 3000 (Invitrogen Life Technologies, USA). [score:2]
Nevertheless, the luciferase reporter assay revealed that CYP3A5 is not directly regulated by miR-142. [score:2]
was significantly decreased by transfection of mimics of miR-27b, miR-206, miR-21, and miR-142 into the human primary hepatocytes, while was significantly increased by inhibitors of miR-27b and miR-206, compared to the control (Fig. 5c). [score:2]
The relative level of CYP3A4 mRNA was significantly decreased by mimics of miR-27b, miR-142, miR-206 and miR-130a, compared with negative controls, while the level of CYP3A4 mRNA was increased by inhibitors of miR-27b and miR-142. [score:2]
Among the 13 miRNAs tested, miR-27b, miR-130a, miR-21, and miR-142 were significantly negatively associated with CYP3A4 mRNA in the human liver. [score:1]
Similarly, the luciferase activities of both the pRB/CYP3A5 wild-type and mutant plasmids were unaffected by miR-27b and miR-142 (Supplementary Fig. S2c,d). [score:1]
Liver cancer, CYP3A5*3 polymorphism, and miR-142 were independent factors for the variability of CYP3A5 mRNA with the mo del R [2] = 0.35. [score:1]
MiR-142, miR-21 (r = −0.31, P = 0.020, FDR = 0.043) were negatively associated with CYP3A activity. [score:1]
Therefore, a total of 13miRNAs, namely miR-21-5p, miR-27a-3p, miR-27b-3p, miR-103a-3p, miR-106a-5p, miR-107, miR-126-5p, miR-130a-3p, miR-142-5p, miR-206, miR-371b-5p, miR-491-3p, and miR-1260b, were selected. [score:1]
MiR-142, miR-130a, and miR-21 were marginally negatively associated with CYP3A5 mRNAs. [score:1]
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We show that IL1A is a target for miR-142-3p and that the down-regulation of this miRNA might confer a selective advantage to the EBV-infected cell by elevating IL1A levels. [score:6]
thymus we found a reduced expression of miR-142-3p and miR-20b by PCR but a slight up-regulation in the lymphomas by sequencing. [score:6]
We then analysed the HaCaT cell line which is known to express IL1A; transient expression of miR-142-3p also resulted in an approx. [score:5]
Identification of the Pro-inflammatory Cytokine IL1A as a Target of the Deregulated miR-142-3p. [score:4]
Concomitant with the decrease in miR142-3p, the mRNA levels for IL1A were up-regulated in EBV -positive lymphomas and we could indeed prove that the IL1A 3′-UTR contains a binding site for this miRNA. [score:4]
Except for the direct regulation of IL1A by miR-142-3p found in this study, the miRNA has also an indirect influence on IL1A. [score:4]
It was already reported that AC9 is regulated by miR-142-3p and that the inhibition of AC9 resulted in a reduced amount of cAMP [34]. [score:4]
The down-regulation of miR-142-5p and miR-142-3p in the EBV -positive NK/T-cell lymphomas as compared to the EBV -negative lymphomas was also confirmed by the qRT-PCR analysis including a comparison between CD56+ primary cells and the NK/T-cell lines and the tumor tissues (supporting Figure S4). [score:3]
When compared to primary thymus tissue, the tested miRNAs miR-142-3p, -145, -181b, -200c, -205 and –424 all were down-regulated in the tumor tissues and the cell lines tested, with the exception of miR-181b and miR-424 that essentially showed no change in the primary, frozen tissue of the NK/T-cell lymphoma. [score:3]
As shown in Figure 3G, the amount of IL1A in the supernatant of the miR-142-3p expressing cells was reduced by about 15% which is statistically significant (p = 0.0007). [score:3]
We further identified the 3′-UTR of the IL1A gene as a potential target for miR-142-3p, miR-181a and miR-181b which are repressed in EBV -associated lymphomas. [score:3]
D: Relative expression change of miR-142-3p and IL1A between EBV -associated NK/T-cell and EBV -negative T-cell lymphomas analysed by a quantitative Real-Time PCR presented as log2. [score:3]
Lastly, we could demonstrate that miR-142, when ectopically expressed in a human cell line, reduced the protein levels of IL1A and also reduced the levels of secreted IL1A. [score:3]
Accordingly, miR-142 negatively regulated a reporter construct featuring the IL1A-3′-UTR which lost its responsiveness upon binding site mutation. [score:3]
We therefore transfected 293T cells with a full length cDNA clone which also comprised the 3′-UTR; as can be seen in Figure 3E, the band corresponding to IL1A was reduced to about 70% when miR-142-3p was co-expressed. [score:3]
F: Effect of miR-142 on the endogenous IL1A protein expression. [score:3]
The mutated reporter lost its responsiveness towards miR-142-3p demonstrating that the IL1A 3′-UTR is a bona fide target of this miRNA (Figure 3C). [score:3]
When we tried to express miR-142-3p in NK- or T-cell lines that were at our disposal by electroporation employing various systems, we got only a small percentage of transfected cells or a large number of apoptotic cells. [score:3]
As cAMP in turn is able to induce the amount of IL1A, miR-142-3p is able to influence IL1A indirectly by regulating AC9, too [35]. [score:3]
Regulation of IL1A by miR-142. [score:2]
The seed sequence of potential binding site for miR-142-3p on the IL1A 3′-UTR (boxed in Figure 3B) was then changed by site-directed mutagenesis. [score:2]
We analysed the effect of miR-142-3p on the amount of secreted IL1A in HaCaT cells. [score:1]
B: Schematic overview about the predicted binding site of miR-142-3p in the 3′UTR of IL1A. [score:1]
The luciferase reporter analysis showed that miR-142-3p but not the other two miRNAs had a significant effect on the reporter. [score:1]
MiR-590-3p and miR-142-5p were the only miRNAs which were deregulated in EBV -positive lymphomas and at the same time induced in both types of lymphomas compared to normal tissue. [score:1]
The IL1A-levels of supernatants of HaCaT transfected with miR-142 or vector control cells were analysed by. [score:1]
C: Influence of miR-142 on the luciferase activity of the empty vector, the IL1A-3′UTR containing reporter as well as the mutated 3′UTR. [score:1]
G: Influence of miR-142 on the secretion of IL1A. [score:1]
We determined the relative levels of miR-142-3p and IL1A in the EBV -positive vs. [score:1]
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miR-142-3p, miR-181a, b, c and d and miR-185 target the 3’ UTR of the GARP mRNABecause GARP appears to regulate TGF-β1 secretion by T cells and TGF-β1 is important for the suppressive function of Treg cells, we sought to identify mechanisms that control GARP expression. [score:8]
While no functional consequence of the downregulation of miR-181b or d could be identified [38], the reduced expression of miR-142-3p was reported to allow increased Adenylyl Cyclase 9 activity and thus increase cAMP levels in murine Tregs [44]. [score:6]
Therefore, downregulation of miR-142-3p in Tregs may be important for the acquisition or maintenance of at least two immunosuppressive mechanisms. [score:6]
miR-142-3p, miR-181a, b, c and d and miR-185 are expressed at higher levels in human CD4 [+] Th clones than in Treg clonesIf the 6 miRNAs identified above were to play a role in regulating GARP protein levels in human T cells, we expected their expression to be higher in Th than in Treg clones. [score:6]
Here we identified 6 miRNAs, namely miR-142-3p, miR-185 and miR-181a, b, c and d, that are expressed at lower levels in human Treg than in Th clones, and that control GARP protein amounts through direct targeting of the GARP 3’ UTR. [score:6]
Therefore, downregulation of miR-142-3p, miR-185 and miR181a, b, c, d in the course of Treg cell differentiation might be required for the acquisition of a complete immunosuppressive phenotype. [score:6]
miR-142-3p, miR-181a and miR-185 decrease GARP protein levels when overexpressed in polyclonal populations enriched in TregsTo test whether these miRNAs can control endogenous GARP levels in human T cells, we transfected miRNA mimics in T cell populations with endogenous GARP expression. [score:5]
Conversely, mutation of the miR-181 site, but not that of the miR-142-3p site, suppressed the ability of the four m iR-181 family members to decrease reporter activity (Figure 6D). [score:4]
Together, these results demonstrate that a 400-bp region of the GARP 3’ UTR, that is directly targeted by miR-142-3p, miR-185 and the four miR-181, controls GARP protein levels and the amounts of TGF-β1 that are processed and secreted by human CD4 [+] T cells. [score:4]
Mutation of the miR-142-3p binding site, but not that of the miR-181 site, suppressed the ability of the miR-142-3p mimic to decrease reporter activity in 293 cells (Figure 6D). [score:4]
miR-142-3p, miR-181a, b, c and d and miR-185 target the 3’ UTR of the GARP mRNA. [score:3]
Others have reported a reduced expression of miR-142-3p and miR-181 b and d in murine or human Tregs by comparison to Th cells [37, 38, 44, 46]. [score:3]
RT-qPCR analysis indicated that miR-142-3p was expressed at the highest overall levels, and in average 2.5 times more in Th than in Tregs (Figure 8). [score:3]
Six miRNAs, namely miR-181a, b, c and d, miR-142-3p and miR-185, significantly decreased the reporter’s expression (Figure 6A). [score:3]
miR-142-3p, miR-181a, b, c and d and miR-185 are expressed at higher levels in human CD4 [+] Th clones than in Treg clones. [score:3]
miR-142-3p, miR-181a and miR-185 decrease GARP protein levels when overexpressed in polyclonal populations enriched in Tregs. [score:3]
0076186.g007 Figure 7Endogenous GARP levels in Tregs are reduced after transfection of miR-181a, miR-142-3p and miR-185 mimics. [score:1]
GARP protein was decreased after transfection with miR-142-3p, miR-185, miR-181a, or a mixture of the three, by comparison to a control miRNA (Figure 7). [score:1]
miR-142-3p, miR-185 and miR-181a to d decreased GARP protein levels when cotransfected with the GARP plasmid containing the 3’ UTR, but had no effect in its absence. [score:1]
Endogenous GARP levels in Tregs are reduced after transfection of miR-181a, miR-142-3p and miR-185 mimics. [score:1]
miR-181a to d have very similar sequences and are predicted to bind to a single site in the GARP 3’ UTR, close to the predicted miR-142-3p binding site (Figure 6B). [score:1]
The truncation removes the last 400 bp that contain the binding sites for miR-181a, b, c, d, miR-142-3p, and one of the two miR-185 sites (Figure 6B). [score:1]
During the preparation of this manuscript, others also reported that miR-142-3p controls GARP levels in Tregs [45]. [score:1]
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[+] score: 75
This study provides evidence for an additional mechanism for regulation of gene expression by epigenetics, where DNA hypomethylation may increase miR-142 expression, leading to possible secondary effects on downstream targets. [score:8]
First, the finding that miR-142 upregulation is significantly correlated with hypomethylation of the gene promoter provides further evidence of the primary role that epigenetics plays in mediation of gene expression in the autism brain. [score:6]
In addition, miR-142-3p targets and decreases the translation of D1 dopamine receptors [38]. [score:5]
Of these microRNAs we studied, real-time PCR analysis detected significant upregulation of five microRNAs (Fig.   1), including miR-142-5p (p = 0.0003), miR-142-3p (p = 0.003), miR-21 (p = 0.022), miR-451a (p = 0.007), and miR-144-3p (p = 0.0001). [score:4]
In addition, we suggest a connection between DNA methylation dysregulation and the overexpression of miR-142 in autism. [score:4]
Each graph represents a correlation between miR-142-5p and a separate CpG site that was analyzed by pyrosequencing To gain further insight into the biological meaning of the dysregulation of miR-142-5p, miR-142-3p, miR-21-5p, miR-144-3p, and miR-451a in the autism brain samples, we performed gene ontology analysis on the targets of these microRNAs, using the DIANA-lab software [23]. [score:4]
Therefore, we can directly correlate between decreased methylation of the miR-142 promoter and increased expression of the miR-142 transcripts in the brain samples of individuals diagnosed with asd. [score:4]
These results suggest a role for epigenetic dysregulation in miR-142 overexpression in the autism brain samples. [score:4]
We determined that miR-142-5p, miR-142-3p, miR-451a, miR-144-3p, and miR-21-5p are overexpressed in the asd brain. [score:3]
In addition, Spearman’s correlation analysis found a significant inverse correlation between the methylation levels at each specific CpG and expression levels of miR-142-5p (Fig.   2d–f) and miR-142-3p (Additional file 4). [score:3]
Fig. 3Gene ontology analysis of predicted targets of miR-142-5p, miR-142-3p, miR-21-5p, miR-144-3p, and miR-451a. [score:3]
d– f Spearman’s correlation coefficient, including p value between miR-142-5p gene expression and DNA methylation. [score:3]
Correlation analysis between miR-142 expression levels and DNA methylation of miR-142 promoter. [score:3]
MiR-142-5p downregulates the transcription of monoamine oxidase A (MAOA) by decreasing the amounts of sirtuin1, a transcription factor that is involved in the transcription of MAOA [37]. [score:3]
Fig. 1miR-451a, miR-142-5p, miR-142-3p, miR-144-3p, and miR-21-5p are overexpressed in the autism brain samples. [score:3]
a Scheme of nucleotide sequence directly surrounding the transcription start site (TSS) of miR-142. [score:2]
MicroRNA-142 overexpression correlates with decreased methylation of its promoter region in the brain of individuals diagnosed with asd. [score:2]
c Pyrosequencing analysis of the three CpGs directly upstream of the TSS of miR-142. [score:2]
Furthermore, the promoter region of the miR-142 gene is hypomethylated in the same brain samples, suggesting that epigenetics plays a role in dysregulation of microRNAs in the brain. [score:2]
These include three CpGs that are found within ten nucleotides of the transcription start site for miR-142 (marked in red in Fig.   2a). [score:1]
Therefore, both miR-142-5p and miR-142-3p have important roles in the dopaminergic and monoamine pathways in the brain. [score:1]
b DNA methylation microarray analysis of miR-142 gene, showing five CpGs that are significantly hypomethylated. [score:1]
We tested three CpG sites in the promoter of microRNA-142. [score:1]
Fig. 2Promoter of miR-142 is hypomethylated in autism brain. [score:1]
MiR-142 has previously been implicated in regulating proteins involved in neurotransmitter function. [score:1]
Of great interest, five CpGs in the promoter region of the miR-142 gene were hypomethylated in the autism brain samples, according to the microarray analysis (Fig.   2a, b). [score:1]
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A simple mo del to explain the upregulation of miR-142 and miR-150 in human breast CSCs is that suppression of the APC protein expression by miR-142 increases the activity of the canonical Wnt signaling pathway and thereby enhances miR-150 expression. [score:10]
The multiple miRNAs dysregulated in the breast CSCs, such as miR-142, miR-146, miR-200, and miR-141, cooperatively activate the Wnt signaling pathway by targeting or upregulating the expression of its components. [score:9]
Knockdown of miR-142 upregulates the APC expression, reduces the clonogenicity of human breast CSCs in vitro, and suppresses the tumor growth initiated by the human breast CSCs in vivo [100]. [score:9]
The regulation of the Wnt signaling pathway by miR-142 and other miRNAs is described in more detail later in Section 4.3. miR-214, together with miR-199a-2, is located inside the sequence of the long non-coding Dynamin 3 opposite strand (Dnm3os) transcript on mouse and human chromosome 1. miR-214 is upregulated or downregulated in human tumors [101]. [score:8]
We and others show that miR-142 targets APC and activates the canonical Wnt signaling pathway and further activates the transcription of miR-150 which is also upregulated in human breast CSCs. [score:6]
miR-142 is broadly expressed in various hematopoietic lineages, and plays important functions in hematopoiesis, immune responses, and T cell differentiation [92, 93, 94, 95]. [score:3]
Furthermore, aberrantly proliferating dysplastic mammary tissues are formed when the mammary stem cells overexpressing miR-142 are transplanted into the mammary fat pad of the syngeneic mouse. [score:3]
We and others show that miR-142 targets APC and activates the canonical Wnt signaling pathway (Figure 4) [97, 100, 141, 146, 148]. [score:3]
The promoter region of miR-150 precursor is targeted by T-cell factor (TCF)/β-catenin and the transcription of miR-150 is activated by miR-142 which activates the canonical Wnt signaling pathway (Figure 4) [100]. [score:3]
miR-142 is very highly expressed in a human breast CSC population, but is undetectable in a normal mammary stem cell population [24, 100]. [score:3]
In contrast, miR-142 is expressed at low levels in many other cell types. [score:3]
The profile of a set of the 37 miRNAs is mostly shared between human breast CSCs and the stem/progenitor cells of human or murine normal mammary tissues, but miR-142 is exceptional; miR-142 is very highly expressed in the human breast CSC population, but is undetectable in a normal mammary stem cell population [24, 100]. [score:3]
For example, miRNAs, such as miR-135, miR-27, mir-155, miR-129, miR-106b, let-7, miR-125, miR-663, and miR-142, target APC and activate canonical Wnt signaling [100, 138, 139, 140, 141, 142, 143, 144, 145, 146]. [score:3]
These findings propose a novel mechanism for the activation of the Wnt signaling in breast cancers in which the gene mutations involved in the activation of the Wnt signaling pathway are less frequent; the Wnt signaling pathway is epigenetically transactivated by miR-142 in human breast CSCs. [score:2]
Consistent with these findings, miR-142 -null mice and miR-142 gene trap mice show the impairment of hematopoietic lineage formation [97, 98]. [score:1]
3.4. miR-142. [score:1]
miR-142 is located at a genomic locus associated with t(8;17) translocation in B-cell leukemia and is mutated in diffuse large B-cell lymphoma [96]. [score:1]
Analyses of bulk tumor will be unable to identify the important roles of miR-142 in breast cancer because CSCs are a minority population in human breast cancers (usually less than 10%). [score:1]
The transcription start site of miR-142 is located 1205 base pairs upstream of the precursor sequence within a highly conserved CpG island and the transcription of the pri-miR-142 is epigenetically repressed by DNA methylation [99]. [score:1]
However, unlike miR-142, miR150 does not induce the dysplastic change of the mammary tissue. [score:1]
Hu W. Ye Y. Zhang W. Wang J. Chen A. Guo F. miR142-3p promotes osteoblast differentiation by modulating Wnt signaling Mol. [score:1]
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Table 1 The role of miRNAs in autoimmune diseases miRNA Predicted/Identified targets Function Related diseases miR-22 IRF8Enhances CD11c [+]CD11b [+]B220 [−] cDC generation at the expense of pDCs miR-142 IRF8Plays a pivotal role in the maintenance of CD4 [+] DCs miR-142-3p IL-6 Specifically inhibits IL-6 expression by moDC MS miR-21 IL-12p35, Wnt1 Negatively regulates the production of IL-12 by moDC; negatively regulate the development of moDC SLE, IBD, UC, MS miR-10a IL-12/IL-23p40 Suppress the production of IL-12 and IL-23 by moDC SLE miR-148/152 Calcium/Calmodulin- dependent protein kinase IIa Suppress the production of IL-12 and IL-6 SLE miR-23b Notch1, NF-κB Inhibits the production of IL-12 while promotes IL-10 production UC miR-155 SOCS1, SHIP1, TAB2 Positively regulates the production of several pro-inflammatory cytokines including IL-6, IL-23, IL-12, and TNF-α RA, IBD miR-146a IRAK1, TRAF6 Negatively regulates TLR4-NF-κB pathway in monocytes RA, SLE, IBD miR-34a JAG1 Negatively regulates the development of moDC MS miR-223 C/EBPβNegatively regulates LCs -mediated antigen-specific CD8 [+] T cell proliferation, production of inflammatory cytokine TNFα, IL-1β, and IL-23 by intestinal DCs. [score:25]
MiR-142-3p was also identified as a key negative regulator of IL-6. In contrast to miR-155, which is strongly up-regulated after LPS stimulation, miR-142-3p is constitutively and highly expressed in resting moDCs but down-regulated after LPS stimulation. [score:10]
By analyzing miRNA expression profiles for distinct myeloid populations, including BM-resident progenitors, monocytes, and mature splenic DC subsets, miR-142 was found to be highly expressed in classic FLT3-L–dependent CD4 [+] cDCs, whereas reduced expression was observed in CD8α [+] or CD4 [−]CD8α [−] cDCs (Mildner et al., 2013). [score:7]
Comparison of the expression profiles of WT and miR-142 [−/−]CD4 [+] cDC equivalents using ingenuity pathway analysis revealed an up-regulation of the transcription factors HoxA9, IRF8, and Meis1 in miR-142 [−/−]CD4 [+] cDCs. [score:6]
The up-regulation of IRF8 may suggest a function for miR-142 in the specification of CD4 [+] versus CD8α [+] cDCs through regulation of the IRF8 pathway (Mildner et al., 2013). [score:5]
MiR-142-3p directly targets IL-6 mRNA and thus specifically affects IL-6 expression (Sun et al., 2011). [score:5]
Another important miRNA involved in DC homeostasis is miR-142. [score:1]
Moreover, mice deficient for miR-142 displayed an impairment of CD4 [+] cDC homeostasis both in vitro and in vivo. [score:1]
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Colorectal cancer pathway with interaction between significant up-regulated miRNAs, let-7f-5p, miR-455-3p, miR-98, miR-155-5p, and down-regulated miRNAs, miR-1, miR-127-5p, miR-142-5p, miR-202-5p after radiation and SN38 treatments and their target genes. [score:9]
Moreover, from EBarrays, we found miRNAs, such as let-7f-5p, miR-455-3p, miR-98, miR-155-5p, up-regulated to the highest degree and miRNAs, miR-1, miR-127-5p, miR-142-5p, miR-202-5p were down-regulated most, after the radiation and SN38 treatment. [score:7]
Heatmap of four most significant up-regulated miRNA, let-7f-5p, miR-455-3p, miR-98 and miR-155-5p, as well as four most down-regulated miRNA, miR-1, miR-127-5p, miR-142-5p and miR-202-5p after radiation and SN38 treatments, and different pathways by clustering from pathway union. [score:7]
In case of miR-127-5p and miR-142-5p the most notable down-regulation was found in HCT116 [p53+/+] and HCT116 [p53+/−] cells after the treatment, whereas miR-127-5p and miR-142-5p were up-regulated in HCT116 [p53−/−] cells after the radiation treatment. [score:7]
We also found in KM12C and KM12L4a cells with p53 mutation, let-7f-5p, miR-455-3p, miR-98, miR-155-5p and miRNAs were up-regulated, whereas miR-1, miR-127-5p, miR-142-5p and miR-202-5p remained undetected after the radiation and SN38 treatment. [score:5]
In summary, after radiation and SN38 treatment, we found that most significant up- or down-regulation and interactions of 8 miRNAs (let-7f-5p, miR-455-3p, miR-98, miR-155-5p, miR-1, miR-127-5p, miR-142-5p, miR-202-5p), 7 cytokines (IL-1β, IL-4, IL-6, IL-10, IFN- γ, VEGF, TNF- α) and 2 chemokines (IL-8, MIP-1-α) were dependent on p53 status in colon cancer cells. [score:4]
The results showed that let-7f-5p, miR-455-3p, miR-98 and miR-155-5p were up-regulated in KM12C (Supplementary Figure S1) and KM12L4a (Supplementary Figure S2) cell lines after radiation and SN38 treatment, whereas miR-1, miR-127-5p, miR-142-5p and miR-202-5p were undetected in KM12C and KM12L4a cell lines after radiation and SN38 treatment. [score:4]
In miR-127-5p and miR-142-5p the highest degree of down-regulation was found in HCT116 [p53+/+] and HCT116 [p53+/−] cells after the radiation treatment. [score:4]
RNA22 and DIANA-microT describe possible interactions with VEGF, while RNA22 alone foretells about its interaction with TNF- α. miR-142-5p: miRanda points towards possible interactions of has-miR-142-5p with IL-6. miR-202-5p: TargetScan, PicTar, and miRanda foretell about miR-202-5p interaction with IL-6. RepTar describes two interaction sites of has-miR-202 in IL-10. [score:3]
To validate our results found in HCT116 cells, we further examined the expression of miRNAs, let-7f-5p, miR-455-3p, miR-98, miR-155-5p, miR-1, miR-127-5p, miR-142-5p and miR-202-5p in KM12C and KM12L4a human colon cancer cell lines. [score:3]
miR-142-5p is un regulated after NGX6 transfection in colon cancer cells [47]. [score:2]
let-7f-5p demonstrates the highest number of cytokine interaction, all other miRNAs, except miR-142-3p, exhibit interactions with multiple cytokines. [score:1]
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Other miRNAs from this paper: hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-30a, hsa-mir-32, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-107, hsa-mir-129-1, hsa-mir-30c-2, hsa-mir-139, hsa-mir-181c, hsa-mir-204, hsa-mir-212, hsa-mir-181a-1, hsa-mir-222, hsa-mir-15b, hsa-mir-23b, hsa-mir-132, hsa-mir-138-2, hsa-mir-140, hsa-mir-129-2, hsa-mir-138-1, hsa-mir-146a, hsa-mir-154, hsa-mir-186, rno-mir-324, rno-mir-140, rno-mir-129-2, rno-mir-20a, rno-mir-7a-1, rno-mir-101b, hsa-mir-29c, hsa-mir-296, hsa-mir-30e, hsa-mir-374a, hsa-mir-380, hsa-mir-381, hsa-mir-324, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-15b, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19b-2, rno-mir-19a, rno-mir-21, rno-mir-23a, rno-mir-23b, rno-mir-24-1, rno-mir-24-2, rno-mir-27a, rno-mir-29c-1, rno-mir-30e, rno-mir-30a, rno-mir-30c-2, rno-mir-32, rno-mir-92a-1, rno-mir-92a-2, rno-mir-93, rno-mir-107, rno-mir-129-1, rno-mir-132, rno-mir-138-2, rno-mir-138-1, rno-mir-139, rno-mir-142, rno-mir-146a, rno-mir-154, rno-mir-181c, rno-mir-186, rno-mir-204, rno-mir-212, rno-mir-181a-1, rno-mir-222, rno-mir-296, rno-mir-300, hsa-mir-20b, hsa-mir-431, rno-mir-431, hsa-mir-433, rno-mir-433, hsa-mir-410, hsa-mir-494, hsa-mir-181d, hsa-mir-500a, hsa-mir-505, rno-mir-494, rno-mir-381, rno-mir-409a, rno-mir-374, rno-mir-20b, hsa-mir-551b, hsa-mir-598, hsa-mir-652, hsa-mir-655, rno-mir-505, hsa-mir-300, hsa-mir-874, hsa-mir-374b, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-874, rno-mir-17-2, rno-mir-181d, rno-mir-380, rno-mir-410, rno-mir-500, rno-mir-598-1, rno-mir-674, rno-mir-652, rno-mir-551b, hsa-mir-3065, rno-mir-344b-2, rno-mir-3564, rno-mir-3065, rno-mir-1188, rno-mir-3584-1, rno-mir-344b-1, hsa-mir-500b, hsa-mir-374c, rno-mir-29c-2, rno-mir-3584-2, rno-mir-598-2, rno-mir-344b-3, rno-mir-466b-3, rno-mir-466b-4
These miRNAs were chosen as representative of the different patterns that were observed: up-regulation (miR-9a-5p) or down-regulation (miR-598-5p) during latency, down-regulation in the late latency - first spontaneous seizure period (miR-381-3p) and down regulation in the chronic stage (miR-142-5p). [score:11]
We identified a single miRNA, miR-142-3p that was altered both in plasma and in the brain, but the pattern of expression was different in that it was down-regulated in the former and up-regulated in the latter. [score:9]
The patterns of dysregulation, however, were totally different: miR-142-3p was up-regulated in the GCL during latency and down-regulated in plasma in the chronic period. [score:8]
First, a subgroup of miRNAs (miR-15b-5p, miR-17-5p, miR-18a-5p, miR-19a-3p, miR19b-3p, miR-20a-5p, miR-20b-5p, miR-21-5p, miR-23b-5p, miR-24-3p, miR-27a-3p, miR-92a-3p, miR-93-5p, miR-142-3p, miR-344b-2-3p, miR-431, miR-466b-5p and miR-674-3p) displayed increased expression levels during latency (4 and 8 days after SE), decreased their expression levels at the time of the first spontaneous seizure and returned to control levels in the chronic phase (Fig. 2, Supplementary Fig. S1). [score:5]
Finally, miR-30c-2-3p, miR-101b-3p, miR-142-3p, miR-142-5p, miR-181a-1-3p, miR-374-5p, miR-466c-3p, miR-1188-3p, miR-3065-3p and miR-3582 were significantly down-regulated in the chronic stage (Supplementary Fig. S7D). [score:4]
Cluster 3 was composed by two up-regulated microRNAs, miR-142-3p and miR-146a-5p. [score:4]
All these miRNAs displayed a peak in expression levels 8 days after SE, except for miR-21-5p, miR-27a-3p, miR-142-3p and miR-674-3p that peaked earlier (4 days after SE). [score:3]
The other 24 performed the analysis in plasma samples obtained from the trunk blood, reporting an increase in miR-142-5p levels during the acute phase, miR-21-5p in the early stage and of miR-146a-5p in the chronic stage, that reflect parallel changes in miRNAs expression observed in the brain. [score:3]
In fact, the expression patterns of miR-20b-5p, miR-142-3p, miR-181d-5p, miR-212-5p, miR-344b-5p and miR-674-3p were identical to those observed using the microarray, and those of miR-21-5p and miR-146a-5p were very similar, although not identical (Fig. 4). [score:3]
The only miRNA dysregulated both in the GCL and in plasma was miR-142-3p. [score:2]
MiR-9a-3p and miR-142-3p were chosen for validation in the same cohort of samples, displaying the same patterns observed in the microarray, even if they did not reach statistical significance. [score:1]
Cluster 3 (that includes miR-142-3p and miR-146a-5p) and cluster 4 (including miR-181c-5p and miR-181c-5p) are connected to the “cytokine-cytokine receptor interaction” signaling pathway, which suggests a neuroinflammatory role for those miRNAs. [score:1]
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In addition, pair-wise analyses revealed 42 common targets for miR-182 and miR-142-3p, 34 common targets for miR-182 and miR-223, and 7 common targets for miR-142-3p and miR-223 (Table S1, Fig. 2A). [score:7]
The most noteworthy novel finding was that in skeletal muscle, HRT use associates with down-regulation of miR-182, miR-223, and miR-142-3p, which modulate the expression of central players in the insulin/IGF-1 pathway, namely IGF-1R and FOXO3A. [score:6]
Figure 6The effects of estrogen stimulation on the expression of miR-182, miR-223, and miR-142-3p and their targets in infant female quadriceps femoris-derived myoblasts. [score:5]
Identification of common pathways targeted by miR-182, miR-223, and miR-142-3p was obtained using the DIANA-microT 3.0 target prediction program (http://diana. [score:5]
Figure 5MiR-182, miR-223, and miR-142-3p expression and their target mRNA and protein levels under estrogen stimulation in MCF-7 cells. [score:5]
Both miR-223 and miR-142-3p were down-regulated by 100 n m E [2], the difference being highly significant for miR-142-3p (Fig. 6A). [score:4]
Putative pathways affected by miR-182, miR-223, and miR-142-3p are reported in Table 2. Among the putative target pathways, we found the insulin/IGF1 pathway (Fig. 2B). [score:3]
Validation by quantitative PCR (qPCR) confirmed that the expression levels of miR-182, miR-223, and miR-142-3p in the HRT users were approximately one-third of that of nonusers (P = 0.05, 0.001 and 0.003, respectively; Fig. 1C), while miR-142-5p and miR-451 were not significantly different between HRT users and their nonuser co-twins. [score:3]
Table S1 Common targets for hsa-miR-142-3p (250 elements), hsa-miR-182 (841 elements) and hsa-miR-223 (202 elements). [score:3]
Consequently, miR-142-3p was here excluded from the further analyses, as it was not predicted to target other components of the insulin/IGF-1 pathway. [score:3]
In the present study, we confirmed that estrogen-regulated miRNAs, that is, miR-182, miR-223 and miR-142-3p, exist in skeletal muscle of postmenopausal women. [score:2]
As recently we reported that estrogen -based hormone therapy is associated with increased activity in the same pathway (Pöllänen et al., 2010; Ahtiainen et al., 2012a), we focused here on IGF-1R, FOXO3A, and FOXO1A, which in our analysis proved to be regulated by miR-182, miR-223, and miR-142-3p, as described in Fig. 2. Table 2Common pathways of miR-142-3p, miR-182, and miR-223. [score:2]
As recently we reported that estrogen -based hormone therapy is associated with increased activity in the same pathway (Pöllänen et al., 2010; Ahtiainen et al., 2012a), we focused here on IGF-1R, FOXO3A, and FOXO1A, which in our analysis proved to be regulated by miR-182, miR-223, and miR-142-3p, as described in Fig. 2. Table 2Common pathways of miR-142-3p, miR-182, and miR-223. [score:2]
MiR array data showed miR-142-3p, miR-142-5p, miR-223, miR-182, and miR-451 to be hypo-expressed in the HRT users compared to nonusers (Fig. 1B). [score:2]
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30
[+] score: 40
In conclusion, a more sensible and specific quantification of miRNAs by absolute Q-PCR analysis highlighted common up-regulation of miR-206, miR-223, miR-199a-5p, miR-199b*, miR-27a, miR-128a, miR-31 and miR-142-5p, and down-regulation of miR-17 in dystrophic fibres isolated from TA, DIA and VA of the adult mdx mouse (Figure S1). [score:7]
MiR-206, miR-31, miR-21, miR-335-5p, miR-27a, miR-142-5p and miR-223 were significantly up-regulated afterwards muscle damage respect damaged muscle. [score:4]
Data obtained evidenced a group of miRNAs whose expression does not change during muscle repair afterwards acute damage (miR-15b, miR-17, miR-128a, miR-221, miR-199a-5p miR-199b and miR-199b*) (Table 1), and a group of miRNAs that are triggered afterwards CTX delivery (miR-206, miR-31, miR-21, miR-335-5p, miR-27a, miR-142-5p and miR-223) (Table 1), suggesting major involvement of the latter in muscle regeneration. [score:3]
In this study we have also shown the expression of non-muscle enriched miRNAs, such as the granulocytes -associated miR-223 and haematopoietic miR-142-5p, in single muscle fibres. [score:3]
We identify fourteen miRNAs associated to dystrophic fibres (miR-15b, miR-17, miR-21, miR-27a, miR-31, miR-128a, miR-142-5p, miR-199a-5p, miR-199b, miR199b*, miR-206, miR-221, miR-223 and miR-335-5p) that may mediate muscle regeneration and remo delling in animal mo dels of MDs and acute muscle damage, and confirm over -expression of the previously identified regeneration -associated myomiR-206. [score:3]
Moreover expression of miR-223 and miR-142-5p in single muscle fibres might reflect the common mesodermic origin of muscle and hematopoietic tissues. [score:3]
In agreement with our finding, previously published data demonstrated expression of miR-223 and miR-142-5p not limited to granulocytes or haematopoietic lineage. [score:3]
Dystrophic muscle fibres isolated from different animal mo del of MDs were commonly characterized by the over -expression of several miRNAs (miR-15b, miR-21, miR-27a, miR-31, miR-128a, miR-142-5p, miR-199a-5p, miR-199b, miR199b*, miR-206, miR-221, miR-223 and miR-335-5p) with an expression profile strictly dependent on muscle impairment and damage accumulation (Figure 7). [score:3]
The expression levels of miR-21, miR-142-5p, miR-199a-5p, miR-199b*, miR-206, miR-223 and miR-335-5p were instead strictly related to the type of muscle considered, underling a relationship with muscle-type dependent impairment (Figure 2B). [score:2]
In particular, the dysregulation was limited to miR-199b*, miR-31, miR-142-5p and miR-221 in dystrophic TPZ; to miR-128a, miR-21, miR-221 and miR-35-5p in dystrophic DIA; and to miR-15b, miR-17, miR-27a, miR-142-5p, miR-128a, miR-335-5p, miR-21, miR-31 in dystrophic VA (Figure 3B). [score:2]
Fourteen miRNAs were found dysregulated in dystrophic muscle fibres of the mdx mouse with differences linked to the originating muscle (miR-206, miR-199a-5p, miR-223, miR-199b, miR-199b*, miR-21, miR-221, miR-17, miR-15b, miR-31, miR-128a, miR-142-5p, miR-335-5p and miR-27a). [score:2]
Only 7 of the 14 miRNAs associated to dystrophic fibres (miR-206, miR-31, miR-21, miR-335-5p, miR-27a, miR-142-5p and miR-223) were triggered by CTX injury. [score:1]
A more accurate and sensible quantification of miRNAs by Q-PCR analysis, extended the miRNA signature common to dystrophic single fibres of TA, DIA and VA to miR-128a, miR-31 and miR-142-5p (Figure S1). [score:1]
MiR-15b, miR-17, miR-31, miR-128a, miR-142-5p and miR-335-3p were specifically induced in single muscle fibres of dystrophic DIA (Figure 1). [score:1]
In agreement with data already published characterizing the miRNome of mdx and DMD muscle [15], [16], [17], the over -expression of several miRNAs (miR-21, miR-31, miR-199a-5p, miR-199b, miR-142-5p, miR-221, miR-223 and miR-335-5p) was confirmed in murine dystrophic single muscle fibres. [score:1]
In particular, miR-223 was localized in cardiomyocytes, with prominent peri-nuclear staining, and in non-myocytes by in situ hybridization on cryosection of heart [48]; and miR-142-5p was detected in embryonic stem cells (ESC) where it is involved in cardiac differentiation [49]. [score:1]
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[+] score: 39
a Over -expression of miR-31 restores chemo-response by reducing stathmin expression; miR-101/stathmin pathway contributes to radioresistance in human NPC; down-regulation of miR-193b promotes migration and proliferation of tumor cells by targets stathmin; miR-223 regulates stathmin by JNK signaling pathway to regulate MPM cell motility; b up-regulation of miR193b reduces proliferation and migration by inhibiting stathmin and uPA; silencing of miR-210 promotes proliferation of cancerous cells; transfection of miR-142 and miR-223 decreases expression of stathmin and IGF-1R to inhibit proliferation of cancerous cells; c microrna-9 inhibits cell proliferation, vasculogenic mimicry and tumor growth through controlling stathmin expression; miR-101 suppresses autophagy via targets stathmin and down-regulation of miR-101 is linked to the increase of cellular proliferation and invasiveness. [score:32]
Specific transfection of miR-142 and miR-223 influences post-transcriptional regulation of proteins in hepatocellular carcinoma (HCCs), which has a suppressive effects on proliferation of hepatocellular carcinoma cells by regulating expressions of stathmin and insulin-like growth factor-1 receptor (IGF-1R) [74] (Fig.   5b). [score:7]
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32
[+] score: 39
In a previous pilot study, using samples from heart transplant patients treated at Skane University Hospital (Lund, Sweden), we demonstrated proof-of-principle that the profile of serum microRNAs is altered during ACR and that miR-142-3p can discriminate significantly between histologically-verified normal and diseased states[11]. [score:3]
Related to allograft rejection, the alteration of miR-142-3p expression profile in the biopsy samples of ACR has been demonstrated both in human and animal mo del[29– 32]. [score:3]
The relative expression of serum miR-142-3p and miR-101-3p levels in serum were analysed over time post-transplantation. [score:3]
To investigate whether the overall immunosuppression intensity in the heart-transplanted patients could modulate the serum levels of miR-142-3p and miR-101-3p, correlation between the levels of calcineurin inhibitors and miR-142-3p or miR-101-3p in the circulation of heart transplant patients was analysed. [score:3]
Calcineurin inhibitor level does not correlate with miR-142-3p and miR-101-3p in serum. [score:3]
MiR-142-3p is highly expressed in T lymphocytes, the main player in ACR, and has been shown to play a role in regulatory T cells and in promoting tolerance in solid organ transplantation[28, 29]. [score:3]
Second, there was no correlation between CRP level and miR-142-3p or miR-101-3p levels (Fig 4B). [score:1]
In summary, our study shows that miR-142-3p and miR-101-3p can accurately discriminate heart transplant patients with ACR from those with no rejection. [score:1]
0170842.g002 Fig 2 Patients with and without acute cellular rejection could be discriminated by miR-142-3p (AUC = 0.78, CI [95%] = 0.67 to 0.89), miR-101-3p (AUC = 0.75, CI [95%] = 0.62 to 0.87), miR-424-5p (AUC = 0.73, CI [95%] = 0.60 to 0.86), miR-27a-3p (AUC = 0.72, CI [95%] = 0.59 to 0.85), miR-339-3p (AUC = 0.71, CI [95%] = 0.57 to 0.84), miR-144-3p (AUC = 0.70, CI [95%] = 0.56 to 0.83) and miR-326 (AUC = 0.69, CI [95%] = 0.56 to 0.82). [score:1]
ACR = 10.4 ug/L, p = 0.4) and (B) There are no correlations between miR-142-3p fold change and tacrolimus (n = 29; R [2] = 0.05; p = 0.25) or cyclosporin (n = 6; R [2] = 0.07; p = 0.61) and there are no correlations between miR-101-3p fold change and tacrolimus (n = 29; R [2] = 0.01; p = 0.10) or cyclosporine (n = 6; R [2] = 0.05; p = 0.68). [score:1]
MiR-142-3p and miR-101-3p had the best diagnostic test performance among the microRNAs tested. [score:1]
Creatinine levels do not correlate with miR-142-3p and miR-101-3p. [score:1]
ROC analysis of miR-142-3p. [score:1]
This study demonstrated two microRNAs, miR-142-3p and miR-101-3p, that could be relevant as non-invasive diagnostic tools for identifying heart transplant patients with acute cellular rejection. [score:1]
To assess the relationship between miR-142-3p and miR-101-3p serum levels with kidney function in heart transplant patients, correlation between creatinine levels and miR-142-3p and miR-101-3p was analysed. [score:1]
ACR = 3.5 mg/L, p = 0.1) and (B) There is no correlation between CRP level in heart transplant patients and miR-142-3p fold change (n = 11; R [2] = 0.06 and P = 0.47) or miR-101-3p fold change (n = 11; R [2] = 0.01 and P = 0.75). [score:1]
However, from the ROC analysis, miR-142-3p and miR-101 have the best diagnostic test performance among the seven microRNAs tested. [score:1]
For samples collected between 6 months and 1 year post-transplantation, miR-142-3p levels were numerically higher but the difference was not statistically significant. [score:1]
MiR-142-3p and miR-101-3p levels stratified by time post-transplantation. [score:1]
Moreover, in the diagnostic test that combines sensitivity and specificity, the levels of miR-142-3p and miR-101-3p are shown to have the best performance among the seven microRNAs tested that yield AUC-ROC score of 0.78 and 0.75, respectively. [score:1]
The fact that miR-142-3p originates from immune cells, not from the graft tissue, raise the possibility to predict rejection prior to organ damage. [score:1]
Patients with and without acute cellular rejection could be discriminated by miR-142-3p (AUC = 0.78, CI [95%] = 0.67 to 0.89), miR-101-3p (AUC = 0.75, CI [95%] = 0.62 to 0.87), miR-424-5p (AUC = 0.73, CI [95%] = 0.60 to 0.86), miR-27a-3p (AUC = 0.72, CI [95%] = 0.59 to 0.85), miR-339-3p (AUC = 0.71, CI [95%] = 0.57 to 0.84), miR-144-3p (AUC = 0.70, CI [95%] = 0.56 to 0.83) and miR-326 (AUC = 0.69, CI [95%] = 0.56 to 0.82). [score:1]
The present study validates that seven microRNAs, miR-142-3p, miR-339-3p, miR-326, miR-144-3p, miR-101-3p, miR-27a-3p and miR-424-5p are present in serum samples from heart transplant patients and adequately distinguish ACR from NR. [score:1]
MiR-142-3p and miR-101-3p had the best diagnostic performance among the seven microRNAs tested, making them the potential candidates as non-invasive biomarkers for ACR surveillance post heart-transplantation. [score:1]
Increased serum level of miR-142-3p and miR-101-3p is not indicative of general inflammation. [score:1]
These results are encouraging as there is no association between either of these factors and the levels of miR-142-3p and miR-101-3p. [score:1]
All seven microRNA tested could significantly discriminate between ACR and NR, with AUC of 0.78, 0,75, 0.73, 0.72, 0.71, 0.70 and 0.69 for miR-142-3p, miR-101-3p, miR-424-5p, miR-27a-3p, miR-339-3p, miR-144-3p, and miR-326, respectively (Fig 2). [score:1]
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[+] score: 38
While expression of some of these miRNAs seemed to be specifically dysregulated in certain tumor stages, 12 miRNAs, including 4 up-regulated (miR-200c, miR-487a, miR-491-3p and miR-452) and 8 down-regulated miRNAs (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299-3p, miR-29a, miR-429, and miR-532-5p), were identified to be commonly dysregulated in all ccRCC tumors at different stages (Table 1). [score:11]
Eleven commonly dysregulated miRNAs, including 3 up-regulated (miR-487a, miR-491-3p and miR-452) and 8 down-regulated (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299-3p, miR-29a, miR-429, and miR-532-5p), were identified in ccRCC tumor samples as compared with adjacent nontumorous samples. [score:7]
Eleven miRNAs were identified to be commonly dysregulated, including three up-regulated (miR-487a, miR-491-3p and miR-452) and eight down-regulated (miR-125b, miR-142-3p, miR-199a-5p, miR-22, miR-299-3p, miR-29a, miR-429, and miR-532-5p) in tumor tissues as compared with adjacent normal tissues. [score:7]
Due to its down-regulation in ccRCC in our study, we hypothesized that miR-142-3p may also exert tumor suppressive functions in ccRCC. [score:6]
MiR-142-3p functions as a tumor suppressor by targeting CD133, ABCG2, and Lgr5 in colon cancer cells. [score:4]
For example, miR-142-3p has been shown to function as a tumor suppressor in colon cancer [30]. [score:3]
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[+] score: 37
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-27a, hsa-mir-29a, hsa-mir-101-1, dme-mir-1, dme-mir-2a-1, dme-mir-2a-2, dme-mir-2b-1, dme-mir-2b-2, dme-mir-10, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-101a, mmu-mir-124-3, mmu-mir-126a, mmu-mir-133a-1, mmu-mir-137, mmu-mir-140, mmu-mir-142a, mmu-mir-155, mmu-mir-10b, mmu-mir-183, mmu-mir-193a, mmu-mir-203, mmu-mir-143, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-183, hsa-mir-199b, hsa-mir-203a, hsa-mir-210, hsa-mir-222, hsa-mir-223, dme-mir-133, dme-mir-34, dme-mir-124, dme-mir-79, dme-mir-210, dme-mir-87, mmu-mir-295, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, dme-let-7, dme-mir-307a, dme-mir-2c, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-137, hsa-mir-140, hsa-mir-143, hsa-mir-126, hsa-mir-193a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-29a, mmu-mir-27a, mmu-mir-34a, mmu-mir-101b, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-155, mmu-mir-10a, mmu-mir-210, mmu-mir-223, mmu-mir-222, mmu-mir-199b, mmu-mir-124-1, mmu-mir-124-2, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-378a, mmu-mir-378a, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-411, hsa-mir-193b, hsa-mir-411, mmu-mir-193b, hsa-mir-944, dme-mir-193, dme-mir-137, dme-mir-994, mmu-mir-1b, mmu-mir-101c, hsa-mir-203b, mmu-mir-133c, mmu-let-7j, mmu-let-7k, mmu-mir-126b, mmu-mir-142b, mmu-mir-124b
iso1 was upregulated by 2.3-fold in psoriatic skin (Supplementary Table S10) and shown to repress targets distinct from the targets of miR-142-3p. [score:8]
iso1 (Supplementary Table S10) was upregulated 2.3-fold in psoriatic involved skin (PP) versus normal skin (NN), suggesting a role of miR-142-3p. [score:4]
Consistently, mmu-miR-142 and its 5′-isomiR had similar effects on their exclusive targets in the miR-142 knockout data (4.1E-07 versus 5.0E-08 on 8mer in Supplementary Table S9). [score:4]
Taken together, the high abundance and upregulation of 5′-isomiRs of hsa-miR-203 and hsa-miR-142 may indicate their functional roles in inflammatory and hyperproliferative phenotype of psoriatic lesions. [score:4]
For example, miR-142-3p has a 2.5-fold upregulation in psoriatic lesions (35); consistently, miR-142-3p. [score:4]
For example, miR-142 had a high 5′-heterogenity among all the mammalian small -RNA datasets that were examined, indicating a ubiquitous expression of 5′-isomiRs from miR-142 hairpin (Supplementary Tables S2 and S3). [score:3]
5′-isomiRs have also been noticed on both the 5p and 3p arms of hsa-miR-142 hairpin in T cells where miR-142 is the most highly expressed miRNA in naive T cells (70). [score:3]
Microarray datasets of mmu-miR-223 and mmu-miR-142 knockout experiments (GSE22004, GSE42325, Supplementary Table S1B) were collected in recent studies (21, 46). [score:2]
Our recent study has revealed the epidermal infiltration of the hematopoietic-specific miR-142-3p in psoriatic lesions (35). [score:1]
In light of the function of many miRNAs (e. g. miR-203 and miR-142) in skin and psoriasis, DE 5′-isomiRs (such as miR-203-3p. [score:1]
Another 5′-isomiR, miR-142-3p. [score:1]
In addition, the mmu-miR-142 hairpin had similar arm abundances between miRNA and 5′-isomiR (45% versus 55%) in dendritic cells (GSM539853). [score:1]
iso1 and miR-142-3p. [score:1]
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35
[+] score: 36
miR-142-3p and miR-144* showed a trend of upregulation in the diseased group, whereas let-7c was slightly downregulated in DCM dogs. [score:9]
For miR-142-3p and miR-144*, we found a trend for upregulation in DCM diseased dogs both in the microarrays and the results, although interindividual variation was very high. [score:6]
In humans with chronic heart failure caused by nonischemic DCM, miR-142-3p was found to be upregulated in peripheral blood cells [52]. [score:4]
In accordance with our findings, miR-142-3p has been shown previously to be upregulated in human patients with chronic heart failure caused by nonischemic DCM [52]. [score:4]
With p-values > 0.05 for all tested target assays, revealed no statistically significant difference between diseased and healthy dogs (mmu-miR-142-3p: p = 0.771; mmu-miR-144*: p = 0.421; cfa-let-7c: p = 0.634; cfa-miR-21: p = 0.940; cfa-miR-92a: p = 0.873). [score:4]
Therefore, miR-142-3p is currently discussed as a part of potential therapeutic targets for the treatment of cardiac hypertrophy [92]. [score:3]
For further analysis, we selected five miRNAs which have been earlier mentioned in literature as being involved in cardiovascular pathology and which also showed a trend for differential expression in the microarray (miR-142-3p, miR-144*, miR-21, let-7c and miR-92a). [score:3]
miR-142-3p and miR-144* were up regulated about two-fold in the DCM group compared to the control group, while let-7c appears to be slightly down regulated. [score:2]
miR-142-3p showed a 2.18-fold change (p: 0.0042), miR-144* a 2.20-fold change (p: 0.0016), miR-21 a 1.67-fold change (p: 0.0089) and let-7c was negatively 1.53-fold changed (p: 0.0340). [score:1]
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[+] score: 35
For the four miRNAs (miR-26a, miR-24, miR-26b, and miR-142-3p) chosen from the class of up-regulation in adults, their expression patterns were also confirmed by showing up-regulation (P < 0.0001) in the adults as compared to the preterm infants and the children, with three of them (miR-26a, miR-26b, and miR-24) being down-regulated from infancy to childhood (Fig. 3B). [score:11]
For the four miRNAs (miR-26a, miR-24, miR-26b, and miR-142-3p) chosen from the class of up-regulation in adults, their expression patterns were also confirmed by showing up-regulation (P < 0.0001) in the adults as compared to the preterm infants and the children, with three of them (miR-26a, miR-26b, and miR-24) being down-regulated from infancy to childhood. [score:11]
Third, miR-142-3p, let-7a, and miR-30e-5p were constantly expressed from infancy and childhood, up-regulated in young adulthood, and then showed expression diminishing with aging (Fig. 4C). [score:8]
Six (miR-1, miR-486, miR-26a, miR-24, miR-26b, and miR-142-3p) of seven top 5% differentially expressed miRNAs in the classes with age-limited or age-related expression were confirmed in a validation set using qPCR. [score:5]
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[+] score: 34
In these genes, LMO2-L has different regulatory functions, to inhibit the expression of miR-142[15] and up-regulate the other two in the presence of its partner molecules [14, 16]. [score:9]
It was found that cells over -expressing LMO2-L had miR-142 level down-regulated and c-kit level increased, On the other hand, cells over -expressing LMO2-S had all the three genes decreased significantly. [score:8]
Then the same cell samples were used to detect the relative expression levels of the three target genes GPA, c-kit and miR-142 (Fig. 6C). [score:5]
GPA, c-kit and miR-142 were all known target genes of the LMO2 complex and normally expressed in myeloid cells. [score:5]
Till now several LMO2 targets have been identified, including c-kit[13], GPA[14] and miR-142[15] in hematopoietic cells and VE-Cadherin[16] in vessel endothelial cells. [score:3]
There were several known targets of LMO2, including early-progenitor genes c-kit[13], runx1[19], erythrocyte specific gene GPA[14], p4.2[20] and T cell related gene miR-142[15] and RALDH2[21]. [score:3]
So far, three different arrangement forms of LMO2 binding elements have been identified in the promoter region of GPA, VE-Cadherin and miR-142, respectively, as shown in Fig. 4A. [score:1]
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[+] score: 33
Focusing on the conserved miRNAs presented in Table 1, we found that of the 14 miRNAs downregulated in our study relative to normal bone, six were published as upregulated in osteosarcoma relative to osteoblasts, namely the miRNAs miR-126, miR-142-3p, miR-195, miR-223, miR-451 and miR-497, while miR-31/miR-31* was upregulated compared to bone and downregulated compared to osteoblasts. [score:11]
The inverse deregulation of miRNAs compared to bone or osteoblasts is consistent with previous publications, Jones et al. [10] identified miR-126, miR-142-5p, miR-195, miR-223 and miR-451 to be downregulated in osteosarcoma versus bone while Lulla et al. [11] reported a subset of these, miR-126, miR-142-3p, miR-223 and miR-451, to be upregulated when compared to osteoblasts. [score:6]
miR-451 and miR-497 showed a trend towards being significantly decreased, miR-31 showed a heterogenous expression pattern, and miR-19b, miR-29b and miR-142-3p were expressed at comparable level in clinical samples and bone. [score:5]
Among these, miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-486-5p and members of the miR-1/miR-133a, miR-144/miR-451, miR-195/miR-497 and miR-206/miR-133b clusters were found to be downregulated in osteosarcoma cell lines. [score:4]
The highly downregulated miRNAs presented in Table 1 were miR-126/miR-126*, miR-142-3p, miR-150, miR-223, miR-363, miR-486-5p and members of the miR-1/miR-133a, miR-206/miR-133b, miR-451/miR-144 and miR-497/miR-195 clusters. [score:4]
A set of miRNAs, miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-142-3p, miR-133b, miR-144, miR-195, miR-223, miR-451 and miR-497 was identified with an intermediate expression level in osteosarcoma clinical samples compared to osteoblasts and bone, which may reflect the differentiation level of osteosarcoma relative to the undifferentiated osteoblast and fully differentiated normal bone. [score:2]
As predicted, the 13 miRNAs miR-1, miR-18a, miR-18b, miR-19b, miR-31, miR-126, miR-133b, miR-142-3p, miR-144, miR-195, miR-223, miR-451 and miR-497 showed opposite regulation when the osteosarcoma clinical samples were compared against bone or osteoblasts. [score:1]
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[+] score: 30
So we hypothesized that, if lmo2 gene regulates expression of cdh5/miR-142 transcriptionally and miR-142a-3p regulates cdh5 gene post-transcriptionally, then lmo2, cdh5 and miR-142a-3p may be part of an interacting network that could regulate angiogenesis and vasculature remo deling in zebrafish embryos. [score:6]
Studies conducted on human cancers by other groups from have indicated that LMO2, a transcription factor expressed in blood and vasculature acts as a transcriptional suppressor of miR-142 [32]. [score:5]
Recently, it has been shown that inhibition of miR-142-3p specifically resulted in abnormal cardiac development in developing zebrafish embryos [38]. [score:4]
We speculate that endogenous miR-142-3p could have other targets that may be involved in vascular development. [score:4]
Taken together we speculate that lmo2, in addition to its known role as a transcriptional regulator of CDH5 and miR-142, may also regulates cdh5 post-transcriptionally through miR-142a-3p in zebrafish embryos. [score:3]
The negative regulation of miR-142 by the oncogene lmo2 and its co-factors has also been documented in cell culture mo dels [32]. [score:2]
Based on our study, we suggest a potential new function of miR-142-3p in regulating the levels of cdh5 required for normal angiogenesis and vascular remo deling in zebrafish embryos. [score:2]
The oncogene lmo2 has been previously shown to transcriptionally regulate both VE-Cadherin and miR-142 in human cell culture mo dels [32], [33]. [score:2]
To rule out the possibility of non-specific effect generated by the action of any one of single strand of the miRNA we also conducted separate microinjections of the sense and antisense strand of miR-142-3p. [score:1]
B – Synteny analysis of human miR-142 on chromosome 17 with zebrafish miR-142a on chromosome 5. Arrow in genes indicates strand information on chromosome. [score:1]
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Furthermore, the enforced expression of miR-142-3p, a uniquely expressed miRNA, causes a significant decrease in primitive erythrocyte progenitor cells and HSCs. [score:5]
Interestingly, the gata1, cmyb and runx1 expression were all markedly decreased when miR-142-3p was ectopically expressed (Figure 7), indicating that miR-142-3p affects HSC formation in zebrafish. [score:5]
To study the hematopoietic phenotype caused by increased miR-142-3p signaling, we overexpressed miR-142-3p using miR-142-3p duplex overexpression. [score:5]
However, the scl expression was comparable to the control embryos, suggesting that miR-142-3p is not required for early hemangioblast formation. [score:3]
We further confirmed that one of the uniquely expressed miRNAs, miR-142-3p, plays a critical role during erythrocyte progenitor cell and HSC formation. [score:3]
Using O-dianisidine hemoglobin staining, a significant decrease of mature erythroid cells was detected when miR-142-3p was overexpressed. [score:3]
In addition, several hematopoietic miRNA signatures are uniquely expressed in RPS24 MO such as miR-142-3p and miR-29a, which have been previously reported to be required for the formation and differentiation of hematopoietic stem cells [19, 20]. [score:3]
Overall, these data suggest that increased miR-142-3p represses primitive erythroid progenitor cell and HSC formation. [score:1]
miR-142-3p is required for primitive erythroid progenitor cell and HSC formation. [score:1]
Furthermore, all of the above hematopoietic phenotypes were alleviated by co-injection of miR-142-3p mimics and MO (data not shown). [score:1]
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-23a, hsa-mir-25, hsa-mir-26a-1, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-96, hsa-mir-99a, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-16-2, hsa-mir-198, hsa-mir-199a-1, hsa-mir-148a, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10a, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-203a, hsa-mir-204, hsa-mir-210, hsa-mir-212, hsa-mir-181a-1, hsa-mir-214, hsa-mir-215, hsa-mir-216a, hsa-mir-217, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-mir-224, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-27b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-130a, hsa-mir-132, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-145, hsa-mir-191, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-134, hsa-mir-146a, hsa-mir-150, hsa-mir-186, hsa-mir-188, hsa-mir-193a, hsa-mir-194-1, hsa-mir-320a, hsa-mir-155, hsa-mir-181b-2, hsa-mir-128-2, hsa-mir-194-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-219a-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-99b, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-362, hsa-mir-369, hsa-mir-375, hsa-mir-378a, hsa-mir-382, hsa-mir-340, hsa-mir-328, hsa-mir-342, hsa-mir-151a, hsa-mir-148b, hsa-mir-331, hsa-mir-339, hsa-mir-335, hsa-mir-345, hsa-mir-196b, hsa-mir-424, hsa-mir-425, hsa-mir-20b, hsa-mir-451a, hsa-mir-409, hsa-mir-484, hsa-mir-486-1, hsa-mir-487a, hsa-mir-511, hsa-mir-146b, hsa-mir-496, hsa-mir-181d, hsa-mir-523, hsa-mir-518d, hsa-mir-499a, hsa-mir-501, hsa-mir-532, hsa-mir-487b, hsa-mir-551a, hsa-mir-92b, hsa-mir-572, hsa-mir-580, hsa-mir-550a-1, hsa-mir-550a-2, hsa-mir-590, hsa-mir-599, hsa-mir-612, hsa-mir-624, hsa-mir-625, hsa-mir-627, hsa-mir-629, hsa-mir-33b, hsa-mir-633, hsa-mir-638, hsa-mir-644a, hsa-mir-650, hsa-mir-548d-1, hsa-mir-449b, hsa-mir-550a-3, hsa-mir-151b, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-454, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-708, hsa-mir-216b, hsa-mir-1290, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-378b, hsa-mir-3151, hsa-mir-320e, hsa-mir-378c, hsa-mir-550b-1, hsa-mir-550b-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, hsa-mir-219b, hsa-mir-203b, hsa-mir-451b, hsa-mir-499b, hsa-mir-378j, hsa-mir-486-2
Similarly, down-regulation of miR-146a promoted AML disease progression by TRAF6 -mediated induction of NF-κB [93] and miR-142 promoted the development of lymphoid and myeloid leukemia and was found recurrently mutated in AML [94]. [score:7]
It should be noted that the tyrosine kinase inhibitor (TKI) Dasatinib affected miR-let-7d, miR-let-7e, miR-15a, miR-16, miR-21, miR-130a and miR-142-3p expressions, while Imitanib affected miR-15a and miR-130a levels [47]. [score:5]
Analyses of 238 intermediate-risk cytogenetic AML patients showed that reduced expression of miR-135a and miR-409-3p is associated with a higher risk of relapse [106], while higher miR-142 expression was associated with a better overall survival in these same patients [111]. [score:5]
miR-142 was highly expressed in mature hematopoietic cells and had an essential role during T-lymphocyte development although its role in leukemogenesis is unclear. [score:4]
In contrast, deregulation of the expression of miR-9, miR-33, miR-92a, miR-142-3p, miR-146a, miR-181a/c, miR-210, miR-215, miR-369-5p, miR-335, miR-454, miR-496, miR-518d, and miR-599 was associated with an unfavorable long-term clinical outcome in ALL patients [65, 67– 73]. [score:4]
Interestingly, a recent study based on whole genome sequencing of CLL patients identified 8 somatic mutations of miR-142 in five cases, although the role of these mutants in CLL pathogenesis is unclear [20]. [score:2]
A distinct miRNA signature is characterized by an alteration of miR-29, miR-125, miR-142, miR-146 and miR-155 expression, which has been reported to play a role in AML progression and pathogenesis [87]. [score:1]
Analyses of over 430 miRNAs in 50 clinical T-ALL samples revealed a common signature: miR-223, miR-19b, miR-20a, miR-92, miR-142-3p, miR-150, miR-93, miR-26a, miR-16 and miR-342 [59]. [score:1]
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Among the remaining seven predictions, six were validated by more recent studies: miR-92a was determined to directly target the anti-apoptosis molecule BCL-2-interacting mediator of cell death (BIM) in CN tissues and an anti-miR-92a antagomir led to the apoptosis of CN cell lines [67]; overexpressed miR-199a-3p (the 3p arm of the pre-miRNA for miR-199a) contributed to the late TNM stage in CN and transfecting miR-199a-3p inhibitor into CN SW480 cells could significantly limit the cell proliferation [68]; miR-142-3p (the 3p arm of the pre-miRNA for miR-142) functioned as a CN suppressor through targeting CD133, leucine-rich-repeat-containing G-protein-coupled receptor 5 (Lgr5) and ATP binding cassette (ABCG2) [69]; miR-146b enhanced the proliferation of CN by targeting the calcium-sensing receptor (CaSR) and impairing the anti-proliferative and pro-differentiating actions of calcium [70]; miR-150 was found to be a tumor suppressor in CN by targeting c-Myb [71]; overexpressed miR-122 and its concomitantly suppressed target gene, cationic amino acid transporter 1 (CAT1), would contribute to the development of CN liver metastasis [72]. [score:25]
Overexpressed miR-142-5p (the 5p arm of the pre-miRNA for miR-142) was observed in gastric MALT lymphoma, playing a pivotal role in pathogenesis of this cancer [76]. [score:3]
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A comprehensive list of potential miRNA targets for AML therapy is summarized in Table 2. Table 2 miRNA target genes or pathways References miR-141 PI3K/Akt/mTOR[113] miR-125a ErbB pathway[10] miR-125b Mcl-1[11, 12] miR-22-3p, let-7e-5p PLK1[114] miR-34a PD-L1[80] miR-638 CDK2[34] miR-181a, b and c PRKCD, CTDSPL and CAMKK1[6, 36, 96, 97] miR-191-5p, miR-142-3p PPP2R2A[19, 115] miR-181b MDR[36] miR-21, miR-196b HOX[98] miR-29a/b/c Dnmts[19, 22] Both single miRNAs and panel of miRNAs have potential prognostic value complementing information gained from cytogenetics, gene mutations, and altered gene expression. [score:8]
Furthermore, co-transfection of both miR-29a and miR-142-3p inhibited both their common target, cyclin T2 (CCNT2), and their individual target genes cyclin -dependent kinase 6 (CDK6) and TGF-β activated kinase 1/MAP3K7 binding protein 2 (TAB2), respectively, leading to a larger synergistic reduction in myeloid differentiation [19- 21]. [score:7]
miR-142-3p inhibits TAB2 expression and therefore an increase in miR-142-3p pushes monocytic precursors to differentiate into macrophages rather than osteoclasts. [score:5]
miR-29a and miR-142-3p promote monocytopoiesis by suppressing CCNT2, which reduces pRb protein levels and cell proliferation. [score:3]
Increased miR-29a or miR-142-3p leads to increased differentiation into granulocytes and monocytes, while reduction of either miR-29a or miR-142-3p suppressed myeloid differentiation in leukemia cell mo dels. [score:3]
Wang X, et al [19] saw that miR-29a and miR-142-3p were significantly increased in peripheral blood mononuclear cells (PBMNCs) and bone marrow (BM) white blood cells from AML patients. [score:1]
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CD84 and IL-10 are predicted targets of miR-142-3p, while signaling lymphocytic activation molecule -associated protein (SAP) is a potential target of miR-142-5p. [score:5]
miR-126, miR-142-3p, and miR-142-5p are predicted to target genes associated with SLE, which implicates their aberrant expression in CD4 [+] T cells in LN pathogenesis. [score:5]
Decreased expression of miR-142-3p and miR-142-5p in SLE CD4 [+] T cells was confirmed in studies by Ding et al. [73]. [score:3]
These results indicate that reduced expression of miR-142-3p and miR-142-5p in CD4 [+] T cells of SLE patients contributes to T cell hyperactivity and B cell hyperstimulation [73]. [score:3]
Although many miRNAs are expressed in T cell subsets, one study found 7 miRNAs (miR-16, miR-21, miR-142-3p, miR-142-5p, miR-150, miR-15b, and let-7f) account for almost 60% of all T cell miRNAs. [score:3]
SAP protein production was decreased after inhibition of mir-142-5p. [score:3]
When miR-142-3p was inhibited in CD4 [+] T cells from healthy donors, protein levels of CD84 and IL-10 increased. [score:3]
In addition, the expression of miR-142-3p and miR-142-5p was reduced to less than half in SLE CD4 [+] T cells compared to CD4 [+] T cells from healthy controls. [score:2]
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Non-infected (Fold-change) miRNA [1] (fold change)MX1 myxovirus (influenza virus) resistance 1 [27]Z23168+11.46gga-miR-155(+3.55)gga-miR-206(−2.86)Interleukin 8 (IL8) [28]M16199+11.03gga-miR-32(+7.98)Interferon regulatory factor 7 (IRF7) [29]U20338+2.11gga-miR-142-5p(+2.84)Interleukin1receptor-like1, transcript variant1 [51]AB041738+1.65gga-miR-460 (only expressed in infected lungs)TNF receptor superfamily, member 19 [30]BX931334−1.85gga-miR-187(−4.35)Tipartite motif-containing 7.1 [52]BX934475−1.81NA [2]RAC serine/threonine-protein kinase3 (ATK3) [53]BX950472−1.65NAC-fringe 1 [54] U97157 −1.52 NANote: [1]miRNAs targeting on differentially expressed immune related genes; [2] No miRNAs targeting on the gene; +: Up-regulated with AIV infection; –: Down- regulated with AIV infection. [score:14]
In the current study, gga-miR-142-3p was down-regulated in layers and up-regulated in broilers, which indicate that host immune response to AIV infection mediated by gga-miR-142-3p in broiler chickens may be different from layer. [score:7]
For example, differential expression of miR-142-3p in conventional CD4 [+] T cells and CD25 [+] T [REG] cells in mice control the functions of both effector and suppressor cells. [score:5]
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Other miRNAs from this paper: mmu-mir-142a, mmu-mir-142b
Here we show that IDLVs can be used to express transgenes for a window of time in the liver as long as the expression is stringently targeted to hepatocytes with transcriptional and miR-142–mediated regulation. [score:8]
8 The vectors carried target sequences for miR-142 in the transgene 3′-untranslated region (3′-UTR; ET. [score:5]
These results indicate that the pattern of OVA expression driven by miR-142–regulated IDLVs in the liver favored the conversion of transgene-specific naive CD4 [+] T cells into transgene-specific FOXP3 [+] -induced Tregs (Fig. 7B,C). [score:4]
142T: miR-142 target sequence made of 4 tandem copies of a sequence perfectly complementary to miR-142. [score:3]
The frequency of CD4 [+]CD25 [+]FOXP3 [+] regulatory T cells (Tregs; FOXP3 = forkhead box P3) increased in the liver after treatment with both IDLV types 3 weeks after vector administration; however, the ratio of Tregs to CD8 [+] effector cells was much higher in the mice treated with miR-142-regulated vector than in control vector treated mice (Fig. 5C,D). [score:3]
CD8 [+] T cell infiltration was well detected 1 week after IDLV treatment independently of the presence or absence of miR-142 regulation. [score:2]
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Decreased expression of mmu-miR-142-3p leads to increased expression of target gene IRAK-1, an inhibitor of TLR signaling (Ghorpade et al., 2012). [score:9]
When comparing M. tuberculosis to M. smegmatis infection, miR-142-3p is up regulated rapidly (peaking at 1 h for mouse macrophages and 4 h for human macrophages; Bettencourt et al., 2013), but down regulated at a later stage of the infection (24 h post-infection in mouse macrophages; Martinez et al., 2013). [score:3]
Early induction of miR-142-3p interfered with phagocytosis, a required cellular process for the macrophage antimicrobial response, via targeting the mRNA of the actin binding protein N-WASP (Bettencourt et al., 2013). [score:3]
A separate study supports the hypothesis that time-sensitive regulation of microRNA can have a significant impact on the outcome of infection by showing that in contrast to virulent M. tuberculosis, infection with the non-virulent M. bovis BCG results in early down regulation of mmu-miR-142-3p (Xu et al., 2013). [score:3]
Another microRNA, miR-142-3p, is also differentially regulated by virulent and non-virulent mycobacteria. [score:2]
Actin -binding protein regulation by microRNAs as a novel microbial strategy to modulate phagocytosis by host cells: the case of N-Wasp and miR-142-3p. [score:2]
This disparity between regulation of miR-142-3p at early and late time points by M. tuberculosis may be a reflection of the pathogen’s ability to elicit microRNAs that counteract the sequential stages of the macrophage response. [score:2]
M. tuberculosis infection SHIP1Enhancement of TNF-α, and decreased M. tb intracellular survival miR-142-3p (human and mouse) Macrophages↑ M. tuberculosis vs. [score:1]
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MiR-150 was reported to function as a key regulator in the tumorigenesis and progression of CN by targeting c-Myb [39]; miR-92a played a critical role in the CN development and an anti-miR-92a antagomir could lead to the apoptosis of CN cells [40]; miR-199a-3p, the 3p arm of the pre-miRNA for miR-199a, exhibited a higher expression in CN tissues, resulting a significantly lower survival rate for the patients [41]; miR-142-3p, the 3p arm of the pre-miRNA for miR-142, could suppress the CN cell growth via downregulating three CN -associated proteins CD133, Lgr5, and ABCG2 [42]; an inverse correlation observed between the levels of miR-101 and the EP4 receptor protein in CN suggested that miR-101 might serve as a therapeutic target for the cancer [43]; miR-146b, with its expression inhibited, would lead to a high CsSR protein receptor level and reduce CN proliferation [44]. [score:18]
Shen WW Zeng Z Zhu WX Fu GH MiR-142-3p functions as a tumor suppressor by targeting CD133, ABCG2, and Lgr5 in colon cancer cellsJ. [score:4]
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Ultimately, four down-regulated plasma miRNAs (i. e., miR-26a, miR-142-3p, miR-148a and miR-195) were selected as the candidates for the fist-stage validation (Table 2). [score:4]
In summary, our study revealed four down-regulated miRNAs, miR-148a, miR-142-3p, miR-26a, and miR-195, in GC patients. [score:4]
The plot showed that the expression levels of four miRNAs were statistically significant in the GC tissues (P = 0.001, P = 0.002, P < 0.001 and P = 0.003 for miR-26a, miR-142-3p, miR-148a and miR-195, respectively, Figs 2A–2D). [score:3]
0151345.g002 Fig 2(A-D) Relative expression levels of miR-26a, miR-142-3p, miR-148a, miR-195, in 50 paired gastric cancer tissues and corresponding noncancerous tissues (log [10] scale on Y -axis). [score:3]
0151345.g004 Fig 4 ROC curves were constructed to show AUCs of miR-26a (A), miR-142-3p (B), miR-148a (C), miR-195 (D) and the combination of four miRNAs (E). [score:1]
0151345.g003 Fig 3Box plots showed the plasma levels of miR-26a (A), miR-142-3p (B), miR-148a (C) and miR-195 (D) in 200 gastric cancer patients and 200 age- and gender-matched healthy controls. [score:1]
At the cut-off value of 0.585 for miR-142-3p, the sensitivity was 74.4% and the specificity was 84.1% with an AUC of 0.839 (95% CI = 0.800–0.879) (Fig 4B). [score:1]
S2 Fig The combination of miR-26a, miR-142-3p and miR-148a (A), the combination of miR-26a, miR-142-3p and miR-195 (B), the combination of miR-26a, miR-148a and miR-195 (C) and the combination of miR-142-3p, miR-148a and miR-195 (D) yielded the largest AUCs. [score:1]
Box plots showed the plasma levels of miR-26a (A), miR-142-3p (B), miR-148a (C) and miR-195 (D) in 200 gastric cancer patients and 200 age- and gender-matched healthy controls. [score:1]
Comparing TLDA analysis and the result of tissue microarray, four miRNAs(miR-26a, miR-142-3p, miR-148a and miR-195) reduced in GC were selected. [score:1]
ROC curves were constructed to show AUCs of miR-26a (A), miR-142-3p (B), miR-148a (C), miR-195 (D) and the combination of four miRNAs (E). [score:1]
S1 Fig The combination of miR-26a and miR-142-3p (A), the combination of miR-26a and miR-148a (B), the combination of miR-26a and miR-195 (C), and the combination of miR-142-3p and miR-148a (D), the combination of miR-142-3p and miR-195(E) and the combination of miR-148a and miR-195 (F) yielded the largest AUCs. [score:1]
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We constructed a bidirectional vector whereby the reporter gene mCherry is conjugated with perfectly complementary miRNA target sites for miR-223, miR-155, miR-142-3p and EGFP expressed in the anti-sense direction conjugated with miR-302a and miR-302d (miR-302 a/d). [score:7]
The miRNA target sequence for miR-142-3p was inserted after the transgene and expressed in the same mRNA transcript in the context of a lentiviral vector. [score:5]
Concomitantly, mCherry expression was slightly reduced in the cells, reflecting expression of one or more of the differentiation specific miRNAs miR-223, miR-155, or miR-142-3p. [score:5]
In contrast, the hiPSCs express mCherry at high levels similar to hESCs, reflecting the absence of miR-223, miR-155, or miR-142-3p in the hiPSCs. [score:3]
Whereas miR-223, miR-155, and miR-142-3p are enriched in differentiated cells [14], [22], miR-223 and miR-142-3p are found in cells of primarily hematopoietic origin [23]. [score:1]
For example, miR-223, miR-142-3p, and miR-155 are enriched primarily in cells of hematopoietic origin [22], [23]. [score:1]
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Brown et al. demonstrated that mir-142-3p effectively suppressed transgene expression in hematopoietic lineages in mice, whereas expression was maintained in non-hematopoietic cells [64]. [score:7]
let-7g-5p, miR-142-3p, miR-16-5p and miR-223-3p were expressed at high levels in all 5 lineages, while miR-134, miR-517c-3p/519a-3p, miR-518d-3p, miR-520d-5p/518a-5p/527 and miR-562 were expressed at low levels in all 5 lineages (Table S5B). [score:5]
Amongst miRNAs exhibiting high expression in at least two of the hematopoietic cell lineages, we identified miR-142-5p, miR-29a-3p, miR-150-5p and miR-93-5p as selectively reduced in one or more primary cell types (Table S7). [score:3]
This data is consistent with the identification of mir-142-3p as one of 5 highly expressed miRNAs among human peripheral blood cells in our current study. [score:3]
The patterns of miRNA expression in transformed cell lines showed little or modest correlation with primary hematopoietic cells (Table S4A; in Figure 3C, right set of heatmaps, compare miR-126-3p in the megakaryocyte/platelet lineage, miR-142-3p in the lymphocytic lineage, etc. [score:3]
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017−3.45 (0.29)miR-210.017−4.35 (0.23) UpregulatedmiR-302c0.047−3.46 (0.29)miR-28–3p0.041−3.30 (0.30)miR-30d0.0012.14miR-90.016−3.39 (0.30) UpregulatedmiR-23a0.0144.32miR-30c0.012−3.80 (0.26)miR-18a0.0422.35miR-142–3p0.0214.36miR-320a0.034−5.42 (0.18)miR-142–3p0.0223.71miR-1430.03710. [score:7]
However, compared to controls, curcumin pretreatment upregulated 14 H [2]O [2]-modulated miRNAs of which seven miRNAs (miR-20a: p=0.001, FC=2.89; miR-126: p=0.006, FC=4.35; miR-146a: p=0.037, FC=2.89; miR-150: p=0.005, FC=4.59; miR-155: p=0.049, FC=2.40; miR-29b: p=0.016, FC=4.02; and miR-142–3p: p=0.036, FC=20.57) were also significantly upregulated by curcumin treatment alone. [score:6]
Of the miRNAs that were affected by both treatments, the direction (up- or downregulation) was opposite in all cases except one, miR-142–3p. [score:5]
Based on statistical significance (p<0.05) and 2 -FC, curcumin alone significantly increased the expression of nine miRNAs (miR-18a, miR-22, miR-20a, miR-29b, miR-126, miR-142–3p, miR-146a, miR-150, and miR-155). [score:3]
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Differential expression of RNAseq data identified 12 miR with changes in relative expression during follicular trachoma, of which 9 were confirmed as differentially expressed by qPCR (miR-155, miR-150, miR-142, miR-181b, miR-181a, miR-342, miR-132, miR-4728 and miR-184). [score:7]
MiR-155-5p, miR-142-5p, miR-142-3p, miR-132-3p and miR-147-3p amongst others were up-regulated during Cm infection of the murine cervix in response to an attenuated strain of Cm, relative to a virulent strain of Cm [16]. [score:4]
are shown in Table  2. MiR-155, miR-150, miR-142, miR-181b, miR-181a and miR-342 were up-regulated in all 3 comparisons (Fig.   2). [score:4]
MiR-155, miR-150, miR-142, miR-181b, miR-181a, miR-342 and miR-132 were differentially expressed during current Ct infection. [score:3]
MiR-155, miR-150 and miR-142 are thought to be specific for hematopoietic cells [55] (although miR-155 expression has been reported in epithelial cell lines [56, 57]) and miR-155, miR-150, miR-181a, miR-146 and miR-10a have roles in hematopoiesis (reviewed in [58]). [score:3]
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Tumorigenesis in CRC E-cadherin[41, 42] miR-135b HCC cell metastasis; CRC proliferation HSF1, MSH2[44, 45] miR-29b Apoptosis promotion Bcl-2 and Mcl-1, MMP-2[47, 48] miR-142-3p HCC and CRC proliferation RAC1, CD 133, Lgr 5, ABCG2[60, 62, 107] miR-210 HCC metastasis; overexpressed in CRC VMP1, CPEB2[51, 52] miR- 181a Oncogenic role in HCC; poor survival in patients with CRC CDX2, GATA6, NLK, EGFR[64, 65] miR- 224 Oncogenic role in HCC; prognostic marker in CRC SMAD4, API-5[49, 63]Previous studies indicated that miR-34a inhibits tumor growth, miR-21 promotes apoptosis resistance of tumor cells proliferation while the miR-200 family is strongly associated with the epithelial- mesenchymal transition (EMT) [18, 19]. [score:5]
We have revealed common small non-coding RNA molecules (miR-26a, miR-195, miR- miR-126, miR-122, miR-21, miR-155, miR-9, miR-135b, miR-29b, miR-142-3p, miR-210, miR-181, miR- 224) in HCC and CRC, which suppress the expression of multiple genes involved in tumor- stromal interactions, immune invasion and tumor angiogenesis. [score:5]
Tumorigenesis in CRC E-cadherin[41, 42] miR-135b HCC cell metastasis; CRC proliferation HSF1, MSH2[44, 45] miR-29b Apoptosis promotion Bcl-2 and Mcl-1, MMP-2[47, 48] miR-142-3p HCC and CRC proliferation RAC1, CD 133, Lgr 5, ABCG2[60, 62, 107] miR-210 HCC metastasis; overexpressed in CRC VMP1, CPEB2[51, 52] miR- 181a Oncogenic role in HCC; poor survival in patients with CRC CDX2, GATA6, NLK, EGFR[64, 65] miR- 224 Oncogenic role in HCC; prognostic marker in CRC SMAD4, API-5[49, 63] Previous studies indicated that miR-34a inhibits tumor growth, miR-21 promotes apoptosis resistance of tumor cells proliferation while the miR-200 family is strongly associated with the epithelial- mesenchymal transition (EMT) [18, 19]. [score:5]
More interestingly, a miR-142-3p inhibitor named Propofol blocked tumor growth in mice through macrophage activation, and also stimulated tumor -associated macrophages (TAMs) to produce MVs, which secreted miR-142-3p to HCC cells, resulting in the inhibition of HCC cell migration [60, 61]. [score:5]
A stromal- to- tumor MVs- mediated transfer from macrophages to HCC cells transported miR-142-3p. [score:1]
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55
[+] score: 19
In silico target prediction software was used among mRNA (messenger RNA) targets of the three miRNAs that were significantly associated with phenol or phthalate levels (miR-185, miR-142-3p, miR-15a-5p). [score:5]
For three miRNAs—miR-142-3p, miR15a-5p, and miR-185—we detected associations between Σphthalates or Σphenols on expression levels (p < 0.05). [score:3]
Expression of miR-142 seemed to be induced by the nonparabens, which were also significantly associated this miRNA (–0.09; 95% CI: –0.17, –0.02). [score:3]
Genes contributing to the enrichment (unadjusted p < 0.0001) of biological processes among predicted targets of miRNAs associated with EDC burden (miR-185, miR-142-3p, miR-15a-5p). [score:3]
We found three miRNAs for which we detected a significant association with either phenol or phthalate levels on expression: miR-142-3p, miR15a-5p, and miR-185. [score:3]
A log(mol/L) increase in Σphenols was associated with a 0.13 [95% confidence interval (CI): –0.23, –0.03] decrease in miR-142 ΔCt. [score:1]
After adjusting for multiple testing, 10 genes were found to be significantly correlated with miR-142-3p, 20 were correlated with miR-185, and miR-15a-5p was not associated with any genes (see, Figure S6). [score:1]
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56
[+] score: 18
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-22, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-98, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-15b, mmu-mir-101a, mmu-mir-126a, mmu-mir-130a, mmu-mir-133a-1, mmu-mir-142a, mmu-mir-181a-2, mmu-mir-194-1, hsa-mir-208a, hsa-mir-30c-2, mmu-mir-122, mmu-mir-143, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-122, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-143, hsa-mir-126, hsa-mir-194-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-208a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29c, mmu-mir-98, mmu-mir-326, rno-mir-326, rno-let-7d, rno-mir-20a, rno-mir-101b, mmu-mir-101b, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-181b-2, mmu-mir-17, mmu-mir-19a, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-19b-1, mmu-mir-181b-1, mmu-mir-181c, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-101-2, hsa-mir-26a-2, hsa-mir-378a, mmu-mir-378a, hsa-mir-326, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-181b-2, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-15b, rno-mir-16, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19a, rno-mir-22, rno-mir-26a, rno-mir-26b, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30c-2, rno-mir-98, rno-mir-101a, rno-mir-122, rno-mir-126a, rno-mir-130a, rno-mir-133a, rno-mir-142, rno-mir-143, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-194-1, rno-mir-194-2, rno-mir-208a, rno-mir-181a-1, hsa-mir-423, hsa-mir-18b, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, ssc-mir-122, ssc-mir-15b, ssc-mir-181b-2, ssc-mir-19a, ssc-mir-20a, ssc-mir-26a, ssc-mir-326, ssc-mir-181c, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-18a, ssc-mir-29c, ssc-mir-30c-2, hsa-mir-484, hsa-mir-181d, hsa-mir-499a, rno-mir-1, rno-mir-133b, mmu-mir-484, mmu-mir-20b, rno-mir-20b, rno-mir-378a, rno-mir-499, hsa-mir-378d-2, mmu-mir-423, mmu-mir-499, mmu-mir-181d, mmu-mir-18b, mmu-mir-208b, hsa-mir-208b, rno-mir-17-2, rno-mir-181d, rno-mir-423, rno-mir-484, mmu-mir-1b, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, ssc-mir-17, ssc-mir-130a, ssc-mir-101-1, ssc-mir-101-2, ssc-mir-133a-1, ssc-mir-1, ssc-mir-181a-1, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-378-1, ssc-mir-133b, ssc-mir-499, ssc-mir-143, ssc-mir-423, ssc-mir-181a-2, ssc-mir-181b-1, ssc-mir-181d, ssc-mir-98, ssc-mir-208b, ssc-mir-142, ssc-mir-19b-1, hsa-mir-378b, ssc-mir-22, rno-mir-126b, rno-mir-208b, rno-mir-133c, hsa-mir-378c, ssc-mir-194b, ssc-mir-133a-2, ssc-mir-484, ssc-mir-30c-1, ssc-mir-126, ssc-mir-378-2, ssc-mir-451, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, mmu-mir-101c, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-18b, hsa-mir-378j, rno-mir-378b, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-mir-451b, ssc-let-7d, ssc-let-7f-2, ssc-mir-20b-1, ssc-mir-20b-2, ssc-mir-194a, mmu-let-7k, mmu-mir-126b, mmu-mir-142b, rno-let-7g, rno-mir-15a, ssc-mir-378b, rno-mir-29c-2, rno-mir-1b, ssc-mir-26b
Our study revealed miR-181 and miR-142-3p with relatively high expression in thymus (Figure 2C), and miR18a and miR-20a appeared to be weakly expressed in thymus (Figure 2D). [score:5]
miR-142-3p, a hematopoietic-specific miRNA [56], exhibits distinct expression patterns during T-cell development and maturation [55]. [score:4]
Additionally, miR-1 and miR-133 in the heart, miR-181a and miR-142-3p in the thymus, miR-194 in the liver, and miR-143 in the stomach showed the highest levels of expression. [score:3]
Some miRNAs, including miR-208, miR-101, miR-18a, miR-20 and miR-142-3p, showed a weaker expression than other miRNAs tested by small RNA blot analyses (Figures 2 and 3). [score:3]
Several miRNAs (miR-1, miR-133, miR-499, miR-208, miR-122, miR-194, miR-18, miR-142-3p, miR-101 and miR-143) have distinct tissue-specific expression patterns. [score:3]
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57
[+] score: 18
MiR-142-3p was upregulated in human T-leukemic cell lines and primary T-leukemic cells, and could induce glucocorticoid resistance by decreasing GRa protein expression through directly targeting the 3′UTR of GRa mRNA. [score:8]
The suppression of the GRa was concomitant with the higher expression of miR-142-3p in T-ALL patients with poor prognosis as compared to those with good prognosis [57]. [score:4]
MiR-142-3p has been shown to be highly expressed in human T-leukemic cells and has been correlated with poor prognosis of T-cell leukemia patients. [score:2]
MiR-142-3p targets the cAMP/PKA pathway to promote leukemic T-cell proliferation [57]. [score:2]
MiR-142-3p acted in an oncogenic role in T-ALL by promoting leukemic cell growth and inducing glucocorticoid (GC) resistance through targeting both glucocorticoid receptor alpha (GRa) and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathways [57]. [score:2]
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58
[+] score: 17
Importantly, restoration of miRNA-142-3p expression significantly reduced FZD7 expression, cell proliferation and invasion, thus identifying miRNA-142-3p and FZD7 as attractive therapeutic targets for cervical cancer therapy [203]. [score:7]
Moreover, subsequent studies from the same lab demonstrated FZD7 to be a direct target of miRNA-142-3p, which is normally expressed at low levels in cervical cancer cells. [score:6]
Deng B. Zhang Y. Zhang S. Wen F. Miao Y. Guo K. MicroRNA-142-3p inhibits cell proliferation and invasion of cervical cancer cells by targeting FZD7 Tumour Biol. [score:4]
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59
[+] score: 16
Other miRNAs from this paper: mmu-mir-142a, mmu-mir-142b
To further demonstrate that cells of hematopoetic origin were important in the cytokine response and severe outcome of infection with the 6:2 Tky/05 virus, we engineered a recombinant virus (NPr142-Tky/05) that harboured four copies of a microRNA target sequence in the NP gene for a microRNA specifically expressed in cells of haematopoetic origin, MiR142, as previously described by Langlois et al [56]. [score:4]
The sequence contained 231bp of codon optimized open reading frame upstream of the stop codon, four tandem copies of miRNA142 target sequence or scrambled control sequence, and 146bp duplicated segment 5 packaging sequence. [score:3]
The miRNA142 target was the same as previous described [56]. [score:3]
Moreover the decrease in lung type I IFN levels during infection with the Mir142 targeted RG virus confirms that a proportion of the cytokines that contribute to the proinflammatory response during H5N1 virus infection were secreted in vivo by infected haematopoetic cells. [score:2]
The insertion of the MiR142 target sequence, that reduced the extent of replication in cells of hematopoietic origin, resulted in reduced weight loss that correlated with a lower IFN-α level in the lung (Fig 7E and 7G). [score:2]
A recent article, as well as our own nucleotide BLAST analysis, have revealed a high degree of similarity between mouse miRNA-142 and an unannotated miRNA in the ferret genome, but further research is necessary to understand whether this putative miRNA-142 displays similar cell-type specific effects in ferrets as it does in mice [37]. [score:1]
However, in GM-DCs, vRNA accumulation following infection with the virus containing MiR142 target sites was significantly reduced compared to control virus (Fig 7C) and this led to a decreased level of IFN-α mRNA in these cells (Fig 7D). [score:1]
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60
[+] score: 16
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-17, hsa-mir-18a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-21, hsa-mir-23a, hsa-mir-31, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-96, hsa-mir-98, hsa-mir-99a, hsa-mir-106a, mmu-let-7g, mmu-let-7i, mmu-mir-23b, mmu-mir-99a, mmu-mir-127, mmu-mir-128-1, mmu-mir-136, mmu-mir-142a, mmu-mir-145a, mmu-mir-10b, mmu-mir-182, mmu-mir-183, mmu-mir-187, mmu-mir-193a, mmu-mir-195a, mmu-mir-200b, mmu-mir-206, mmu-mir-143, hsa-mir-139, hsa-mir-10b, hsa-mir-182, hsa-mir-183, hsa-mir-187, hsa-mir-210, hsa-mir-216a, hsa-mir-217, hsa-mir-219a-1, hsa-mir-221, hsa-mir-222, hsa-mir-224, hsa-mir-200b, mmu-mir-302a, mmu-let-7d, mmu-mir-106a, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-128-1, hsa-mir-143, hsa-mir-145, hsa-mir-127, hsa-mir-136, hsa-mir-193a, hsa-mir-195, hsa-mir-206, mmu-mir-19b-2, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-21a, mmu-mir-23a, mmu-mir-31, mmu-mir-92a-2, mmu-mir-96, mmu-mir-98, hsa-mir-200c, mmu-mir-17, mmu-mir-139, mmu-mir-200c, mmu-mir-210, mmu-mir-216a, mmu-mir-219a-1, mmu-mir-221, mmu-mir-222, mmu-mir-224, mmu-mir-19b-1, mmu-mir-92a-1, mmu-mir-128-2, hsa-mir-128-2, mmu-mir-217, hsa-mir-200a, hsa-mir-302a, hsa-mir-219a-2, mmu-mir-219a-2, hsa-mir-363, mmu-mir-363, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-371a, hsa-mir-18b, hsa-mir-20b, hsa-mir-452, mmu-mir-452, ssc-mir-106a, ssc-mir-145, ssc-mir-216-1, ssc-mir-217-1, ssc-mir-224, ssc-mir-23a, ssc-mir-183, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-128-1, ssc-mir-136, ssc-mir-139, ssc-mir-18a, ssc-mir-21, hsa-mir-146b, hsa-mir-493, hsa-mir-495, hsa-mir-497, hsa-mir-505, mmu-mir-20b, hsa-mir-92b, mmu-mir-302b, mmu-mir-302c, mmu-mir-302d, hsa-mir-671, mmu-mir-216b, mmu-mir-671, mmu-mir-497a, mmu-mir-495, mmu-mir-146b, mmu-mir-708, mmu-mir-505, mmu-mir-18b, mmu-mir-493, mmu-mir-92b, hsa-mir-708, hsa-mir-216b, hsa-mir-935, hsa-mir-302e, hsa-mir-302f, ssc-mir-17, ssc-mir-210, ssc-mir-221, mmu-mir-1839, ssc-mir-146b, ssc-mir-206, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-128-2, ssc-mir-143, ssc-mir-10b, ssc-mir-23b, ssc-mir-193a, ssc-mir-99a, ssc-mir-98, ssc-mir-92a-2, ssc-mir-92a-1, ssc-mir-92b, ssc-mir-142, ssc-mir-497, ssc-mir-195, ssc-mir-127, ssc-mir-222, ssc-mir-708, ssc-mir-935, ssc-mir-19b-2, ssc-mir-19b-1, ssc-mir-1839, ssc-mir-505, ssc-mir-363-1, hsa-mir-219b, hsa-mir-371b, ssc-let-7a-2, ssc-mir-18b, ssc-mir-187, ssc-mir-218b, ssc-mir-219a, mmu-mir-195b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, ssc-let-7d, ssc-let-7f-2, ssc-mir-20b-1, ssc-mir-20b-2, ssc-mir-31, ssc-mir-182, ssc-mir-216-2, ssc-mir-217-2, ssc-mir-363-2, ssc-mir-452, ssc-mir-493, ssc-mir-671, mmu-let-7k, ssc-mir-7138, mmu-mir-219b, mmu-mir-216c, mmu-mir-142b, mmu-mir-497b, mmu-mir-935, ssc-mir-9843, ssc-mir-371, ssc-mir-219b, ssc-mir-96, ssc-mir-200b
Low miR-142 expression can respond to differentiation cues [55]. [score:3]
The bimodally expressed microRNA miR-142 gatesexit from pluripotency. [score:3]
Ssc-miR-142-5p was also more highly expressed in mpiPSCs than that in hpiPSCs. [score:3]
Additionally, ssc-miR-216, ssc-miR-217, ssc-miR-142-5p, ssc-miR-96-5p, ssc-miR-182 and ssc-miR-183 have higher expression levels in mpiPSCs than that in hpiPSCs (Fig 3A). [score:3]
It is reported that miR-142 is bimodally expressed in mESCs. [score:3]
It indicated that ssc-miR-142-5p makes contribution to maintenance pluripotency in mpiPSCs. [score:1]
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61
[+] score: 15
Other miRNAs from this paper: hsa-mir-20a, hsa-mir-23b, hsa-mir-106b, hsa-mir-34b
In contrast, among the predicted miRNAs that might target SETD2, the expression of miR-23b-5p, miR-34b-3p, miR-106b-5p and miR-142–5p were significantly higher in ccRCC cell lines and tissues, while miR-20a-5p showed no significant difference (Figure 1G). [score:5]
The miRNA inhibitors (anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p, anti-miR-20a-5p), miRNA inhibitor negative control, miR-106b-5p mimic and negative control mimic were designed and synthesized by RiboBio. [score:5]
To investigate whether the predicted microRNAs could regulate the expression of SETD2, we respectively transfected 100 nM synthesized antagomirs against miR-23b-5p, miR-34b-3p, miR-106b-5p, miR-142–5p and miR-20a-5p into 786-O as well as SN12-PM6 cells. [score:2]
The microRNAs including miR-23b-5p, miR-34b-3p, miR-106b-5p, miR-142–5p and miR-20a-5p were tested among HK-2,786-O and SN12-PM6 cell lines (F) as well as ccRCC tissues (G) by real-time RT-PCR, using U6 as an internal control. [score:1]
786-O and SN12-PM6 cells were transfected for 72 h with 100 nM anti-miR negative control, anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p or anti-miR-20a-5p. [score:1]
Figure 2786-O and SN12-PM6 cells were transfected for 72 h with 100 nM anti-miR negative control, anti-miR-23b-5p, anti-miR-34b-3p, anti-miR-106b-5p, anti-miR-142–5p or anti-miR-20a-5p. [score:1]
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62
[+] score: 15
For top 10 downregulated microRNAs (hsa-miR-106b-5p, hsa-miR-26b-5p, hsa-miR-494, hsa-miR-425-5p, hsa-miR-363-3p, hsa-miR-15b-5p, hsa-miR-185-5p, hsa-miR-150-5p, hsa-miR-223-3p, hsa-miR-142-5p), we included those have been shown to be deregulated in cancer (having no controversial expression status; some of these microRNAs have been shown to be upregulated in some cancer types, whereas, downregulated in other cancer types), and have either expression data or functional studies in stem cells. [score:15]
[1 to 20 of 1 sentences]
63
[+] score: 15
miR-142-3p is associated with the development, migration, and invasion of hepatocellular carcinoma via RAC1 protein levels and function regulation [141]. [score:3]
Using cell lines, Shende et al. demonstrated that miR-142-3p and miR-494 overexpression decreases endogenous BMAL1 levels and increases PER2 oscillations, suggesting that both microRNAs play an important role in post-transcriptional modulations of core molecular clockworks in this cell lines [140]. [score:3]
Tan X. Zhang P. Zhou L. Yin B. Pan H. Peng X. Clock-controlled miR-142-3p can target its activator, Bmal1 BMC Mol. [score:3]
miR-494, miR-152, and miR-142-3p have been detected in mouse blood serum and were predicted to target 3′ UTR BMAL1 mRNA [141, 148, 149]. [score:3]
Wu L. Cai C. Wang X. Liu M. Li X. Tang H. MicroRNA-142-3p, a new regulator of RAC1, suppresses the migration and invasion of hepatocellular carcinoma cells FEBS Lett. [score:3]
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64
[+] score: 15
By this design, the expression of exogenous protein from this construct is supposed to be suppressed in antigen-presenting cells, which has abundant miR-142-3p as hematopoietic cells. [score:5]
Brown and coworkers exploited the tissue specific expression pattern of miR-142-3p in hematopoietic cells. [score:3]
Thus, for the mice challenged with the control lentiviral vector lacking the miR-142-3p sites, there were no GFP expression by day 14 due to the immune clearance. [score:3]
In contrast, they observed long-term GFP expression till 120 days post transduction specifically in nonhematopoietic cells, by the lentivirus containing miR-142-3p binding sites. [score:3]
They placed multiple complementary binding sites to miR-142-3p in the 3’ UTR of the lentivirus vector carrying the gene encoding GFP and challenged the mice with this construct. [score:1]
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65
[+] score: 15
In the present study, we showed that the expression of several miRNAs is altered during the development of PC and that licofelone reverses the altered expression of the majority of these miRNAs with up-regulation of miR-21, miR-222, Let-7, miR-125, miR-142 and down-regulation of miR-1, miR-122 and miR-148. [score:12]
For example, Lee EJ 2007 et al. [44] showed that the miRNAs miR155, miR21, miR222, Let7, miR376a, miR301, miR100, miR125, miR142 and others are overexpressed significantly in human PC. [score:3]
[1 to 20 of 2 sentences]
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[+] score: 15
Nevertheless, we were not able to demonstrate an increase of pri-miR-142-3p processing following inhibition of miR-706 with a hairpin inhibitor against this miRNA [43]. [score:5]
Remarkably, enforced expression of miR-181a led to a doubling of B cells while persistent expression of miR-223 or miR-142 increased the number of T cells by 30–40% [47]. [score:5]
miR-181a is preferentially expressed in the B-lineage, miR-223 in the myeloid lineage and mir-142 in both B and myeloid lineages [47]. [score:3]
Relevant to myelopoiesis, miR-706 is predicted to bind perfectly to a hemopoeitic-specific miR-142-3p, which is known to play an essential role in granulocyte homeostasis and maturation [43, 56]. [score:1]
More than a decade ago, three miRNAs, miR-181a, miR-223 and miR-142 were recognized as key players in myeloid and lymphoid cell differentiation [47]. [score:1]
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67
[+] score: 15
In detail, we selected two miRNAs with high fold changes among the up-regulated (miR-625-5p and miR-183-5p) and four miRNAs with high fold changes among the down-regulated ones (miR-181d-5p, miR-206, miR-142-5p and miR-339-5p). [score:7]
The RT-qPCR showed the same direction of expression changes as the microarray analysis for six miRNAs namely miR-181d-5p, miR-142-5p, miR-1233-3p, miR-206, miR-339-5p and miR-625-5p. [score:4]
The RT-qPCR showed the same direction of expression changes as the microarray analysis for five miRNAs namely miR-181d-5p, miR-142-5p, miR-206, miR-339-5p and miR-625-5p. [score:4]
[1 to 20 of 3 sentences]
68
[+] score: 15
mRNA, messenger RNA Table 1circRNA-miRNA-mRNA network elements for those circRNA-miRNA interactions predicted by both miRanda and RNAHybrid, with a miRanda match score > = 180 and mRNA targets that are differentially expressed (uncorrected P < 0.05) with log2(fold change) >= 2 or =< − 2 (high stringency network) Circular RNA microRNA target Number of binding sites predicted Target genes (differentially expressed) X:47,431,299–48,327,824 hsa-miR-139-5p 6 NOTCH1, STAMBP, TPD52 8:144,989,320–145,838,888 hsa-miR-320a 2 METTL7A, PBX3, PLS1, SEC14L1, VCL, VIM, VOPP1, YPEL2 8:144,989,320–145,838,888 hsa-miR-320b 2 RTKN, VCL, VOPP1 X:47,431,299–48,327,824 hsa-miR-449a 1 BAZ2A, MFSD8, NOTCH1, TSN, ZNF551 8:144,989,320–145,838,888 hsa-miR-125a-3p 1 ANKRD62, C15orf40, COL18A1, MFSD11, MPEG1, MUL1, TTC31, WDR12, ZNF641 X:47,431,299–48,327,824 hsa-miR-125a-5p 1 CD34, MEGF9, PANX1, RIT1, TP53INP1 8:144,989,320–145,838,888 hsa-miR-125a-5p 1 CD34, MEGF9, PANX1, RIT1, TP53INP1 X:47,431,299–48,327,824 hsa-miR-324-5p 1 FOXO1, MEMO1, PSMD4, SMARCD2 14:23,815,526–24,037,279 hsa-miR-142-3p 1 BTBD7, CLDN12, CPEB2, CSRP2, DAG1, KIF5B, PTPN23, WHAMM 4:88,394,487–89,061,166 hsa-miR-133b 1 FAM160B1 4:88,394,487–89,061,166 hsa-miR-448 1 DDIT4, PURG 4:88,394,487–89,061,166 hsa-miR-339-5p 1 AXL, HLA-E, METTL7A, ZNF285, ZNRF3 MetaCore pathway analysis on the 255 filtered differentially expressed target genes from the previous analysis revealed 112 perturbed pathways (corrected P < 0.01; Table  2, Additional file  8: Table S5). [score:15]
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69
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Also, miR-142-3p, which is underexpressed in Treg cells, plays an antagonizing role in the suppressor function of Treg through regulation of cyclic AMP [15]. [score:6]
However, due to the reduced expression of miR-142-3p, CD4 [+]CD25 [+] nTreg cells keep the AC9/cAMP pathway active and exploit a high level of cAMP for their suppressor function. [score:5]
miR-142-3p regulates the production of cAMP by targeting adenylyl cyclase (AC) 9 mRNA in T cells [15]. [score:4]
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70
[+] score: 15
Among the miRNAs that were down-regulated between normal and pre-neoplasic cervical samples, but had increased expression in cervical cancer samples, were miR-106a, miR-205, miR-197, miR-16, miR-27a and miR-142-5p. [score:6]
Six miRNAs displayed relative decreased expression in the transition from normal cervix to atypical dysplasia and increased expression in the transition from atypical dysplasia to cervical carcinoma, namely miR-106a, miR-205, miR-197, miR-16, miR-27a and miR-142-5p (Figure 4B). [score:5]
Interestingly, miR-142-5p is located in 17q23, which is in proximity to the t(8, 17) breakpoint in B cell acute leukemia and also within the minimal amplicon in breast cancer and near the FRA17B site, a target for HPV16 integration in cervical tumours [14]. [score:3]
For example, miR-142-5p is located in FRA17B, while miR-196a and miR-29a are located in FRA12A and FRA7H, respectively. [score:1]
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71
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P Observed up Observed down <0.05 mir-99b, 375, 462, 639 mir-142-5p, 155, 211, 489, 494, 594, 597 <0.02 mir-429, 642 mir-142-3p, 324-5p, 515-3p Another complementary method of analyzing the miRNA expression data is to identify pairs of miRNAs that are co-regulated in their expression, up or down, across individuals within a single group. [score:6]
Almost half of the combined down-regulated miRNAs are encoded at chromosomal loci near another miRNA on the list (Table 2 ) and are possibly transcribed by the same primary miRNA gene transcripts [32], [35]: a) mir-142-5p and 142-3p; b) mir-494, 376a*, 496, and 369-3p; c) mir-23b, 27b and 24-1*; d) mir-34b* and 34c; and e) mir-17* and 20a. [score:4]
Only two of the miRNAs were significantly down-regulated in the depressed group (mir-142-5p and 146a, neither of them hubs). [score:4]
In addition, three pairs of miRNAs are encoded at distances greater than 100 kb but still lie within the same chromosomal region: a) mir-424 and 20b at Xq26.2-3, 377 kb apart; b) mir-142 and 301a at 17q22, 820 kb apart; and c) mir-324-5p and 497 at 17p13.1, 205 kb apart. [score:1]
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72
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Huang et al. showed an indirect effect of miR-142-3p on FOXP3 expression by targeting AC9 mRNA [56]. [score:6]
Very recently, Skapenko’s group showed that miR-142-3p targeted GARP in CD4 [+]CD25 [+] T cells [55] and Sophie Lucas’ group described that GARP is regulated by microRNAs (miR-142-3p, −181a and −185) and controls latent TGF-β production by human CD4 [+] Treg cells [71]. [score:4]
For example, miR-142-3p can regulate GARP expression in CD4 [+]CD25 [+] T cells [55]. [score:4]
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73
[+] score: 14
miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their target [30]. [score:5]
The expression levels of miR-142-5p and miR-155 are significantly increased in MALT lymphomas that do not respond to H. pylori eradication [30]. [score:3]
We previously reported that a hematopoietic-specific miRNA, miR-142, and an oncogenic miRNA, miR-155, are overexpressed in MALT lymphoma lesions [30]. [score:3]
The expression levels of miR-142-5p and miR-155 are associated with the clinical courses of gastric MALT lymphoma cases and these miRNAs may have a potential application as novel biomarkers for gastric MALT lymphoma. [score:3]
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74
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miR-96, miR-182, and miR-183 are downregulated and miR-1, miR-133, and miR-142 are upregulated consistently in multiple mouse mo dels of retinitis pigmentosa, suggesting that this may be a miRNA signature of retinal degeneration [39, 40]. [score:7]
In the murine experimental autoimmune uveoretinitis mo del, miR-142-5p and miR-21 were found to be upregulated, and miR-182 was found to be downregulated [46]. [score:7]
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75
[+] score: 13
let-7a-3p, on the other hand, is expressed in an intergenic region harboring several ncRNAs and flanked by strong BORIS and CTCF binding sites, indicating a potential regional control of its expression by BORIS, while miR-142-5p is located in a 15-kb region expressing several noncoding RNA, without obvious binding of BORIS in the vicinity. [score:7]
miR-142-5p has been shown to induce apoptosis in non-blood cancer cells [130] and inhibit cell cycle via beta-catenin/WNT signaling [131]. [score:3]
The most dramatic effect among highly expressed known miRNA was observed for let-7a-3p, as well as: let-7i-5p, miR-1296-3p, miR-340-5p, miR-3184-3p, miR-7-5p, miR-142-5p, and miR-224-3p (Supplementary Table S4). [score:3]
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76
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Both ssc-miRNA-142-3p and ssc-miRNA-142-5p were also differentially expressed in several comparison groups in M pig, and down-regulation of these two miRNAs was found to be critical in cardiac hypertrophy [60]. [score:6]
In addition, mmu-miR-142-3p and mmu-miR-142-5p were shown to be up-regulated in adipose tissue during the development of obesity in mice [48]. [score:5]
Repression of miR-142 by p300 and MAPK is required for survival signalling via gp130 during adaptive hypertrophy. [score:1]
In addition, we identified 199, 127, 140, and 37 DE miRNAs in the 60/120, 120/150, 150/180, and 180/210 dpn comparisons, respectively, in M pig, among which nine miRNAs (ssc-miR-23a, ssc-miR-new-276, ssc-miR-142-3p, ssc-miR-142-5p, ssc-miR-499-5p, ssc-miR-15a, ssc-miR-new-386, ssc-miR-new-421, and ssc-miR-144) were common (S4 Fig and S7 Table). [score:1]
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77
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miR-107, miR-153 and miR-142-3p indirectly reduce p21 expression through targeting the upstream regulators, FOXO1, PTEN and FOXO4, respectively [50– 52]. [score:7]
For example, miR-107, miR-153, and miR-142-3p had been shown to reduce p21 expression through targeting the upstream regulators, FOXO1, PTEN and FOXO4, respectively [50– 52]. [score:6]
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78
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Mtb induced expression of miR-142-3p targets N-Wasp leading to reduced phagocytosis (Bettencourt et al., 2013). [score:5]
miR-125a-3p, miR-33, miR-144-3p, miR-23a-5p, and miR-142-3p are potential inhibitors of autophagy in Mycobacterium tuberculosis (Mtb) infection. [score:3]
miR-142-3p targets Neural Wiskott-Aldrich syndrome protein (N-Wasp) leading to reduced phagocytosis. [score:3]
Actin -binding protein regulation by microRNAs as a novel microbial strategy to modulate phagocytosis by host cells: the case of N-Wasp and miR-142-3p. [score:2]
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79
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Other miRNAs from this paper: hsa-mir-200c
It is noteworthy that Chiou et al. reported a paracrine feedback regulatory loop between miR142-3p and IL-6 in GBM cells [33], in which IL-6 suppresses miR142-3p expression through increasing its promoter methylation, while miR142-3p inhibits IL-6 expression and secretion by directly targeting IL-6 3′UTR. [score:13]
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80
[+] score: 13
Expression levels of miR-155 (a), miR-142.3p and miR-142-5p (b) and of members of the miR-17~92 cluster (c) were determined by single specific qPCR in the indicated sorted human CD8 [+ ]T cell subsets (a), and are expressed as fold change relatively to levels in naive cells (n = 9; *: p < 0,05; **: p < 0,01). [score:5]
Since the TLDA analysis showed that both miR-142-3p and miR-142-5p were among the most expressed microRNAs in CD8 [+ ]T cells (Table 1), their expression levels were assessed in the different subsets. [score:5]
Interestingly, these microRNAs include miR16, miR-21, miR-142-3p and miR-142-5p, which were also found in the group A in human CD8 [+ ]T lymphocytes, with miR-142-3p showing the highest relative expression levels (Table 1). [score:3]
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81
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The expression patterns of three other miRNA (miR-451, miR-144, and miR-142) predicted to be expressed in erythroid cells were also examined (Figure 2C). [score:5]
C. Relative expression patterns of the GATA-1 regulated miRNA, miR-451 and miR-144, and hematopoietic tissue-specific microRNA, miR-142. [score:4]
miR-142 is specifically expressed in hematopoietic tissues [17]. [score:3]
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82
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Moreover, the upregulation of miR-142-5p, miR-221, miR-30, miR-32, miR-374, miR-99a, miR-122 and miR-101 and the downregulation of miR-145, miR-195 and miR-98 observed in JEV-infected PK-15 cells in our study have been reported in the brains of mice infected with West Nile virus (WNV), another mosquito-borne flavivirus [34]. [score:7]
In this study, we identified a subset of miRNAs (including miR-10a-5p, miR-10a-3p, miR-10b, miR-101, miR-126-5p, miR-142-5p, miR-155-5p, miR-17-3p, miR-18a, miR-19a, miR-181a, miR-196b, miR-221-3p, miR-98, let-7d-3p, let-7d-5p) that are significantly differentially expressed after challenge with JEV. [score:3]
In this study, the miRNAs associated with autophagy, including miR-30a/c, miR-374a, miR-195, miR-101, miR-181a, miR-98, miR-142, miR-196, miR-210, miR-17 and miR-155, were identified. [score:1]
These include miR-10, miR-101, miR-106a, miR-126, miR-142-3p, miR-146, miR-150, miR-155, miR-17-92 cluster (seven members: miR-17-5p, -17-3p, -18a, -19a, -20a, -19b and -92a), miR-181a, miR-196b, miR-21, miR-221, miR-223, miR-326, miR-34,miR-424, miR-9, miR-98, the let-7 family (nine members: let-7, mir-48, -84, -241, -265, -793, -794, -795 and -1821), and so on [47, 48, 49]. [score:1]
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83
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Many of these miRNAs (such as miR-142-3p, miR-155, miR-21 and miR-210) that were known to function as ‘oncogenes’ in previous studies were observed to be uniformly up-regulated, while other potential ‘tumor suppressors’ such as let-7c and miR-214 were down-regulated in our study (reviewed by Ramiro Garzon et al. [19] and Aurora Esquela-Kerscher et al. [20]). [score:9]
Our analysis identified a number of annotated cancer -associated miRNAs such as miR-142-3p, miR-155, miR-21, miR-210, let-7c and miR-214 exhibiting consistent deregulation in TCC, TGCT and ccRCC, which may suggest their general effects on human cancer development. [score:3]
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84
[+] score: 12
MiR-99b, miR-193a-5p, miR-322-3p and miR-142-5p respectively regulated 25, 20, 2 and 1 targets (Table B in S1 File). [score:4]
The seven miRNAs (miR-99b, miR-142-5p, miR-152, miR-193a-5p, miR-323-3p, miR-335, miR-494) associated with Zirconium levels with FDR P < 0.1, were selected for downstream target prediction analysis. [score:3]
In the present study on an obese population, we found that the exposure to Zr levels traced in hair is associated with a distinct signature of 7 miRNAs (miR-99b, miR-142-5p, miR-152, miR-193a-5p, miR-323-3p, miR-335, miR-494) expressed in peripheral blood. [score:3]
Seven miRNAs (miR-99b, miR-142-5p, miR-152, miR-193a-5p, miR-323-3p, miR-335, miR-494) resulted specifically associated with Zr levels. [score:1]
Using an FDR linear step-up adjustment for multiple comparisons (FDR P < 0.1), we found 7 miRNAs (miR-99b, miR-142-5p, miR-152, miR-193a-5p, miR-323-3p, miR-335, miR-494) specifically associated with Zr levels traced in the hair (Table 2). [score:1]
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85
[+] score: 11
[117] ATP Brain tissue and lymphoblasts 36 subjects (total) Transcription and alternative splicing study Accelerated decrease of MS gene transcription across ageing found in ASD patient cerebral cortex samples[347] ATP Brain tissue 73 subjects Methylation studyCorrelation found between reduced expression of MECP2 and increased methylation on the promoter region[110] ATP Brain tissue 24 subjects Methylation studyHypomethylation of mir142 and upregulation of mi -RNAs targeting OXTR gene in prefrontal cortex of ASD brains[348] ATP Brain tissue 24 subjects Signal transduction study Downregulation of PI3K-Akt genes observed in fusiform gyrus tissue of ASD patients. [score:11]
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86
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In particular, these studies identified miR15/miR-16, miR-26, miR-29, miR-107, miR-142, miR-342, and let7 between the miRNAs significantly induced, whereas miR-181b was found to be downregulated by ATRA. [score:4]
Among the deregulated miRNAs in AML, these studies identified miRNAs already known to be hematopoietic specific (e. g., miR-142-5p, miR-223, and miR-181) or reported to be highly expressed in other hematological malignancies and solid tumours (e. g., miR-221, miR-222, miR-17-92 cluster and miR-155) [6, 18, 20, 21, 69]. [score:4]
Ectopic expression for some of these miRNAs, such as miR-26a, miR-29a, miR-142-3p and miR-342, has been produced and, similarly to miR-223, it stimulated granulocytic differentiation of AML cells [38, 41, 43, 44]. [score:3]
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87
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Interestingly, miR-142-3p has been found to be upregulated in the adipose tissue of mice fed an HFD [130], and miR-182 has also been found to be upregulated in the liver of mice fed an HFD [160]. [score:7]
Olivieri et al. found a downregulation of miR-182, miR-223 and miR-142-3p in the skeletal muscle of postmenopausal women [159]. [score:4]
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88
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Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-107, hsa-mir-16-2, hsa-mir-198, hsa-mir-148a, hsa-mir-30d, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181c, hsa-mir-182, hsa-mir-183, hsa-mir-205, hsa-mir-210, hsa-mir-181a-1, hsa-mir-222, hsa-mir-224, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-27b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-132, hsa-mir-137, hsa-mir-140, hsa-mir-141, hsa-mir-143, hsa-mir-144, hsa-mir-153-1, hsa-mir-153-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-134, hsa-mir-136, hsa-mir-146a, hsa-mir-150, hsa-mir-184, hsa-mir-185, hsa-mir-186, hsa-mir-206, hsa-mir-320a, hsa-mir-200c, hsa-mir-128-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-299, hsa-mir-26a-2, hsa-mir-373, hsa-mir-376a-1, hsa-mir-342, hsa-mir-133b, hsa-mir-424, hsa-mir-429, hsa-mir-433, hsa-mir-451a, hsa-mir-146b, hsa-mir-494, hsa-mir-193b, hsa-mir-455, hsa-mir-376a-2, hsa-mir-33b, hsa-mir-644a, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-301b, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-320e, hsa-mir-3613, hsa-mir-4668, hsa-mir-4674, hsa-mir-6722
Song and Kim (2017) showed that miRNA-142-5p plays an important role in the pathogenesis of AD, as it is upregulated in the brains of AD patients and inhibition of miRNA-142-5p resulted in the rescue of synaptic dysfunction in Aβ42 -treated SH-SY5Y cells. [score:6]
Identification of the role of miR-142-5p in Alzheimer’s disease by comparative bioinformatics and cellular analysis. [score:3]
At the terminal stage of prion infection miRNA-146a-5p, miRNA-142-3p, miRNA-143-3p, miRNA-145a-5p, miRNA-451a, miRNA-let-7b, miRNA-320, and miRNA-150-5p were elevated. [score:1]
While in terminal stage of prion infection miRNA-146a-5p, miRNA-142-3p, miRNA-143-3p, miRNA-145a-5p, miRNA-451a, miRNA-let-7b, miRNA-320, and miRNA-150-5p are significantly elevated in the brains of prion-infected animals. [score:1]
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89
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The miRNA -mediated 3′-oligouridine addition with the exact numbers of uridine bases to the cleaved target mRNA fragments was further confirmed at the 3′-ends of specific 5′-fragments in the cleaved HMGA2 (high-mobility group AT-hook 2) mRNA targeted by miR-142-3p activity in HeLa cells by a U-track–specific SLA–RT-PCR and Sanger sequencing (Fig. 3). [score:5]
Eight uridine residues were detected on the 3′ termini of the HMGA2 mRNA fragment, as confirmed by sequence alignment to the seed region of the hsa-miR-142-3p target site on the HMGA2 mRNA, which was revealed by deep sequencing data available in miRbase databases. [score:3]
Verification of 3′-oligouridine Addition in Cleaved HMGA2 mRNA Fragments Targeted by miR-142-3p. [score:3]
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90
[+] score: 11
We found that ten of the down-regulated miRNAs (miR101, miR26a, miR26b, miR30a, miR30b, miR30d, miR30e, miR34b, miR-let7 g and miRN140) were grouped together in a functional network (Figure 3A) and nine of the down-regulated miRNAs (miR-130a, miR-133a, miR-142, miR-150, miR15a, miR-16, miR-29b, miR-30c and miR-99a) were grouped together in a second network (Figure 3B). [score:7]
With the aid of IPA pathway designer, we found that 27 of the 31 down-regulated miRNAs were linked to one or more mRNA networks and 20 of them (let-7 g, miR-101, miR-126, miR-133a, miR-142-5p, miR-150, miR-15a, miR-26b, miR-28, miR-29b, miR-30a, miR-30b, miR-30c, miR-30d, miR-30e, miR-34b, miR-99a, mmu-miR-151, mmu-miR-342 and rno-miR-151) were involved in all of the top 4 networks. [score:4]
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91
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MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene. [score:4]
Expression and prognostic significance of hsa-miR-142-3p in acute leukemias. [score:3]
MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. [score:2]
miR-142. [score:1]
miR-142 IN NORMAL AND MALIGNANT HEMATOPOIESIS. [score:1]
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92
[+] score: 10
A global transcriptomic analysis of Mø infected with M. smegmatis, revealed among the most differentially regulated miRNAs miR-142-3p;-5p; miR-32 (upregulated) and miR-106b-5p (downregulated). [score:8]
Curiously, one of the miRs we showed to be more differentially regulated during mycobacteria infection, in addition to miR-106-b was miR-142-3p (Figure 1A). [score:2]
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93
[+] score: 10
Evidence of the concerted interplay of miRNAs regulated by CpG-ODN and their potential target mRNAs was observed (Fig. 4) for 2 miRNAs upregulated (hsa-miR-302b and hsa-miR-374b) and for 13 miRNAs downregulated in CpG-ODN -treated mice (hsa-miR-135a, hsa-miR-136, hsa-miR-340, hsa-miR-445-5p, hsa-miR-424, hsa-miR-96, hsa-miR-142-3p, hsa-miR-140-5p, hsa-miR-542-3p, hsa-miR-18a, hsa-miR-18b, hsa-miR-101, and hsa-miR-99a). [score:10]
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94
[+] score: 10
In HPV -negative tumors, miR-431-5p and miR-517c-3p were the most upregulated and miR-150-5p and miR-142-3p the most downregulated miRNAs. [score:7]
Twelve miRNAs in group 5 (miR-196b, miR-485-3p, miR-589, miR-324-3p, miR-342-3p, miR-92a1#, miR-155, miR-146b, miR-142-3p, miR-1260, miR-143, and miR-142-5p) have strong loading (absolute value ≥ 0.8). [score:1]
Twelve miRNAs in this group (miR-196b, miR-485-3p, miR-589, miR-324-3p, miR-342-3p, miR-92a-1#, miR-155, miR-146b, miR-142-3p, miR-1260, miR-143, and miR-142-5p) seem to be influential on patient prognosis. [score:1]
The majority of these miRNAs have been reported as prognostic markers in different types of cancers, while miR-324-3p, miR-155, miR-142-3p, and miR-143 have been identified as prognostic indicators in head and neck tumors of different locations [69– 73]. [score:1]
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95
[+] score: 10
Among downregulated cellular miRNAs were hsa-miR-142-3p, which targets the pro-inflammatory IL-1α, and hsa-miR-205, which targets the oncogenic protein BCL6 [146]. [score:8]
In PEL cells, hsa-miR-142-3p presented a very similar processing pattern, and hsa-miR-142-3p variants’ seed sequence matched those from kshv-miR-K12-10 variants [166, 183]. [score:1]
For instance, kshv-miR-K12-10 is a viral orthologue of hsa-miR-142-3p. [score:1]
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96
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For example, BTG2 was shown to be suppressed by miR-21 [18]; over -expression of miR-142-5p leads to down-regulation of BTG3 [19]; and TOB2 was shown to be a target gene of miR-322 [20]. [score:10]
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97
[+] score: 10
Other miRNAs from this paper: hsa-let-7c, hsa-let-7d, hsa-mir-16-1, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-28, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-99a, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-99a, mmu-mir-101a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-128-1, mmu-mir-9-2, mmu-mir-142a, mmu-mir-144, mmu-mir-145a, mmu-mir-151, mmu-mir-152, mmu-mir-185, mmu-mir-186, mmu-mir-24-1, mmu-mir-203, mmu-mir-205, hsa-mir-148a, hsa-mir-34a, hsa-mir-203a, hsa-mir-205, hsa-mir-210, hsa-mir-221, mmu-mir-301a, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-126, hsa-mir-185, hsa-mir-186, mmu-mir-148a, mmu-mir-200a, mmu-let-7c-1, mmu-let-7c-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-21a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-31, mmu-mir-34a, mmu-mir-148b, mmu-mir-339, mmu-mir-101b, mmu-mir-28a, mmu-mir-210, mmu-mir-221, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, mmu-mir-128-2, hsa-mir-128-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-301a, hsa-mir-151a, hsa-mir-148b, hsa-mir-339, hsa-mir-335, mmu-mir-335, hsa-mir-449a, mmu-mir-449a, hsa-mir-450a-1, mmu-mir-450a-1, hsa-mir-486-1, hsa-mir-146b, hsa-mir-450a-2, hsa-mir-503, mmu-mir-486a, mmu-mir-542, mmu-mir-450a-2, mmu-mir-503, hsa-mir-542, hsa-mir-151b, mmu-mir-301b, mmu-mir-146b, mmu-mir-708, hsa-mir-708, hsa-mir-301b, hsa-mir-1246, hsa-mir-1277, hsa-mir-1307, hsa-mir-2115, mmu-mir-486b, mmu-mir-28c, mmu-mir-101c, mmu-mir-28b, hsa-mir-203b, hsa-mir-5680, hsa-mir-5681a, mmu-mir-145b, mmu-mir-21b, mmu-mir-21c, hsa-mir-486-2, mmu-mir-126b, mmu-mir-142b, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Furthermore, some of the differentially expressed miRNAs have been reported to play a role in the metastasis of other types of cancer, for example, the up-regulated miRNAs, let-7i, miR-9, miR-30a, miR-125b, miR-142-5p, miR-151-3p, miR-450a and the down-regulated miRNAs, miR-24, mir-145, miR-146b-5p, miR-185, miR-186, miR-203 and miR-335. [score:9]
The miR-30a, miR-142-5p and miR-450a have roles in metastatic breast and colon cancer [61] and the miR-151-3p can enhance hepatocellular carcinoma cell mobility [66]. [score:1]
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[+] score: 9
For the acute stage, 9 mature miRNA sequences were identified as consistently differentially expressed: 8 were up-regulated (miR-132-3p, miR-21-5p, miR-21-3p, miR-212-3p, 2137, miR-711, miR-882 and miR-142-5p) and one was down-regulated (miR-302b-5p) (Table  2). [score:9]
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Notably, two of the ten most significantly deregulated miRNAs in our study, namely hsa-miR-142-3p and hsa-miR-223, have previously been found to be differentially expressed in hematopoietic cell lineages. [score:4]
hsa-miR-142-3p is also highly expressed in T-cells [16], [17]. [score:3]
The ten miRNAs that were most significantly deregulated included hsa-miR-145 (1.46·10 [−7]), hsa-miR-186 (2.89·10 [−7]), hsa-miR-664 (5.25·10 [−5]), hsa-miR-20b (1.48·10 [−4]), hsa-miR-422a (1.48·10 [−4]), hsa-miR-142-3p (1.54·10 [−4]), hsa-miR-584 (1.56·10 [−4]), hsa-miR-223 (1.63·10 [−4]), hsa-miR-1275 (1.16·10 [−4]) and hsa-miR-491-5p (2.83·10 [−4]). [score:2]
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Of the miRNAs upregulated in differentiated mature brown adipocytes, miR-142-3p and -19a were also up-regulated in the present list of 35 BAT-enriched miRNAs predicted to target genes involved in growth and differentiation. [score:9]
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