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482 publications mentioning hsa-mir-15a (showing top 100)

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-15a. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 311
Other miRNAs from this paper: hsa-mir-16-1, hsa-mir-15b
Identifier MicroRNA-15/16-1 Expression 13q14 Deletion Status CLL 01 Down-regulated Deleted CLL 02 Down-regulated Deleted CLL 03 Down-regulated Not Deleted CLL 04 Normal Not Deleted CLL 05 Normal Not Deleted CLL 06 Down-regulated Deleted CLL 07 Normal Not Deleted CLL 08 Down-regulated Deleted CLL 09 Down-regulated Deleted CLL 10 Down-regulated Deleted CLL 11 Down-regulated Not Deleted CLL 12 Down-regulated Deleted CLL 13 Down-regulated Not Deleted Discrepancies are highlighted in bold. [score:32]
These targets included 2 genes (BAZ2A and RNF41) that were significantly up-regulated (p<0.05) and 3 genes (RASSF5, MKK3 and LRIG1) that were significantly down-regulated (p<0.05) in CLL patients with down-regulated MIR-15a/16-1 expression. [score:14]
Of these 5 differentially expressed genes, 2 (BAZ2A and RNF41) were up-regulated (Figure 2) and 3 (RASSF5, MKK3, and LRIG1) were down-regulated (Figure 3) in CLL patients with low levels of MIR-15a/16-1 expression. [score:11]
Boxplot graphs representing the relative down-regulation of genes RASSF5, MKK3 and LRIG1 in CLL patients with down-regulated miR-15a/16-1 expression compared with CLL patients with normal miR-15a/16-1 expression. [score:10]
Boxplot graphs representing the relative up-regulation of genes BAZ2A and RNF41 in CLL patients with down-regulated miR-15a/16-1 expression compared with CLL patients with normal miR-15a/16-1 expression. [score:10]
Significantly up-regulated genes in CLL patients with down-regulated miR-15a/16-1 expression. [score:9]
Our study identified significantly lower levels of MKK3 expression in CLL patients with down-regulated MIR-15a/16-1. This is consistent with CLL patients harbouring chromosome 13q14 deletions, and hence MIR-15a/16-1 down-regulation, displaying a more favourable prognosis [2]. [score:9]
Significantly down-regulated genes in CLL patients with down-regulated miR-15a/16-1 expression. [score:9]
The removal of one regulatory element, such as MIR-15a/16-1, may be compensated for by the altered expression of other regulatory elements, thus maintaining the normal expression of the target gene. [score:9]
0007169.g003 Figure 3Significantly down-regulated genes in CLL patients with down-regulated miR-15a/16-1 expression. [score:9]
These genes may be indirect targets of MIR-15a/16-1, their expression perhaps being repressed by another, as yet unidentified, direct target of the MIR-15a/16-1 cluster. [score:9]
The 5 genes specifically regulated by MIR-15a/16-1 expression included 2 genes (BAZ2A and RNF41) that were significantly up-regulated in CLL patients with low MIR-15a/16-1 expression (Figure 2). [score:9]
Down-regulated miR-15a/16-1 expression in CLL patients was defined as a ≥50% reduction in the expression levels of either MIR-15a or MIR-16-1 when compared with the average MIR-15a and MIR-16-1 expression levels in the normal control subjects. [score:9]
0007169.g002 Figure 2Significantly up-regulated genes in CLL patients with down-regulated miR-15a/16-1 expression. [score:9]
A further 3 genes (RASSF5, MKK3 and LRIG1) were expressed at significantly lower levels in CLL patients with down-regulated MIR-15a/16-1 expression (Figure 3). [score:8]
The anti-apoptotic gene was also up-regulated in CLL patients with low MIR-15a/16-1 expression compared to those with normal expression levels of the miRNAs, however, this did not reach the level of significance (p = 0.161) probably due to the small sample size in this study. [score:7]
P-values; * represents <0.05, and ** represents <0.01 Of the 92 gene targets assessed, analysis identified 5 (5%) that may be specifically deregulated by the down-regulation of the MIR-15a/16-1 cluster. [score:7]
In the majority of cases, down-regulation of MIR-15a/16-1 correlated with chromosome 13q14 deletion status (Table 1), but in three cases (CLL 03, CLL 11 and CLL 13) the MIR-15a/16-1 cluster was down-regulated in the absence of an identifiable 13q14 deletion. [score:7]
Of the 92 gene targets assessed, analysis identified 5 (5%) that may be specifically deregulated by the down-regulation of the MIR-15a/16-1 cluster. [score:7]
The genes identified here as being subject to MIR-15a/16-1 regulation could represent direct or indirect targets of these miRNAs. [score:6]
Genes specifically deregulated by the down-regulation of the MIR-15a/16-1 cluster. [score:5]
Protein expression analysis of the putative MIR-15a/16-1 target genes. [score:5]
We have identified 35 genes that are deregulated in patients with CLL and 5 genes that are specifically deregulated by low levels of MIR-15a/16-1 expression. [score:5]
MicroRNA-15a/16-1 expression was down-regulated in the majority of CLL patients (10/13, 77%), including each patient with an identified deletion at 13q14. [score:5]
A total of 99 and 145 potential gene targets were predicted by the web -based programmes (TargetScanS and PicTar) for MIR-15a and MIR-16-1 respectively. [score:5]
It is therefore possible that MIR-15a/16-1 may regulate the expression of genes, other than BCL2, which may be important in the development of CLL. [score:5]
Genes were selected for inclusion on the cards if the following criteria were satisfied: (1) the genes were predicted as targets of MIR-15a/16-1 by both computational programmes (TargetScanS and Pictar), and (2) Searches with Pubmed showed good biological evidence for potential involvement in tumorigenesis (Eg. [score:5]
The aim of this study was to examine the expression patterns of computationally-predicted targets of MIR-15a/16-1 to identify further novel candidate genes involved in the aetiology of CLL. [score:5]
The majority (87/92, 95%) of the computationally-predicted targets investigated in this study were not differentially regulated in CLL patients with varying levels of MIR-15a/16-1 expression. [score:4]
We identified 35 genes that are deregulated in CLL patients, 5 of which appear to be specific targets of the MIR-15a/16-1 cluster. [score:4]
Deregulated targets of the MIR-15a/16-1 cluster were analysed for the presence of AU-rich elements which have been reported to mediate mRNA stability (ref). [score:4]
This may also explain why our study identified so few differentially regulated MIR-15a/16-1 targets. [score:4]
Two miRNAs, MIR-15a and MIR-16-1, are located at chromosome band 13q14 and are down-regulated in the majority of patients with CLL [21]. [score:4]
These genes may represent direct biological targets of the MIR-15a/16-1 cluster. [score:4]
The miRNAs, MIR-15a/16-1, at chromosome band 13q14 are down-regulated in the majority of patients with chronic lymphocytic leukaemia (CLL). [score:4]
As such, down-regulation of MIR-15a/16-1 has been associated with the pathogenesis of CLL, although this remains controversial [23]. [score:4]
de/) were used to predict potential targets of MIR-15a/16-1 for inclusion on the cards. [score:3]
Each 96-gene set included 92 predicted targets of MIR-15a/16-1 as well as four endogenous control genes; 18S, ACTB, GUSB and B2M. [score:3]
Where possible, protein expression analysis of the putative MIR-15a/16-1 target genes in CLL was investigated using the ‘The Human Protein Atlas’ bioinformatics tool (http://www. [score:3]
Our data indicates that the regulation of BCL2 may be influenced by MIR-15a/16-1 as well as other regulatory elements, exerting a combinatorial effect. [score:3]
Although not specifically regulated by the MIR-15a/16-1 cluster, these deregulated genes may represent important contributors to the process of leukaemogenesis. [score:3]
In conclusion, our work has investigated the expression patterns of computationally-predicted targets of MIR-15a/16-1 in patients with CLL using analysis. [score:3]
We have measured the expression of MIR-15a/16-1, and 92 computationally-predicted MIR-15a/16-1 target genes in CLL patients and in normal controls. [score:3]
The functions of the identified MIR-15a/16-1 target genes are discussed further below. [score:3]
We have investigated the expression patterns of 92 computationally-predicted targets of MIR-15a/16-1 in 13 patients with CLL and 5 normal controls using analysis. [score:3]
Cimmino et al (2005) demonstrated that MIR-15a/16-1 negatively regulate BCL2 [22], although this relationship remains controversial [23]. [score:2]
Summary of MicroRNA-15a/16-1 expression levels and chromosome band 13q14 deletion status. [score:2]
We identified 35 genes that are differentially regulated in patients with CLL compared with normal controls and 5 genes which may be specifically regulated by the MIR-15a/16-1 cluster at chromosome band 13q14. [score:2]
The putative MIR-15a/16-1 targets were investigated for the presence of AU-rich elements, which have been implicated in regulation of mRNA stability. [score:2]
MicroRNA-15a/16-1Expression. [score:2]
MicroRNA-15a/16-1 expression was determined for each sample using the TaqMan MicroRNA assays kit (Applied Biosystems, Foster City, USA), according to the manufacturer's instructions. [score:1]
Indeed, a recent study combining experimental and bioinformatic data identified a MIR-15a/16-1 gene signature in leukaemic cells [24]. [score:1]
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[+] score: 249
Studies showed that miR-200 inhibits EMT by targeting ZEB1 and ZEB2[52] and our studies showed that overexpression of miR-200a, miR-200b, miR-15a, miR-429, and miR-203 decreased the protein expression of Mesenchymalmarkers i. e. N-cadherin, Vimentin, Snail, β-Catenin (Fig 3A, 3B and 3C) showing these miRNAs can promote mesenchymal to epithelial transition (MET). [score:9]
Overexpression of miR-200a, miR-200b, miR-15a, miR-429 and miR-203 not only down-regulated the expression of BMI1protein, but also that of RING1A and RING1B, which also belong to PRC1 complex(Figs 1B, 2A and 2B). [score:8]
Ourstudies show that altering the expression of a group of miRNAs that include miR-15a, miR-200a, miR-200b, miR-429, and miR-203 produced a significant down-regulation of the expression of BMI1 in the breast cancer cell lines, MDAMB-231 and BT549. [score:8]
Cells with miR-15a and cisplatin treatmentalso showed down-regulation in the expression ofBCL2 an anti-apoptotic marker, MDM2 the negative regulator of p53 andATP -binding cassette sub -family G member 2 (ABCG2) which is a multi-drug resistance marker along with elevation of pro-apoptotic proteins like BID, BAX andCaspase-3 (Fig 7C). [score:7]
miR-15a and miR-16 cluster, located on chr13q14, serves as tumor suppressor and inhibits the expression of BCL2 in Chronic lymphocytic leukemia (CLL)[40, 41]. [score:7]
A significant down-regulation in the expression of BMI1 was seen in cells having the ectopic expression of miR-15a, miR-200a, miR-200b, miR-429 and miR-203 when compared to control cells transfected with scrambled miRNAs (Fig 1B). [score:7]
Our previous experiments demonstrated that the ectopic expression of miR-200a, miR-200b, miR-15a, miR-429, miR-203 inhibited the expression of PRC1 group of protein BMI1. [score:7]
Overexpression of miR-200a, miR-200b, miR-15a, miR-429 and miR-203 leads to inhibition ofPRC-1 group of protein expression. [score:7]
Our results uniquely showed that miR-200a, miR-200b, miR-15a, miR-429, miR-203 significantly down-regulatedprotein expression levels of Ub-H2A in MDAMB-231 and BT-549 cells (Fig 2A and 2B). [score:6]
Interestingly, overexpressionof miR-200a, miR-200b, miR-15a, resulted in the down-regulation of BMI1 and UbH2A in the CD44+ Cancer Stem Cell population of MDAMB-231 cells(Fig 6A, 6B and 6C) demonstrating a definite role in maintaining gene silencing and maintainingcancer stemness. [score:6]
0190245.g003 Fig 3 Level of expression of N-cadherin, Vimentin, β-Catenin, ZEB-1, Snailin MDAMB-231cells having overexpressed miR-200a, miR-200b, miR-15a, miR-429, and miR-203(A). [score:5]
studies in the cells having overexpressed miR-15a followed by treatment with cisplatin also showed an alleviation of ABCG2 expression (Fig 7F) confirming that indeed miR-15a was capable of inducing apoptosis by sensitizing cells to cisplatin. [score:5]
miR-15a/16 families have also reached preclinical studies and have shown promising tumor suppressive activity bytargeting mesothelioma and thoracic cancer[54]. [score:5]
Our earlier studies have shown that modulating the expression of miR-15a/16 lead to alteration in the expression of BMI1[25]. [score:5]
Expression of BMI1, Ub-H2A protein in MDAMB-231cells transfected with Anti-miR- 200a, Anti-miR-200b, Anti-miR-15a, Anti-miR-449, Anti-miR-203 (C) BMI1, RING1A localization in MDAMB-231 cells having overexpressed miR-200a, miR-200b, miR-15a, miR-449, miR-203under confocal microscopy (D, E). [score:5]
Level of expression of N-cadherin, Vimentin, β-Catenin, ZEB-1, Snailin MDAMB-231cells having overexpressed miR-200a, miR-200b, miR-15a, miR-429, and miR-203(A). [score:5]
We also show for the first time that the sensitivity of MDAMB-231 cells to cisplatinand histone deacetylase inhibitor (HDACi) SAHAis elevated upon overexpressing miR-15a and miR-200a, miR-200b, miR-203. [score:5]
0190245.g002 Fig 2 Expression of BMI1, RING1A, RING1B and Ub-H2A in MDAMB-231(A) and BT549 (B) cells having overexpression of miR-200a, miR-200b, miR-15a, miR-429, miR-203. [score:5]
Our studies with qRT-PCR show that a limited set of miRNAs(miR-200a, miR-200b, miR-15a, miR-429, and miR-203)are up-regulated upon knock-downof PRC1 complex of protein BMI1(Fig 1A). [score:5]
miR-200a, miR-200b and miR-15a down-regulated BMI1 and Ub-H2A116, CD44 expression when compared to other miRNAs and scramble transfected control cells (Fig 6C and S5 Fig). [score:5]
Protein expression of BMI1wasanalyzed by performing western blotting in BT-549 cells having overexpressed miR-200a, miR-200b, miR-15a, miR-429, and miR-203. [score:5]
Expression of BMI1, RING1A, RING1B and Ub-H2A in MDAMB-231(A) and BT549 (B) cells having overexpression of miR-200a, miR-200b, miR-15a, miR-429, miR-203. [score:5]
S5 Fig Expression of CD44 in CSCs cells having overexpression miR-200a, miR-200b, miR-15a, miR-429, miR-203. [score:5]
miR-200a, miR-200b, miR-15a, miR-429, and miR-203 were overexpressed in MDAMB-231 cells and the expression of mesenchymal markers, N-cadherin, Vimentin, ZEB-1, snail andβ-catenin were checked at protein level. [score:5]
showing expression of BMI1, Ub-H2A, ABCG2, MDM2, pro-apoptotic and anti-apoptotic proteins like BAX, BID, BCL2, Caspase-3 in miR-15a overexpressed cells with cisplatin treatment. [score:5]
miR-200a, miR-200b, miR-15a inhibits CD44 expression in CSCs. [score:5]
To confirm that miR-15a, miR-200a, miR-200b, miR-203 and miR-429, have the binding sites in 3′UTRs of BMI1 and regulates the expression of BMI1 in MDAMB-231, cells were seeded in 12-well plates and co -transfected with the individual miRNA along with wild (wt) BMI1in psiCHECK2 vector as well as with mutant (Mut) BMI1psiCHECK2 reporter plasmids separately. [score:4]
We have shown that the miR-200a, miR-200b, miR-15a, miR-429 and miR-203 coordinately regulate expression of PRC1 group of proteins and also affect the rate of Mesenchymal to Epithelial transition (MET) in MDAMB-231 cells. [score:4]
miR-200a, miR-200b, miR-15a, miR-429, miR-203 inhibits migration and cell proliferation. [score:3]
miR-15a/miR-16 induces mitochondrial dependent apoptosis in breast cancer cells by suppressing oncogene BMI1. [score:3]
S2 Fig data showing expression of RING1B in MDAMB-231cells upon transfection with miR-15, miR-200a, miR-200b, miR-429 and miR-203. [score:3]
Antagonizing miR-15a, miR-200a, miR-200b, miR-429, and miR-203 reversed the effects generated by overexpression of these miRNAsconfirming the roles of these miRNAs on BMI1 protein and Ub-H2A116 (Fig 2C). [score:3]
Overall the results indicate that overexpressing miR-15a sensitizes MDAMB-231 cells to the chemotherapeutic drug cisplatin. [score:3]
MDAMB-231cells having overexpressedmiR-200a, miR-200b, miR-15a, miR-429, miR-203 were allowed to incubate for 48hrs and plated in a Transwell chamber and further allowed to incubate for 24hrs. [score:3]
To see whether these miRNAs have any effect on the expression of Ki-67, which in turn controls cell proliferation, we performedimmunocytochemistry and western blotting studies in MDAMB-231 cells transfected withmiR-200a, miR-200b, miR-15, miR-429, miR-203. [score:3]
Tocorroborate specifically that these miRNAstarget BMI1, MDAMB-231 cells were transfected with anti-miR-15a, anti-miR-200a, anti-miR-200b, anti-miR-429 and anti-miR-203. [score:3]
Protein expression of BMI1 and Ub-H2A in CD44+ population transfected with miR-200a, miR-200b, miR-15a, miR-429 and miR-203 (C). [score:3]
Expression of miR-15a, miR-200a, miR-200b, miR-429, miR-203 were elevated in BMI1 knock-down samples in both MDAMB-231 and BT-549 cells compared to un -transfected MDAMB-231 and BT-549 cells that served as control(Fig 1A). [score:3]
indicated a significant increase in miR-200a, miR-200b and miR-203 expression whereas miR-15a, miR-429, did not show any significant change(Fig 6D). [score:3]
studies showed a reduced N-cadherin, Vimentin signal upon miR-200a, miR-200b, miR-15a, miR-15a, miR-429, and miR-203 overexpression compared to control cells transfected with scramble miRNA vector(Fig 3B and 3C) confirming that miR-200a, miR-200b, miR-15a, miR-429, and miR-203 plays a very crucial role in METby regulating BMI1. [score:3]
Cells were transfected with overexpressedmiR-200a, miR-200b, miR-15a, miR-429, miR-203, and subjected to treatment with 5 μg/ml of cisplatin. [score:3]
Both MDAMB-231 and BT-549 cells were treated with 2μM of SAHA and the expression levels of miR-200a, miR-200b, miR-15a, miR-429, and miR-203 was checked. [score:3]
After 24 hrs, miR-15a, miR-200a, miR-200b, miR-429 and miR-203 were ectopically expressed and the cells were incubated for 48 hrs. [score:3]
After 24 hrs, miR-15a, miR-200a, miR-200b, miR-429 and miR-203 were ectopically expressed and the cells were incubated for 24 hrs. [score:3]
S6 Fig cell proliferation assay upon overexpression of miR-200a, miR-200b, miR-15a, miR-429 and miR-302 in MDAMB-231 cells. [score:2]
S7 Fig Trypan Blue assay shows cell viability upon overexpression of miR-200a, miR-200b, miR-15a, miR-429 and miR-302 in MDAMB-231 cells. [score:2]
Cell viability assay upon overexpression of miR-200a, miR-200b, miR-15a, miR-429 miR-302 in MDAMB-231 cells. [score:2]
miR-200a, miR-200b, miR-15a, miR-429, miR-203 regulate PRC1 proteins in MDAMB-231 cells. [score:2]
s from both these assays indicated that cells with overexpression of miR-15a showed a reduction in proliferation rate with increased cytotoxicity unlikethe cells transfected with other miRNAs and scramble miRNA (Fig 7A and 7B). [score:2]
Also to check the cell viability upon overexpression of miR-200a, miR-200b, miR-15a, miR-429, miR-203 we perfomed the trypan blue assay. [score:2]
The binding sites of the miR-200a, miR-200b, miR-15a, miR-203 and miR-429 on BMI1 3’ UTR and EZH2 3’ UTR were identified with the help of the software tool, miRTarBase (http://mirtarbase. [score:1]
miR-200a, miR-200b, miR-15a, miR-429, miR-203reduces cell proliferation of MDAMB-231 cells. [score:1]
Anti-miR-15a (Exiqon, cat #. [score:1]
miR-200a, miR-200b, miR-15a, miR-429, and miR-203 reduces rate of migration invasion and anchorage-independent growth ofMDAMB-231 cells. [score:1]
To see whether the same set of miRNAs produce any effect on anchorage independent growth, MDAMB-231 cells transfected with miR-15a, miR-200a, miR-200b, miR-429, miR-203were trypsinized after 48hrsof incubation and further allowed to incubate in soft agar for 3 weeks. [score:1]
miR-15a therefore,augments the response of MDAMB-231 towards anti-cancer drugs. [score:1]
miR-200a, miR-200b, miR-15a, miR-429, and miR-203 were transfected into the cells. [score:1]
MDAMB-231 cells transfected with miR-15a and treated with 5μM cispaltin, were washed with DPBS. [score:1]
PMIRH000PA-1; miRNA-15a Cat#. [score:1]
miR-15a, miR-200a, miR-200b, miR-429 and miR-203 showed a clear binding to the 3’UTR of BMI1 (S1 Fig). [score:1]
Antagonizing miR-200a, miR-200b, miR-15a, miR-429, and miR-203 enhances BMI1. [score:1]
miR-15a sensitized MDAMB-231 cells to cisplatin. [score:1]
Caspase-3 assay and Tunel assay were performed in MDAMB-231 containing ectopically expressed miR-15a with cisplatin treatment. [score:1]
miR-15a sensitized MDAMB-231 cells to the chemotherapeutic drugcisplatin. [score:1]
To further our observation we next performed immunocytochemistry in MDAMB-231 cells transfected with miR-200a, miR-200b, miR-15a, miR-429, and miR-203. [score:1]
miR-200a, miR-200b, miR-15a, miR-429and miR-203 promote Mesenchymal to Epithelial transition. [score:1]
wt-BMI1 3’ UTR and Mut-BMI1 3’UTR were overexpressed along with miR-200a, miR-200b, miR-15a, miR-429, miR-203 and luciferase activity was measured (C,D). [score:1]
miR-200a, miR-200b, miR-15a, miR-429 and miR-302 reduced cell proliferation in MDAMB-231 cells. [score:1]
Amongst six of these wells, cells from two of the wells were transfected with miR-15a and cells from the other two were treated with cisplatin. [score:1]
Anti-proliferative activity of miR-200a, miR-200b, miR-15a, miR-429, miR-203 in various cancers has been previously reported [25, 27]. [score:1]
No significant change was observed upon co-transfection of Mut-3’BMI1 UTR with miR-15a, miR-200a, miR-200b, miR-429, and miR-203(Fig 1D). [score:1]
Intriguingly, cellstransfected with miR-15a combined with cisplatin treatment showed higher levels of cytotoxicity, lower cell proliferation, higher Caspase-3 activity and increased DNA fragmentation. [score:1]
Levels of miR-200a, miR-200b, miR-15a, miR-429 and miR-203 in MDAMB-231 and BT-549 cells treated with SAHA. [score:1]
The vector with the wild-type BMI1 3’UTR was co -transfected along with miR-15a, miR-200a, miR-200b, miR-429, and miR-203 respectively into MDAMB-231 cells. [score:1]
miR-200a, miR-200b, miR-15a, miR-429, and miR-203 could bring an exciting new dimension in the field of clinical management of human cancer in coming future. [score:1]
Here we illustrate the unique role of miRNAsin their dramatic participation in breast cancer cells and our data demonstrates that the levels of PRC group of proteins in breast cancer cell lines MDAMB-231 and BT-549 can be altered by using the miRNAs i. e. miR-200a, miR-200b, miR-15a, miR-429and miR-203 which have possible binding sites at the 3’UTR sequences of BMI1. [score:1]
miR-200a, miR-200b, miR-15a, miR-429 and miR-203 were transfected to BT-549 and MDAMB-231cells in 60 mm dishes and the cells were incubated for 48 hrs. [score:1]
miR-200a, miR-200b, miR-15a, miR-429 and miR-203 weretransfected into both MDAMB-231(Fig 2A) and BT-549 (Fig 2B) cells. [score:1]
After 24 hrs, cells were transfected with miR-200a, miR-200b, miR-15a, miR-429 and miR-203. [score:1]
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3
[+] score: 184
The anti-mir-15a and miR-148a inhibitors, MC10235 and MC10263, were obtained from Ambion®, Thermo Scientific, whereas a negative control inhibitor, mirVana™ miRNA inhibitor negative control #1, were used as the scrambled miRNA inhibitor. [score:9]
Taken together, these lists of target genes with the overexpressed genes in CCFs studied by cDNA microarray [8] and highly expressed proteins in the CM (unpublished data), propose several target genes of interest for miR-15a including VEGFA, PAPPA, NRG1, FGF2, PAI-2, AXIN2, FGF7, and WNT3A (Fig.   3a) and for miR-148a are TNFRSF6B, CD62L (L-selectin), TGFA, WNT1, and WNT10B (Additional file  7: Figure S4A). [score:9]
Ectopic overexpression of miR-15a mimic in C096 cells downregulated PAI-2 expression in CM (Fig. 4b). [score:8]
The potential target genes of miR-15a and miR-148a were determined using TargetScanHuman 6.2 (http://targetscan. [score:7]
Indeed, human CCA tissues with low expression of miR-15a showed high expression of PAI-2. Importantly, patients with high expression of PAI-2 showed poor prognosis. [score:7]
Cells (SFs) were transfected with 75 nM of miR-15a inhibitor, miR-148a inhibitor and negative control miRNA inhibitor using Lipofectamine RNAi Max. [score:7]
d Expression of PAI-2 in miR-15a inhibitor transfected SFs. [score:5]
Expression of miR-15a in CCA cases was lower than its average expression in normal liver tissues (Fig.   5a). [score:5]
The mRNA expression levels of these two target genes of miR-15a were checked in CCFs, SFs and CCA cell lines (KKU-213 and KKU-055). [score:5]
Bars represent mean ± SD of three measurements To predict the potential mRNA targets of miR-15a and miR-148a, TargetScan miRNA target prediction database was used. [score:5]
Moreover, we confirmed that the miR-15a inhibitor increased the expression of VEGFA and PAI-2 in SFs (Fig. 3d and Additional file 8: Figure S5B). [score:5]
miR-15a was identified as a downregulated miRNA in CCFs. [score:4]
Here, miR-15a and miR-148a were downregulated in both in vitro CCFs and clinical CCA tissues. [score:4]
Downregulation of miR-15a in CCFs leads to the increased secretion of PAI-2 and VEGFA (Fig. 5e). [score:4]
Lower expression of miR-15a and higher expression of PAI-2 were observed in human CCA samples compared with normal liver tissues. [score:4]
b The expression levels of eight predicted target genes of miR-15a in 6 CCFs compared to 2 SFs. [score:4]
In this study, we focused on downregulated miRNAs including miR-15a and miR-148a. [score:4]
In this study, changes of miRNA expression of CCA CCFs were investigated and miR-15a and miR-148a were selected as the most promising down-regulated miRNAs. [score:4]
Fig. 3Identification of miR-15a target genes. [score:3]
In 14 CCA and 2 normal liver tissues, expressions of miR-15a and PAI-2 were examined by real-time PCR. [score:3]
Moreover, CM from miR-15a mimic -transfected CCFs suppressed migration of CCA cells. [score:3]
b of miR-15a, miR-148a and miR-486 expression levels in 5 CCFs and 2 SFs. [score:3]
Moreover, the CM from miR-15a mimic -transfected C096 CCFs significantly inhibited the migration of CCA cells in comparison with that from scrambled miRNA transfected cells (Fig. 4e). [score:3]
The expression levels of PAI-2 and VEGFA after transfection of miR-15a mimic in CCFs were examined. [score:3]
Moreover, VEGFA has been shown to be the target of miR-15a [32, 33]. [score:3]
a Four criteria for finding the candidate target genes of miR-15a. [score:3]
These findings highlight the miR-15a/PAI-2 axis as a potential therapeutic target in CCA patients. [score:3]
The expression levels of these miRNAs in CCFs and SFs were examined and only miR-15a and miR-148a showed decreased levels in all CCFs in comparison to those in SFs (Fig. 2b). [score:3]
From a literature review, among 15 miRNAs, miR-15a, miR-148a and miR-486 targeted several secreted proteins (Additional file  5: Table S3). [score:3]
c Expression of PAI-2 in miR-15a mimic -transfected C096 cells by real-time PCR. [score:3]
Interestingly, expression of PAI-2 in CCF was higher than that in CCA cells (Fig. 3e and f), suggesting that CCFs may be a major source of PAI-2 protein, although cancer cells could also produce PAI-2. In the following experiments, we focused on the miR-15a-PAI-2 axis. [score:3]
Moreover, PAI-2 was identified as a novel target gene of miR-15a. [score:3]
VEGFA is a target gene of miR-15a. [score:3]
This is the first study to identify PAI-2 as a target of miR-15a. [score:3]
In this study, the focus was on PAI-2 and VEGFA as targets of miR-15a. [score:3]
miR-15a, together with miR-16, can target several onco-products i. e. Bcl-2, Bmi-1, Wnt family members, and VEGF, IL-6 [31]. [score:3]
Suppression of PAI-2 production from CCFs by transfection of miR-15a mimic attenuated the migration of CCA cells. [score:3]
Interestingly, rPAI-2 treatment partially rescued the inhibitory effect of migration by CM from miR-15a mimic -transfected CCFs in both CCA cell lines (Fig. 4e). [score:3]
Identification of miR-15a target genes in CCFs. [score:3]
Reduced expressions of PAI-2 and VEGFA were observed by miR-15a mimic-transfection compared to control miRNA transfection (Fig. 3c and Additional file  8: Figure S5A). [score:2]
To investigate whether miR-15a can directly target PAI-2 by interacting with its 3′-UTR in vitro, we amplified the full-length of 3’-UTR from genomic DNA. [score:2]
Cells (CCFs) were transfected with 5 nM hsa-miR-15a, hsa-miR-148a and used as the negative control miRNA mimic using Lipofectamine RNAi Max (Invitrogen) according to the manufacturer’s protocol. [score:1]
miR-15a-PAI-2 axis in CCFs promotes migration of CCA. [score:1]
b Secreted PAI-2 in CM from miR-15a mimic -transfected C096 CCFs examined by. [score:1]
e The proposed mechanism of miR-15a-PAI-2 axis in microenvironment of CCA tissue Seventy-two clinical samples of CCA cases were enrolled in the immunohistochemistry experiment with the clinicopathological data including sex, age, clinical staging, histological grading, vascular invasion, lymph node (LN) metastasis and overall survival time (Table 1). [score:1]
Subsequently, miR-15a mimic or control miRNA was co -transfected with these reporter vectors into 293 T cells. [score:1]
The putative miR-15a binding sequences are TGCTGCT. [score:1]
The level of miR-15a in CCFs was increased after transfection without any cytotoxic effect (data not shown). [score:1]
We deleted a deletion mutant of putative miR-15a binding sequences from full-length 3′-UTR of human PAI-2 construct and used as a negative control. [score:1]
For PAI-2, we also generated a deletion mutant of putative miR-15a binding sequences, TGCTGCT, from full-length 3′-UTR of human PAI-2 construct. [score:1]
The role of miR-15a in CAFs in controlling cancer growth, invasion and resistance to therapy has been identified in prostate cancer [13]. [score:1]
The product numbers MH10235 and MH1026 were used as a miR-15a and miR148a mimics. [score:1]
The miR-15a mimic significantly decreased the relative luciferase activity of the wild type 3′-UTR reporter vector, but not statistical significance for the deletion mutant (Fig.   4a). [score:1]
Our findings provide the opportunity for exploring therapies aimed at reconstituting the miR-15/PAI-2 axis in CCA and the potential of using PAI-2 levels as a poor prognosis marker in these patients. [score:1]
These findings suggest that the miR-15a-PAI-2 axis in CCFs may be involved in the progression of CCA. [score:1]
a of miR-15a in 14 CCA tissues and 2 normal liver tissues. [score:1]
e The proposed mechanism of miR-15a-PAI-2 axis in microenvironment of CCA tissueSeventy-two clinical samples of CCA cases were enrolled in the immunohistochemistry experiment with the clinicopathological data including sex, age, clinical staging, histological grading, vascular invasion, lymph node (LN) metastasis and overall survival time (Table 1). [score:1]
Fig. 4The miR-15a-PAI-2 axis promotes migration of CCA cells. [score:1]
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In the current study, we demonstrated that NF-κB activation was inhibited by miR-15a/16 overexpression in cultured REC with exposure to high glucose, which was confirmed in our miR-15a/16 conditional knockout mice. [score:6]
Therefore, we suggest that miR-15a/16 offer a novel potential target for the inhibition of inflammatory mediators in diabetic retinopathy. [score:5]
In addition to VEGF, pro-inflammatory signaling molecules (TLR5/8, IRAK1, TRAF6) are predicted targets of miR-15a (targetscan. [score:5]
Downstream molecules of the insulin signaling pathway are predicted targets of miR-15a and miR-16 (targetscan. [score:5]
However, overexpression of miR-15a/16 resulted in significant decreases of the inflammatory signaling in REC (Fig.   2), suggesting miR-15a/16 plays a role in suppressing pro-inflammatory signaling, specifically IL-1β and TNFα, in REC under high glucose conditions. [score:5]
Therefore, this is the first evidence we are aware of that miR-15a/16 can regulate retinal leukostasis, potentially by suppressing pro-inflammatory signaling. [score:4]
Data are mean ± SEM In addition to the inhibitory effects of miR-15a/16 on the levels of pro-inflammatory cytokines, we also wanted to confirm the regulatory roles of miR-15a/16 on the phosphorylation of NF-κB in vivo. [score:4]
In vivo data demonstrated that the loss of miR-15a/16 in vascular cells led to increased retinal leukostasis and CD45 levels, together with upregulated levels of IL-1β, TNFα, and NF-κB. [score:4]
Retinal leukostasis, a histological indication of retinal inflammation, can be induced by vascular endothelial growth factor (VEGF) [13, 14], which is a direct target of miR-15a in HUVEC [15]. [score:4]
Thus, we suggest that miR-15a/16 is a potential target for the development of therapeutic strategies on diabetic retinopathy. [score:4]
Thus, data strongly suggest that miR-15a/16 play a role in the suppression of pro-inflammatory signaling in the retina. [score:3]
Our results demonstrated that REC overexpressing miR-15a/16 showed reduced levels of NF-κB phosphorylation in high glucose conditions (Fig.   3). [score:3]
Thus, the outcome suggests that miR-15a/16 play an important role in reducing retinal leukostasis, through suppressing inflammatory signaling of IL-1β, TNFα, and NF-κB in the retina. [score:3]
miR-15a expression was decreased in high glucose conditions in REC. [score:3]
Overall, we showed that high glucose conditions decreased expression of miR-15a/16 in REC. [score:3]
The data indicate that miR-15a/16 play significant roles in reducing retinal leukostasis, potentially through inhibition of inflammatory cellular signaling. [score:3]
Fig. 1Decrease of miR-15a expression in high glucose conditions, and transfection -induced fold changes. [score:3]
a Fold change of miR-15a expression is shown. [score:3]
In such conditions, overexpression of miR-15a/16 decreased pro-inflammatory mediators IL-1β, TNFα, and NF-κB in cultured REC. [score:3]
Also, it was reported that miR-15a was highly expressed in early endothelial progenitor cells [11]. [score:3]
miR-15a is predicted to target TLR5/and 8, and the TLR signaling mediates the activation of NF-κB [18– 20, 23, 24]. [score:3]
A representative blot is shown Our in vitro data suggest that miR-15a/16 play a role in inhibiting pro-inflammatory signaling in diabetic conditions. [score:3]
In this study, we wanted to examine whether miR-15a/16 overexpression could decrease IL-1β and TNFα levels in REC cultured under high glucose conditions. [score:3]
miR-15a/16 inhibited leukostasis in vivo. [score:3]
Overexpression of miR-15a/16 with the mimic significantly decreased pro-inflammatory signaling of IL-1β, TNFα, and NF-κB in REC. [score:3]
Collectively, our results showed a moderate but statistically significant increase in the influx of CD45+ leukocytes in the retinal tissue lacking miR-15a/16 expression. [score:3]
miR-15a/16 suppressed NF-κB activation in high glucose conditions. [score:3]
miR-15a/16 suppressed IL-1β and TNFα signaling in vivo. [score:3]
Therefore, our in vitro study suggests that miR-15a/16 plays a role in the suppression of pro-inflammatory signaling in high glucose conditions. [score:3]
We demonstrated that high glucose conditions decreased expression of miR-15a/16 in cultured REC. [score:3]
miR-15a/16 are inhibitory to TLR4 inflammatory signaling in mouse macrophages treated with LPS [17]. [score:3]
miR-15a/16 inhibits NF-κB activation in vivo. [score:3]
Our previous study showed altered expression of miR-15 family members, miR-15b and miR-16, in retinal endothelial cells (REC) cultured in high glucose conditions [9]. [score:3]
We generated conditional knockout mice in which miR-15a/16 are eliminated in vascular endothelial cells. [score:2]
Both TNFα and IL-1β levels can be regulated through toll-like receptor (TLR) signaling, which is reduced by miR-15a/16 in LPS -treated macrophages [17]. [score:2]
As one potential molecular mechanism of miR-15a/16 regulation of retinal inflammation, altered insulin signaling could be a candidate. [score:2]
After 3 days of REC culture in high glucose (25 mM) medium, miR-15a expression was reduced (0.4-fold reduction) compared to that in normal glucose (NG; 5 mM) group. [score:2]
The levels of miR-15a expression were increased 84-fold in REC treated with mimics compared to cells transfected with control (Fig.   1b). [score:2]
In the present study, we found that high glucose also decreased the miR-15a expression by 0.4-fold compared to normal glucose (Fig.   1a). [score:2]
To perform this study, we utilized REC in normal and high glucose conditions for in vitro work and miR-15a/16-conditional knockout mice for in vivo analysis. [score:2]
To get a more quantitative view of whether miR-15a/16 regulate inflammatory cells, we performed flow cytometry on retinal tissue separated from unmanipulated eyes of miR-15a/16 Cre-LoxP and miR-15a/16 floxed mice. [score:2]
To generate conditional knockout mice in which miR-15a/16 is eliminated in vascular endothelial cells, we crossed miR-15a/16 floxed mice with cdh5-Cre mice. [score:2]
The miR-15a/16 floxed mice were crossed with cdh5-Cre mice to generate conditional knockout mice in which miR-15a/16 is eliminated in vascular endothelial cells. [score:2]
Moreover, we demonstrated the loss of miR-15a/16 in retinal endothelial cells increased inflammatory signaling of IL-1β, TNFα, NF-κB, and retinal leukostasis in the retina of conditional knockout mice. [score:2]
Therefore, our outcomes indicate that miR-15a/16 in REC play a crucial role in the regulation of leukocyte adhesion in vivo. [score:2]
From our in vivo study using miR-15a/16 Cre-loxP mice, we found that the loss of miR-15a/16 resulted in significant increase of leukostasis and inflammatory cells in the retina. [score:1]
Fig. 4Effects of miR-15a/16 on retinal leukostasis. [score:1]
In contrast, elevated levels of hsa-miR-15a were found in eyes with proliferative diabetic retinopathy (PDR) [10]. [score:1]
In addition, miR-15a levels were decreased in high glucose conditions in human umbilical vein endothelial cells (HUVEC) [8]. [score:1]
A final concentration of 30 nM was used when transfected separately (miR-15a and miR-16), and 15 nM was used in combination (miR-15a + miR-16). [score:1]
miR-15a/16 floxed mice (B6-129S-mirc30. [score:1]
Fig. 3Effects of miR-15a/16 on NF-κB (Ser 536) phosphorylation in vitro. [score:1]
b Fold changes of miR-15a/16 after transfection in REC. [score:1]
As is shown in Fig.   4 bottom panels, the loss of miR-15a/16 in the retina led to a significant increase in the frequency and absolute number of CD45+ leukocytes. [score:1]
Although we have not examined the efficiency of deleting miR-15/16 cluster from the vascular endothelium of miR-15a/16 Cre-loxP mice, our results from in vivo studies strongly support successful deletion of the miR-cluster in the vascular endothelial cells. [score:1]
Fig. 7Effects of miR-15a/16 on NF-κB (Ser 536) phosphorylation in mouse retina. [score:1]
REC were transfected with mimics (30 nM of final concentration) of miR-15a and/or miR-16 in high glucose conditions. [score:1]
Wang et al. [36] demonstrated clear effects of miR-15a on maintaining retinal permeability in the retinas of Tie2-miR-15a transgenic mice. [score:1]
N = 3 (miR-15a/16 floxed), 3 (miR-15a/16 Cre-LoxP) As we showed inhibitory roles of miR-15a/16 on pro-inflammatory signaling in cultured REC, we next investigated whether miR-15a/16 has the same effects on the levels of IL-1β and TNFα in vivo. [score:1]
This is consistent with previous studies showing the reduction of miR-15a levels in HUVEC cultured under high glucose conditions [8] and in the plasma of patients with prevalent DM [7]. [score:1]
was performed using the peripheral blood and bone marrow samples collected from control floxed and miR-15a/16 Cre-loxP mice. [score:1]
To assess this, flow cytometry was carried out on the peripheral blood and bone marrow samples obtained from control floxed and miR-15a/16 Cre-loxP mice. [score:1]
However, eyes with PDR showed increased levels of hsa-miR-15a [10], which may reflect a key characteristic of miRNA, where expression and function are both cell- and tissue-specific. [score:1]
The purpose of our study was to investigate the hypothesis that miR-15a/16 inhibit pro-inflammatory signaling to reduce retinal leukostasis. [score:1]
miR-15a/16 reduced the levels of IL-1β and TNFα in high glucose conditions. [score:1]
miR-15a/16 IL-1β TNFα NF-κB Leukostasis Hyperglycemia and diabetes have clear influences on the dysfunction of vascular endothelial cells, leukocyte adhesion, and inflammatory signaling [1– 3]. [score:1]
At 3 months of age, both male and female mice from miR-15a/16 floxed and miR-15a/16 Cre-LoxP groups were used for further analyses. [score:1]
Higher levels of NF-κB were found in miR-15/16 knockout mice compared to miR-15a/16 floxed mice. [score:1]
Generation of miR-15a/16 Cre-LoxP mice. [score:1]
Our previous studies and literature implicate the involvement of miR-15a/16 in the pathology of diabetes. [score:1]
We studied whether miR-15a/16 plays a role in reducing leukostasis in the retina. [score:1]
In our studies, we found that REC cultured in high glucose conditions had decreased levels of miR-15a/16. [score:1]
More CD45 -positive cells were observed in miR-15a/16 Cre-LoxP mice than miR-15a/16 floxed mice, and some of CD45 -positive cells were found outside of the vessels (arrows). [score:1]
It is possible that miR-15a and miR-15b exert similar functions as they share the same seed sequence [35], and we will explore this further in future studies. [score:1]
At 3 months of age, we collected whole retinas from miR-15a/16 floxed and Cre-LoxP mice and analyzed the retinal lysates using ELISA. [score:1]
Retinas were isolated from miR-15a/16 floxed and miR-15a/16 Cre-LoxP mice at 3 months of age. [score:1]
miR-15a may be a key miRNA in the diabetic retina, as lower levels of miR-15a were found in the plasma of patients with prevalent diabetes mellitus (DM) [7]. [score:1]
Single-cell suspensions were prepared from neuronal retinal tissue of the miR-15a/16 floxed, miR-15a/16 cre/loxP mice by incubating with 0.05% trypsin for 30 min at 37 °C. [score:1]
Transfection was performed on REC in high glucose with miRNA mimic (hsa-miR-15a-5p, hsa-miR-16-5p). [score:1]
Therefore, our results demonstrated that miR-15a/16 play a role in reducing retinal leukostasis in vivo. [score:1]
Fig. 5Effects of miR-15a/16 on the number of circulating leukocytes. [score:1]
demonstrated that mutant mice, miR-15a/16 Cre-LoxP, were positive for Cre and homozygous for floxed allele (Additional file 1). [score:1]
Thus, we aimed to investigate the hypothesis that miR-15a/16 inhibit the pro-inflammatory signaling of TNFα, IL-1β, and NF-κB to reduce retinal leukostasis. [score:1]
Even though retinas were not perfused prior to the analysis, our results suggest that circulating pool of leukocytes is not accountable for an increased number of CD45+ cells seen in the retinal tissue of miR-15a/16 Cre-loxP mice. [score:1]
The results indicate that loss of miR-15a/16 in retinal endothelial cells induces increased levels of NF-κB phosphorylation. [score:1]
These results clearly indicate that circulating pool of leukocytes is not accountable for an increased accumulation of CD45+ cells seen in the retinal tissue of miR-15a/16 Cre-loxP mice. [score:1]
REC were transfected with miRNA mimic (hsa-miR-15a-5p and hsa-miR-16-5p) (Invitrogen, Carlsbad, CA) using Oligofectamine (Invitrogen) following manufacturer instructions. [score:1]
In the present study, we showed that miR-15a/16 play a significant role in the reduction of pro-inflammatory signaling (IL-1β and TNFα) in vitro, as well as in vivo. [score:1]
Our flow cytometry data of the bone marrow and blood showed a comparable number of circulating CD45+ cells in both control floxed and miR-15a/16 Cre-loxP mice. [score:1]
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Other miRNAs from this paper: mmu-mir-150, hsa-mir-150, mmu-mir-15a
To investigate the spectrum of genes affected by miR-15a, we first performed a single molecule RNA-FISH analysis of several critical transcripts and showed that forced miR-15a expression in malignant B1 cells could suppress otherwise overly up-regulated target mRNAs such as Pax5 and IL10 (Figure 6B and 6C). [score:8]
Since many of miR-15a target genes are expressed in early B lineage cells, we employed NZB cell line (LNC) to uncover potentail additional targets which may also play a role in stem cell commitment to the B1 lineage. [score:7]
1 following exogenous delivery of miR-15a could have been due to down-regulation of cMyb, a known suppressor of PU. [score:6]
Expectedly, cMyb, a known target of miR-15a, was up-regulated in HSC and B1P sources with decreased miR-15a (Figure 4B). [score:6]
Whereas Pax5, which is a master B cell regulatory gene known to be dysregulated in NZB mouse mo del, appeared to be aberrantly overexpressed in DBA [−/−] spleens only (Figure 1H) suggesting a more intricate regulation between miR-15a defect and this transcript levels. [score:6]
1, were found to be up-regulated after exogenous overexpression of miR-15a/16 (Figure 6C). [score:6]
Furthermore, our results suggest that miR-15a/16 may also indirectly regulate miR-150 whose deficiency was shown to result in an expansion of B1 cells by directly targeting c-Myb transcript [29]. [score:6]
In addition, we found two novel potential targets Mmp10 and Mt2 that are differentially affected by miR-15a expression. [score:5]
On the other hand, miR-15a overexpression led to a significant increase in Mt2 gene expression (Figure S6C). [score:5]
Mmp10 transcript was dramatically suppressed in LNCs expressing exogenous miR-15a (Figure S6C). [score:5]
Surprisingly, only two transcripts showed a significant change of expression levels in LNC cells with exogenously overexpressed miR-15a. [score:5]
Recently, we have demonstrated that mir-15a mutation and deletion in NZB mouse are responsible for its decreased expression levels and this is due to a blockage of Drosha -mediated cleavage of primary transcript [9]. [score:4]
To fill in this gap in our understanding regarding the role of B1Ps in CLL, we utilized lymphoid precursors or pluripotent stem cells from the murine mouse mo del of CLL New Zealand Black (NZB) strain and newly generated DBA [−/−] congenic mice (both of which have decreased miR-15a expression due to the presence of mutations in those loci) to ask the question if they can reproduce CLL-like phenotype (splenomegaly and increased B1 percentage in the spleen) both in vitro and in vivo. [score:4]
Given the fact that miR-15a is targeting an anti-apoptotic Bcl-2 gene [28], its deficiency in B1P progenitors might provide them with survival advantage during B cell development which is supported by their elevated percentage in the bone marrow of miR-15a -deficient congenic animals. [score:4]
On the contrary, Mt2 gene was found to be the sole, significantly up-regulated transcript upon exogenous transduction of miR-15a. [score:4]
Thus miR-15a deficiency can affect their expression via cMyb which is known to play a critical role in both myeloid and T cells development [36, 37]. [score:4]
In fact, both miR-150 and miR-15a/16 are confirmed suppressors of this transcription factor [30]. [score:3]
Gene expression analysis of NZB B cell line (LNC) transduced with miR-15a lentiviral construct. [score:3]
In addition, the levels of miR-15a in differentiated NZB ES cells followed the expression of Pax5, PU. [score:3]
In the indolent form of CLL, the most frequent abnormality is a decreased expression of microRNA miR-15a/16-1 [3] from the host Dleu2 gene located in the frequently deleted 13q14 region. [score:3]
Before the adoptive transfer, the analysis of HSC sources showed significantly decreased miR-15a expression levels in both NZB and DBA [−/−] sources (Figure 4A, left panel), whereas B1P cells demonstrated significantly decreased miR-15a only in the DBA [−/−] congenic sources (Figure 4A, right panel). [score:3]
In addition, the levels of cMyb, which is a direct target of miR-15a, were significantly higher in NZB but not DBA [−/−] when compared to DBA LSK at day 11 of co-culture (Figure 3F). [score:3]
This population was sorted and used for analysis in panels C and D. C. Quantification of B1 (left) and B2 (right) cells in DBA, NZB and DBA−/− congenic mice spleen; n = 3. D. TaqMan PCR levels of miR-15a and miR-150 in sorted B2 subpopulation from spleen; RQ is relative quantification normalized to snRNA U6 expression; E. Flow cytometry quantitative analysis of immature IgM+IgDlow B cells; columns are means, bars are SEMs; n≥3. [score:3]
This suggests that miR-15a targets genes that are critical for the survival of the malignant B1 cells. [score:3]
1 and Pax5 seems to be critical for that matter and as we have shown can be restored by forced miR-15a expression (Figure 6D). [score:3]
It possesses several genetic defects other than mir-15a/16-1 mutation hence it is not an ideal mo del to study effects of individual mutations. [score:3]
This could reflect the fact that at this stage of development miR-15a deficiency alone is not capable of affecting PU. [score:2]
DBA [−/−] congenic mice exhibit B cell maturation defects accompanied by B1 and T cells expansionIn order to study the effects of the miR-15a/16-1 deficiency on the mouse B cell development the congenic mice were generated by consecutive crossbreeding wild type DBA and CLL mouse mo del NZB mice with mutant mir-15a/16-1 selection. [score:2]
DBA [−/−] HSCs and B1Ps produce B1 cells in NSG recipientsTo further test if mir-15a mutation alone can contribute to B1 cell expansion, the HSCs and B1P cells derived from the bone marrow of DBA, NZB and DBA [−/−] congenic mice were transferred into sub-lethally irradiated immunodeficient NSG recipients. [score:2]
This data implies that early events associated with point mutation in mir-15a locus alone can be partially responsible for B1 cells expansion. [score:2]
Thus a generation of DBA [−/−] iPS cells would provide benefits for studying an individual effect of mir-15a mutation on early lineage commitment in vitro. [score:2]
In summary, decreased miR-15a/16 levels alone have a significant effect on HSC and B1P cell differentiation with a bias towards B1 and T cell development at the expense of conventional B2 program. [score:2]
Our work uncovers previously unknown early miR-15a deficiency associated developmental events in a mouse mo del of CLL and provides evidence for the role of B1 progenitors as a novel potential source population for origin of CLL. [score:2]
We have previously discovered a point mutation and deletion in the 3′ flanking region of the mir-15a/16-1 locus in NZB mouse which are also found in some CLL patients. [score:2]
Additionally, RNA-seq analysis on LNC cells showed that miR15a is capable of down -regulating a number of critical genes such as IL10 and Mmp10. [score:2]
Further work in this direction could uncover putative links between miR-15a deficiency and MT -mediated immunomodulation in CLL. [score:2]
This feature has not been yet directly linked to miR-15a defects. [score:2]
In order to study the effects of the miR-15a/16-1 deficiency on the mouse B cell development the congenic mice were generated by consecutive crossbreeding wild type DBA and CLL mouse mo del NZB mice with mutant mir-15a/16-1 selection. [score:2]
To further test if mir-15a mutation alone can contribute to B1 cell expansion, the HSCs and B1P cells derived from the bone marrow of DBA, NZB and DBA [−/−] congenic mice were transferred into sub-lethally irradiated immunodeficient NSG recipients. [score:2]
Overall, even though the DBA [−/−] LSK phenotypical profile appeared to be similar but not identical to NZB counterpart due to other factors present in the latter, our data indicate that miR-15a/16-1 deficiency alone can lead to maturation abnormalities in the course of early B cell development in vitro. [score:2]
This can create an auto-regulatory loop in which low levels of miR-15a would allow suboptimal PU. [score:2]
Recently, we reported generation of a DBA congenic mouse mo del with an NZB-derived mutated mir-15a/16 locus, and showed that this mutation is responsible for reduced levels of mature miR-15a due to the defects in microRNA processing [9]. [score:2]
Previously, we have shown that BSAP can modulate miR-15a levels by directly binding to Dleu2 promoter [23]. [score:2]
The first possibility is supported by our data on diminished maturation capacity observed in miR-15a deficient mouse strains both in vitro (Figure 3B and 3C) and in vivo (Figure 1D and 1E). [score:1]
We had previously found that higher levels of miR-15a in LNC cells result in decreased viability and proliferation [23]. [score:1]
The fact that DBA [−/−] congenic bone marrow contains significantly less pre-B CFUs can be explained by at least two mechanisms in which decreased miR-15a/16 might mediate this effect. [score:1]
Collectively, our data shows that miR-15a has a negative effect on critical CLL -associated genes such as IL10 and Pax5. [score:1]
LNC cell transduction with a construct bearing a wild type murine miR-15a/16 locus resulted in a significant increase in mir-15a levels (Figure 6A). [score:1]
Mmp10 is also an important mediator of cell migration and invasion [34] and considering our in vivo data on DBA [−/−] -derived B1 progenitors' accumulation in the spleen and PerC of NSG recipients, it is reasonable to suggest that miR-15a deficient B1Ps might have a migrational advantage and stronger ability to “invade” peripheral organs. [score:1]
In vitro differentiation of bone marrow progenitors from miR-15a -deficient mice. [score:1]
A. TaqMan real-time PCR quantification of miR-15a and miR-150 levels in sorted B1a subpopulations from spleen; N = 3, columns represent mean RQs, bars are SEMs; B. Flow cytometry staining for B1 CD5+, B220 [dull] cells (gated on CD3-CD19+). [score:1]
Several approaches have been exploited in this work to further understand the role of miR-15a in B cell development using this mouse mo del coupled with both in vitro and in vivo assays. [score:1]
Collectively, our data shows that miR-15a deficiency alone can affect B cell maturation and lead to accumulation of B1 and T cells at the expense of B2 cells compartment in vivo. [score:1]
Four cell lines including the non-NZB B cell line A20, the NZB cell line, LNC and two sublines of LNC which had been transduced with a lentivirus containing GFP (LNC-GFP) or LNC transduced with a lentivirus containing both GFP and miR-15a/16 (LNC-miR-GFP) were studied:. [score:1]
Figure 1Comparison of splenic phenotype in control DBA, NZB and DBA congenic (DBA [−/−]) mice A. TaqMan real-time PCR quantification of miR-15a and miR-150 levels in sorted B1a subpopulations from spleen; N = 3, columns represent mean RQs, bars are SEMs; B. Flow cytometry staining for B1 CD5+, B220 [dull] cells (gated on CD3-CD19+). [score:1]
1, C. cMyb, D. miR-15a, E. miR-150 in ES (left panels) and iPS (right panels) cells during in vitro differentiation. [score:1]
Effects of exogenous miR-15a/16 on mature B1 cells. [score:1]
Both NZB and DBA [−/−] sources showed decreased levels of miR-15a (Figure 3A) and produced more immature AA4.1 [+]B220 [+] early B cell progenitors relative to DBA LSKs (Figure 3B and 3C). [score:1]
The percentage of B-1 cells was increased in DBA congenic mice with mutated mir-15a/16 loci whereas the numbers of conventional B2 cells decreased relative to the DBA wild-type control spleens (Figure 1C). [score:1]
This mechanism would offer migratory advantage to mir-15a/PU. [score:1]
To this end, miR-15a deficiency can actually favor B1 overexpansion by allowing high levels of cMyb with concurrently low PU. [score:1]
Indeed, the results obtained from our adoptive transfer experiments have underlined the contribution of miR-15a into early fate decision making in the B cell compartment. [score:1]
First of all, we have been able to confirm that miR-15a deficiency alone is able to alter the mouse phenotype that has manifested in overproduction of B1 and T cells at the expense of conventional B2 cells. [score:1]
This highlights that additional genetic modifications other than decreased miR-15a/16 are responsible for the abnormalities observed in the CLL strain, NZB. [score:1]
For LNC transduction experiments, the custom miR-15a-lenti-GFP lentiviral construct and the empty lenti-GFP vector (SBI, Mountain View, CA) were used to generate pseudo-lentiviral particles by means of 293T cell transfection. [score:1]
These results show that HSCs and B1Ps with mir-15a defect alone can reproduce CLL like phenotype in vivo. [score:1]
Importantly, mir-15a/16-1 locus deletion (not whole MDR) leads to a less aggressive CLL course [4]. [score:1]
Although, the purified B1P cells produced a significant amount of B2 cells in the recipients reflecting their possible contamination with other progenitors, the enrichment for miR-15a -deficient DBA [−/−] B1P cells using defined surface markers led to a higher number of B1 cells in the spleens of the recipients relative to HSC source. [score:1]
Figure 6Four cell lines including the non-NZB B cell line A20, the NZB cell line, LNC and two sublines of LNC which had been transduced with a lentivirus containing GFP (LNC-GFP) or LNC transduced with a lentivirus containing both GFP and miR-15a/16 (LNC-miR-GFP) were studied:. [score:1]
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[+] score: 166
MiR-15a suppresses cell viability by regulating WNT3A and FGF7, and miR-214 potentially downregulates ING4 to inhibit apoptosis induced by GEM. [score:9]
Overexpression of exogenous miR-15a inhibited the viability of pancreatic cancer cells, suggesting that downregulation of miR-15a might be involved in the progression of pancreatic cancer. [score:8]
Because miR-15a was downregulated in pancreatic cancer, we hypothesized that miR-15a might function as a tumor suppressor in the disease, a role it has been shown to play in other cancers [15- 18]. [score:8]
Luciferase expression in cells expressing the WNT3A and FGF7 reporters was significantly suppressed (18% and 20%, respectively) when co -transfected with miR-15a mimics (Figure 3A and 3C). [score:7]
MiR-15a downregulation and miR-214 upregulation in human pancreatic cancer. [score:7]
Downregulation of miR-15a might contribute to proliferation of pancreatic cancer cells, whereas upregulation of miR-214 in pancreatic cancer specimens might be related to the poor response of pancreatic cancer cells to chemotherapy. [score:7]
MiR-15a directly targets multiple genes relevant in pancreatic cancer, suggesting that it may serve as a novel therapeutic target for treatment of the disease. [score:7]
MiR-15a was frequently downregulated in the cancer samples relative to the benign tissues samples, whereas miR-214 was upregulated. [score:7]
MiR-214 was upregulated more than 14-fold in BxCP-3 cells after transfection, whereas miR-15a was upregulated about 6-fold (Figure 2A); this result indicated better transfection efficiency of miR-214. [score:7]
In vitro experiments showed that overexpression of miR-15a inhibited the viability of pancreatic cancer cells, whereas overexpression of miR-214 decreased the sensitivity of the cells to gemcitabine (GEM). [score:7]
As for miR-15a, a tumor suppressor that has been reported in various cancers, its functions in pancreatic cancer are unknown; however, it was the only one downregulated in our examination. [score:6]
MiR-15a and miR-214 were found to be aberrantly expressed in human pancreatic cancer and to play different roles in the development of the disease. [score:6]
MiR-15a directly targets multiple genes relevant in pancreatic cancer, suggesting that it may serve as a novel therapeutic target in pancreatic cancer. [score:5]
MiR-15a directly targets multiple genes relevant in pancreatic cancer and therefore may serve as a novel therapeutic target in pancreatic cancer. [score:5]
Furthermore, we identified WNT3A and FGF7 as potential targets of miR-15a and ING4 as a target of miR-214. [score:5]
MiR-15a inhibited the activity of WNT3A and FGF7 3'-UTR reporters, whereas miR-214 inhibited the activity of the ING4 3'-UTR reporter. [score:5]
We detected the expression patterns of miRNAs in 10 pancreatic cancer tissues and their adjacent benign tissues by quantitative real time-PCR (qRT-PCR) and found that miR-15a and miR-214 were dysregulated in the tumor samples. [score:4]
In pancreatic cancer, miR-15a directly regulates WNT3A and FGF7, and miR-214 might regulate ING4. [score:4]
Here, we demonstrated that WNT3A may also be a direct target of miR-15a. [score:4]
Figure 1 Expression patterns of miR-15a and miR-214. [score:3]
MiR-15a overexpression reduces cell viability, whereas miR-214 decreases sensitivity to GEM in pancreatic cancer cells. [score:3]
These data indicate that WNT3A and FGF7 might be targets of miR-15a. [score:3]
Aberrant expression of miRNAs such as miR-15a and miR-214 results in different cellular effects in pancreatic cancer. [score:3]
qRT-PCR was performed to detect (A) miR-214 and (B) miR-15a expression in 10 pancreatic cancer tissues and their adjacent benign pancreatic tissues. [score:3]
Moreover, we confirmed that WNT3A and FGF7 are potential targets of miR-15a. [score:3]
These results indicate that the expression level of miR-15a is important for pancreatic cancer cell growth. [score:3]
In addition, we found that overexpression of miR-15a could reduce the viability of pancreatic cancer cells, whereas miR-214 counteracted the pro-apoptotic effect of gemcitabine (GEM) in BxCP-3 cells. [score:3]
Among the candidate targets of miR-15a chosen for experimental validation were PIM1, CDC25A, BCL2L2, WNT3A, SMAD7, LRP6 and FGF7, each of which has been reported to play a role in cell proliferation (Table 2). [score:3]
Moreover, we identified FGF7, a fibroblast growth factor, as another potential target of miR-15a. [score:3]
Figure 3 Target validation of miR-15a and miR-214. [score:3]
To further study the mechanisms of both miR-15a and miR-214 in pancreatic cancer cells, we predicted and validated potential targets for both miRNAs. [score:3]
In this study, we demonstrated that miR-15a and miR-214 were significantly dysregulated in pancreatic cancer specimens. [score:2]
To identify dysregulated miRNAs, we used qRT-PCR to measure the expression of seven mature miRNAs (miR-15a, miR-27a, miR-100, miR-125b, miR-181a, miR-200a and miR-214) in 10 pancreatic cancer tissues and their adjacent benign tissues. [score:2]
The detailed mechanisms and signaling pathways regulated by miR-15a and miR-214 in pancreatic cancer deserve further study. [score:2]
Only one miRNA, miR-15a, showed decreased expression in cancer tissues compared with matched benign pancreatic tissues; this effect was evident in 7 of 10 (70%) samples (Figure 1B). [score:2]
Figure 2 MiR-15a and miR-214 have different roles in pancreatic cancer cells. [score:1]
The CCK-8 assay showed that overexpression of miR-15a significantly decreased the viability of BxCP-3 cells compared with the control (p < 0.05) (Figure 2B). [score:1]
Therefore, miR-214 and miR-15a were chosen for further study. [score:1]
Transient transfection was performed in 293T cells with 100 nM miR-15a or miR-214 mimics and 0.1 μg of psi-CHECK-control or psi-CHECK-3'UTR fluorescence reporter constructs. [score:1]
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[+] score: 142
Finally, silencing Dicer in DU145 mPGES-1 [−/−] cells promoted VEGF expression/secretion (Figure 5A and 5B) and down-regulated miR-15a and miR-186 (Figure 5C), indicating that mPGES-1/PGE-2 signaling decreases the miR-15a and miR-186/VEGF pathways through inhibition of Dicer expression. [score:10]
Another caveat concerns the observed magnitude of mPGES-1 effect in tumor xenografts on VEGF/HIF-1α up-regulation and tumor growth, suggesting that other miRNAs than miR-15a and −186, downstream to Dicer inhibition, and other target than VEGF, might be involved [25– 28]. [score:8]
Immunohistochemical analysis of mPGES-1 expression revealed that the enzyme was strongly expressed in human tumors with high Gleason score, VEGF, and HIF-1α as well as with microvessel density, and low expression of Dicer, miR15a and miR-186. [score:7]
mPGES-1 expression in human prostate cancers is associated with elevated CD31, VEGF, and HIF-1α expression and reduced Dicer, miR-15a and −186 expression. [score:7]
We also found that treatment of mPGES-1 [+/+] cells with miR-15a, miR-103 or miR-186 mimics (50 nM), besides increasing the endogenous pool of their respective miRNAs (Supplementary Figure S4B), down-regulated VEGF expression/production (p < 0.001, Supplementary Figure S4C, S4D, S4E and Figure 4A). [score:6]
miR-15a and miR-186 controls VEGF expression in vitroAmong the miRNAs down-regulated by mPGES-1/PGE-2 signaling in DU145 cells, some have been involved in angiogenesis, others in inflammation or stemness (Supplementary Table S1). [score:6]
Moreover, high levels of miR-15a and −186 were more frequently expressed in organ-confined than in advanced tumor samples, demonstrating a direct association between the two miRNAs and VEGF expression. [score:6]
mPGES-1 down-regulates miR-15a and miR-186 upstream of VEGF expression. [score:6]
miRNA mimics and inhibitors target the following mature miRNA sequences: for miR-186-5p (5′-CAAAGAAUUCUCCUUUUGGGCU-3′), for miR-15a-5p (5′-UAGCAGCACAUAAUGGUUUGUG-3′) and for miR-103-3p (5′-AGCAGCAUUGUACAGGGCU AUGA-3′). [score:5]
Five miRNAs (miR-15b, miR-93 miR-15a, miR-186 and miR-103) have been predicted to target VEGF and HIF-1α on the basis of DianaMT, PICTAR5, miRanda, miRBASE, miRWALK and Target Scan analysis (Supplementary Table S2). [score:5]
We observed that 66.7% of OC samples expressed significant levels of miR-15a and miR-186, whereas only 30% and 20% of AC samples expressed significant levels of miR-15a and miR-186, respectively (Figure 7A). [score:5]
The opposite emerged from experiments on mPGES-1 [−/−] cells incubated with synthetic antagomirs, where we observed a large increase in VEGF output and a rich network of cord-like structures of endothelial cells, similar to that obtained after exposure to PGE-2. PGE-2 showed a surprising ability to reverse the up-regulation of miR-15a and miR-186 in mPGES-1 [−/−] cells, which indicates that the effect occurred up-stream of the miRNA system. [score:4]
These data indicate that VEGF 3′UTR is a specific direct target of miR-15a and miR-186. [score:4]
PGE-2 -mediated downregulation of miR-15a and miR-186 is specifically related to VEGF production and angiogenesis. [score:4]
analysis provided further evidence of down-regulation of miR-15a, miR-186 and miR-103 in mPGES-1 [+/+] cells (Supplementary Figure S4A). [score:4]
Moreover, MF63 increased levels of both miRs in mPGES-1 [+/+] cells (Figure 4C), and miR-15a and miR-186 were up-regulated with respect to mPGES-1 [+/+] tumors in DU145 mPGES-1 [−/−] xenografts in vivo (Figure 4D). [score:4]
However, miR-15a and miR-186 had no effect on luciferase activity of pMir-target vector (Figure 4B). [score:3]
A weak but negative association among miR-15a or miR-186 and mPGES-1 and VEGF expression in OC and AC tissue was noted. [score:3]
Conversely, in mPGES-1 [−/−] cells, antagomirs for miR-15a and miR-186 (50 nM), which decreased the amount of detectable endogenous miR-15a or miR-186 (Supplementary Figure S5A), induced VEGF expression/production (Supplementary Figure S5B, S5C and S5D). [score:3]
As recommended by EEC gui delines and Italian National laws for animal experimentation, to investigate the role of miR-15a and miR-186 mimics and inhibitors on VEGF expression and growth of DU145 and PC3 xenografts, we minimized the number of animals focusing on miR-186 mimic. [score:3]
Consistently, PGE-2 treatment (1 μM) reversed miR-15a and miR-186 expression in mPGES-1 [−/−] cells (Supplementary Figure S6A and S6B, DU145 cells), corroborating the indication that mPGES-1/PGE-2 signaling is upstream of miRNAs. [score:3]
3 × 10 [4] cells were exposed to 10% FBS or to PGE-2 (1 μM) for 48 h or siRNA -transfected for Dicer or transfected with mimics for miR-15a, miR-186, miR-103 or with miRNA inhibitors for miR-15a and miR-186. [score:3]
Reduced expression of miR-15a has been reported to be associated with anti-apoptotic, proliferative, invasive and angiogenic properties of cancer cells [31– 33]. [score:3]
The miRNA mimics and inhibitors for miR-103, miR-186 and miR-15a were from Qiagen and transfection was performed with Lipofectamine 2000 (Life Technologies) following the manufacturer's protocol. [score:3]
Finally, silencing of Dicer in DU145 mPGES-1 [+/+] cells increased HUVEC -mediated sprouting in the co-cultured mo del (Supplementary Figure S7D, panel B, and C), indicating that mPGES-1/PGE-2 promotes activation of endothelial cells in prostate cancer cells by reducing Dicer, miR-15a and miR-186 expression, thus promoting VEGF secretion. [score:3]
Bars show expression of the VEGF 3′UTR reporters in DU145 and PC3 mPGES-1 [+/+] cells treated with miR-15a and miR-186 mimics. [score:3]
miR-15a and miR-186 controls VEGF expression in vitro. [score:3]
Other evidence documents the role of miR-15a and miR-186 as pro-oncogenic molecules [25, 26], as clinical studies have observed that reduced expression of these miRNAs is associated with poor clinical prognosis in prostate cancer, and other tumors [25, 27, 28]. [score:3]
In addition, as previously described for miR-15a, deregulated miRNAs might also affect stroma cell functions supporting tumor progression and angiogenesis [29, 30]. [score:2]
Genome-wide sequencing of miRNAs in mPGES-1 [+/+] compared to mPGES-1 [−/−] cells revealed repression of miR-15a and miR-186, both associated with VEGF expression. [score:2]
To verify the putative direct interaction between miR-15a and miR-186 and the VEGF 3′-UTR, the 3′-UTR-luciferase reporter construct of VEGF and the control construct were independently transfected into the DU145 and PC3 mPGES-1 [+/+] cells. [score:2]
Figure 4(A) ELISA for VEGF in DU145 and PC3 mPGES-1 [+/+] cells (1% FBS, 48 h) transfected with miR-15a, miR-186 or miR-103 mimics (50 nM). [score:1]
Conversely, antagomirs for miR-15a and miR-186 (50 nM) induced abundant sprouting in mPGES-1 [−/−] cells (Supplementary Figure S7C panel B, C, and D). [score:1]
In 6 OC and 10 AC samples we also investigated miR-15a and miR-186 expression. [score:1]
Considering the influence of miR-15a and miR-186 on angiogenesis and VEGF output in prostate cancer cells, we suggest that these miRs could be potential candidates for attenuating the aggressive traits of prostate cancer. [score:1]
In line with the above results we found that treatment of DU145 mPGES-1 [+/+] cells with miR-15a or miR-186 mimics (50 nM) reduced the ability of HUVEC to form cord-like structures (Supplementary Figure S7B, panel B, C, and D). [score:1]
Collectively, these results suggest miR-15a and miR-186 as potential prognostic biomarkers in advanced prostate cancer linking high mPGES-1 levels with enhanced VEGF/angiogenic features. [score:1]
MiR-186 decreased in response to PGE-2 in a time dependent manner, while miR-15a showed a more complex kinetic, which might be associated with the complexity of the system or the technical issue [21]. [score:1]
Combination of miR-15a and miR-186 mimics or antagomirs did not show addictive effects. [score:1]
Further analysis (QPCR) pointed to three miRNAs (miR-15a, −103, and −186). [score:1]
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[+] score: 139
Other miRNAs from this paper: hsa-mir-16-1, hsa-mir-16-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2
However, so far a definite causative link between the presence of these mutations and miR-15a/16-1 expression and CLL development has not been established. [score:5]
However, miR15a/16-1 expression was found to be low even in patients without 13q14 deletions and pointed towards alternate mechanisms for miR15a/16-1 repression such as epigenetic silencing and promoter inhibition [9, 10]. [score:5]
We have recently shown the therapeutic benefit of restoring miR-15a/16-1 expression by two independent methods– 1) In vivo lentiviral delivery; 2) De-repression of the host gene promoter using HDAC inhibitor [10, 38]. [score:5]
Unpublished data from Raveche Lab indicates that reduced expression of miR-15a/16-1 skews the differentiation of hematopoietic stem cells towards B-1 progenitors via aberrant expression of PU. [score:5]
This data suggests that the presence of the NZB mutation/ deletion in the mir-15a/16-1 loci gives rise to decreased expression of miR-15a. [score:4]
Studies have indicated that decreased expression of miR-15a/16-1 is one of the earliest abnormalities associated with the development of MBL [7]. [score:4]
In addition, findings from the DBA congenic mice show that downregulation of miR-15a/16-1 plays an important role in B-1 expansion. [score:4]
A T → A point mutation and G deletion on the negative strand in the 3’ flanking region of mir-16-1 was discovered NZB mice (de novo mouse mo del of CLL) and was associated with 50% reduction in expression of mature miR-15a/16-1 [11– 13]. [score:4]
The reduced mature miR-15a/16-1 expression associated with the NZB loci could be attributed to either reduced transcription or to impaired processing. [score:3]
Level of miR-15a is expressed as a RQ value. [score:3]
In summary, the results presented here show that the alterations found in the mir-15a/16-1 loci of NZB lead to decreased processivity resulting in decreased expression of mature miR-15a and miR-16-1, which in turn gives rise to B-1 expansion. [score:3]
The presence of such conserved alterations in both mouse and human suggest that miR-15a/16-1 expression is important for CLL pathogenesis. [score:3]
Although these alterations have been associated with the reduced expression of mature miR-15a/16-1 [12, 13], no causal relationship has been established. [score:3]
Chr13q14 (region that encodes miR-15a/16-1 in humans) deletion is the most common chromosomal abnormality in CLL, occurring in 50–60% of patients [8] and is a major mechanism for reduced expression of these two microRNAs. [score:3]
Following this analysis, there were two areas (1028.4 cm [-1] and 883.8 cm [-1]) in which there was a detectable shift in the spectra between samples with high and low miR-15a/16-1. Samples expressing low miR-15a/16-1 exhibit a dip in absorbance at 1028.4 cm [-1] indicating a reduction in nucleic acid content (Fig 3B). [score:3]
Preliminary results also shown that mid-IR spectroscopy may be used to differentiate between cells expressing high and low levels miR-15a/16-1 as seen from our hierarchical cluster analysis. [score:3]
Hence here we have studied the CLL associated mutation and deletion in mir-15a/16-1 in relation to the effect of these mutations on microRNA processing and B-1 expansion. [score:3]
Primary miR-15a/16-1 transcripts with the NZB mutation and deletion (miR-/-) or without the mutation and deletion (miR+/+) were processed in vitro using either NZB or non-NZB cell extract. [score:3]
Presence of mutation in DLEU2 loci of NZBThe sequence of NZB mice differ from all other strains tested to date and possess a mutation in the 3’flanking region of the mir-15a/16-1 loci, similar to that reported for human CLL patients [13] (Fig 1A). [score:3]
In order to examine the effect of the mir-15a/16-1 mutation status on B-1 expansion, cells from tissue sources were examined by flow cytometry. [score:2]
B) Amount of miR-15a in DBA congenic mice which are heterozygous (D [miR+/-]) or homozygous (D [miR-/-]) for the NZB point mutation and deletion. [score:2]
We have shown that the NZB mutation and deletion in the mir-15a/16-1 loci blocks Drosha mediated cleavage of the primary transcript. [score:2]
Reduced mature miR-15a/16-1 in DBA congenic mice (D [miR-/-]) and its reverse in NZB congenic mice (N [miR+/-]) is a further proof that the NZB mir-15a/16-1 locus is the cause for reduction in mature miR-15a/16-1. Given the synteny between mouse and human in this loci, it is likely that a similar processivity block is present in the CLL patients with germline mutations in miR-16-1 as reported by Calin et al [13, 44]. [score:2]
To determine if the mutation and deletion in mir-15a/16-1 (found in NZB strain) is responsible for the reduced level of mature miR-15a/16-1 observed in NZB mice, congenic mice were analyzed for the levels of miR-15a. [score:2]
0149331.g001 Fig 1Presence of mutations in mir-15a/16-1 loci. [score:2]
Presence of mutations in mir-15a/16-1 loci. [score:2]
NZB mir-15a/16-1 (with mutation and deletion [MD]) plus 100bp upstream and downstream sequence was cloned into a pGEM4 plasmid (Referred to as pri-miR [MD]). [score:2]
Processing of the in vitro transcribed miR-15a/16-1 with the mutation and deletion mimics the NZB phenotype (decreased pre-miR) whereas the wild type primary transcript is cleaved to precursor form. [score:2]
DBA congenic mice which remained homozygous wild-type (D [mir+/+]) had significantly higher levels of miR-15a in the blood than did similar congenics which had the mutation/ deletion mir-15a/16-1 loci (D [mir-/-]) (Fig 4B). [score:2]
We employed FTIR absorption spectra analysis to determine whether the NZB mir-15a/16-1 mutation/ deletion is associated with global macromolecular alterations. [score:2]
The miR-15a/16-1 mutation status is indicated above each histogram, n = 1 per group. [score:2]
DBA congenic mice possessing mutations in both alleles of the mir-15a/16-1 loci (D [mir-/-]) had pronounced expansion of B-1 cells in the spleen (Fig 5A and 5B) relative to congenic mice with wild-type mir-15a/16-1 (D [mir+/+]). [score:2]
The sequence of NZB mice differ from all other strains tested to date and possess a mutation in the 3’flanking region of the mir-15a/16-1 loci, similar to that reported for human CLL patients [13] (Fig 1A). [score:2]
Starting at backcross 6, intercrosses were performed to generate homozygous mutant mir-15a/16-1 loci. [score:1]
C) Amount of miR-15a in NZB congenic mice which are heterozygous for the DBA wild-type sequence (N [miR+/-]) or remain homozygous for the NZB mutated mir-15a/16-1 loci (N [miR-/-]) (bottom bar graph). [score:1]
S1 File Fig A. Genotyping of Congenic using Sanger Sequencing: The miR-15a/16-1 locus was amplified from tail DNA and visualized using FinchTV software. [score:1]
Replacement of the wild type mir-15a/16-1 loci with the NZB mutation and deletion gave rise to a significant reduction in the level of mature miR-15a/16-1 as compared to heterozygotes (Fig 4B). [score:1]
In order to sequence the mir-15a/16-1 loci, mice were ear tagged at around 5–6 weeks. [score:1]
The D [mir-/-] congenics have the lowest levels of miR-15a (Fig 4B) and high B1/B2 ratio (Fig 5C). [score:1]
Further dissection of the sub-populations in the SP revealed that 64% of the SP cells in D [miR-/-] were B-1 cells (CD5 [+]B220 [dull/+]) versus only 7.7% and 7.3% in heterozygous (D [miR+/-]) and wild type homologous (D [miR+/+]) miR-15a/16-1 loci respectively (Fig 6A Middle). [score:1]
In vitro processing of mir-15a/16-1. Spectroscopic analysis of spleen cells. [score:1]
We wished to determine if decreased miR-15a/16-1 alone could result in alterations in B cells. [score:1]
The percentage of primitive Sca-1 [+]c-Kit [+] cells was also increased in the homozygous NZB mir-15a/16-1 loci (D [miR-/-]) (Fig 6A Bottom). [score:1]
Fig A. Genotyping of Congenic using Sanger Sequencing: The miR-15a/16-1 locus was amplified from tail DNA and visualized using FinchTV software. [score:1]
Role of miR-15a/16-1 levels on B-1 cells in congenic mice. [score:1]
Previous studies have shown that reduced miR-15a/16-1 promotes CLL cell survival and increases chemoresistance. [score:1]
B) Representative flow cytometry data for the analysis of B cells in the spleens of DBA congenic mice which differ in the mir-15a/16-1 locus. [score:1]
Wild type and NZB mir-15a/16-1 sequence was analyzed using the RNA mFold software (http://mfold. [score:1]
Bar graphs indicate the amount of mature miR-15a in the peripheral blood of these mice. [score:1]
Effect of NZB miR-15a/16-1 locus on Side Population (SP) cells. [score:1]
mir-15a/16-1 was amplified using proofreading Accuprime Pfx DNA polymerase (Invitrogen, Carlsbad, CA). [score:1]
An increase in SP cells (which are enriched in stem cells) was observed in congenic mice with reduced miR-15a/16-1 levels (Fig 6B). [score:1]
Spectroscopic Analysis (FTIR) identifies miR-15a/16-1 differences. [score:1]
Spleen cells obtained from DBA congenic mice which differed in the mir-15a/16-1 loci were analyzed for the presence of the sidepopulation (SP). [score:1]
Interestingly in the cell source with reduced miR-15a/16-1 (D [miR-/-]) the percentage of B-1 cells was greatly increased. [score:1]
Side-population and SP B-1 in relation to miR-15a/16-1 status. [score:1]
In addition, NZB mice have a significant decrease in the levels of mature miR-15a and miR-16 (Fig 1B). [score:1]
In addition, decreased levels of miR-15a/16-1 are found in the majority of CLL. [score:1]
0149331.g006 Fig 6Side-population and SP B-1 in relation to miR-15a/16-1 status. [score:1]
A) Partial DNA sequence of mouse and human mir-15a/16-1 loci which is located in the intronic region of Dleu2 in both human and mice. [score:1]
Effect of mir-15a/16-1 loci on B-1 expansion. [score:1]
Level of pri, pre and mature miR-15a/16-1 in NZB versus non-NZB cell line. [score:1]
Two congenic strains, were generated 1) DBA mice with NZB mir-15a/16-1 loci (D [miR-/-]) and 2) NZB mice with the wild-type mir-15a/16-1 loci (N [miR+/+]) (Fig 4A). [score:1]
mir-15a/16-1 is encoded within the intronic region of Dleu2. [score:1]
At each backcross, progeny are selected for one copy of the each parental mir-15a/16-1 sequence. [score:1]
Changes in absorbance at 883 cm [-1] observed by mid-IR spectroscopy in mutant miR-15a/16-1 cells versus the wildtype is further indicative of structural changes. [score:1]
This decrease in miR-15a/16-1 levels is not restricted to only the putative CLL precursor subpopulation of B cells (B-1) but is present in all B cells. [score:1]
Backcross mice with heterozygous mir-15a/16-1 loci were used in the subsequent backcross. [score:1]
A) Breeding Scheme in which the two inbred parental strains NZB (which is homozygous mutant mir-15a/16-1) and DBA/2 (which is homozygous wild type for mir-15a/16-1) are crossed. [score:1]
The percentage of B-1 cells was related to the mir-15a/16-1 loci. [score:1]
Likewise, the NZB congenic mice which were no longer homozygous mutant but rather heterozygous (N [mir+/-]) had higher levels of miR-15a than NZB (N [mir-/-]) (Fig 4C bottom). [score:1]
In vitro processing of mir-15a/16-1Labeled microRNA primary transcripts can be processed in vitro using either cell extract or immunoprecipitated Drosha complex [31]. [score:1]
0149331.g005 Fig 5Effect of mir-15a/16-1 loci on B-1 expansion. [score:1]
Mid-infrared spectra were collected from spleen cells from DBA mice (normal constitutive elevated levels of miR-15a/16-1) and from NZB mice (constitutive low levels of miR-15a/16-1) in transmission mode using fiber optic based Fourier transform infrared (FTIR) spectrometer (Vertex 70, Bruker Optiks, Ettlingen, Germany) [24– 26]. [score:1]
Thus, introduction of the NZB mir-15a/16-1 loci to a wild-type strain is sufficient to give rise to a B-1 cell expansion. [score:1]
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[+] score: 127
In total, nine genes harbored exclusive targets within Alu (referred to as ‘Alu-miRNA targets’ in the subsequent sections), of which miR-15a-3p targets seven genes - NR2C1, GTSE1, FHL2, RAD1, FKBP9, CAD and SMA4, and miR -302d-3p targets two - ADD1 and UBE2I (Supplementary Table S3). [score:9]
Ectopic expression of target reporter both in the presence and absence (partial knockdown by anti-miR) of miR-15a-3p was used to confirm target specificity. [score:8]
All the target reporters for Alu-miRNA targets of NR2C1, GTSE1, RAD1 and FKBP9 show upregulation in the presence of miR-15a-3p anti-miR, when compared with the endogenous miRNA levels. [score:7]
A consensus of target predictions by miRanda and TargetScan, revealed 398 and 917 genes to be the putative targets for miR-302d-3p and miR-15a-3p, respectively (Supplementary Table S2). [score:7]
Of these, only the skin cell line (WM266-1) showed more than 3-fold up-regulation for miR-15a-3p, reinforcing the spatio-temporal expression of miRNAs. [score:6]
We observed that there is no significant difference in their expression, in response to anti-miR mediated knockdown of miR-15a-3p or overexpression of miR-302d-3p (p = 0.1585 for RAD1, 0.0569 for GTSE1, 0.0594 for FKBP9, 0.2826 for NR2C1, 0.0985 for UBE2I; Student’s t-test). [score:6]
The ectopic expression of target sites shows significantly higher values, reaching up to 1.5-fold following knockdown of miR-15a-3p (Fig. 1C). [score:6]
The ectopic overexpression of 2.4 nM miR-15a-3p shows significant downregulation of both GTSE1 (p = 0.022) and RAD1 (p = 0.042), compared to scrambled, at the protein level. [score:5]
Downregulation of expression to ~50% compared to the levels of miRNAs during heat shock response in untransfected cells was observed for both miR-15a-3p and miR-302d-3p, validated by qPCR. [score:5]
We validated miR-15a-3p targets in Alus and found that the target genes are involved in cell cycle and DNA damage response. [score:5]
Interestingly, miR-15a-3p is also reported to be upregulated in response to UV exposure to skin and forms a regulatory network affecting extrinsic skin aging 47. [score:5]
miR-302d-3p has its target within 55 genes and miR-15a-3p in 94; eight of them being common targets. [score:5]
Although, it is known that the introduction of any foreign nucleic acid into the cell tends to block its division by arresting cells at G1, our result highlights the specific role of miR-15a-3p in downregulating GTSE1 which allows cells to cross the G2/M checkpoint. [score:4]
miR-15a-3p is shown to be functionally involved in skin pigmentation 46 and we have detected upregulation of this miR-15a-3p in skin cells. [score:4]
Consequences of miR-15a-3p overexpression at the cellular level. [score:3]
Overall the results indicate that an increased level of miR-15a-3p targets Alu-miRNA sites within GTSE1 and RAD1 to promote cell survival during stress response. [score:3]
A representative figure from UCSC shows that all transcripts of RAD1 in humans have an extended 3′UTR, harboring Alus with functional targets for miR-15a-3p. [score:3]
To further ascertain the functional consequence of miR-15a-3p overexpression in increasing G2/M cell population, we checked if it actually results in cell proliferation. [score:3]
For the overexpression experiments, mimics for miR-302d-3p and miR-15a-3p were synthesized by Sigma-Aldrich. [score:3]
The G1 cell population for miR-15a-3p overexpression is comparable to that of the untreated as well as scrambled -treated cells. [score:3]
miR-15a-3p targets within CAD and SMA4 were present in pseudogenes and hence, were not carried forward for validation. [score:3]
miR-15a-3p targets the principal transcript isoforms of GTSE1 and RAD1, proteins that are crucial for cell survival in response to stress. [score:3]
Both miR-302d-3p and miR-15a-3p were checked for their differential expression in response to heat shock, across four different cell lines belonging to skin (WM266-1), liver (HepG2), pancreas (MIA PaCa-1) and brain (SH-SY5Y). [score:3]
For this, we ectopically overexpressed miR-15a-3p using its mimic. [score:3]
For checking the target specificity of miR-15a-3p and miR-302d-3p, we designed LNA modified anti-miRs. [score:3]
Anti-miR mediated knockdown showed approximately 50% reduction in the levels of both miR-15a-3p and miR-302d-3p during heat shock response (Fig. 1A). [score:2]
We observed an increase in the G2/M cell population after 2.4 nM miR-15a-3p transient transfection (Fig. 2C), although the difference from scrambled treatment was not significant (Student’s t-test, p = 0.227). [score:1]
To check whether this post-transcriptional regulation is also reflected at the protein level, we carried out transient transfection assay of miR-15a-3p mimic in HeLa cells. [score:1]
At 2.4 nM treatment with miR-15a-3p mimic, DNA damage is induced; however, it does not result in an extensive fragmentation of genomic DNA (no significant difference in tail length among untreated, mimic and scrambled treated). [score:1]
We wanted to specifically probe the consequences of increased levels of miR-15a-3p in cellular stress response. [score:1]
Anti-miR against miR-15a-3p was used for NR2C1, GTSE1, FHL2, RAD1 and FKBP9 whereas miR-302d-3p anti-miR was used for ADD1 and UBE2I. [score:1]
We found that both 2.4 and 4.8 nM treatment with miR-15a-3p mimic causes a marked proliferation of cells, unlike that of the scrambled probe which leads to a lot of cell death (Fig. 2D). [score:1]
The sequence of the oligos are, miR-15a-3p - 5′- TGAGG CAGCA CAATA TGGCC TG-3′ and miR-302d-3p - 5′-A CACT CAAACA TGGAAG CACT TA-3′. [score:1]
To check this, we sorted miR-15a-3p transfected cells using FACS and quantified the population of cells in different stages of the cell cycle. [score:1]
We believe that interaction of miR-15a-3p with Alus may have role in skin aging and adaptation of skin to stress in primates, similar to what has been shown before for interaction of exonized Alu with miR-661, in apoptosis 29 48. [score:1]
Treatment with 2.4 nM miR-15a-3p mimic but not with that of scrambled, increases the population of cells in G2/M phase. [score:1]
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[+] score: 118
Prediction tools revealed that miR-15a, miR-185, and miR-211 targeted IL-10Rα whereas none of the miRNAs exclusively downregulated in G361 cells targeted IL-10Rβ. [score:8]
Here we showed that miR-15a, miR-185, and miR-211 mimics inhibited and miRNA inhibitors increased the proliferation of IL-10 -treated melanoma cells through IL-10 signaling, since the silencing of IL-10Rα cancelled the effects of miRNA inhibitors on the proliferation (Fig.   5). [score:7]
We found that as many as three out of four miRNAs (namely miR-15a, miR-185, and miR-211) were increased in cells with low expression of IL-10Rα, and that these regulatory molecules targeted the IL-10Rα gene (Fig.   2). [score:6]
For example, downregulation of miR-15a, which is observed in several cancers including melanoma, led to an overexpression of several oncogens, such as Bcl-2, Cyclin D1, and Mcl-1 [23]. [score:6]
Three out of the four miRNAs upregulated in G361 and OCM-1 and unchanged in GR-M were predicted to have seed regions able to bind to the 3′UTR of IL-10Rα (miR-15a was reported in all the miRNA target prediction systems, miR-185 in microRNA and PITA; miR-211 in microRNA and PITA). [score:6]
These data suggest the potential usefulness of a combined therapeutic strategy targeted to the expression of miR-15a, miR-185, and miR-211 in melanoma cells. [score:5]
Ectopic expression of individual miR-15a, miR-185, and miR-211, and even more their co -expression, caused a marked decrease in the proliferation rate of all the cell lines. [score:5]
c Cells were transfected with individual or combined miR-15a, miR-185, and miR-211 inhibitors for 48-hr and, where indicated, co -transfected with siRNA against IL-10Rα or non -targeting control siRNA. [score:5]
Knockdown of miR-15a, or miR-185, or miR-211 markedly promoted the proliferation in all the cell lines and the combined inhibitors further increased growth. [score:4]
Luciferase reporter and western blot assays showed that IL-10Rα expression is directly regulated by miR-15a, miR-185, and miR-211, either alone or in combination. [score:4]
miR-15a, miR-185, miR-211, and miR-30d were upregulated in G361 and OCM-1 cells, remaining at similar levels in GR-M cells. [score:4]
IL-10Rα is a target of miR15a, miR185, and miR211To validate the direct interaction of miR15a, miR185, and miR211 with IL-10Rα mRNA (Fig.   3a), we constructed a luciferase reporter system containing a binding site (IL-10Rα-3′-UTR-wt) or a mutated site (IL-10Rα-3′-UTR-mut). [score:4]
Fig. 3 IL-10Rα is the direct target of miR-15a, miR-185, and miR-211 a Schematic representation of the predicted interaction of miR-15a, miR-185, and miR-211 with IL-10Rα 3′UTR site. [score:4]
Taken together, findings reported in the present study suggest that the IL-10Rα expression in melanoma cells is post-transcriptionally regulated by miR-15a, miR-185, and miR-211. [score:4]
Interestingly, miR-15a, miR-185, and miR-211 are thought to function as tumor suppressors in melanocytes, as they repress many genes implicated in the melanomagenesis. [score:3]
An inverse expression pattern between IL-10Rα, on one side, and miR-15a, miR-185, and miR-211 on the other one was also shown in melanoma samples. [score:3]
The vectors were co -transfected into G361, GR-M, and OCM-1 cells with miR15a, miR185, and miR211 mimics or inhibitors. [score:3]
These results suggest that the 3′-UTR of IL-10Rα mRNA might be the target of miR15a, miR185, and miR211. [score:3]
Fig. 4IL-10/IL-10R system and miR-15a, miR-185, miR-211 expression in cutaneous and uveal melanoma samples. [score:3]
Figure  2 (sections B and C) shows that, as compared to NHEM, only 4 miRNAs (miR-15a, miR-185, miR-211, and miR-30d) were upregulated in G361 and OCM-1 cells, while remaining at similar levels in GR-M cells. [score:3]
The IL-10/IL-10R system and miR-15a, miR-185, miR-211 expression in cutaneous and uveal melanoma samples. [score:3]
The expression profile of IL-10/IL-10R, miR-15a, miR-185, and miR-211 observed in cutaneous and uveal melanoma tissues exhibited the same trend observed in melanoma cell lines (Fig.   4). [score:3]
MiR-15a, miR-185, and miR-211 mimics/inhibitors (Qiagen, Milan, Italy) were transfected either alone or in combination into melanoma cells using HiPerFect according to the manufacturer’s protocols (Qiagen). [score:3]
IL-10Rα is a target of miR15a, miR185, and miR211. [score:3]
Four mutant plasmids were generated with the mutation sequence without complementary sequence of miR-15a (pGL3- IGF-1 3′-UTR mut 1), miR-185 (pGL3- IGF-1 3′-UTR mut 2), and miR-211 (pGL3- IGF-1 3′-UTR mut 3) or all of them (IL-10Rα 3′-UTR mut-full-length). [score:2]
For the luciferase reporter assay, cells were seeded on 24-well plates and co -transfected using Lipofectamine 2000 (Invitrogen) with 100 ng per well of the resulting luciferase UTR-report vector, 2 ng per well of pRLCMV vector (internal control, Promega), and 20 ng per well of miR-15a, miR-185, and miR-211 mimics or inhibitors following the manufacturer’s instructions (Qiagen, Milan, Italy). [score:2]
Therefore, treatment with100 U/ml of IL-10 for 36-hr was used for cell proliferation assays in the presence of miR-15a, miR-185, and miR-211 mimics or inhibitors. [score:2]
To validate the direct interaction of miR15a, miR185, and miR211 with IL-10Rα mRNA (Fig.   3a), we constructed a luciferase reporter system containing a binding site (IL-10Rα-3′-UTR-wt) or a mutated site (IL-10Rα-3′-UTR-mut). [score:2]
Next, we further investigated the regulation of IL-10Rα protein expression by miR-15a, miR-185, and miR-211. [score:2]
Figure  4 shows significant higher levels of IL-10Rα (section A) accompanied by a correspondent decrease in miR-15a, miR-185, and miR-211 (section B) in tumor specimens. [score:1]
Total RNA was extracted from 35 normal skin specimens, 52 cutaneous melanomas, and 41 uveal melanomas, reverse-transcribed, and analyzed by qPCR to determine the relative amounts of IL-10, IL-10Rα, IL-10Rβ mRNA (a) and miR-15a, miR-185, miR-211 (b). [score:1]
Effects of miR-15a, miR-185, and miR-211 on IL-10 -induced melanoma cell proliferation. [score:1]
Fig. 5Effects of miR-15a, miR-185, and miR-211 on IL-10 -induced melanoma cell growth. [score:1]
Significant ** p < 0.01 and *** p < 0.001, as compared to cells transfected with mimic control Next, we proceeded to explore the expression of the members of IL-10/IL-10R system, miR-15a, miR-185, and miR-211 in cutaneous and uveal melanoma samples as compared to normal skin. [score:1]
b Cells were transfected with individual or combined miR-15a, miR-185, and miR-211 mimics for 48-hr and then treated with rIL-10 (100 U/ml) for 36-hr. [score:1]
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[+] score: 110
Figure 5 The loss of the retinoblastoma tumor suppressor (RB ) expression plays a role in Smurf2 downregulation in triple -negative breast cancer (TNBC) cells, via upregulation of miR-15, miR-16 and miR-128. [score:11]
We also have revealed that microRNAs such as miR-15a, miR-15b, miR-16 and miR-128, whose expression is increased by inactivating mutations of the retinoblastoma (RB) gene, downregulate translation of Smurf2 protein in TNBC cells. [score:9]
Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple -negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. [score:9]
miRNAs such as miR-15/16 and miR-128, whose upregulation is linked to the inactivation of RB, play important roles in the downregulation of Smurf2. [score:7]
Therefore, RB inactivation accounts at least partly for Smurf2 downregulation in the TNBC cells, via deregulated expression of the miR-15 family and miR-128. [score:7]
Low expression of Smurf2 protein was also observed in several TNBC cell lines, which had RB mutations and high expression of miR-15a, miR-15b, miR-16 and miR-128. [score:6]
Therefore, we hypothesized that RB inactivation could result in elevated expression of the miR-15 family and possibly miR-128, which contributed to the downregulation of Smurf2. [score:6]
To further delineate the role of the miRNAs in Smurf2 downregulation observed in BT549, MDA-MB-436 and DU4475 cells, cells were transfected with miRNA inhibitors (antagomirs) against miR-15a, miR-15b, miR-16 or miR-128 (Figure  4). [score:6]
Forced expression of GFP-RB resulted in a significant increase in cellular levels of Smurf2 protein, accompanied by substantial decreases in the expression of miR-15a, miR-15b, miR-16 and miR-128b (Figure  5C). [score:5]
Whereas deletion of miR-15a and miR-16 was reported in some non-small cell lung cancers [19], miRNA expression profiling in human breast cancer subtypes showed that basal-like TNBCs expressed higher levels of miR-15b than other subtypes [20]. [score:5]
miR-15/16 and miR-128 mediate Smurf2 downregulation. [score:4]
A recent study demonstrated that miR-15 and miR-16 are direct targets of the E2F transcription factors [16]. [score:4]
It was previously demonstrated that miR-15 and miR-16 are direct transcriptional targets of E2F-1, and these miRNAs in turn restrict E2F activities [16, 19]. [score:4]
Figure 4 MicroRNAs such as miR-15, miR-16 and miR-128 are involved in downregulation of Smurf2 protein in triple -negative breast cancer. [score:4]
Human triple -negative breast cancer cell lines, BT549, MDA-MB-436 and DU4475 cells, were transfected with microRNA inhibitors against miR-15a, miR-15b, miR-16 and miR-128, or nonspecific ssRNA as negative control (NC), and cellular levels of Smurf2 protein were determined at 24 h (A, B) or 48 h (C) post-transfection by immunoblotting. [score:3]
Figure 3 Expression levels of miR-15a, miR-15b, miR-16 and miR-128 in breast cancer cell lines. [score:3]
In contrast, MDA-MB-231 cells, which had high levels of Smurf2 mRNA and protein, showed no major change in the expression of these miRNAs, except for a decrease in miR-15a. [score:3]
Also in MCF-7 cells, the levels of miR-15a, miR-15b and miR16 were low, whereas the expression of miR-128 was modestly higher. [score:3]
Cells were transfected with Ambion® Anti-miR™ miRNA Inhibitors specifically against miR-15a, miR-15b, miR-16 and miR-128 (Ambion/Invitrogen, Carlsbad, CA), using the Lipofectamine® RNAiMAX transfection reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s protocol. [score:3]
BT549 cells exhibited increased expression of miR-15a, miR-15b and miR-16. [score:3]
The miR-15 family and miR-128 have been implicated for the regulatory network in breast cancer initiating cells [14, 15]. [score:2]
Our finding that miR-15/16 and miR-128 are involved in provides a new pathway to the miRNA -mediated biological processes in breast cancer. [score:1]
The analysis led us to candidates such as miR-128 (binding to Smurf2 3′UTR, 5′-CACUGUGA-3′) and the miR-15 family miRNAs including miR-15a, miR-15b and miR-16 (binding to Smurf2 3′UTR, 5′-GCUGCUA-3′). [score:1]
Thus, we measured the expression of miR-15a, miR-15b, miR-16 and miR-128b in the breast cancer cell lines (Figure  3). [score:1]
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[+] score: 92
Moreover, restoring expression of miR-15a/16-1 indirectly affects expression of miR-34 family by modulating p53 expression and downregulation of miR-29 and miR-181b in aggressive CLL contributes to overexpression of Tcl1 [43]. [score:13]
MiR-15a/16-1 and BCL2 expression levels were found inversely correlated in CLL [23], and downregulation of these microRNAs in leukemic cell lines resulted in an increase of Bcl2 expression with consequent inhibition of apoptosis [23]. [score:9]
Besides, miR-15a/16-1 target TP53 while miR-34 targets ZAP-70 mRNA expression [32]. [score:7]
11q deleted region includes the miR-34b/c cluster locus [30], while deletion of 17p leads to abrogation of the p53 tumor suppressor [31], and 13q deletion involves miR15a/16-1 downregulation. [score:6]
MicroRNA-34b/c and microRNA-34a11q deleted region includes the miR-34b/c cluster locus [30], while deletion of 17p leads to abrogation of the p53 tumor suppressor [31], and 13q deletion involves miR15a/16-1 downregulation. [score:6]
Accordingly, miR-15a/16-1 expression was found downregulated in ~66% of CLL cases [18]. [score:6]
MiR-15/16 cluster, miR-34b/c, miR-29, miR-181b, miR-17/92, miR-150, and miR-155 family members, the most deregulated microRNAs in CLL, were found to regulate important genes, helping to clarify molecular steps of disease onset/progression. [score:5]
Indeed, in the majority of CLLs, monoallelic deletion is sufficient for complete loss of mir-15a/16-1 function rather than a twofold downregulation. [score:4]
A point mutation causing a decrease of miR-16-1 expression in NZB lymphoid tissues and elevated levels of Bcl-2 was found in the miR-15a/16-1 precursor (located in the mouse genomic region homologous to 13q14) [20]. [score:4]
In these patients, TP53 is not upregulated because miR-15a/16-1 are not deleted and this condition is associated with lower control on apoptosis. [score:4]
Additional factors regulate miR-15a/16-1 expression besides chromosomal deletion. [score:4]
In 13q deleted patients, the loss of miR-15a/16-1 expression shifts the balance not only toward higher levels of anti-apoptotic Bcl2 [10, 23] but also toward higher levels of pro-apoptotic p53. [score:3]
MiR-34 family members are involved in a fine-regulated feedback circuitry with p53 and miR-15a/16-1 in 13q deleted CLL, suggesting bidirectional interplay between microRNAs and genes. [score:3]
Several TP53 binding sites were found upstream miR-15a/16-1 on chromosome 13, miR-34b/c on chromosome 11, and miR-34a on chromosome 1. Thus, TP53 could induce the expression of these microRNAs [32]. [score:3]
These authors designed a mo del with conditional alleles that either resembled the loss of the minimal deleted region (Mdr), spanning entirely the host gene Dleu2 gene [26], or the specific miR-15a/16-1 cluster deletion, without altering the expression of Dleu2 [25]. [score:3]
MiR-15a/16-1 deletion is an initializing step in CLL, eliciting the control on Bcl2 expression. [score:2]
Mdr knockout (KO) animals lived less than wild-type (WT) siblings and succumbed to leukemia, while the differential survival between miR-15a/16-1 KO and their WT littermates was not statistically significant, indicating that the latter were affected by a milder phenotype than the former [25]. [score:2]
Interestingly, the mRNA levels of pri-miRNA processing cofactors were not decreased, and CLL cells retained the ability to cleave other microRNA precursors, suggesting that DROSHA processing is specifically impaired for mir-15a/16-1 and possibly other specific miRNAs [28]. [score:1]
In 2002, a cluster of two microRNA genes, miR-15a and miR-16-1, was located within the 13q14.3 deleted region [18]. [score:1]
Moreover, microarray experiments performed on CLL patients with high vs low levels of miR-15a/16-1 identified a gene signature which also contains MCL1, an antiapoptotic BCL-2 family member associated with B-CLL cell survival and chemotherapy resistance [24]. [score:1]
Normally, one allele of miR-15a/16-1 is transcribed by RNA polymerase II together with DLEU2 and the other by RNA polymerase III independently of the host gene. [score:1]
MicroRNA-15a/16-1. MicroRNA-34b/c and microRNA-34a. [score:1]
The importance of miR-15a/16-1 was confirmed in a study in New Zealand black (NZB) mice, the only mouse strain that naturally develops CLL [20]. [score:1]
Furthermore, CLL cells show a reduced amount of processed intermediates pre-miR-15a/16-1, while the precursor pri-miR-15a/16-a was not decreased, indicating a block of miRNA maturation at the DROSHA processing step. [score:1]
The first genetic manipulation in mice that confirmed the importance of miR-15a/16-1 deletion in CLL was carried out by Dr. [score:1]
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[+] score: 88
As a control we included SMAD7 (Gene ID: 4092) that is a predicted target of miR-15a (TargetScan6.2 algorithm), and a negative modulator of NF-kB activity [68] but has not been validated as a target so far. [score:7]
The tumor suppressor mechanism at 13q14.3 is multifactorial and is likely to involve other genetic elements than miR-15a/16-1, since (i) knocking out miR-15a and miR-16-1 in mice leads to a lymphoproliferative disease [16], but rare cases of CLL have been described where the deletion at 13q14.3 does not encompass the miRNA genes [10], [17], [18]. [score:6]
Interestingly, the levels of mature miR-15a and miR-16 also remained unchanged, which is in line with a recent report where incubation of CLL cells with a inhibitor of histone deacetylases (HDACi) led to upregulation of miR-15a and miR-16-1 in only 35% of patient samples [53]. [score:6]
Therefore to validate an involvement of miR-15/-16 in NF-kB signalling we sought to identify target genes that modulate NF-kB in addition to the previously reported target genes that are associated with cell cycle progression. [score:5]
In contrast, expression of the protein-coding genes in the region and the miR-15a/-16-1 host gene DLEU2 were positively correlated with DNA-methylation levels (Figure 3D; correlation coefficients F, G), suggesting an indirect regulation by DNA-demethylation e. g. via the lncRNA genes. [score:5]
The miR-15/miR-16 family of miRNAs has been reported to target several genes involved in NF-kB signalling: IKKa/CHUK, the NF-kB activating kinase itself (Gene ID: 1142) [66], TAB3 (Gene ID:257397), an adaptor protein connecting TRAF6 with the NF-kB activating kinase TAK1 [60], and the transcriptional coregulator NCOR2/SMRT (Gene ID: 9612) [67]. [score:4]
Thus we reproduced previously reported findings on gene targets of the miR-15/miR-16 family that modulate NF-kB transcription factor activity either directly (NCOR2/SMRT) or via upstream kinases (IKKa/CHUK) or upstream adaptor proteins (TAB3). [score:4]
miR-15/miR-16 family represses genes that modulate NF-kB activityThe miR-15/miR-16 family of miRNAs has been reported to target several genes involved in NF-kB signalling: IKKa/CHUK, the NF-kB activating kinase itself (Gene ID: 1142) [66], TAB3 (Gene ID:257397), an adaptor protein connecting TRAF6 with the NF-kB activating kinase TAK1 [60], and the transcriptional coregulator NCOR2/SMRT (Gene ID: 9612) [67]. [score:4]
The strong induction of NF-kB by the miR-15/miR-16 family in our screen however suggests that additional genes are targeted by these miRNAs that are part of the NF-kB circuitry. [score:3]
In order to delineate the molecular mode of induction of NF-kB activity by miR-15a, miR-15b and miR-16, the respective miR -mimics were cotransfected with luciferase reporter constructs containing 3′UTRs or parts of the 3′UTRs of the candidate target genes into HEK293T cells. [score:3]
After recent reports have shown 13q14.3 genes to be inhibitors of NF-kB signalling [60], [61], here we demonstrate that the miR-15a/16 cluster, KPNA3 (and KPNA4 from 3q25.33) and RFP2 are positively correlated with NF-kB function (Figure 6C): the miRNA15/16 family of genes were among the strongest inducers of NF-kB in an unbiased screen, KPNA3 is the transporter of p65 and RFP2 induces canonical NF-kB signalling. [score:3]
While constructs containing 3′UTRs of genes previously reported to be targets of miR-15a and/or miR-16 (CHUK/IKKa, SMRT and TAB3) showed lower luciferase activity after miRmimics-15a/-16 transfection, luciferase activity from the control reporter SMAD7 selected using in-silico prediction remained constant (Figure 4F). [score:3]
Impact of miR-15a, miR-15b, and miR-16 on the expression of TAB3, IKKa/CHUK, SMRT, and SMAD7. [score:3]
To this end, 4×10 [5] cells were seeded in the wells of 24 well plates with 0.45 µg of pMIR-Report, 0.05 µg TK Renilla and 10 pmol of either miR-15a-3p, miR-15a-5p, miR-15b-5p or miR-16 miR -mimics or miR -inhibitors (Life Technologies, Darmstadt, Germany), respectively. [score:3]
MiR-15/16 are among the most strongly and ubiquitously expressed miRNA genes in human cells [12] and appear to exert a crucial role in tumorigenesis [13]. [score:3]
As activation of NF-kB has been shown in CLL cells to prevent apoptosis [38]– [40], an inducive effect of miR-15/-16 of this pathway is difficult to reconcile with their tumorsuppressive role at least in the tissue analysed here. [score:3]
In line with this finding, NF-kB target genes like IL6, IL8, CXCL1 and TNFalpha were induced in three different cell lines derived from embryonic kidney and breast cancer, albeit with different induction patterns (Figure 4C–4E), suggesting that the modulation of NF-kB by the miR-15/16 miRNA family can occur in different tissues. [score:3]
Levels of mature miR-15a and miR-16 showed no significant correlation with DNA-methylation levels, probably because they are subject to additional posttranscriptional deregulation (Allegra et al., manuscript submitted). [score:2]
Examples are miR-15a and miR-16-1, for which a role in regulation of the cell cycle has been shown [16], [57]– [59]. [score:2]
Thus, in addition to their previously reported role in regulation of cell-cycle associated genes [16], [58], [65], the miR-15/-16 family of genes is capable of inducing NF-kB. [score:2]
No correlation could be found with levels of mature miR-15a and miR-16, probably because these transcripts are also deregulated by a posttranscriptional processing defect in CLL cells (Allegra, manuscript submitted). [score:2]
DLEU2 splicing variants have been suggested to represent the primary transcripts (pri-miR) of miR-15a (Gene ID: 406948) and miR-16-1 (Gene ID: 406950) because of their localization and coregulation [11]. [score:2]
MiR-15/miR-16 family is the strongest inducer of NF-kB. [score:1]
Of 810 miR -mimics transduced into HEK293 cells, the miR-15a/miR-16 family (miR-15a, miR-15b, miR-16, miR195, miR424, miR497) showed the strongest induction of NF-kB of all tested miRNA families (Figure 4A). [score:1]
In addition, we performed an unbiased screen of 810 human miRNAs and showed the miR-15/16 family of genes to be the strongest inducers of NF-kB activity. [score:1]
TRIM proteins: 57% similarity, e value: 1e-65; ARL proteins: 62% similarity, e value: 2e-53; KPNA proteins 92% similarity, e value: 0. Similarly, sequence alignment of hsa-mir-16-1 and hsa-mir-16-2 showed 68,9% identity of a 90 bp overlap and alignment of hsa-mir-15a and hsa-mir-15b showed 56,1% identity of a 98 bp overlap. [score:1]
Interestingly, for these miRNA genes and for several additional gene products at 13q14.3, an involvement in the NF-kB pathway has been postulated: miR-15a and miR-16-1 (inducing NF-kB) [60] and DLEU7 (repressing NF-kB) [61] modulate this central signalling pathway. [score:1]
MiR-15/miR-16 gene family is the strongest inducer of NF-kB in the miRNome. [score:1]
The miRNA genes miR-15a and miR-16-1 were identified together with other members of this miR family to be among the strongest activators of NF-kB activity. [score:1]
In vitro methylation was performed using SssI methylase (NEB) according to manufacturer's instructions but incubating for 4 h at 37°C and adding 1 µl fresh SAM after 2 h. To measure the impact of miR-15a, miR-15b and miR-16 on potential target genes, parts of or the whole 3′UTRs of TAB3, CHUK, SMAD7 and SMRT were cloned into the vector pMIR-Report (Applied Biosystems). [score:1]
1003373.g004 Figure 4 MiR-15/miR-16 family is the strongest inducer of NF-kB. [score:1]
miR-15/miR-16 family represses genes that modulate NF-kB activity. [score:1]
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14
[+] score: 82
On the other hand, mRNA levels of E2F1 and Bcl2 were downregulated in UVB -treated cells (Additional file 4: Table S1 and data not shown), although three miRNAs known to target E2F1 (miR 20a, 20b and 93) and one miRNA known to target Bcl2 (miR-15a) were all significantly downregulated in UVB -treated cells (Figure  3). [score:11]
Expression of miRNAs encoded by the miR-15/16 cluster inhibits cell proliferation, promotes apoptosis of cancer cells, and suppresses tumorigenicity both in vitro and in vivo. [score:7]
To further validate the bioinformatics -based target selection, regulation of several newly identified candidate genes by specific microRNAs was addressed in HDF overexpressing miR-15a, miR-20a, and miR-93, respectively. [score:6]
In contrast to their function as tumor suppressors, miR-15 can also promote tumor growth and progression, when expressed in cancer -associated fibroblasts [48]. [score:5]
Whereas these findings establish CDKN2B, RUNX1 and RARB as functional target genes for miR-15a and miR-20A, respectively, the binding of these microRNAs to the 3'-UTR of the target genes remains to be confirmed by additional experiments. [score:5]
Expression levels for miR-15a, miR-20a, miR-20b, miR-93, and miR-101 are shown in Figure  3, along with their established target mRNAs. [score:5]
Thereby, eight miRNAs (miR-15a, miR-17, miR-20a, miR-20b, miR-34, miR-93, miR-101, miR-155) were identified for which regulated mRNA targets were found with high confidence. [score:4]
miRNA expression levels for miR-20a, miR-20b, miR-15a, and miR-93 were determined by. [score:3]
Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. [score:3]
of the bioinformatic analysis suggested PAPPA, APOD, RRAS2, Runx1, RARB, BTG2, Notch3 and SFRP1 as potential targets for miR-15 (Figure  5B). [score:3]
Figure 5 Correlation networks of miR-93/miR-15 and their high confidence target genes. [score:3]
miR-15a, along with miR-16, is commonly deleted in human chronic lymphocytic leukemia [32] and known to target multiple oncogenes, including BCL2, MCL1, CCND1, and WNT3A [33]. [score:3]
To achieve the overexpression of microRNA in HDFs, cells were reverse transfected with Pre-miR™ miRNA Precursor for miR-15a, miR-20a, miR-93, miR-101, and Pre-miR™ miRNA Precursor Molecules-Negative Control #2 for negative control (Applied Biosystems, Austria) using siPORT™ NeoFX™ Transfection Agent (Ambion, Austria) according the manufacturer’s protocol. [score:3]
miR-15a and miR-20a were overexpressed in HDF as indicated. [score:3]
The identification of VEGFA as relevant target for miR-15 in the context of UVB -induced senescence is consistent with these data. [score:3]
Together the results obtained in this study suggest important roles for microRNAs miR-15, miR-20a/b, miR-93 and miR-101, and their mRNA targets, during UVB -induced senescence of human diploid fibroblasts. [score:3]
miR-15a and miR-16-1 function by targeting multiple oncogenes, including BCL2, MCL1, CCND1, and WNT3A [33, 47]. [score:3]
For the genes RARB, RUNX1 and CDKN2B, we found that overexpression of the appropriate microRNA species (miR-15a and miR-20a, respectively) reduced protein levels of the respective gene products (Additional file 6: Figure S4). [score:3]
In these experiments, data obtained by the miRNA array for miR-15a, miR-20a, miR-20b, miR-93, and miR-101 were confirmed (Figure  2); whereas miR-17, miR-34 and miR-155 were also regulated in UVB -treated cells in accordance with the miRNA array results, the observed differences did not reach statistical significance (data not shown). [score:2]
miR-15a, along with miR-16, was the first microRNA linked to cancer because both genes are commonly deleted in human chronic lymphocytic leukemia [32]. [score:1]
Our analysis confirmed a high confidence interaction between miR-15a and vEGF-A in UVB -induced senescence (Figure  5B), thereby validating the analytical procedure. [score:1]
of the analysis are presented here for miR-93 (A), and miR-15 (B). [score:1]
In addition, 7 other microRNAs (hsa-miR-155, hsa-miR-15a, hsa-miR-17, hsa-miR-20a, hsa-miR-20b, hsa-miR-34a, hsa-miR-93) were chosen for qPCR confirmation of array data using the Taqman qPCR platform (Life Technologies). [score:1]
[1 to 20 of 23 sentences]
15
[+] score: 75
Endothelial dysfunction is an important hallmark of the development of shock MicroRNA-15a, -27a, and -34a are differentially expressed in the plasma of septic patients who develop shock The expression of these microRNAs predict the presence of shock with very good accuracy In silico analyses predict that these microRNAs target and inhibit a number of genes that regulate the cell cycle, apoptosis, NF-κB signaling, LPS-stimulated MAP kinase signaling, and intercell permeability of endothelial cells. [score:10]
Shaded bars represent pathways of potential relevance to endothelial dysfunction in sepsis Review of the TargetScan and miRanda databases identified 20 total genes that have been experimentally validated (solid lines) to be targets of miR-15a, -27a, or -34a and are also associated with pathways of potential relevance in sepsis (Fig.   5). [score:5]
MiRNA-34a expression was significantly increased in the group who developed shock (p = 0.03) while miR-15a and miR-27a expressions were significantly decreased in this group (p = 0.006 and 0.03, respectively). [score:5]
First, both miR-15a and miR-27a are known to or are predicted to target and inhibit genes that increase vascular permeability in the setting of sepsis including VEGFA, VEGFC and MYLK [41– 44]. [score:5]
Shaded bars represent pathways of potential relevance to endothelial dysfunction in sepsisReview of the TargetScan and miRanda databases identified 20 total genes that have been experimentally validated (solid lines) to be targets of miR-15a, -27a, or -34a and are also associated with pathways of potential relevance in sepsis (Fig.   5). [score:5]
Altered plasma expression levels of miR-15a, -27a, and -34a are associated with the development of shock in patients with severe sepsis. [score:4]
Therefore, reduced levels of circulating miR-15a and miR-27a could disinhibit these genes and contribute to the development of shock. [score:4]
MiR-15a and -27a were significantly underexpressed in septic subjects who experienced shock compared to those who did not (p = 0.0062 and p = 0.03, respectively) while miR-34a was overexpressed (p = 0.03) in the shock group (Fig.   2). [score:4]
Although the data presented here represent only associations, there are several potential mechanisms by which the differential expression or miR-15a, -27a, and -34a could impact the development of endothelial dysfunction and shock. [score:4]
Finally, miR-15a may target several members of the NF-κB pathway and reduced circulating miR-15a could functionally augment NF-κB signaling leading to increased inflammatory cytokine production and increased endothelial injury. [score:3]
Fig. 5Gene target network of miR-15a, -27a, and -34a in pathways of relevance to endothelial dysfunction in sepsis. [score:3]
Since this also represents a single point in time in a disease with a protracted course, a time course study of serum miR-15a and VEGFA levels is warranted to definitively establish whether an association between the two exists. [score:3]
A notable exception is VEGFA, which is targeted by miR-15a and is secreted extracellularly. [score:3]
Future work will focus on validating the differential expression of miR-15a, miR-27a, and miR-34a in independent cohorts. [score:3]
Yin KJ Olsen K Hamblin M Zhang J Schwendeman SP Chen YE Vascular endothelial cell-specific microRNA-15a inhibits angiogenesis in hindlimb ischemiaJ Biol Chem. [score:3]
These data demonstrate that miR-15a, -34a, and -27a were all differentially expressed in patients whose course was complicated by shock and their combination was able to discriminate which patients had or developed shock with reasonable accuracy. [score:3]
In addition to providing mechanistic insight into the endothelial dysfunction of septic shock, the differential expression of miR-15a, -27a, and -34a may also offer prognostic biomarker capability. [score:3]
Fig. 4Canonical pathways predicted by Ingenuity Pathway Analysis to be modulated by miR-15a, -27a, and -34a. [score:1]
MiR-15a was the most predictive single miRNA for distinguishing between sepsis patients with and without shock with an AUC of 0.70 [95 % confidence interval (CI) 0.57–0.84]. [score:1]
When analyzed, no association could be identified between VEGFA and miR-15a levels in subjects’ serum (data not shown). [score:1]
The final multiple marker mo del included miR-15a, -27a, and -34a. [score:1]
Wang H Zhang P Chen W Feng D Jia Y Xie LX Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjectsClin Chem Lab Med. [score:1]
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16
[+] score: 73
They have been found deregulated in a diverse range of cancers, including CLL, myeloma, lymphomas, and prostate cancer [1, 83, 84], absent or reduced expression has been found secondary to deletion of the DLEU2 gene at chromosome 13q14.3 [19] and/or mutational change [2, 20, 21], evidence for their natural tumour suppressor function has been supported through various xenograft mouse mo dels and in the CLL-prone NZB mouse mo del [3, 20, 21], and the antiapoptotic protein Bcl2 [15], as well as others [60, 77], has been experimentally validated as a direct target of miR-15a/16-1 [4]. [score:10]
Only 60% of CLL patients demonstrate the 13q14.3 deletion [18], meaning that high BCL2 expression in most patients cannot be explained by miR15a/16-1 downregulation alone. [score:6]
To confirm that downregulation of miR15a/16-1 leads to apoptosis, the same group identified apoptotic DNA fragments in MEG-01 cells transfected with these miRNAs, and subsequent immunoblot assays identified activation of APAF-1-caspase-9-PARP pathway, illustrating that Bcl2 downregulation and subsequent apoptosis by miR-15a/16-1 are mediated through the intrinsic apoptotic pathway [15]. [score:6]
Finally, Jing et al. demonstrated an extended role of miR-15a/16-1 showing that in addition to posttranscriptional silencing, miR-16 may function to target AU-rich elements (AREs) in target mRNA, mediating their decay [100]. [score:5]
In the CLL-prone New Zealand black (NZB) mouse mo del, reduced expression of miR-16-1 was identified secondary to a point mutation in the 3′DNA adjacent to the miR-16-1 region [20], and Calin et al. demonstrated that a minority of CLL patients possess germline mutations in pre-miR-15a/16-1 that affect subsequent processing [21]. [score:5]
miR-15a/16-1 are also deregulated in over 50% of myeloma patients [77], and patient studies showed significant downregulation of miR-15a/16-1 in CD135+ myeloma cells in comparison to normal counterparts [80, 81]. [score:5]
It has been suggested that four types of evidence can strengthen the argument for miRNA acting directly as tumour suppressors or promoters (Table 3) [75]; not only was the identification of miR-15a/16-1 the first reported link between miRNA and cancer [12], but also continuous research has allowed these miRNAs to fulfil all four of these criteria. [score:4]
Complementarity between these miRNAs and BCL2 was found conserved both in humans and mice [15], and the direct interaction of miR-15a and miR-16-1 was demonstrated through reduced expression of a luciferase reporter construct containing the BCL2 3′UTR [15]. [score:4]
At the molecular level, miR-15a/16-1 have been shown to inhibit cyclin-D1, cyclin-D2, and CDC25A, key regulators of cell cycle progression [77], as well as protein kinase B (AKT) and nuclear factor-kappa B (NF- κB) pathways involved in oncogenesis [80]. [score:4]
The oncogenic miR-17-92 cluster and the tumour suppressors miR-15a/16-1 have been shown to be proangiogenic and antiangiogenic, respectively [86, 87]. [score:3]
Also implicated in AML is the miR-15a/16-1 cluster, shown to act as tumour suppressor genes [59]. [score:3]
Other work has further characterised roles of miR-15a/16-1 in regulation of cell cycle control, with many predicted targets of these miRNAs acting as important regulators of the G0/G1 transition [16, 17]. [score:3]
These data demonstrate that miR-15a/16-1 may act as bona fide tumour suppressor genes and loss of function of these miRNAs possibly contributes to CLL pathogenesis. [score:3]
Cimmino et al. demonstrated an inverse correlation between expression levels of miR-15a/16-1 in CLL cells in comparison to normal CD5+ lymphoid cells extracted from patients or healthy controls, respectively [15]. [score:3]
Additionally, the majority of 13q14.3 deletions are monoallelic [16], suggesting additional aberrations of the remaining alleles are required in order for miR-15a/16-1 to fulfil roles as tumour suppressor genes according to Knudson's two-hit hypothesis [19]. [score:3]
Most cases of multiple myeloma demonstrate deregulation of one or more cyclin-D genes [82], which in this case might be explained by reduced miR-15a/16-1 levels. [score:2]
Combined with the role of these miRNAs in lymphomas and leukaemia, miR-15a/16-1 provide evidence that a single miRNA can have multiple and complex effects in cell biology [77]. [score:1]
Despite controversy over the mechanisms by which miR-15a/16-1 mediate their effects, it is clear that these miRNAs play an important role in CLL pathogenesis. [score:1]
In an attempt to further understand chromosome 13q14.3 deletions, it was found that miR-15a/16-1 were the only genes localised to this region [14]. [score:1]
The well-characterised functions of miR-15a/16-1 demonstrate that a single miRNA can have far reaching and multiple effects in cells and in cancer progression, targeting a variety of cancer associated genes. [score:1]
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17
[+] score: 64
In this section, we will discuss the roles of certain miRNAs in prostate cancer as summarized in Table 2. Table 2 miRNAs that influence PCa progression miRNA Role in PCa Function Study miR-15a and miR-16 Tumor suppressors Inhibit cell proliferation, invasion and angiogenesis through regulation of multiple targetsAqeilan 2010 [25], Musumeci 2011[72] miR-21 Onco-miRNA Increases tumor growth, invasion and metastasisSi 2007 [79], Selciklu 2009 [80], Li 2009 [81], Ribas 2009 [82] miR-125b Onco-miRNA Increases cell proliferation and inhibits apoptosisLee 2005 [84], Shi 2007 [26], Vere White 2009 [85] miR-143 Tumor suppressor Inhibits cell proliferation and migration by regulating KRAS, MAPK pathways and cell cycle. [score:15]
In this section, we will discuss the roles of certain miRNAs in prostate cancer as summarized in Table 2. Table 2 miRNAs that influence PCa progression miRNA Role in PCa Function Study miR-15a and miR-16 Tumor suppressors Inhibit cell proliferation, invasion and angiogenesis through regulation of multiple targetsAqeilan 2010 [25], Musumeci 2011[72] miR-21 Onco-miRNA Increases tumor growth, invasion and metastasisSi 2007 [79], Selciklu 2009 [80], Li 2009 [81], Ribas 2009 [82] miR-125b Onco-miRNA Increases cell proliferation and inhibits apoptosisLee 2005 [84], Shi 2007 [26], Vere White 2009 [85] miR-143 Tumor suppressor Inhibits cell proliferation and migration by regulating KRAS, MAPK pathways and cell cycle. [score:15]
Studies have also shown that miR-15a, miR-16-1 are down regulated in pituitary adenomas in comparison with normal pituitary, which basically enhances the assumption that they work as tumor suppressors and that their knock down by allelic loss may contribute to tumorigenesis. [score:5]
The in vivo knock down of miR-15a, miR-16-1 resulted in hyperplasia associated with CCD1 and WNT3A up regulation, all of the above evidence suggest that loss of miR-15a and miR-16-1 may be a significant pathogenic event during the development of PCa [25]. [score:4]
Lately, it was also proposed that miR-15 and miR-16 direct the expression of VEGF and IL-6, two factors that stimulate tumor angiogenesis and bone metastasis, respectively. [score:4]
It was reported that miR-15a, miR-16-1 sequences and BCL2 mRNA sequences share a complementary homology, and thus the previous information collectively suggests that miR-15a, miR-16-1 could suppress BCL2 by post transcriptional repression [25]. [score:3]
Moreover, it was shown that re -expression of miR-15 and miR-16 in cancer -associated fibroblasts (CAFs) will cause attenuation of the stromal support capability, and this will result in the decrease in cell proliferation and migration in primary and metastatic tumors [72]. [score:3]
It has been reported that miR-15a, miR-16-1 cluster targets not only BCL2 but also CCD1 (encoding cyclin D1) and WNT3A mRNAs, which promote many prostate carcinogenic features including; survival, proliferation, and invasion [25]. [score:3]
These observations lead us to conclude that in the context of prostate cancer, miR-15 and miR-16 are tumor suppressors, at least, on two levels such as at the levels of tumor cell and stromal cells. [score:3]
The miR-15 and miR-16 have a tumor suppressor activity on both cancer cell level and at the stromal microenvironment [72]. [score:3]
In a recent study, the expression of miR-15a, miR-16-1 in PCa samples showed consistent down regulation of these genes in around 80% of cancer samples compared with that of normal samples [25]. [score:3]
The miR-15 and miR-16 are usually down-modulated in the tumor sustaining stroma, an observation that can be explained by the effect of cancer cells on the stroma [72]. [score:1]
The miR-15a and miR-16 are both located at 13q14.3, and the deletions at this location have been reported in many malignancies including: CLL, MM, Mantle cell lymphoma, and Prostate carcinoma [25]. [score:1]
The role of miRNA-15a and miRNA-16. [score:1]
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18
[+] score: 60
Regarding the molecular mechanism underlying the oncolytic adenovirus -mediated MCL1 suppression, we demonstrated that OBP-301 upregulated MCL1 -targeted miRNAs, such as miR-15, miR-16 and miR-29, and miR-29 overexpression efficiently suppressed MCL1 expression in human osteosarcoma cells. [score:14]
OBP-301 dose -dependently upregulated the expression of E2F1 and MCL1 -targeted miRNAs (miR-15a, miR-16, miR-29a) in SaOS-2 and MNNG/HOS cells (Fig. 5a,b). [score:8]
However, miR-15a, miR-16 and miR-29a may not be the only MCL1 -targeted miRNAs because we cannot exclude the possible involvement of other miRNAs in regulating MCL1 expression. [score:6]
To investigate the underlying mechanism of OBP-301 -mediated MCL1 suppression, we determined whether OBP-301 upregulates MCL1 -targeted miRNAs (miR-15, miR-16, miR-29) via E2F1 activation in human osteosarcoma cells. [score:6]
miR-15, miR-16, and miR-29 suppress MCL1 expression in human malignant tumor cells 22. [score:5]
The expression levels of miR-15a, miR-16, and miR-29a were defined from the threshold cycle (Ct), and relative expression levels were calculated using the 2 [−ΔΔCt] method after normalization with reference to the expression of U6 small nuclear RNA. [score:5]
Moreover, Ad-E2F1 significantly increased the expression of miR-15a, miR-16, and miR-29a in SaOS-2 cells, although MNNG/HOS cells showed increased expression of miR-15a and miR-16, but not miR-29a, after Ad-E2F1 infection (Fig. 5d). [score:5]
Moreover, a recent report has suggested that miR-16 and miR-29 are downregulated and miR-15 is associated with chemosensitivity in human osteosarcoma cells 23. [score:4]
After synthesis of cDNA from 10 ng of total RNA using the TaqMan MicroRNA Reverse Transcription Kit (Applied Biosystems), the expression of miR-15a, miR-16, or miR-29a was determined by quantitative real-time RT-PCR (qRT-PCR) using the Applied Biosystems StepOnePlus [TM] real-time PCR system. [score:3]
Cells were transfected with 10 nM MCL1 siRNA, control siRNA, Pre-miR-15a, Pre-miR-16, Pre-miR-29a, or control Pre-miRNA (Applied Biosystems, Foster City, CA, USA) 48 hours before chemotherapy treatment and treated with CDDP or DOX at the indicated doses for 24 hours. [score:1]
The values of miR-15a, miR-16, and miR-29a at 0 MOI were set at 1, and the relative levels of miR-15a, miR-16, miR-29a at the indicated MOIs were plotted as fold induction. [score:1]
To evaluate the expression of miR-15a, miR-16, and miR-29a in tumor cells after OBP-301 infection, SaOS-2 and MNNG/HOS cells were seeded on 6-well plates at a density of 2 × 10 [5] cells/well and 24 hours later infected with OBP-301 at MOIs of 0, 1, 5, 10, 50, or 100 PFU/cell. [score:1]
To evaluate the effect of MCL1 -targeted miRNAs in the chemosensitivity of human osteosarcoma cells, we introduced exogenous miR-15a, miR-16, miR-29a or control miRNA into SaOS-2 and MNNG/HOS cells. [score:1]
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19
[+] score: 58
Tijsen et al. (2014[155]) also demonstrated that when mice were injected subcutaneously with locked nucleic acid (LNA) -based antimiR-15b, the loss of the miR-15 family members (miR-15-5p, miR-16-5p, miR-195-5p, miR-322 (mouse homolog to human miR-424-5p), and miR-497-5p resulted in a significant up-regulation of TGFβR1 and SMAD3 mRNA, and a trend towards up-regulation of p38, TGFβR2, TGFβR3, SMAD4, SMAD7, and endoglin mRNA. [score:7]
Although Tijsen et al. (2014[155]) demonstrated that multiple miR-15/107 family members, including miR-16-5p, were up-regulated in human diseased heart samples they did not investigate whether or not endoglin mRNA and/or protein levels were reduced in these samples, especially since their TargetScan analyses suggested that human endoglin would not be regulated by this miRNA family. [score:7]
Importantly, miRNA expression profiling experiments have identified a subset of miRNAs expressed in the normal heart and which are modulated during cardiovascular disease, including the miR-15/107 family described above (Hullinger et al., 2012[73]; Nigam et al., 2010[123]; Porrello et al., 2011[134], 2013[135]; van Rooij et al., 2006[159]; Zampetaki et al., 2014[177]). [score:7]
6)) given that it is down-regulated in prostate cancer (Srivastava et al., 2014[150]) and the miR-15/107 family and miR-628-5p that are regulated by IL-3, GM-CSF and G-CSF in acute myeloid leukemia (Favreau et al., 2012[52]). [score:5]
The miR-15/107 family includes miR-15a-5p, miR-15b-5p, miR-16-5p, miR-103-3p, miR-107 (which are expressed in all vertebrates), miR-195-5p, miR-424-5p, miR-497-5p, miR-503-5p (which are expressed in mammals), and miR-646 (human specific) (Finnerty et al., 2010[53]). [score:5]
Therefore, we hypothesize that some or all of the miR-15/107 family members may regulate endoglin expression. [score:4]
Therefore, their data regarding the decreased endoglin mRNA expression in miR-15b mimic transfected rat neonatal cardiomyocytes (Tijsen et al., 2014[155]) is confusing given that the miR-15/107 family 3′-UTR MRE is not conserved in rat endoglin mRNA. [score:3]
8)) focused their attention on the miR-15/107 family since some members are expressed in both cardiomyocytes and fibroblasts (Hullinger et al., 2012[73]). [score:3]
Interestingly, Tijsen et al. (2014[155]) only utilized TargetScan to interrogate the human, mouse, and rat endoglin mRNAs and came to the conclusion that only mouse endoglin mRNAs harbor a miR-15/107 family MRE. [score:3]
Mouse TargetScan analysis predicted miR-15/107 family 3′-UTR MREs in canonical TGFβ (TGFβR1, TGFβR2, TGFβR3, endoglin, SMAD2, SMAD3, SMAD4, SMAD7), and in non-canonical TGFβ (TGFβR1, TGFβR2, TRAF6, TAK1, p38) signaling pathways (Tijsen et al., 2014[155]). [score:3]
Importantly, members of the miR-15/107 family have been demonstrated to play key roles in gene regulation involved in cell division, metabolism, stress response, and angiogenesis (reviewed in Finnerty et al., 2010[53]). [score:2]
This was an important oversight given that, like mouse and rat endoglin mRNAs, human endoglin mRNA isoforms harbor algorithm-identified miR-15/107 family MREs and therefore may also be regulated by miR-15/107 family members. [score:2]
Taken together, these investigators concluded that the miR-15/107 family is a novel regulator of cardiac hypertrophy and fibrosis through the inhibition of the TGFβ-signaling pathway (Tijsen et al., 2014[155]). [score:2]
8); References in Table 8: miR-5739: Yoo et al., 2011[173]; miR-6087: Yoo et al., 2012[174]; miR-208a-5p: Shyu et al., 2013[147]; miR-208a-5p: Wang et al., 2014[165]; miR-15 family: Tijsen et al., 2014[155]; miR-370-3p: Chen et al., 2014[30]). [score:1]
However, Diana-microT-CDS found that this site was conserved in rat endoglin mRNAs and actually predicted an additional miR-15/107 family 3′-UTR MRE within mouse endoglin mRNAs (5′ UGCUGCU 3′, 7mer “seed” region) located 864 nts downstream from the stop codon. [score:1]
Again, it is important to note that the miR-15/107 family members, miR-16-5p, miR-103a-3p, and miR-107 were identified to interact with human endoglin mRNAs by the HITS-CLIP technique (Table 7 (Tab. [score:1]
It is now clear that miR-16-5p, miR-103-3p, and miR-107 belong to a group of paralogous, evolutionarily-conserved miRNAs termed the miR-15/107 family (Finnerty et al., 2010[53]). [score:1]
Notably, mouse endoglin mRNA was predicted to harbor a miR-15/107 family 3′-UTR MRE (5′ UGCUGCU 3′, 7mer “seed” region, -0.18 total context score) located 442 nts downstream from the stop codon. [score:1]
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20
[+] score: 56
miRNA Function (A animal studies, H human studies) References miR-17-92 cluster important in lung development and homeostasis (A)[69, 76, 77] miR-155 important for normal lung airway remo delling (A)[70] alteration of T-cell differentiation (A)[71] miR-26a highly expressed within bronchial and alveolar epithelial cells, important for lung development (H)[75] let-7 highly expressed in normal lung tissue, functions as a tumor suppressor in lung cells (H)[78] miR-29 functions as tumor suppressor in lung cells (H)[79] miR-15, miR-16 function as tumor suppressor genes (H)[80, 81] miR-223 control of granulocyte development and function (A)[82] miR-146a/b central to the negative feedback regulation of IL-1β -induced inflammation (H)[83, 84] miR-200a, miR-223 contribution to the extreme virulence of the r1918 influenza virus (A)[85] miR-17 family, miR-574-5p, miR-214 upregulated at the onset of SARS infection (A, H)[86]Two miRNAs, miR-146a and miR-146b, have been shown to play central role in the negative feedback regulation of IL-1β -induced inflammation; the mechanism is down-regulation of two proteins IRAK1 and TRAF6 involved in Toll/interleukin-1 receptor (TIR) signalling [83, 84]. [score:22]
miRNA Function (A animal studies, H human studies) References miR-17-92 cluster important in lung development and homeostasis (A)[69, 76, 77] miR-155 important for normal lung airway remo delling (A)[70] alteration of T-cell differentiation (A)[71] miR-26a highly expressed within bronchial and alveolar epithelial cells, important for lung development (H)[75] let-7 highly expressed in normal lung tissue, functions as a tumor suppressor in lung cells (H)[78] miR-29 functions as tumor suppressor in lung cells (H)[79] miR-15, miR-16 function as tumor suppressor genes (H)[80, 81] miR-223 control of granulocyte development and function (A)[82] miR-146a/b central to the negative feedback regulation of IL-1β -induced inflammation (H)[83, 84] miR-200a, miR-223 contribution to the extreme virulence of the r1918 influenza virus (A)[85] miR-17 family, miR-574-5p, miR-214 upregulated at the onset of SARS infection (A, H)[86] Two miRNAs, miR-146a and miR-146b, have been shown to play central role in the negative feedback regulation of IL-1β -induced inflammation; the mechanism is down-regulation of two proteins IRAK1 and TRAF6 involved in Toll/interleukin-1 receptor (TIR) signalling [83, 84]. [score:22]
In another study, bronchial airway epithelial cells from current and never smokers differed in the expression of 28 miRNAs (especially miR-218, miR-15a, miR-199b, miR-125a/b, miR-294) in comparison to smokers, whereas the majority of deregulated miRNAs were downregulated in smokers [97]. [score:7]
Other miRNAs found to be involved in the pulmonary homeostasis are members of let-7 family [78], miR-29 [79], miR-15 and miR-16 [80, 81], which function as tumor suppressors in lung cells. [score:3]
Several miRNAs such as miR-155, miR-26a, let-7, miR-29, miR-15/miR-16, miR-223, miR-146a/b and the miR-17-92 cluster have been shown to be involved in homeostasis and in the lung development (Table 4). [score:2]
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[+] score: 55
Loss of miR-15 and miR-16 reflects their tumor-suppressor function via uncontrolled expression of their anti-apoptotic target protein BCL2 in an in vitro mo del as well as in patient specimens of B-CLL (14). [score:7]
The importance of genetic lesions reducing miR-15/16-1 cluster expression in CLL was furthermore confirmed by the identification of a point mutation located in the 3` flanking region of miR-16 that reduces miR-16 expression in a naturally occurring CLL mouse mo del, the New Zealand black (NZB) mouse, that develops a hematological disorder similar to the human CLL (16). [score:6]
However, the same authors also demonstrated that the size of 13q14 deletions, where the miR-15/16-1 cluster is located, influences the phenotype of lymphoproliferative disorders and potentially the severity of disease, suggesting a tumor suppressor function for genetic elements besides miR-15a/16-1 and their host gene DLEU2 (18). [score:5]
In fact, the De Maria group demonstrated that, in prostate cancer, miR-15a/miR-16 levels are strongly down-regulated in the vast majority of cases (up to 85% of the analyzed samples) (20). [score:4]
Even more definitive genetic evidence of the tumor-suppressive effects of miR-15 and miR-16 came recently from the Dalla-Favera lab where miR-15/16 knock-out mice were generated (17). [score:4]
Furthermore, they also demonstrated that miR-15 and miR-16 are down-regulated in fibroblasts surrounding the prostate tumors. [score:4]
Similar to the down-regulation of the miR-15/16-1 cluster, another miRNA frequently lost in cancer is represented by the miR-34 family. [score:4]
Furthermore, a sequencing -based screen for miRNAs dysregulated in familial CLL patients identified a germ-line mutation in the primary precursor of miR-15a/16-1 that impairs their processing, highlighting that not only deletions but also mutations may lead to miRNAloss of function (15). [score:4]
Specifically, miR-15a/16-1 deletion accelerates the proliferation of both human and mouse B-cells by modulating the expression of genes controlling cell cycle progression like cyclin D3, cyclin E, CDK6, CHK1, and MCM5. [score:3]
Increased miR-15 and miR-16 expression in cancer -associated fibroblasts impaired tumor growth and expansion of prostate tumors in xenograft mo dels through the reduced post-transcriptional repression of Fgf-2 and its receptor Fgfr1 (21). [score:3]
Targeted deletion of miR-15 and miR-16 in mice at the age of 18 months recapitulates the spectrum of CLL -associated lymphoproliferations in humans, including CLL, CD5(+) monoclonal B-cell lymphocytosis, and CD5- non-Hodgkin lymphomas (17). [score:3]
In fact, an additional deletion of a 0.69 mb-large region telomeric to miR-15/16-1 increased the appearance of CLL, and mice seemed to succumb to their disease faster than miR-15/16-1- deleted mice. [score:3]
Interestingly, intraprostatic injection of miRNA antisense RNA oligonucleotide (‘antagomirs’) specific to miR-15a and miR-16 in 6-week-old male BALB/c mice resulted in marked hyperplasia, and knock-down of miR-15a and miR-16 promoted survival, proliferation, and invasiveness of untransformed prostate cells, which became tumorigenic in immunodeficient NOD-SCID mice (20). [score:2]
Deletion of the miR-15/16-1 cluster also occurs in other forms of tumors, such as multiple myeloma (19) and prostate cancer (20), indicating that the loss of these miRNAs could be relevant to other pathogenic events. [score:1]
We identified that the miR-15 and miR-16 genomic locus is heterozygously deleted in 68% of all patients with B-cell chronic lymphocytic leukemia (CLL) (13). [score:1]
To date, over 1000 miRNAs have been reported in humans (miRbase: 1527 at November 2011), and hundreds of them map to chromosomic regions that are known to be altered in human cancer, such as loss of heterozygosity regions (LOH) (e. g. miR-15a/16-1), amplified regions (e. g. miR-17–92 cluster, miR-155), and breakpoint regions and fragile sites (FRA) (e. g. let-7 family members) (12). [score:1]
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22
[+] score: 49
Given that E2F1 induces expression of miR-17-92 [69], it might be that downregulation of the miR-17-92 cluster, similar to miR-15/16, is based on decreased E2F1 levels as well. [score:6]
Alternatively, photoaging -associated SIRT4 increase in the dermis may occur independently from miR-15b expression, possibly associated with downregulation of other miR-15/16 family members as observed in gamma-irradiated human dermal fibroblasts (suppl. [score:6]
In addition to miR-15b human dermal fibroblasts also express miR-15a and miR-16-1 at high and comparable copy numbers, whereas the expression levels of miR-16-2, miR-195, and miR-497 were clearly lower (suppl. [score:5]
It is thus tempting to speculate that E2F1 is a major regulator of the miR-15/16 – SIRT4 axis during cellular senescence, with decreased E2F1 causing reduced miR-15/16 levels resulting in increased SIRT4 expression. [score:4]
To gain insight into the regulation of miR-15/16 family members during photoaging, we determined the transcript levels of SMC4 and DLEU2, which can be assumed to be coexpressed with miR-15b/16-2 and miR-15a/16-1, respectively [63]. [score:4]
Thus, the expression of miR-15/16 family members is not co-regulated with their host genes during aging. [score:4]
In this regard, miR-15 and miR-16 are direct transcriptional targets of E2F1 and become induced during mitogenic signaling to prevent replicative stress [66, 67]. [score:4]
Interestingly, besides miR-15b, miR-15a (but not miR-16-1) was also stress-responsive and significantly downregulated upon γIR treatment (suppl. [score:4]
MicroRNA-15a is also stress responsive and downregulated uponγirradiation in primary human dermal fibroblasts. [score:3]
Thus, SIRT4 expression may be repressed by both miR-15b and miR-15a during cellular senescence and aging, probably in a cell-type and senescence stimulus dependent manner. [score:3]
However, it should be noted that this binding site can also be targeted by additional miRNAs (miR-15a/16/195/424/497; suppl. [score:3]
However, we cannot exclude the possibility that additional miRNAs, like miR-15a, which underlie stress regulation (suppl. [score:2]
Members of the miR-15/16 group are genomically embedded in two host genes, SMC4 (structural maintenance of chromosomes 4) and pseudogene DLEU2 (deleted in leukemia 2). [score:1]
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23
[+] score: 45
MicroRNA Expression in cancer Function Mechanism of deregulation Targets Let-7a-2 Down in breast, lung, colon, ovarian, and stomach cancer Tumor suppressor Repressed by MYC KRAS, HMGA2, MYC, DICER, BCLXL, IMP-1, CDC34, IL6 miR-15/16 Down in CLL, prostate cancer, and pituitary adenomas Tumor suppressor Genomic loss, mutated, activated by p53 BCL2, COX2, CHECK1, CCNE1, CCND1, CCND2, BMI-1, FGF2, FGFR1, VEGF, VEGFR2, CDC25a miR-29 family Down in AML, CLL, lung and breast cancer, lymphoma, hepatocarcinoma, rhabdomyosarcoma Tumor suppressor Genomic loss, activated by p53, repressed by MYC CDK6, MCL1, TCL1, DNMT1, DNMT3a, DNMT3b miR-34 family Down in colon, lung, breast, kidney, and bladder cancer Tumor suppressor Repressed by MYC SIRT1, BCL2, NOTCH, HMGA2, MYC, MET, AXL. [score:14]
For example, overexpression of the oncogene, miR-21, frequently highly expressed in solid and hematologic malignancies, represses strong tumor suppressors as PTEN or programed cell death 4 (PDCD4) while loss of the tumor-suppressor miR-15a/miR-16-1 in CLL induces the overexpression of the anti-apoptotic BCL2 (Cimmino et al., 2005; Meng et al., 2007; Asangani et al., 2008). [score:11]
The authors also showed that the region containing the up-regulated miR-182 was amplified in 28.9% of ovarian carcinomas, whereas, miR-15a was deleted in 23.9% of ovarian carcinomas, as previously also shown for CLL (Calin et al., 2002). [score:4]
Frequent deletions and down-regulation of micro -RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. [score:4]
miR-15 and miR-16 induce apoptosis by targeting BCL2. [score:3]
These signatures included three known tumor-suppressors miRNAs, mir-15a, mir-34a, and mir-34b. [score:3]
A mouse mo del that mimics the minimal deletion region 13q14.3 or that specifically deletes the miR-15a/16-1 cluster exhibited a full spectrum of CLL -associated phenotypes, consistent with the miR-15a/16-1 locus having a tumor-suppressor role in the B-cell lineage (Klein et al., 2010). [score:3]
The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. [score:1]
As previously described, Coukos’s laboratory identified a consistent amplification of miR-182 region and deletion of miR-15 in ovarian carcinomas (Zhang et al., 2008). [score:1]
The more characterized and first identified tumor-suppressor miRNA is represented by the miR-15/16 cluster, deleted in 68% of Chronic Lymphocytic Leukemia (CLL) patients carrying a 13q14.3 translocation (Calin et al., 2002). [score:1]
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24
[+] score: 44
We focused on three differentially expressed miRNA: miR-181C, miR-15a and miR-20b, which were found to be down-regulated in a diabetic-like environment and up-regulated after the addition of calcitriol. [score:9]
MiR-15a, miR-20b and miR-181C were found to be down-regulated in a diabetic-like environment and up-regulated after the addition of calcitriol; they were chosen for further investigation at the level of their gene targets, which have been shown to be involved in the modulation of endothelial function. [score:7]
MiR-126, miR-411, miR-20b, miR-15a and miR-181c were down-regulated under diabetic conditions and over-expressed after calcitriol was added. [score:6]
Mir-15a was also found to be up-regulated in endothelial cells and vascular smooth muscle cells after stimulation with KLF4, which indicate an option to suppress proliferative vascular disorders [35]. [score:5]
TXNIP, a pro-apoptotic protein, which is known to regulate endothelial cell metabolism, growth, and inflammation [22, 23] and IL8, an inflammatory-related protein [24] are putative targets of miR-20b and miR-15a. [score:4]
MiR-15a was down-regulated in the plasma of diabetic patients [27] and in β-cells exposed to high glucose (33 mM equivalent to 600 mg/dl) for long periods [34]. [score:3]
Gene target and pathway analysis of miR-181C, miR-15a and miR-20b. [score:3]
In order to determine the potential genes involved in HUVEC exposed to a diabetic-like environment and calcitriol, we analyzed the predicted target genes of these 3 miRNA (miR-15a, miR-20b and miR-181c). [score:3]
From the miRNA list presented in Table  1 and from the corresponding Venn diagram (Figure  1C), we validated several miRNA (marked in bold in Table  1) that are known to be modified in a diabetic environment (miR-510, miR-15a, miR-20b, miR-126, and miR-181C). [score:1]
In addition, miR-15a has been correlated with different pathophysiological events in the liver, which are also side-effects of anabolic steroids [33]. [score:1]
In addition, 10 [-10] mol/l calcitriol was given to the cells 1 h after stimulation for an additional 23 h. The miRNA set that included (A) miR-659, (B) miR-510, (C) miR-181C, (D) miR-411, (E) miR-126, (F) miR-15a, and (G) miR-20b was validated using real time PCR. [score:1]
MiR-181c, miR-15a, miR-20b, miR-411, miR-659, miR-126 and miR-510 were selected for further analysis because they are known to be modified in DM and in other biological disorders. [score:1]
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25
[+] score: 42
In 2005, miR-15a and miR-16-1 were reported to have lower expression in both GH-secreting and PRL-secreting pituitary adenomas than in normal tissues, and their downregulation was correlated with greater tumor volume and impaired secretion of p43, a potent anticancer cytokine, suggesting that miR-15a and miR-16-1 may function as tumor suppressors and their inactivation may contribute to tumor growth in pituitary adenomas [26]. [score:8]
In another study on ACTH-secreting pituitary tumors, miR-15a and miR-16 were also expressed at a lower level [27], but no association between miRNAs expression and tumor size was observed in this study. [score:5]
Regarding the deregulation in pituitary adenomas, miR-15a and miR-16-1 may exert their roles as tumor suppressors by regulating cell cycle. [score:5]
In CLL, some other apoptosis related genes were identified to be targets of miR-15a and miR-16-1 cluster, such as MCL1, which could enhance cell survival by inhibiting apoptosis. [score:5]
This is in accordance with the result of a subsequent report which showed no correlation between downregulation of miR-15a and GH-secreting pituitary tumor size [28]. [score:4]
Recently, a study revealed that miR-15a and miR-16-1 cluster could modulate prostate cancer by targeting multiple genes, including cyclin D1 [68]. [score:3]
Therefore, it is possible that, in pituitary adenomas, miR-15a and miR-16-1 influence apoptosis by targeting multiple antiapoptotic genes. [score:3]
miR-15a and miR-16-1 are the first two miRNAs shown to have differential expression in pituitary adenomas. [score:3]
miR-15a and miR-16-1 were demonstrated to induce apoptosis by targeting Bcl-2 in CLL [73]. [score:3]
In addition to the decrease of let-7a, miR-15a, and miR-16, they also found underexpression of miR-21, miR-141, miR-143, miR-145, and miR-150 in ACTH-secreting pituitary adenomas compared with normal pituitary tissues [27]. [score:2]
miR-15a and miR-16-1 genes are located at chromosome 13q14, a region which is frequently deleted in pituitary tumors [24]. [score:1]
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26
[+] score: 42
Detailed pathway analysis of the upregulated targets of the lost miR-15/16 family identified biological categories of pathways in cancer, endometrial cancer, transcription, melanoma, apoptosis, signaling pathways including insulin, MAPK, mTOR, VEGF, ErbB, JAK/STAT signaling, and cell-cell adhesion and cytoskeleton remo deling (see Supplemental Table 3) We also identified a subset of upregulated genes that are predicted as targets of both miR-200a/b and miR-15/16 microRNAs from the regions of deletion overlap on Chr1 and Chr3 (Table 3), including ACTR1A, BACH2, BCL2, CDC14B, CLASP1, CYP26B1, E2F3, EVI5, FUBP1, IKBKB, IRS2, IRS2, LRIG1, OTUD4, PCDH9, PCDH9, PELI2, PHF21A, PPAP2B, SLC2A3, SNTB2, TMCC1 and TUBB. [score:11]
Detailed pathway analysis of the upregulated targets of the lost miR-15/16 family identified biological categories of pathways in cancer, endometrial cancer, transcription, melanoma, apoptosis, signaling pathways including insulin, MAPK, mTOR, VEGF, ErbB, JAK/STAT signaling, and cell-cell adhesion and cytoskeleton remo deling (see Supplemental Table 3)We also identified a subset of upregulated genes that are predicted as targets of both miR-200a/b and miR-15/16 microRNAs from the regions of deletion overlap on Chr1 and Chr3 (Table 3), including ACTR1A, BACH2, BCL2, CDC14B, CLASP1, CYP26B1, E2F3, EVI5, FUBP1, IKBKB, IRS2, IRS2, LRIG1, OTUD4, PCDH9, PCDH9, PELI2, PHF21A, PPAP2B, SLC2A3, SNTB2, TMCC1 and TUBB. [score:11]
These findings indicated that alteration (loss) of two overlapping genomic regions (7.09 Mb of Chr1 1p36.33-p36.23 and 24.56 Mb of Chr3 3q26.1-q27.2 harboring cancer related miRNAs may be related to the tumorigenesis of a subset of ULMs via deregulation of the miR200a/b and miR-15/16 gene targets and in part this process may be due to the loss of convergent inhibitory action of the miR-200 family and miR-15 and miR-16 on a small group of the same downstream target genes. [score:8]
Conversely, loss of miR-200 shown to modulate growth as well as the UtLM morphology (Figure 4C,D), may lead to upregulation of genes (some of them convergent targets of lost miR-15/16) that contribute to the progression of ULM tumorigenesis. [score:6]
Table S3 Predicted target genes and pathways downstream of miR-200s amd miR-15/16. [score:3]
Similarly, loss of miR-15/miR-16 cluster is associated with aggressive tumor growth [32]. [score:1]
We also found that additional members of the oncogenic miR15/16 family (miR-15a and miR-16) as well as the members of the miR-17-92 polycistron were lost with the 13q12.12-q33.2 region of a single patient B4 (Table 3). [score:1]
Candidate role of the loss of miR-200 family and miR-15 and miR16 in ULMs. [score:1]
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27
[+] score: 41
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-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-142, 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
An inverse correlation between miR-15a/16-1 and BCL2 expression has been reported in CLL, and inhibition of this microRNA expression in leukemic cell lines led to increased BCL2 expression and resistance to apoptotic signals. [score:9]
However, additional mechanisms, such as overexpression of histone deacetylases (HDACs), also down-regulateed expression of miR-15 and miR-16 [3]. [score:8]
Nearly two-thirds of CLL cases presented a down-regulation of miR-15a/16-1 expression. [score:6]
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]
The miR-15/16 cluster, miR-34b/c, miR-29, miR-181b, miR-17/92, miR-150, and miR-155 represent the most frequently deregulated miRNAs reported in CLL, and these microRNAs have been associated with disease progression, prognosis, and drug resistance [1] (Table  1). [score:4]
Down-regulated miR-15a and miR-16-1 in CLL patients has been associated with a good prognosis, consistent with previous reports that correlated 13q14.3 deletions with a favorable course of CLL [7]. [score:4]
The expression of miR-223 and the miR-15/16 family was increased in ALL patients treated with systemic glucocorticoid monotherapy [61, 78]. [score:3]
Comparative microarray analysis in CLL patients with high or low levels of miR-15a/16-1 identified a gene signature that contains the anti-apoptotic BCL2 family member MCL-1, which was associated with B-CLL cell survival and chemotherapy resistance [4– 6]. [score:1]
In fact, miR-15a and miR-16-1 are located in the locus 13q14.3, a genomic region frequently deleted in CLL patient samples [2]. [score:1]
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[+] score: 39
Although miR-15 and miR-16 are mainly reported to be tumor suppressors, they have been reported to be upregulated in various kinds of cancer and be correlated with tumor cells metastasis, indicating their potential roles as oncomiRs 5. miR-660 expression was used as a good candidate for prognosis prediction in breast cancer 19. [score:8]
Among the 18 upregulated expression of miRNAs, 4 miRNAs including miR-15a, miR-16-2, miR-28 and miR-660 were validated in a large cohort of patients. [score:6]
Among these miRs, up-regulation of miR-16, miR-15a, miR-28 and miR-660 were also seen significantly changes in high HIP1 expressers in a large and independent cohort of TCGA patients (Fig. 3). [score:6]
Specifically, among these 1137 aberrantly expressed genes, 84 genes were predicted to be targeted by miR-28-5p, 100 by miR-15a, 100 by miR-16 and 58 by miR-600 (Figure S6–9). [score:5]
For example, CCND3 gene regulated by miR-28-5p involved in P53 pathway, Wnt signaling pathway, cell cycle and Jak-STAT signaling pathway (Table S7), several targeted genes (ZYX, VCL, PDPK1, MAPK9, COL1A1, Tables S8 and 9) of miR-15/16 were involved in adhesion or migration processes; LFNG in notch signaling pathway was regulated by miR-660 (Table S10), etc. [score:5]
By means of miRNA-mRNA integrative analysis, we found several targeted genes of miR-28-5p, miR-15a, miR-16 and miR-660. [score:3]
In the KEGG analysis, these targeted genes of miR-28-5p, miR-15a and miR-16, miR-660 respectively involved in 77, 70, 83 and 33 different metabolic networks with oncogenic potential (Table S7–10). [score:3]
Importantly, HIP1 interference in THP-1 cell line dramatically reduced the expression of miR-16, miR-15a, miR-28 and miR-660 (Fig. 5A). [score:3]
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[+] score: 34
We identified five downregulated miRNAs (miR-26b, miR-125b, miR-203, miR-218, and miR-373) and one upregulated miRNA (miR-15a) when we compared miRNA expression in HNSCC cells versus primary human keratinocytes (Figure 1A). [score:8]
To assess the function of the deregulated miRNAs in HNSCC, we generated two YFP-luciferase -expressing cell lines—SCC13 (established facial SCC; Rheinwald and Beckett, 1981) and SJG15 (primary lingual SCC; Goldie et al., 2012)—in which we knocked down miR-15a or stably overexpressed miR-26b, miR-125b, miR-203, miR-218, or miR-373 using lentiviral approaches (Figure S1A). [score:7]
Overexpression of miR-203 or knockdown of miR-15a suppressed metastasis in both cell lines, as determined by endpoint lung metastatic burden, ex vivo fluorescence microscopy, and histology (Figures 1E and S1E–S1H). [score:6]
Since miR-15a is a tumor suppressor (Aqeilan et al., 2010), we expressed miR-15a in otherwise nonmetastatic, miR-15a [low] SCC25 cells (established lingual SCC; Rheinwald and Beckett, 1981; Figure S1B). [score:5]
Xenografting 10 [5] miRNA expressing SCC13 cells revealed that overexpression of miR-203 and knockdown of miR-15a modestly reduced tumor burden after 26 days compared with control. [score:5]
Overexpression of miR-15a did not enhance lung metastatic colonization by SCC25 cells (Figure 1F), so we did not analyze this miR further. [score:3]
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[+] score: 33
Using 15 down-regulated miRNAs (let-7 g, miR-101, miR-133a, miR-150, miR-15a, miR-16, miR-29b, miR-29c, miR-30a, miR-30b, miR-30c, miR-30d, miR-30e, miR-34b and miR-342), known to be associated with cancer, we found 16.5% and 11.0% of our PLS-predicted miRNA-targets, on average, were also predicted as targets for the corresponding miRNAs by TargetScan5.1 and miRanda, respectively (Table 2). [score:10]
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]
These mRNAs are all included in the list of predicted target in Table 2. It was interesting to see that the four remaining miRNAs (miR-100, rno-miR-140, miR15a and miR-26a) were grouped in this network by IPA and not connected through the above cancer-related target mRNAs by the pathway designer and hence two of them (miR-100 and miR-15a) were not included in Figure 4A. [score:5]
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]
Studies suggest that three of these miRNAs, miR-15a, miR-16 [12, 13] and let-7 [14, 15] can function as tumor suppressors, while miR-155 and miR-21 play roles in oncogenesis [16, 17]. [score:3]
C. A sub-network depicting miRNA:mRNA interactions predicted from other cancer -associated miRNAs: let-7 g, miR-101, miR-133a, miR-15a, miR-16, miR-29b and miR-29c. [score:1]
Networks were also developed for the seven miRNAs (let-7 g, miR-101, miR-133a, miR-15a, miR-16, miR-29b and miR-29c) closely related to cancer and their associated mRNAs (Figure 2C). [score:1]
We found that all 15 miRNAs were involved in cancer and tumorigenesis, 12 of them (all except miR-101, miR-15a and miR-29c) were in carcinoma, malignant tumor and primary tumor and 8 of them (all except let-7 g, miR-101, miR-150, miR-15a, miR-16, miR-29c and miR-342) were in angiogenesis as were shown in the last column of Table 5. Furthermore, we examined which associated miRNAs among the 15 cancer-related miRNAs were involved in the canonical pathways associated with cancer. [score:1]
We found that all 15 miRNAs were involved in cancer and tumorigenesis, 12 of them (all except miR-101, miR-15a and miR-29c) were in carcinoma, malignant tumor and primary tumor and 8 of them (all except let-7 g, miR-101, miR-150, miR-15a, miR-16, miR-29c and miR-342) were in angiogenesis as were shown in the last column of Table 5. Furthermore, we examined which associated miRNAs among the 15 cancer-related miRNAs were involved in the canonical pathways associated with cancer. [score:1]
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[+] score: 32
More specifically, experimentally has been shown, the suppression of RAS oncogene by let-7 [40]; the suppression of BCL-2 by miR-15a and miR-1 [51]; the regulation of transcription factor E2F1 activity by miR-17-5p and miR-20 [52]; the downregulation of the KIT oncogene by miR-221 and miR-222 [53], the inhibition of the expression of tumour-supressor LATS2 and the influence on p53 pathway by miR-372 and miR-373 [54], and finally, the downregulation of the proto-oncogene BCL6 by miR-127 [55]. [score:16]
It was found that miR-15a and miR-16 were deleted or downregulated in lymphocytic leukaemia [39]; let-7 was downregulated in lung cancers [40, 41]; the miR-17 cluster was amplified in several types of lymphoma and solid tumours [31, 42, 43]; miR-21 was overexpressed in glioblastoma [44, 45] and breast cancer [46]; levels of miR-143 and miR-145 were decreased in colorectal neoplasia, breast, prostate and cervical cancers [46, 47]; miR155 was upregulated in Burkitt and B-cell lymphomas [48- 50] and also in breast cancer [46]. [score:12]
It has been previously reported that miR-15a and miR-16-1 target BCL2 mRNA [51]. [score:3]
This miRNA, miR-195, shares the same seed region with miR-15 and miR-16 and shows high similarity to the rest of the miR-15 family sequence. [score:1]
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[+] score: 32
The most prominent LIS1 targeting miRNA family contained two downregulated miRNAs, miR-15a and miR-16, with three predicted targets in the LIS1 3′UTR (Table 1). [score:8]
Choosing miR-15a as a representative for this miRNA family, we were able to confirm the predicted targeting, since miR-15a mimic and inhibitor reduced and increased luciferase expression from LIS1 3′UTR reporter, respectively. [score:7]
MiR-15 mimic reduces LIS1 3′UTR luciferase reporter expression, while miR-15 inhibitor slightly increases its expression. [score:7]
Further support for a conserved functional relationships between DCX and miR-204/34c as well as LIS1 and miR-15a comes from the observation that the respective miRNAs can regulate luciferase expression under control of human derived DCX and LIS1 3′UTRs. [score:4]
Mutating the predicted miR-34c, miR-204 and miR-15a target sites individually in the luciferase reporters abolished the observed effects (Figure 2C). [score:3]
Lis1-3′UTR_WT: chr17:2586883-2588130                  1248 bp (All three miR-15a target sites). [score:3]
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33
[+] score: 32
We found that miR-15a-3p (0.1-fold) and miR-30a-5p (0.2-fold) were down-regulated and miR-489-3p up-regulated (2 fold) in ATLOs (Figure 3). [score:7]
Expression in the plasma of AAA compared to PAD patients was significantly down-regulated for miR-15a-3p (0.5-fold, p = 0.03) and miR-30a-5p (0.8-fold, p = 0.04) (Figure 4). [score:5]
We found a similar down-regulation of miR-15a-3p in M1 (0.5-fold) and M2 (0.3-fold) macrophages. [score:4]
The three miRNAs, miR-15a-3p, miR-30a-5p and miR-489-3p, were down-regulated 0.6-, 0.25- and 0.2-fold, respectively (Figure 3). [score:4]
The expression of miR-30a-5p in plasma is similarly modulated as in ATLOs and M1 macrophages, and those of miR-15a-3p is similarly modulated as in ATLOs and both macrophages. [score:3]
In contrast, miR-15a-3p was similarly regulated in the isolated aneurysmal cells tested as well in the whole aorta. [score:2]
Our findings indicate that miR-15a-3p and miR-30a-5p have potential as biomarkers. [score:1]
Despite limitations due to the small sample size in the array and PCR experiments, the miRNA profiling of isolated ATLOs enabled the detection of 164 miRNAs out of 850 miRNAs screened, and the three miRs with the highest expression (miR-15a-3p, miR-30a-5p and miR-489-3p) were further characterized. [score:1]
Our data emphasize the potential of miR-15a-3p and miR-30a-5p not only as biomarkers of AAA, but also as triggers of ATLO evolution. [score:1]
Based on the average of their normalized values, we selected the top three miRNAs with a difference of value <1: miR-15a-3p, miR-30a-5p, miR-489-3p for further analysis by qRT-PCR. [score:1]
Figure 4Relative plasma quantification of the three miRNAs (mir-15a-3p (A); miR-30a-5p (B); miR-489-5p (C)) in patients with AAA (n = 20) and with PAD without AAA (n = 17) by qRT-PCR using the −2ΔΔ C [t] method, with PAD patients as reference and Syn-Cel-miR-39 for calibration. [score:1]
The two miRNAs, miR-15a-3p and miR-30a-5p, significantly modulated in AAA patients are both implicated in the inflammatory response. [score:1]
Mir-15a-3p has been described to be a regulator of angiogenesis through its interaction with Vascular Endothelial Growth Factor [31]. [score:1]
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[+] score: 31
Thus, curcumin can induce miR-15a and miR-16 expression and it can probably serve as potential gene therapy targets for Bcl-2 -overexpressing tumors [355]. [score:7]
Yang J. Cao Y. Sun J. Zhang Y. Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells Med. [score:6]
In breast carcinoma cell lines, it was also found that curcumin was capable to upregulate these miRNA and the use of anti-miRNA15a and anti-miRNA16 promoted a renovation of Bcl-2 expression. [score:6]
Gao S. Yang J. Chen C. Chen J. Ye L. Wang L. Wu J. Xing C. Yu K. Pure curcumin decreases the expression of WT1 by upregulation of miR-15a and miR-16-1 in leukemic cells J. Exp. [score:6]
Cimmino A. Calin G. A. Fabbri M. Iorio M. V. Ferracin M. Shimizu M. Wojcik S. E. Aqeilan R. I. Zupo S. Dono M. miR-15 and miR-16 induce apoptosis by targeting BCL2 Proc. [score:3]
According to the literature, Bcl-2 is a target of miRNA15a and miRNA16 [354]. [score:3]
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[+] score: 30
The first report of altered miRNA expression in cancer was related to the frequent chromosomal deletion and downregulated expression of miR-15 and miR-16, two miRNAs thought to target the antiapoptotic factor B cell lymphoma 2 (BCL2) in chronic lymphocytic leukemia (CLL; Calin et al., 2002). [score:10]
It is well documented that loss of miR-15a and miR-16 in CLL is associated with 13q loss; however, these miRNAs are also often downregulated in CLL samples without observable deletions in 13q, and Sampath et al. (2012) found that overexpression of HDACs (HDAC1, HDAC2, and HDAC3) is associated with downregulation of miR-15a, miR-16, and miR-29b. [score:9]
Frequent deletions and down-regulation of micro -RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. [score:4]
Myc represses miR-15a/miR-16-1 expression through recruitment of HDAC3 in mantle cell and other non-Hodgkin B-cell lymphomas. [score:3]
In another study, MYC interacted with HDAC3, which then colocalized to the promoters of miR-15a/miR-16-1 and their host gene DLEU2, resulting in MYC -induced suppression of these miRNAs in mantle cell lymphoma (Zhang et al., 2012a). [score:3]
Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia. [score:1]
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[+] score: 29
Finally, linking differentially expressed miRNAs to their potential differentially expressed target using the algorithm published by Kertesz et al [25] identified a total of 11 potential miRNA-mRNA pairs: COL21A1 (collagen, type XXI, alpha 1; targeted by hsa-miR-155), CYP46A1 (cytochrome P450, family 46, subfamily A, polypeptide 1; targeted by hsa-miR-342-3p), KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1; targeted by hsa-miR-155), MADCAM1 (mucosal vascular addressin cell adhesion molecule 1; targeted by hsa-let-7i), MRPS26 (mitochondrial ribosomal protein S26; targeted by hsa-miR-15a), OR2T29 (olfactory receptor, family 2, subfamily T, member 29; targeted by hsa-miR-143), RPS9 (ribosomal protein S9; targeted by hsa-miR-132), SLC10A1 (solute carrier family 10 (sodium/bile acid cotransporter family), member 1; targeted by hsa-miR-31), SLC16A8 (solute carrier family 16, member 8 (monocarboxylic acid transporter 3); targeted by hsa-miR-31), SNTG1 (syntrophin, gamma 1; targeted by hsa-miR-21) and TRPC5 (transient receptor potential cation channel, subfamily C, member 5; targeted by hsa-miR-335). [score:29]
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37
[+] score: 28
In addition to miR-15a/miR-16-1 and let-7, miR-29 family members (miR-29a, b, c) were shown to function as tumor suppressor miRNAs, their downregulation being associated with the development and progression of several human malignancies, including CLL, lung cancer, invasive breast cancer and hepatocellular carcinoma [36, 37, 43, 48]. [score:7]
In CLL, the loss of miR-15a and miR-16-1 was associated with decreased apoptotic activity due to the overexpression of the anti-apoptotic protein Bcl-2, while miR-15a/miR-16-1 reconstitution increased apoptosis through repression of Bcl-2 mRNA translation [38]. [score:5]
Calin G. A. Dumitru C. D. Shimizu M. Bichi R. Zupo S. Noch E. Aldler H. Rattan S. Keating M. Rai K. Frequent deletions and down-regulation of micro-rna genes mir15 and mir16 at 13q14 in chronic lymphocytic leukemia Proc. [score:4]
Cimmino A. Calin G. A. Fabbri M. Iorio M. V. Ferracin M. Shimizu M. Wojcik S. E. Aqeilan R. I. Zupo S. Dono M. Mir-15 and mir-16 induce apoptosis by targeting bcl2 Proc. [score:3]
The loss of miR-15a and miR-16-1, due to chromosomal deletion of the locus 13q14 or germline mutation in their primary precursor, was associated with the development of the indolent form of CLL [31]. [score:3]
Bonci D. Coppola V. Musumeci M. Addario A. Giuffrida R. Memeo L. D’Urso L. Pagliuca A. Biffoni M. Labbaye C. The mir-15a-mir-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities Nat. [score:3]
The first indication that miRNA dysregulation could play a role in cancer was provided by Calin and colleagues, who demonstrated that two clustered miRNA genes, miR-15a and miR-16-1, were located in a region of the 13q14 locus that is commonly deleted in patients diagnosed with B-cell chronic lymphocytic leukemia (CLL) [31]. [score:2]
Loss of miR-15a and miR-16-1 has also been observed in prostate cancer and multiple myeloma [40, 41]. [score:1]
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[+] score: 28
As discussed above, miR-15a and miR-16-1 are significantly downregulated in chronic lymphocytic leukemia and their expression inversely correlates with Bcl-2 expression. [score:8]
Further study revealed that miR-15 and miR-16-1 acts as tumor suppressors to induce apoptosis by repressing Bcl-2, an anti-apoptotic protein overexpressed in malignant nondividing B cells and many solid malignancies. [score:5]
[6] They found this region, frequently deleted in B-cell chronic lymphocytic leukemia, actually contains two miRNA genes, miR-15a and miR-16-1. Both genes are deleted or downregulated in the majority of clinical chronic lymphocytic leukemia cases. [score:4]
[121] Since the discovery of miR-15a and miR-16-1 deletions in chronic lymphocytic leukemia, many laboratories around the world have demonstrated the expression of miRNAs is dysregulated in different tumors. [score:4]
Consistent with its oncogenic role, c-Myc also represses transcriptional activity of tumor suppressive miRNAs such as mir-15a, miR-26, miR-29, mir-30 and let-7 families. [score:3]
7, 8 Most importantly, the deletion of miR-15 and miR-16-1 cluster in mice recapitulated chronic lymphocytic leukemia -associated phenotypes observed in humans, which convincingly demonstrated the critical role of these two miRNAs in tumor suppression. [score:3]
The earliest discovery of miRNA gene location change is the loss of miR-15a/16-1 cluster gene at chromosome 13q14, which is frequently observed in B-cell chronic lymphocytic leukemia patients. [score:1]
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[+] score: 28
In agreement with published reports, lentiviral vector mediated overexpression of miR-15a/16-1 in HL60 cells (3-4 fold overexpression) increased CD11b expression after exposure to ATRA, but did not increase CD11b after exposure to TPA or in the absence of these agents as was seen for miR-150 (Figure 7A ) [45]. [score:7]
MYB protein was decreased in both miR-150 and miR-15a/miR-16 expressing HL60 cells after 96 hours of ATRA treatment, but was decreased to the greatest extent in miR-150 expressing cells. [score:5]
MiR-15a and miR-16-1 expression is increased after ATRA exposure and forced overexpression of these miRNAs enhances ATRA -induced differentiation [45]. [score:5]
In all cell lines exposed to ATRA MYB was decreased to the greatest extent in miR-150 expressing cells as compared to control cells or miR-15a/16-1 expressing cells (Figure 7B ). [score:4]
MiR-150 increased CD11b expression in all conditions, including in the absence of differentiating agent or with TPA in contrast to miR-15a/miR-16 and ECV cells. [score:3]
0075815.g007 Figure 7(A) HL60 cells were transduced with pre-miR-150, pre-miR-15a/miR-16, empty control lentiviral (ECV) supernatants and then treated with vehicle control (0.1% DMSO), ATRA (1 µM) or TPA (1 ng/mL) for 96 hours and assayed for CD11b expression by flow cytometry. [score:2]
We compared our results with miR-150 to miR-15a and miR-16-1, which are encoded by the same primary miRNA transcript and also target MYB [44]. [score:2]
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[+] score: 27
These analyses also identified a signature of 60 genes whose expression is downregulated by the miR-15a~16-1 cluster, which preferentially targets genes operant in activating cell cycle progression and survival pathways [58]. [score:8]
Along these lines, intratumoral delivery of miR-15a and miR-16-1 to prostate tumor xenografts induced their regression via apoptosis programs that commenced following miRNA-directed downregulation of Bcl-2, cyclin D1, and WNT3A [59]. [score:5]
Indeed, engineering human MEG-01 chronic myelogenous leukemia cells to overexpress miR-15a~16-1 dramatically suppressed their tumor forming ability when xenografted into nude mice [58]. [score:5]
Interestingly, genome-wide transcriptome profiling analyses indicate the miR-15a~16-1 cluster directly or indirectly regulates as much as 14% of the human genome, particularly for mRNAs housing AU-rich elements (AREs) [58]. [score:4]
Collectively, these findings highlight the potent tumor suppressing activities mediated by restoration of the miR-15a~16-1 cluster. [score:3]
Indeed, the growth of lung tumors in mice was severely compromised by the delivery of miRNA mimics for let-7b and miR-34 [121], as was that of prostate tumors following the administration of miRNA mimics for miR-15a and miR-16 [59]. [score:1]
miR-15a and miR-16-1 cluster. [score:1]
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Downregulated miR-15a can upregulate the expression of CDK4, and high expression of CCND combined with high expression of CDK4/6 and high expression of the oncogene CDC25A promotes DNA replication, thereby inducing mitosis [15]. [score:15]
Low expression of miR-15a, miR-16, miR-26a, and miR-196a in PAs could increase the expression of their target genes HMGA1 and HMGA2. [score:7]
Let-7 [9], miR-26a [10], miR-34a [11], miR-15a/ 16 [12], and miR-503 [11] are differentially expressed in PAs compared with normal tissues, and CCND1 has been predicted to be a potential target [13, 14]. [score:4]
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[+] score: 26
Bao et al. [37] studied a set of miRNAs related to kidney development and diseases (miR-193a, miR-21, miR-15a, miR-16, and let-7e) in a mo del of high-glucose EMT in HPMCs and found miR-193 upregulation, miR-15a and let-7e downregulation, and no significant changes for miR-16 and miR-21 [37]. [score:10]
When the same mo del was analyzed by Zhou et al. [19], peritoneal fibrotic tissues displayed upregulation in 8 miRNAs (miR-205, miR-664, miR-352, miR-146b-5p, predicted miR-160, miR-132, miR-15b, and let-7d) while 15 were downregulated (miR-335, miR-923, miR-801, miR-200a, miR-801, miR-30a, miR-193a-3p, miR-193b, miR-29b, miR-203, miR-148a, miR-709, miR-192, miR-15a, and miR-26b) [19]. [score:7]
Total PDE-derived cells from 110 PD patients (82 new, 28 prevalent) showed significant miRNA upregulation of miR-15a, miR-21, and miR-192 when comparing new, prevalent and UF groups, while miR-17, miR-30, and miR-377 expression was similar between groups [36]. [score:6]
Chen et al. [36] selected the following candidate miRNAs based on a report on EMT and kidney disease [46]: miR-15a, miR-17-92, miR-21, miR-30, miR-192, miR-216a, miR-217, and miR-377 [36]. [score:3]
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[+] score: 26
The target genes and their miRNA regulators are as follows: (1) CNOT7, a gene expressed in colorectal cell lines and primary tumors (Flanagan et al. 2003) (miR-15a); (2) LASS2, a tumor metastasis suppressor (Pan et al. 2001) (miR-15b); (3) ING4, a homolog of the tumor suppressor p33 ING1b, which stimulates cell cycle arrest, repair, and apoptosis (Shiseki et al. 2003) (miR-143); (4) Gab1, encoding multivalent Grb2 -associated docking protein, which is involved in cell proliferation and survival (Yart et al. 2003) (miR-155); and (5) COL3A1, a gene up-regulated in advanced carcinoma (Tapper et al. 2001) (miR-145). [score:13]
Both of these target genes are also targets for another cancer related miRNA, miR-15. [score:5]
Furthermore, miR-15 and miR-16 are down-regulated, or their loci lost, in 68% of B cell chronic lymphocytic leukemias (Calin et al. 2002). [score:4]
Our method predicted cancer-specific (by annotation) gene targets of miR-15a, miR-15b, miR-16, miR-143, miR-145, and miR-155. [score:3]
The miRNAs miR-15 and miR-16 are located within a 30-kb region at Chromosome 13q14, a region deleted in 50% of B cell chronic lymphocytic leukemias, 50% of mantle cell lymphomas, 16%–40% of multiple myelomas, and 60% of prostate cancers (Calin et al. 2002). [score:1]
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[+] score: 25
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-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-24-1, hsa-mir-24-2, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181a-1, hsa-mir-221, hsa-mir-222, hsa-mir-223, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-140, hsa-mir-125b-2, hsa-mir-136, hsa-mir-146a, hsa-mir-150, hsa-mir-206, hsa-mir-155, hsa-mir-181b-2, hsa-mir-106b, hsa-mir-302a, hsa-mir-34b, hsa-mir-34c, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-367, gga-let-7i, gga-let-7a-3, gga-let-7b, gga-let-7c, gga-mir-125b-2, gga-mir-155, gga-mir-222a, gga-mir-221, gga-mir-92-1, gga-mir-19b, gga-mir-20a, gga-mir-19a, gga-mir-18a, gga-mir-17, gga-mir-16-1, gga-mir-15a, gga-mir-1a-2, gga-mir-206, gga-mir-223, gga-mir-106, gga-mir-302a, gga-mir-181a-1, gga-mir-181b-1, gga-mir-16-2, gga-mir-15b, gga-mir-140, gga-let-7g, gga-let-7d, gga-let-7f, gga-let-7a-1, gga-mir-146a, gga-mir-181b-2, gga-mir-181a-2, gga-mir-1a-1, gga-mir-1b, gga-let-7a-2, gga-mir-34b, gga-mir-34c, gga-let-7j, gga-let-7k, gga-mir-23b, gga-mir-27b, gga-mir-24, gga-mir-122-1, gga-mir-122-2, hsa-mir-429, hsa-mir-449a, hsa-mir-146b, hsa-mir-507, hsa-mir-455, hsa-mir-92b, hsa-mir-449b, gga-mir-146b, gga-mir-302b, gga-mir-302c, gga-mir-302d, gga-mir-455, gga-mir-367, gga-mir-429, gga-mir-449a, hsa-mir-449c, gga-mir-21, gga-mir-1458, gga-mir-1576, gga-mir-1612, gga-mir-1636, gga-mir-449c, gga-mir-1711, gga-mir-1729, gga-mir-1798, gga-mir-122b, gga-mir-1811, gga-mir-146c, gga-mir-15c, gga-mir-449b, gga-mir-222b, gga-mir-92-2, gga-mir-125b-1, gga-mir-449d, gga-let-7l-1, gga-let-7l-2, gga-mir-122b-1, gga-mir-122b-2
In addition the miRNAs clusters that were significantly down-regulated miR-15/16 and let-7 are typically down-regulated in stem cells and cancer [62- 64]. [score:7]
Clusters mir-16-1-mir-15a, let-7f-let-7a-1, mir-181a-1-mir-181b-1, let-7j-let-7k, mir-23b-mir-27b-mir-24, and mir-16-2-mir-15b were down-regulated in lungs and mir-181a-1-mir-181b-1 was also down-regulated in tracheae with AIV infection. [score:7]
Based on other immune related miRNA studies in mammals [11, 66], differentially expressed miRNAs of their mammalian homologs and their targets are presented in Table 9. MiR-15a, miR-21 and miR-181a have important functions in lymphocytes development and modulations while miR-122 and miR-24 are related to virus infection and miR-146a, induced by macrophages, can activate Toll like receptor (TLR) and expose antigens to interleukin-1 beta. [score:6]
The miRNAs from five of these clusters (mir-16-1-mir-15a, mir-16-2-mir-15b, let-7f-let-7a-1, let-7j-let-7k and mir-23b-mir-27b-mir-24) identified in both lungs and tracheae were significantly down-regulated in infected lungs compared to non-infected lungs and also had higher expression levels in non-infected lungs than non-infected tracheae. [score:5]
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The immunosuppressive B cell subset (B-10) was reduced following IFN treatment, yet it had the highest miR-15a expression that increased with disease development. [score:8]
Although it is currently unknown whether changes in miR-15a expression are pathogenic or an epiphenomenon, these results suggest that miR-15a is implicated in the development of SLE in NZB/W mice by directing the balance of splenic B cell subsets [69]. [score:5]
miR-15a expression in the pathogenic B cell subset (B-2) only increased upon disease onset. [score:5]
Splenic and plasma miR-15a levels were elevated in diseased mice compared to prediseased mice. [score:4]
Increased autoantibody levels were significantly correlated with increased miR-15a expression. [score:3]
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[+] score: 24
These observations propose a scenario that miR-15a synchronously downregulates both c-myb itself and downstream genes transcriptionally regulated by c-myb, resulting in efficient inactivation of the whole molecular network governed by the hub gene c-myb. [score:5]
Consistent with this study, we found 'transcriptional regulation by myb' as the most relevant pathway to the miR-15a target network (the score = 602; the score p-value = 7.39E-182) (Figure 2 and Additional file 1). [score:4]
A recent study showed that miR-15a targets c-myb, while c-myb binds to the promoter of miR-15a, providing an autoregulatory feedback loop in human hematopoietic cells [17]. [score:4]
By the "neighboring" network-search algorithm, KeyMolnet illustrated a highly complex network of miR-15a targets that has the most statistically significant relationship with the pathway of 'transcriptional regulation by myb'. [score:4]
Red nodes represent miR-15a direct target molecules predicted by Diana-microT 3.0, whereas white nodes exhibit additional nodes extracted automatically from the core contents of KeyMolnet to establish molecular connections. [score:4]
Figure 2 Molecular network of miR-15a targets. [score:3]
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[+] score: 24
Interestingly, the expression of miR-15 family was also shown to be up-regulated in cardiac ischemia and heart failure [12]. [score:6]
Through profiling and comparing miRNA expression between P1 and P10 rat cardiomyocytes, members of the miR-15 family, including miR-195, miR-15a, miR-15b, miR-16, and miR-497, were identified as important regulators of postnatal cardiomyocyte mitotic arrest [11]. [score:4]
Together, these studies suggest that the miR-15 family may play distinct roles in cardiomyocyte proliferation, apoptosis under different developmental and/or pathological conditions, implying their potential to treat cardiac regeneration related disease. [score:4]
Furthermore, it was reported that miR-15 induces apoptosis by targeting anti-apoptotic factor Bcl2 [14]. [score:3]
Cimmino A. Calin G. A. Fabbri M. Iorio M. V. Ferracin M. Shimizu M. Wojcik S. E. Aqeilan R. I. Zupo S. Dono M. miR-15 and miR-16 induce apoptosis by targeting BCL2 Proc. [score:3]
Porrello E. R. Mahmoud A. I. Simpson E. Johnson B. A. Grinsfelder D. Canseco D. Mammen P. P. Rothermel B. A. Olson E. N. Sadek H. A. Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family Proc. [score:2]
Recently, it has been reported that neonatal mammalian hearts can regenerate after myocardial infarction through the proliferation of preexisting cardiomyocytes, and that the miR-15 family of miRNAs participates in this process in neonatal hearts [13]. [score:1]
Porrello E. R. Johnson B. A. Aurora A. B. Simpson E. Nam Y. J. Matkovich S. J. Dorn G. W. van Rooij E. Olson E. N. MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes Circ. [score:1]
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[+] score: 23
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-16-1, hsa-mir-21, hsa-mir-23a, hsa-mir-27a, hsa-mir-29a, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-16-2, hsa-mir-10a, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-181a-1, hsa-mir-223, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-146a, hsa-mir-150, hsa-mir-155, hsa-mir-181b-2, hsa-mir-29c, hsa-mir-101-2, hsa-mir-301a, hsa-mir-378a, hsa-mir-381, hsa-mir-340, hsa-mir-146b, hsa-mir-181d, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-590, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-378d-2, hsa-mir-301b, hsa-mir-548e, hsa-mir-548j, hsa-mir-548k, hsa-mir-548l, hsa-mir-548f-1, hsa-mir-548f-2, hsa-mir-548f-3, hsa-mir-548f-4, hsa-mir-548f-5, hsa-mir-548g, hsa-mir-548n, hsa-mir-548m, hsa-mir-548o, hsa-mir-548h-1, hsa-mir-548h-2, hsa-mir-548h-3, hsa-mir-548h-4, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-548q, hsa-mir-548s, hsa-mir-378b, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-548x, hsa-mir-378c, hsa-mir-23c, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-378f, hsa-mir-378g, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-378h, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-378i, hsa-mir-548am, hsa-mir-548an, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-378j, hsa-mir-548ay, hsa-mir-548az, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
Namely, HHV-6A specifically induced an early up-regulation of miR-590 (1 d. p. i. ), miR-15a and miR-21 (3 d. p. i. ), a sustained up-regulation of miR-29b, miR-101 (3 and 6 d. p. i. ), miR-301a and miR-548e (1 and 6 d. p. i. ) and a late up-regulation of miR-340 and miR-381 (6 d. p. i. ) By contrast, HHV-6B infection specifically up-modulated the expression of miR-301b (2 and 3 d. p. i. ) and miR-548e (1 and 3 d. p. i. ), whereas it down-regulated miR-590 (2 and 3 d. p. i. ) and miR-15a (6 d. p. i. ). [score:15]
miR-29 and miR-15, both increased by HHV-6A infection, have a specific role in regulating the cytotoxic activity of NK cells, inhibiting the production of IFNγ by directly targeting the 3′ UTR of its mRNA (Ma et al., 2011; Leong et al., 2014). [score:7]
Interestingly, HHV-6B, but not HHV-6A, infection down-modulated miR-590 and miR-15, suggesting that the two species might impact differently on NK cell functions. [score:1]
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[+] score: 22
The last number shows the potential diseases that related to this co-function pair The 5th-ranked pair, miR-15b and miR-195, both belong to the miR-15 family, and both of them can target gene BCL2, an important apoptosis inhibitor. [score:7]
The last number shows the potential diseases that related to this co-function pair The 5th-ranked pair, miR-15b and miR-195, both belong to the miR-15 family, and both of them can target gene BCL2, an important apoptosis inhibitor. [score:7]
For example, for the two miRNA pairs that both are members of the miR-15 family (miR-15a/b), the top three possible co-functional targets for the non-cancer diseases are IFNG, MTHFR, RARB, while for cancers are BCL2, CDKN1A and CCND1. [score:5]
For example, a therapy with the vector-encoded pair miR-15a and miR-16-1 has been proposed for the treatment of chronic lymphocytic leukaemia (CLL) [13]; The microRNA cluster miR-216a/217 was reported to target genes PTEN and SMAD7 to induce the epithelial-mesenchymal transition, which can promote the drug resistance and recurrence of liver cancer [14]. [score:3]
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50
[+] score: 22
In addition, downregulation of miR-15a and miR-16 in CAFs in the prostate cancer microenvironment promoted tumor growth and progression by suppressing the posttranscriptional repression of Fgf-2 and its receptor Fgfr1, which enhance tumor-cell survival, proliferation, and migration by acting on both stromal and tumor cells [50]. [score:6]
Taken together, these findings suggest that the DLEU2/miR-15a/16 locus has a tumor-suppressor role in the B-cell lineage in vivo, providing a paradigm for a similar role of other sterile transcripts in human diseases. [score:5]
A recent study from Klein et al., showed that deletion of the miR-15a/16 cluster in B cells may accelerate the G [0]/G [1]-S phase transition by causing a defect in the negative regulation of the expression of molecules critically involved in this transition [33]. [score:4]
Decreased levels of miR-15a and miR-16 during hypoxia have been found to contribute to sustained expression of VEGF, and consequently to the promotion of angiogenesis [13]. [score:3]
In addition to their role in cancer as oncogenes, a tumor-suppressing role under hypoxic conditions has been associated with several miRNAs including miR-15a, 16, 22, 29, 107, 145, and 519c. [score:3]
A minimal deleted region has been identified that includes the deleted in leukemia 2 gene (DLEU2) [31], which encodes a long noncoding RNA (1.0–1.8 kb) that is polyadenylated and spliced [31], and the miR-15a/16 cluster that is located intronic to DLEU2 [30, 32]. [score:1]
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51
[+] score: 22
Cimmino et al. then demonstrated that miR-15a and miR-16-1 expressions were inversely correlated to Bcl2 expression in CLL and that both miRNAs negatively regulated Bcl2 at a posttranscriptional level. [score:6]
Detailed deletion and expression analysis showed that miR-15 and miR-16 are located within a 30 kb region of loss in CLL, and that both genes were deleted or downregulated in approximately 68% of CLL cases [8]. [score:6]
Recently, Garzon et al. showed that all-trans retinoic acid (ATRA) downregulation of Bcl2 and Ras was correlated with the activation of miR-15a/miR-16-1 [12]. [score:4]
Therefore miR-15 and miR-16 were natural antisense Bcl2 interactors that could be used for therapy of Bcl2 -overexpressing tumors [11]. [score:3]
Bottoni et al. found that miR-15a and miR-16-1 were expressed at lower levels in pituitary adenomas as compared to normal pituitary tissue. [score:2]
Calin et al. first made the connection between microRNAs and cancer by showing that miR-15 and miR-16 are located at chromosome 13q14, a region deleted in more than half of B-cell chronic lymphocytic leukemia (CLL). [score:1]
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52
[+] score: 22
Moreover, E2F1 has been shown to enhance hsa-miR-15 expression, which inhibits cyclin E, one of the key transcriptional targets of E2F1 [17]. [score:7]
Our results indicated some minor miRNA expression changes, especially in the case of hsa-miR-15a, however, expression changes were not fully congruent in the three cell types studied, suggesting that the well known, cell type specific expression of miRNAs may contribute to this phenomenon. [score:7]
In the case of hsa-miR-15a, small RNA sequencing detected two-fold alteration in expression in NCI-H295R and HeLa cells as well and qRT-PCR analysis further confirmed some small, but significant expression changes in all three cell types. [score:5]
Therefore, we analyzed expression changes of the hsa-miR-16 family members: hsa-miR-16, hsa-miR-15a and hsa-miR-503 in our high-throughput data (Fig.   4, Panel a-d and Additional file 2: Figure S5, Panel a) and performed qRT-PCR analysis as well (Fig.   4, Panel e-g). [score:3]
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[+] score: 22
In this respect, there is a long list of predicted miRNAs (i. e. from DIANA-microT, miRanda, TargetScanS algorithms) that may target the 3'UTR of APP, including let-7i, miR-15, -26, -29, -93, -101, -106, and miR-181 which are reportedly down-regulated in AD brain [96, 99]. [score:8]
The up-regulation of miR-197 and down-regulation of miR-15, -146b, -181c, and miR-338 are commonly altered in AD brain parenchyma and CSF. [score:7]
The down-regulation of miR-106a/b (Fig. 2), perhaps with other down-regulated miRNAs (let-7i, miR-15, -26, -29, -93 -101), may favor higher APP levels in AD brains. [score:7]
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54
[+] score: 21
miR-15a and miR-16 are implicated in cell cycle regulation in a Rb -dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer. [score:5]
Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. [score:4]
miR-15a and miR-16-1 down-regulation in pituitary adenomas. [score:4]
The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. [score:3]
Tumors were generated by intramuscular injection of an adenovirus expressing Cre recombinase, as previously described (Kirsch et al., 2007) into the hind limb of mice with genotype LSL-Kras [G12D/+]; p53 [fl/fl] (KP) or LSL-Kras [G12D/+]; p53 [fl/fl]; miR-15a/16-1 [fl/fl] (KP miR-16 F/F). [score:3]
The DLEU2/miR-15a/16–1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. [score:1]
Primary soft tissue sarcomas were generated using the previously described alleles: LSL-Kras [G12D] (Jackson et al., 2001), p53 [Fl] (Jonkers et al., 2001) and miR-15a/16-1 [Fl] (Klein et al., 2010), in mice with a mixed genetic background. [score:1]
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[+] score: 21
The expression of miRNAs, including those regulated by miR-15a-5p, could be upregulated via the interaction of E6 with c-MYC [25, 26]. [score:7]
The qRT-PCR results demonstrated that miR-106b-5p (p = 0.000), miR-3653 (p = 0.000), miR-17-5p (p = 0.000), miR-96 (p = 0.000), miR-15a-5p (p = 0.000), miR-20a-5p (p = 0.000), and miR-21-5p (p = 0.000) were highly expressed in cancer tissues, while miR-497-5p (p = 0.016) was expressed at very low levels. [score:5]
Here, we identified eight types of miRNAs, namely, the highly expressed miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, miR-96, miR-106b-5p, and miR-3653 as well as the poorly expressed miR-497-5p. [score:5]
These findings imply that miR-15a-5p, miR-17-5p, miR-20a-5p, miR-21-5p, and miR-106b-5p are molecular targets of HPV in vivo. [score:3]
These miRNAs included miR-106b-5p, miR3653, miR-3188, miR-497-5p, miR-218-5p, miR-17-5p, miR-96, miR-15a-5p, miR-20a-5p, miR-21-5p, and miR-590-5p (Table 3). [score:1]
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[+] score: 20
Therefore, the different trend they observed in miR-30b, miR-15a and let-7i expression comparing to our results could be conferred to the fact that the expression of those miRNA in centenarians is very similar to young people. [score:5]
Then, we represented the expression values of each miRNA (in DCq) for each group and it can be observed that their expression decreases gradually in this ranges, specially in miR-15a, let-7i and let-7g. [score:5]
miR-15a and miR-30b also had a slightly lower expression in this group, but the difference was not statistically significant (RQ=0.632; p-value=0.121 and RQ=0.777; p-value=0.0591, respectively) (Table 5). [score:3]
Moreover, we have confirmed the decreasing expression of miR-15a, miR-30b, let-7i and let-7g with age in and independent cohort by RT-qPCR. [score:3]
Serna et al, had also related those miRNA to human aging but, they found and overexpression of miR-30b, miR-15a and let-7i in centenarians compared to octogenarians[17]. [score:2]
Even if miR-15a and miR-30b did not show a statistically significant change, we decided to include them in further validation experiments. [score:1]
This selection resulted in a list of 5 candidate miRNA: miR-15a, miR-30b, let-7i, let-7g and miR-1281 (Table 5). [score:1]
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Aberrant expression of microRNA-15a and microRNA-16 synergistically associates with tumor progression and prognosis in patients with colorectal cancer. [score:3]
Downstream of Wnt, MYC transcriptionally activates the miR-17-92 locus, but represses expression of miR-15, miR-26 and miR-30. [score:3]
Lastly, several miRNAs have effects on EMT in CRC tumorigenesis, with miR-15/16 and miR-34 (which are transcriptionally activated by TP53) inhibiting this process, while miR-21 enhances EMT. [score:3]
Shi et al. (2014) demonstrated using mouse xenograft mo dels of lung metastasis that the repressive effects of miR-15a/16 on migration, invasion, and EMT are due to their direct repression of TFAP4. [score:2]
As is frequently observed for miRNAs, the authors also uncovered a negative feedback loop, whereby TFAP4 directly represses the transcription of the miR-15a/miR-16-1 locus. [score:2]
Mechanistically, the miR-15a/miR-16-1 locus is induced by TP53 in response to DNA damage and is responsible for directly repressing the pro-metastatic bHLH transcription factor AP-4 (TFAP4) in CRC cells (Shi et al., 2014). [score:2]
p53 -induced miR-15a/16-1 and AP4 form a double -negative feedback loop to regulate epithelial-mesenchymal transition and metastasis in colorectal cancer. [score:2]
miR-15 anti-oncomiR family. [score:1]
The miR-15 family (miR-15, miR-16, miR-195) can also include miR-424 and miR-497. [score:1]
Oncogenic role of miR-15a-3p in 13q amplicon -driven colorectal adenoma-to-carcinoma progression. [score:1]
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[+] score: 20
Interestingly while miR-15b and 16 were downregulated, the miR-15a was upregulated in melanocytes expressing BRaf [V600E]. [score:9]
In addition, we showed that oncogenic BRaf also significantly increased the expression of miR-143, miR-34a, let-7c, miR-15a, miR-29a, miR-100, miR-181a, and miR-181d. [score:3]
Retroviral expression vectors (miR-vec) for miR-100, miR-15a/16-1, and -181a were a kind gift of Reuven Agami. [score:3]
The miR-15/16 family is known to have a negative effect on cell proliferation by targeting mRNAs for various cell-growth -associated genes [34– 36]. [score:3]
miR-15/16 belongs to a very unique group of microRNAs. [score:1]
miR-16 has 2 transcripts—one is called miR-16-1 located on Chromosome (Chr) 13 and shares the same transcript with miR-15a forming the miR-15a/16 cluster. [score:1]
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Other miRNAs from this paper: hsa-let-7a-2, hsa-let-7c, hsa-let-7e, hsa-mir-16-1, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-2, hsa-mir-100, hsa-mir-29b-2, mmu-let-7i, mmu-mir-99b, mmu-mir-125a, mmu-mir-130a, mmu-mir-142a, mmu-mir-144, mmu-mir-155, mmu-mir-183, hsa-mir-196a-1, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, hsa-mir-148a, mmu-mir-143, hsa-mir-181c, hsa-mir-183, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-181a-1, hsa-mir-200b, mmu-mir-298, mmu-mir-34b, hsa-let-7i, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-130a, hsa-mir-142, hsa-mir-143, hsa-mir-144, hsa-mir-125a, mmu-mir-148a, mmu-mir-196a-1, mmu-let-7a-2, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-mir-15a, mmu-mir-16-1, mmu-mir-21a, mmu-mir-22, mmu-mir-23a, mmu-mir-24-2, rno-mir-148b, mmu-mir-148b, hsa-mir-200c, hsa-mir-155, mmu-mir-100, mmu-mir-200c, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-181c, hsa-mir-34b, hsa-mir-99b, hsa-mir-374a, hsa-mir-148b, rno-let-7a-2, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7i, rno-mir-21, rno-mir-22, rno-mir-23a, rno-mir-24-2, rno-mir-29b-2, rno-mir-34b, rno-mir-99b, rno-mir-100, rno-mir-124-1, rno-mir-124-2, rno-mir-125a, rno-mir-130a, rno-mir-142, rno-mir-143, rno-mir-144, rno-mir-181c, rno-mir-183, rno-mir-199a, rno-mir-200c, rno-mir-200b, rno-mir-181a-1, rno-mir-298, hsa-mir-193b, hsa-mir-497, hsa-mir-568, hsa-mir-572, hsa-mir-596, hsa-mir-612, rno-mir-664-1, rno-mir-664-2, rno-mir-497, mmu-mir-374b, mmu-mir-497a, mmu-mir-193b, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-568, hsa-mir-298, hsa-mir-374b, rno-mir-466b-1, rno-mir-466b-2, hsa-mir-664a, mmu-mir-664, rno-mir-568, hsa-mir-664b, mmu-mir-21b, mmu-mir-21c, rno-mir-155, mmu-mir-142b, mmu-mir-497b, rno-mir-148a, rno-mir-15a, rno-mir-193b
Among them are two polycistronic transcripts (miR-15a~16-1 and miR-193b~365-1), and two expressing single miRNAs (miR-148a and miR-155). [score:3]
The predicted genomic coordinates of pri-miRNAs are provided in Additional file 1. Here, we describe in detail the annotation of the pri-miRNA containing miR-15a and miR-16-1. The structure of a polycistronic transcript expressing miR-15a and miR-16-1 is strongly supported by all seven types of transcriptional features. [score:3]
The predicted genomic coordinates of pri-miRNAs are provided in Additional file 1. Here, we describe in detail the annotation of the pri-miRNA containing miR-15a and miR-16-1. The structure of a polycistronic transcript expressing miR-15a and miR-16-1 is strongly supported by all seven types of transcriptional features. [score:3]
The structure of a polycistronic transcript expressing miR-15a and miR-16-1 is strongly supported by all seven types of transcriptional features. [score:3]
These data agree with previous annotation by the VEGA project of non-protein-coding transcripts (accessions: OTTHUMT00000044959 and OTTHUMT00000044961) expressing miR-15a and miR-16-1 in human, called DLEU2 [39]. [score:3]
In human, we predict 8 TSSs with an average distance of 32,242 bp upstream of miR-15a. [score:1]
miR-15a~16-1. Species-specific (Group III and IV) pri-miRNAs. [score:1]
Taking all these features together, we annotate the 5' end of the human pri-miRNA at ~33 kb upstream of miR-15a. [score:1]
The features mapped to the flanking regions surrounding the hsa-mir-15a~16-1 are shown (Figure 6). [score:1]
Figure 6 Transcription features mapped in the flanking regions surrounding the cluster mir-15a~16-1 in human. [score:1]
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[+] score: 20
We selected, for experimental validation, targets to three of these miRNAs: hsa-miR-17-5p (one target: see below), hsa-miR-15a (two targets), and hsa-miR-324-3p (three targets). [score:9]
BCL2 mRNA has previously been validated as a target for has-miR-15a inhibition [30]. [score:5]
Five of the target sites (hsa-miR-15a/TSPYL2, hsa-miR-15a/BCL2, hsa-miR-17-5p/TNFSF12, hsa-miR-324-3p/CREBBP and hsa-miR-324-3p/WNT9B) exhibit perfect WC complementarity in the seed regions, while has-miR-324-3p/DVL2 has one GU pair in the same region (Supplementary Figure S1). [score:3]
This selection was made on the basis of functional association with cancer (hsa-miR-17-5p, hsa-miR-15a) or predicted targets in the Wnt signalling pathway (hsa-miR-324-3p) as described in Supplementary Table S7. [score:3]
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[+] score: 19
Quercetin increased miR-16 expression without affecting the expression levels of miR-15a, 15b, 195, 424, and 497 (Figure 7A). [score:5]
Bandi N. Zbinden S. Gugger M. Arnold M. Kocher V. Hasan L. Kappeler A. Brunner T. Vassella E. miR-15a and miR-16 are implicated in cell cycle regulation in a Rb -dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer Cancer Res. [score:5]
Cimmino A. Calin G. A. Fabbri M. Iorio M. V. Ferracin M. Shimizu M. Wojcik S. E. Aqeilan R. I. Zupo S. Dono M. miR-15 and miR-16 induce apoptosis by targeting BCL2 Proc. [score:3]
The expression of miR-16 was increased by quercetin, but that of miR-15a, 15b. [score:3]
TargetScan analysis indicated that the 3′-UTR of claudin-2 contains putative binding sites for miR-15a, 15b, 16, 195, 424, and 497. [score:3]
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[+] score: 19
These results propose a scenario that miR-15a synchronously downregulates both c-myb itself and downstream genes transcriptionally regulated by c-myb, resulting in more effective inactivation of the whole miR-15a targetome network governed by the hub gene c-myb. [score:7]
Consistent with these observations, we found ‘transcriptional regulation by myb’ as the most relevant pathway to the miR-15a targetome network [17]. [score:4]
Recent evidence indicates that miR-15a targets c-myb, while c-myb binds to the promoter of miR-15a, providing an autoregulatory feedback loop in human hematopoietic cells [45]. [score:4]
Extracellular signal-regulated kinase 1 (ERK1) is identified as a candidate kinase regulated by the miR-15 family responsible for tau phosphorylation. [score:3]
The levels of miR-15a are substantially reduced in AD brains [63]. [score:1]
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[+] score: 19
Other miRNAs from this paper: rno-mir-15a
miR15a overexpression in PCK cholangiocytes decreases Cdc25A levels, inhibits cell proliferation, and reduces cyst growth, indicating a potential therapeutic strategy for the disease. [score:7]
In addition, PCK cholangiocyte hyperproliferation is accompanied by the overexpression of Cdc25A protein and the downregulation of miR15a [26, 57]. [score:6]
The biliary epithelium of CHF overexpresses Cdc25A protein (an isoform of Cdc25), which is accompanied by the downregulation of a microRNA (miR15a) [26]. [score:6]
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64
[+] 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-17, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-30a, hsa-mir-93, hsa-mir-96, hsa-mir-99a, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-105-1, hsa-mir-105-2, hsa-mir-30c-2, hsa-mir-30d, hsa-mir-10a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-205, hsa-mir-212, hsa-mir-181a-1, hsa-mir-222, hsa-mir-224, hsa-let-7g, hsa-let-7i, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-125b-1, hsa-mir-132, hsa-mir-141, 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-146a, hsa-mir-150, hsa-mir-184, hsa-mir-188, hsa-mir-320a, hsa-mir-181b-2, hsa-mir-30c-1, hsa-mir-302a, hsa-mir-34c, hsa-mir-30e, hsa-mir-302b, hsa-mir-302c, hsa-mir-302d, hsa-mir-371a, hsa-mir-372, hsa-mir-376a-1, hsa-mir-378a, hsa-mir-383, hsa-mir-339, hsa-mir-133b, hsa-mir-345, hsa-mir-425, hsa-mir-483, hsa-mir-146b, hsa-mir-202, hsa-mir-193b, hsa-mir-181d, hsa-mir-498, hsa-mir-518f, hsa-mir-518b, hsa-mir-520c, hsa-mir-518c, hsa-mir-518e, hsa-mir-518a-1, hsa-mir-518d, hsa-mir-518a-2, hsa-mir-503, hsa-mir-513a-1, hsa-mir-513a-2, hsa-mir-376a-2, hsa-mir-548a-1, hsa-mir-548b, hsa-mir-548a-2, hsa-mir-548a-3, hsa-mir-548c, hsa-mir-645, hsa-mir-548d-1, hsa-mir-548d-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, hsa-mir-378d-2, hsa-mir-744, hsa-mir-548e, hsa-mir-548j, hsa-mir-548k, hsa-mir-548l, hsa-mir-548f-1, hsa-mir-548f-2, hsa-mir-548f-3, hsa-mir-548f-4, hsa-mir-548f-5, hsa-mir-548g, hsa-mir-548n, hsa-mir-548m, hsa-mir-548o, hsa-mir-548h-1, hsa-mir-548h-2, hsa-mir-548h-3, hsa-mir-548h-4, hsa-mir-302e, hsa-mir-302f, hsa-mir-548p, hsa-mir-548i-1, hsa-mir-548i-2, hsa-mir-548i-3, hsa-mir-548i-4, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, hsa-mir-548q, hsa-mir-548s, hsa-mir-378b, hsa-mir-548t, hsa-mir-548u, hsa-mir-548v, hsa-mir-548w, hsa-mir-320e, hsa-mir-548x, hsa-mir-378c, hsa-mir-548y, hsa-mir-548z, hsa-mir-548aa-1, hsa-mir-548aa-2, hsa-mir-548o-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-548h-5, hsa-mir-548ab, hsa-mir-378f, hsa-mir-378g, hsa-mir-548ac, hsa-mir-548ad, hsa-mir-548ae-1, hsa-mir-548ae-2, hsa-mir-548ag-1, hsa-mir-548ag-2, hsa-mir-548ah, hsa-mir-378h, hsa-mir-548ai, hsa-mir-548aj-1, hsa-mir-548aj-2, hsa-mir-548x-2, hsa-mir-548ak, hsa-mir-548al, hsa-mir-378i, hsa-mir-548am, hsa-mir-548an, hsa-mir-371b, hsa-mir-548ao, hsa-mir-548ap, hsa-mir-548aq, hsa-mir-548ar, hsa-mir-548as, hsa-mir-548at, hsa-mir-548au, hsa-mir-548av, hsa-mir-548aw, hsa-mir-548ax, hsa-mir-378j, hsa-mir-548ay, hsa-mir-548az, hsa-mir-548ba, hsa-mir-548bb, hsa-mir-548bc
In mature MII-stage oocytes, four miRNAs were upregulated and eleven were downregulated in comparison to immature GV-stage oocytes, as can be seen in Figure 2. The RT-PCR analysis of miR-15a and miR-20a expression revealed the concordant dynamic changes of these two miRNAs during meiosis. [score:9]
An antisense construct inhibiting miR-15a increased PCNA, while an antisense construct of miR-188 did not affect PCNA expression. [score:5]
Moreover, the high concentration of FSH in the in vitro maturation medium led to reverse effect on the expression of miR-15a and miR-20a, which confirmed the involvement of these two miRNAs in the oocyte maturation process influenced by FSH [28]. [score:3]
In the next step, two selected antisense constructs blocking the corresponding miRNAs miR-15a and miR-188 were used to evaluate their effects on the expression of PCNA. [score:1]
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65
[+] score: 18
We demonstrate that overexpression of these HMGA1 pseudogenes increases HMGA1 protein levels, and inhibits the suppression of HMGA1 protein synthesis by miRNAs that target the HMGA1 gene, namely, miR-15, miR-16, miR-214, and miR-761 [31- 34]. [score:9]
Figure 2 HMGA1P6 and HMGA1P7 are targeted by HMGA1 -targeting miRNAs (A) qRT-PCR analysis of HMGA1P6 (left), HMGA1P7 (middle) and HMGA1 (right) mRNA from the MCF7 cells transfected with scrambled-oligonucleotide, miR-15, miR-16, miR-214 and miR-761. [score:5]
Within the high homology regions, we found perfectly conserved seed matches for miRNAs that have been predicted (miR-103, miR-142-3p, miR-370, and miR-432) or already demonstrated (miR-15 [31], miR-16 [31], miR-26a [32], miR-214 [33], miR-548c-3p [34] and miR-761 [33]) to target the HMGA1 gene (Figure 1B and 1C). [score:3]
Relative luciferase activity in HEK293 cells transiently transfected with miR-15, miR-16, miR-214, miR-761 and a control scrambled oligonucleotide. [score:1]
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66
[+] score: 18
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]
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]
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]
Levels of miR-15a-5p were also found to significantly decrease with a log(mol/L) increase of Σnonparabens [–0.09 (95% CI: –0.16, –0.01)]. [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]
An increase in the urine concentrations of Σphenols was associated with a significant decrease only in miR-15a-5p in the placenta among female infants (–0.22; 95% CI: –0.38, –0.07). [score:1]
Infant sex significantly modified the association between miR-15a-5p levels and both Σphenols and Σparabens. [score:1]
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67
[+] score: 18
The miR-15 family has been verified to negatively regulate CHK1 and WEE1 at both the mRNA and protein levels, and reduction of CHK1 and WEE1 subsequently prolonged γ-H2AX expression after irradiation, which increased radiosensitivity of cancer cells. [score:4]
For example, almost all of the miR-15 family miRNAs (miR-15a/b, miR-195, miR-424, and miR-497) were downregulated across a number of different cell lines, including endothelial cells, non-small cell lung cancer (NSCLC) cells, and lymphoblasts [97], whereas miR-148b was repressed by IR in endothelial cells, but induced by IR in non-Hodgkin lymphoma [98, 99]. [score:4]
Recently, it was reported that inhibition of the miR-15 family failed to increase radioresistance in breast cancer cells. [score:3]
Another study also found reduced expression of miR-15 family members (miR-15a, miR-15b, miR-16, miR-195, miR-424, and miR-497) and miR-155 in cisplatin-resistant cells. [score:3]
Mei Z. Su T. Ye J. Yang C. Zhang S. Xie C. The miR-15 family enhances the radiosensitivity of breast cancer cells by targeting G2 checkpoints Radiat. [score:3]
Pouliot L. M. Chen Y. C. Bai J. Guha R. Martin S. E. Gottesman M. M. Hall M. D. Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family Cancer Res. [score:1]
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68
[+] score: 18
miRNA miR function Regulation Tissue/cell type Source miR-15a Tumor suppressor Down Primary bronchial epithelial cells Schembri et al. 2009 miR-125bTargets p53, stress response miR‑199b Oncogene activation miR-218 Tumor suppressor miR-31 Apoptosis, tumor suppressor Up Normal and cancer lung cells Xi et al. 2010 miR-21 Fatty acid synthesis, apoptosis Up Human squamous carcinoma cells Zhang et al. 2014 miR-452Targets CDK1 Down Human alveolar macrophages Graff et al. 2012 Izzotti et al. (2009) analyzed miRNA expression patterns in the lungs of mice exposed to passive cigarette smoke, and they established life-course–related miRNA expression changes by comparing miRNA expression in lungs from unexposed newborn, postweaning, and adult mice. [score:18]
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69
[+] score: 18
Twelve of them (miR-10b, miR-15a, miR-19a, miR-26b, miR-30a, miR-30c, miR-125a, miR-125b, miR-148a, miR-148b, miR-195 and miR-320) are down-regulated both in dogs and in humans whereas one (miR-494) is up-regulated in both species and four (miR-29a, miR-181a, miR-196a and miR-374a) are down-regulated in dogs but up-regulated in humans. [score:13]
Further, they did not find any significant difference in miR-9, miR-10b, miR-15a, miR-16, miR-125b, miR-136 and let-7f expression levels among the examined groups [18]. [score:3]
Von Deetzen et al. compared the expression profiles of 16 microRNAs (miR-136, miR-143, let-7f, miR-29b, miR-145, miR-9, miR-10b, miR-203, miR-125b, miR-15a, miR-16, miR-21, miR-101, miR-210, miR-194 and miR-125a) in three types of canine mammary tumours (adenoma, non-metastasising carcinoma, metastasising carcinoma), lymph node metastases and in a normal mammary gland. [score:2]
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70
[+] score: 17
In Xenopus, miR-15/miR-16 regulates early embryonic patterning by targeting Acvr2a (also named as ActRIIA), which is the type II receptor for ActivinA and Nodal [19]. [score:4]
It is noticeable that miR-15/16 restrict the size of the Spemann’s organizer by targeting ActRIIA during embryo development in Xenopus [19]. [score:4]
From literatures of microarray data, miR-195, miR-15b and miR-424 were the three members in miR-15 gene family that exhibited down-regulation in preeclamptic placenta [12], [31]. [score:4]
The binding sites in ActRIIA mRNA for miR-15/16 and miR-195 are conserved, further suggesting that ActRIIA may be an essential target for these members of miR-15 family. [score:3]
MiR-195 is clustered with miR-497 [13] and belongs to miR-15 family [14]. [score:1]
MiR-195 belongs to miR-15 gene family which includes miR-15a/b/c, miR-16a/b/c, miR-497 and miR-424. [score:1]
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71
[+] score: 17
A lower (0.62-fold; p < 0.0001) levels of RECK protein was observed in miR-15b mimic transfected cpLYO cells compared to mimic control transfected cells, while miR-15b knockdown by miR-15 inhibitor transfection resulted in increased (1.20-fold; p < 0.0001) RECK expression as determined by (Fig.   5b). [score:5]
MicroRNA-15 was previously reported to inhibit the expressions of MMP-2, MMP-9 and MMP-14 which involves in breaking down the ECM [46– 49]. [score:4]
Lower (0.85-fold; p < 0.0001) levels of RECK protein was observed in miR-15b mimic transfected cpMYO cells compared to mimic control transfected cells, while miR-15b knockdown by miR-15 inhibitor transfection resulted in increased (1.22-fold; p = 0.003) (Fig.   5c). [score:3]
The relative expression level of miRNA-15 band RECK was analyzed with the comparative cycle threshold method (2 [-ΔΔCT]). [score:3]
MiR-15b is a member of the miR-15/16 superfamily, which possesses a 5’-end AGCAGC sequence, and includes miR-15a, miR-15b, miR-16, miR-195, miR-322, miR-497 among others. [score:1]
The addition of miR-15 mimics resulted in decreased RECK. [score:1]
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72
[+] score: 16
Although miR-15a and miR-16-1 are down-regulated in chronic lymphocytic leukemia, which is consistent with their postulated tumor suppressor function [45], the same miRNAs are paradoxically overexpressed in endocrine pancreatic tumors [46]. [score:8]
For example, the miR-17-92 cluster is overexpressed in B cell lymphoma [38, 42], miR-15a and miR-16-1 exert tumor suppressor effect by inhibiting Bcl-2 function [43], whereas miR-155 is oncogenic through its probable effects on transcription factors C/EBPβ and PU. [score:7]
Calin and colleagues found that a region containing miR-15 and miR-16 at chromosome 13q14 was frequently deleted in the majority of chronic lymphocytic leukemia cases [34]. [score:1]
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73
[+] score: 16
MiRNA expression levels in both tissue types were normalized to individual U6 gene levels and then expressed relative to corresponding amounts of hsa-miR-15a expression. [score:7]
U6-normalized expression levels of hsa-miR-574-5p were favorable compared to individual hsa-miR-15a expression levels in liver (3.8±0.3 relative fold) and heart (1.3±0.7 relative fold). [score:4]
Quantitative RT-PCR gene expression detection of hsa-miR-15a and hsa-miR-574-5p in total RNA isolated from 4 human liver and 4 heart samples showed that both miRNAs were present in all samples (Figure 6). [score:3]
Direct sequencing of real-time PCR products confirmed the specific amplification of our positive control hsa-miR-15a as well as hsa-miR-574-5p. [score:2]
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74
[+] score: 16
The results revealed that let-7d-5p, miR-106b-5p, -130a-3p and -146a-5p were up-regulated, whereas miR-15a-5p and -194-5p were down-regulated in epilepsy patients compared to controls (Fig. 3). [score:6]
For miR-15a-5p and miR-194-5p, no previous literatures have reported their dysregulation in epilepsy or other neurological diseases. [score:4]
We got 361, 48, 8, 19, 87 and 26 intersected targets for let-7d-5p, miR-106b-5p, miR130a-3p, miR-146a-5p, miR-15a-5p and miR-194-5p, respectively (Supplementary Table S3). [score:3]
After 2-stage validation by qRT-PCR, we identified six miRNAs that were significantly dysregulated in the serum of epilepsy patients, namely, let-7d-5p, miR-15a-5p, -194-5p, -106b-5p, -130a-3p and -146a-5p. [score:2]
In addition to group comparisons, we examined the association between each of the 6 dysregualted miRNAs (let-7d-5p, miR-15a-5p, -194-5p, -146a-5p, -106b-5p and -130a-3p) with clinical parameters. [score:1]
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75
[+] score: 16
Of the 186 miRNAs the expression of which was altered, nine were up-regulated at both time points (miR-125a-3p, miR-297c, miR-421, miR-452, miR-483, miR-574-3p, miR-574-5p, miR-669a, miR-720) and 11 were down-regulated at both time points (let-7g, miR-107, miR-10a, miR-15a, miR-15b, miR-199b*, miR-26a, miR-29c, miR-324-5p, miR-331-3p, miR-342-3p). [score:9]
Two of the down-regulated miRNAs, miR-15a and miR-15b, regulate the cell cycle by controlling the expression of BCL2 and several cyclin family members (D1, D2, E1) [21, 22]. [score:7]
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76
[+] score: 15
Twelve radiation -suppressed miRNAs were identified, i. e. let-7d, miR-15a, miR-17, miR-30d, miR-92a, miR-197, miR-221, miR-320b, miR-342, miR-361, miR-501 and miR-671, and a significantly different expression between prostate cancer and the corresponding adjacent part was found, including 11 upregulated and 1 downregulated (Fig. 3B). [score:11]
However, the expression levels of let-7d and miR-15a decreased according to TCGA, which contradicted the results of previous studies (45– 47). [score:3]
In the present study, we also identified radiation-response miRNAs that had been reported in other types of cancer but not in prostate cancer, such as miR-25, miR-15a, miR-30d, miR-125a, miR-221 and miR-342 (21, 56– 63). [score:1]
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77
[+] score: 15
LMP1 upregulates miR-29b to suppress TCL1 oncogene expression, [125] but downregulates miR-203 to increase E2F transcription factor 3 (E2F3) and cyclin G1 expression [126] and miR-15a to promote MYB and cyclin D1 expression. [score:15]
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78
[+] score: 15
While miR-15b, -125a, -125b, -155, -208b, -211, -320, -376a, -411, -520g and -542-5p were down-regulated after 48 h, miR-15a and miR-548b were up-regulated. [score:7]
First evidence that miR down-regulation or deletion, particularly miR-15 and -16, plays a role in leukemogenesis was provided by Calin et al. in 2002 [42]. [score:4]
Calin G. A. Dumitru C. D. Shimizu M. Bichi R. Zupo S. Noch E. Aldler H. Rattan S. Keating M. Rai K. Frequent deletions and down-regulation of micro -RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia Proc. [score:4]
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79
[+] score: 15
In a study that reported the inhibition of miR-15a and miR-16 processing by miR-709 in mouse L929 liver cells, modest upregulation of miR-15a and miR-16 (<2-fold) was detected in anti-miR-709 transfected cells [41]. [score:6]
Whether or not miR-709 fine-tunes the expression of miR-15a and miR-16 in chronic lymphocytic leukaemia remains to be determined. [score:3]
miR-15a and miR-16-1 are established tumor suppressor miRNAs in chronic lymphocytic leukaemia. [score:3]
One of these miRNAs, miR-709, has been reported to bind with perfect complementarity to pri-miR-15a and pri-miR-16-1 and inhibit the biogenesis of these miRNAs [41]. [score:3]
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80
[+] score: 15
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-16-1, hsa-mir-21, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-99a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-16-2, hsa-mir-192, hsa-mir-148a, hsa-mir-10b, hsa-mir-181a-2, hsa-mir-181a-1, hsa-mir-215, hsa-mir-223, hsa-mir-224, hsa-mir-200b, hsa-mir-15b, hsa-mir-27b, hsa-mir-125b-1, hsa-mir-141, hsa-mir-143, hsa-mir-152, hsa-mir-125b-2, hsa-mir-126, hsa-mir-146a, hsa-mir-184, hsa-mir-200c, hsa-mir-155, hsa-mir-29c, hsa-mir-200a, hsa-mir-99b, hsa-mir-296, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-378a, hsa-mir-342, hsa-mir-148b, hsa-mir-451a, ssc-mir-125b-2, ssc-mir-148a, ssc-mir-15b, ssc-mir-184, ssc-mir-224, ssc-mir-23a, ssc-mir-24-1, ssc-mir-26a, ssc-mir-29b-1, ssc-let-7f-1, ssc-mir-103-1, ssc-mir-21, ssc-mir-29c, hsa-mir-486-1, hsa-mir-499a, hsa-mir-671, hsa-mir-378d-2, bta-mir-26a-2, bta-mir-29a, bta-let-7f-2, bta-mir-103-1, bta-mir-148a, bta-mir-16b, bta-mir-21, bta-mir-499, bta-mir-99a, bta-mir-125b-1, bta-mir-126, bta-mir-181a-2, bta-mir-27b, bta-mir-31, bta-mir-15b, bta-mir-215, bta-mir-30e, bta-mir-148b, bta-mir-192, bta-mir-200a, bta-mir-200c, bta-mir-23a, bta-mir-29b-2, bta-mir-29c, bta-mir-10b, bta-mir-24-2, bta-mir-30a, bta-mir-200b, bta-let-7a-1, bta-mir-342, bta-let-7f-1, bta-let-7a-2, bta-let-7a-3, bta-mir-103-2, bta-mir-125b-2, bta-mir-15a, bta-mir-99b, hsa-mir-664a, ssc-mir-99b, hsa-mir-103b-1, hsa-mir-103b-2, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, bta-mir-141, bta-mir-143, bta-mir-146a, bta-mir-152, bta-mir-155, bta-mir-16a, bta-mir-184, bta-mir-24-1, bta-mir-223, bta-mir-224, bta-mir-26a-1, bta-mir-296, bta-mir-29d, bta-mir-378-1, bta-mir-451, bta-mir-486, bta-mir-671, bta-mir-29e, bta-mir-29b-1, bta-mir-181a-1, ssc-mir-181a-1, ssc-mir-215, ssc-mir-30a, bta-mir-2318, bta-mir-2339, bta-mir-2430, bta-mir-664a, bta-mir-378-2, ssc-let-7a-1, ssc-mir-378-1, ssc-mir-29a, ssc-mir-30e, ssc-mir-499, ssc-mir-143, ssc-mir-10b, ssc-mir-486-1, ssc-mir-152, ssc-mir-103-2, ssc-mir-181a-2, ssc-mir-27b, ssc-mir-24-2, ssc-mir-99a, ssc-mir-148b, ssc-mir-664, ssc-mir-192, ssc-mir-342, ssc-mir-125b-1, oar-mir-21, oar-mir-29a, oar-mir-125b, oar-mir-181a-1, hsa-mir-378b, hsa-mir-378c, ssc-mir-296, ssc-mir-155, ssc-mir-146a, bta-mir-148c, 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, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-486-2, hsa-mir-664b, hsa-mir-378j, ssc-let-7f-2, ssc-mir-29b-2, ssc-mir-31, ssc-mir-671, bta-mir-378b, bta-mir-378c, hsa-mir-486-2, oar-let-7a, oar-let-7f, oar-mir-103, oar-mir-10b, oar-mir-143, oar-mir-148a, oar-mir-152, oar-mir-16b, oar-mir-181a-2, oar-mir-200a, oar-mir-200b, oar-mir-200c, oar-mir-23a, oar-mir-26a, oar-mir-29b-1, oar-mir-30a, oar-mir-99a, bta-mir-664b, chi-let-7a, chi-let-7f, chi-mir-103, chi-mir-10b, chi-mir-125b, chi-mir-126, chi-mir-141, chi-mir-143, chi-mir-146a, chi-mir-148a, chi-mir-148b, chi-mir-155, chi-mir-15a, chi-mir-15b, chi-mir-16a, chi-mir-16b, chi-mir-184, chi-mir-192, chi-mir-200a, chi-mir-200b, chi-mir-200c, chi-mir-215, chi-mir-21, chi-mir-223, chi-mir-224, chi-mir-2318, chi-mir-23a, chi-mir-24, chi-mir-26a, chi-mir-27b, chi-mir-296, chi-mir-29a, chi-mir-29b, chi-mir-29c, chi-mir-30a, chi-mir-30e, chi-mir-342, chi-mir-378, chi-mir-451, chi-mir-499, chi-mir-671, chi-mir-99a, chi-mir-99b, bta-mir-378d, ssc-mir-378b, oar-mir-29b-2, ssc-mir-141, ssc-mir-200b, ssc-mir-223, bta-mir-148d
Through target prediction analysis, growth hormone receptor (GHR) was determined to be targeted by miR-15a and functional analyses with a mammary epithelial cell line confirmed that miR-15a inhibited the expression of caseins, epithelial cell number as well as the expression of GHR mRNA and protein (Li et al., 2012e). [score:11]
MiR-15a decreases bovine mammary epithelial cell viability and lactation and regulates growth hormone receptor expression. [score:3]
From lung tissue of pigs infected with Actinobacillus pleuropneumoniae, Podolska et al. (2012) identified miR-664-5p, miR-451, and miR-15a as promising miRNA candidates involved in response to bacterial infection. [score:1]
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81
[+] score: 15
According to TargetScan7.0, CCND1 could be targeted by miR-15, miR-16, and miR-19 at different binding sites. [score:5]
The expression and function of miR-15 and miR-19 have not been reported before. [score:3]
However, none of miR-15a, miR-15b, miR-19a, miR-19b-2 showed consistent differential expression between NE2 and ESCC cells. [score:3]
We detected expression of miR-15a, miR-15b, miR-19a, and, miR-19b-2 but not miR-19b-1 in the cell lines examined. [score:3]
miR-15 has two transcripts (miR-15a and miR-15b), and miR-19 has three transcripts (miR-19a, miR-19b-1, and miR-19b-2). [score:1]
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82
[+] score: 14
Examples are miR-15a and miR-16-1 (targeting MYB mRNA), miR-486-3p (targeting BCL11A mRNA), miR-23a (targeting KLF-2) and miR-27a (targeting Sp1). [score:9]
The identification of microRNAs targeting mRNAs coding for these repressors (data are available for microRNAs miR-15a, miR-16-1, miR-486-3p, miR-23a/27a) [33, 34, 35], could be useful to develop novel approaches for the treatment of β-thalassemia [36]. [score:3]
Sankaran V. G. Menne T. F. Šćepanović D. Vergilio J. A. Ji P. Kim J. Thiru P. Orkin S. H. Lander E. S. Lodish H. F. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13Proc. [score:2]
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83
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6 controlsSerum(miRNeasy Serum/Plasma)qRT-PCR(TaqMan Small RNA)Borges NM, et al. (2016) [22]miR-15a-3pmiR-21-5pmiR-210-5p miR-181a-5pmiR-155-5pmiR-210-3pupregulationupregulationupregulationdownregulationNSNS 33 DLBCL vs. [score:6]
On the other hand, miR-15a, miR-155 and miR-210 were found upregulated or unchanged in patients in the different studies in which they were analyzed. [score:4]
Considering common miRNAs analyzed across different studies, we only identified seven miRNAs found to be significantly deregulated in DLBCL patients in at least two studies (miR-15a, miR-21, miR-29c, miR-34a, miR-145, miR-155, and miR-210) (Table 2) [18– 20, 22– 29]. [score:2]
Regarding the suitability of circulating miRNAs as diagnostic biomarkers in DLBCL, eleven articles were identified, in which a total of seven miRNAs (miR-15a, miR-29c, miR-34a, miR-155 and miR-210) were found at least twice to be significantly deregulated in DLBCL patients [18– 20, 22– 29]. [score:2]
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84
[+] score: 14
Regulating insulin synthesis, miR-15a provides a confirmatory example for this, which targets about 12.7% of the miRNA-regulated tissue-specific proteins in the PIN of pancreas [19]. [score:5]
Especially, 5 miRNAs (miR-1, miR-15a, miR-16, miR-21 and miR-155) regulated the largest number of commonly expressed proteins (n≥40), implying their broad and important roles. [score:4]
For example, miR-15a regulated 12.7% of all miRNA-regulated tissue-specific proteins in the pancreas PIN, but did not affect any tissue-specific proteins in the skeletal muscle PIN. [score:3]
Just recently, the important role of miR-15a in regulating insulin synthesis has been disclosed [19], which is consistent with our analysis result. [score:2]
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85
[+] score: 14
According to previous studies in cancer (MCF-7) cells EGCG up-regulates the expression of miR-16, a member of the miR-15b family (family of miR-16/miR-15a/miR-497/miR-322/miR-195) and consequently, EGCG down-regulates Bcl-2 expression level and thus counteracts cancer progression [25]. [score:11]
A. Cartoon showing the murine mmu-miR-15b (family of miR-16/miR-15a/miR-497/miR-322/miR-195) with STIM2 3’-untranslated region (3’-UTR) with seed sequence. [score:3]
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86
[+] score: 14
Other miRNAs from this paper: mmu-mir-15b, hsa-mir-15b, mmu-mir-15a
The “miR15–17 plant testing dataset” is composed of these 1341 real miRNA:miRNA* duplexes and 100807 pseudo miRNA:miRNA* duplexes. [score:1]
0027422.g016 Figure 16Average distance distributions of MaturePred [88] and MatureBayes over the miR15–17 human and mouse testing dataset, including top 10 candidates. [score:1]
Average distance distributions of MaturePred [88] and MatureBayes over the miR15–17 human and mouse testing dataset, including 5′ arm and 3′ arm candidates. [score:1]
Average distance distributions of MaturePred [88] and MatureBayes over the miR15–17 human and mouse testing dataset, including top 10 candidates. [score:1]
Average distance distributions of MaturePred [86] and MiRPara over the miR15–17 plant testing dataset. [score:1]
Average distance distributions of MaturePred [88] and MiRPara over the miR15–17 animal testing dataset. [score:1]
Prediction results of MaturePred [86] and MiRPara over the miR15–17 plant testing dataset. [score:1]
0027422.g007 Figure 7Average distance distributions of MaturePred [86] and MiRPara over the miR15–17 plant testing dataset. [score:1]
This allows an unbiased analysis since the miR15–17 testing dataset was not used to build the prediction mo del. [score:1]
0027422.g015 Figure 15Average distance distributions of MaturePred [88] and MatureBayes over the miR15–17 human and mouse testing dataset, including 5′ arm and 3′ arm candidates. [score:1]
Average distance distributions over the miR15–17 plant testing dataset. [score:1]
Prediction results of MaturePred [88] and MiRPara over the miR15–17 animal testing dataset. [score:1]
Average distance distributions over miR15–17 plant testing dataset, including 5′ arm and 3′ arm candidates. [score:1]
0027422.g013 Figure 13Average distance distributions of MaturePred [88] and MiRPara over the miR15–17 animal testing dataset. [score:1]
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87
[+] score: 14
Likewise in breast cancer MCF-7 cells, curcumin reduced the expression of Bcl-2 and induced apoptosis by upregulating the expression of miR-15a and miR-16 [61]. [score:8]
First experimental evidence that suggested that miRNAs might participate in human carcinogenesis and hit specific molecular targets came from the realization of the chromosomal deletion (13q14.3) in human chronic lymphocytic leukemia (CLL), in which two miRNAs, miR-15a and miR16-1, were down-regulated in 68% CLL cases [46]. [score:6]
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88
[+] score: 14
Despite many published miRNA profiling studies in 3T3-L1 pre-adipocytes, mouse and human pre-adipocytes only one other study reported miR-15a was upregulated during pre-adipocyte differentiation [61]. [score:4]
Inhibition of miR-15a in pre-adipocytes resulted in a decrease in cell size along with an increase in cell number [72]. [score:3]
Inhibition of miR-15a appears to reduce pre-adipocyte size while promoting adipocyte proliferation [72]. [score:3]
In preadipocytes miR-15a has been shown to target Delta homologue 1 (DLK1) at mRNA and protein level [72]. [score:3]
More studies are needed to fully delineate the role of miR-15a in adipocyte proliferation in humans. [score:1]
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89
[+] score: 14
Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. [score:4]
miR-15a, miR-16, and miR-181a were reported to be downregulated in canine and human CLL (Calin et al., 2002; Gioia et al., 2011; Zhu et al., 2012). [score:4]
In a recent study, the relative expression pattern of 12 canine miRNAs (cfa-let-7a, cfa-miR-15a, cfa-miR-16, cfa-miR-17-5p, cfa-miR-21, cfa-miR-26b, cfa-miR-29b, cfa-miR-125b, cfa-miR-150, cfa-miR-155, cfa-miR-181a, and cfa-miR-223) in CLL was analyzed. [score:3]
According to a recent study, nine miRNAs, let-7f, miR-15a, miR-16, miR-17-5p, miR-21, miR-29b, miR-125b, miR-155, and miR-181b involved in human mammary cancer, appear to follow the same expression pattern in the canine counterpart. [score:3]
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90
[+] score: 14
We demonstrate that HMGA1P7 overexpression increases H19 and Igf2 levels inhibiting their mRNA suppression by miRNAs that target HMGA1P7 gene, namely, miR-15, miR-16, miR-214, and miR-761. [score:9]
To this aim, we transfected miR-15, miR-16, miR-214 and miR-761 (already reported to target HMGA1P7) 17 into NIH3T3 cells, and analyzed H19 and Igf2 mRNA levels by qRT-PCR. [score:3]
The luciferase signal was considerably lower after transfection with miR-15, miR-16, miR-214 and miR-761 in comparison with the cells transfected with the scrambled oligonucleotide (Fig. 4B). [score:1]
Relative luciferase activity in HEK293 cells transiently transfected with miR-15, miR-16, miR-214, miR-761 and a control scrambled oligonucleotide. [score:1]
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91
[+] score: 14
It is also possible that non-coding RNAs, such as microRNAs (miRNAs), may play a role in mediating the effect of SAHA on COX-2 and TIA-1, since some miRNAs, such as miRNA-199a, miRNA-145a and miR-26a, have been reported to target and inhibit specifically COX- 2 [31, 32] and HDAC inhibitors, such as SAHA, can modulate the expression of miRNAs implicated in fibrosis, such as miR-15a, miR-16 and miR-29b and Let-7b [[33], [34], [35]]. [score:9]
Moreover, TIA- 1 mRNA 3′-UTR has been indicated as a putative target of some of the previously reported miRNAs involved in fibrosis, such as miR-16, miR-15, and miR-26b, by the experimentally validated microRNA-target interactions database (miRTarBase, http://mirtarbase. [score:5]
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92
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Several cell cycle-stimulating genes have strong validated or predicted targets for the miR-15/16 family, such as Cyclin E [37], Cyclin D1-3 [37], [38], AKT3, and BCL2 [39] and BCL2L. [score:3]
The data across different melanoma cell lines indicate that the miR-15/16/497 and miR-96/182 family members are the strongest inhibitors of cell viability when introduced as synthetic RNA. [score:3]
This makes the miR-15/16 family an excellent candidate for anti-melanoma therapy, especially in combination with MAPK pathway inhibitors [42]. [score:3]
The miR-15/16/497 and miR-96/182 families target distinct subsets of genes, both affecting melanoma cell proliferation. [score:3]
Two members from the miR-15/16 family, i. e. miR-16 and miR-497, were also identified in our screen. [score:1]
The miR-15a/16-1 locus on chromosome 13 is deleted in more than half of B cell chronic lymphocytic leukemias [36]. [score:1]
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93
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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-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-25, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-92a-1, hsa-mir-93, hsa-mir-98, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, hsa-mir-16-2, hsa-mir-192, hsa-mir-196a-1, hsa-mir-197, hsa-mir-7-1, hsa-mir-7-2, hsa-mir-7-3, hsa-mir-10b, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-182, hsa-mir-183, hsa-mir-196a-2, hsa-mir-205, hsa-mir-181a-1, hsa-mir-221, hsa-mir-222, hsa-mir-200b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-122, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-137, hsa-mir-140, hsa-mir-141, hsa-mir-143, hsa-mir-145, hsa-mir-152, 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-146a, hsa-mir-150, hsa-mir-194-1, hsa-mir-206, hsa-mir-200c, hsa-mir-1-1, hsa-mir-155, hsa-mir-128-2, hsa-mir-194-2, hsa-mir-106b, hsa-mir-29c, hsa-mir-200a, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-26a-2, hsa-mir-372, hsa-mir-374a, hsa-mir-375, hsa-mir-328, hsa-mir-133b, hsa-mir-20b, hsa-mir-429, hsa-mir-449a, hsa-mir-486-1, hsa-mir-146b, hsa-mir-494, hsa-mir-503, hsa-mir-574, hsa-mir-628, hsa-mir-630, hsa-mir-449b, hsa-mir-449c, hsa-mir-708, hsa-mir-301b, hsa-mir-1827, hsa-mir-486-2
Furthermore, a recent study has shown that miR-15a, miR-16-1 cluster and related miR-15b, miR-16-2 cluster are direct transcriptional targets of E2F1 and control E2F -dependent cell proliferation by cyclin E gene repression, thus inhibiting the G1/S transition [129]. [score:6]
Another interesting observation is that in NSCLC the miR-15/16 cluster directly regulates cyclin D1, D2, E1, CDK4/6 and that cyclin D1 and miR-15/16 expression levels are inversely correlated. [score:5]
miR-15 and miR-16 are important negative regulators of cell cycle progression in NSCLC and in many other solid tumors, as well as in hematologic malignancies such as chronic lymphatic leukemia [127- 128]. [score:2]
Moreover it has been demonstrated that, when combined, miR-34a and miR-15a/16 induce a deeper and longer lasting G1 cell cycle arrest than the repression due to only the additive effect of two miRNAs separately, suggesting a strong cooperation between them [130]. [score:1]
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94
[+] score: 13
Downregulation or accumulation of subsets of miRNAs implies a tumor suppressor or oncogenic function, respectively, is often seen in tumor development, as in the examples of downregulated let-7 in lung cancer [5], deleted or downregulated miR-15 and miR-16 in chronic lymphocytic leukemia [6], and miR-17-5p and miR-20a control the balance of cell death and proliferation [7]. [score:13]
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95
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A simple explanation of a low effect might be that miRNA could modulate the expression of a large number of downstream target genes in a highly orchestrated manner to control apoptosis and cell cycle processes Concerning the variations in the DNA copy numbers and genomic aberrations, several reports have shown the deletions of miRNAs that act as tumor suppressors, namely miR-15, miR-16, and miR-34a. [score:7]
For example, miR-15a and miR-16-1, whose genomic regions are deleted and expressions are down-regulated in the majority of chronic lymphocytic leukemia (CLL). [score:6]
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96
[+] score: 13
Myklebust et al., Ofir et al., and Bueno et al. established that expression of miR-15a, miR-15b, and miR-16 is positively regulated by E2F1 and E2F3 [100, 103, 104], suggesting a mechanism for the upregulation of these miRNAs by the E7 oncoprotein. [score:7]
The first report documenting abnormalities in miRNA expression in tumor samples was on B-cell chronic lymphocytic leukemia (B-CLL), where miR-15 and miR-16 are frequently deleted and downregulated in B-CLL patients [9]. [score:6]
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97
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For example, in patients with DLBCL miR-15a was upregulated in blood serum [20] and downregulated in tumor lymph nodes [21] possibly due to distinct regulatory mechanisms. [score:8]
Based on this analysis we chose seven miRs (miR-15a, 16, 17, 106, 21, 155 and miR-34a-5p) whose significant higher expression is specific to DLBCL then observed in other malignancies, suggesting that these miRs may be used as potential candidates’ biomarker for DLBCL diagnosis. [score:3]
Several other miRs considered as biomarkers for DLBCL (miR-17-5p, 145-5p and miR-15a, Figure 2A, 2e) and FL (miR-17-3p and miR-202, Figure 2A, 2f) showed opposite expression levels in different biological sources. [score:2]
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98
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BCL6 modulates the B cell response inducing tolerance to DNA damage -induced apoptosis by suppressing TP53 in GC B cells, [48]; while P53 controls the cell cycle at two distinctive checkpoints (G1/S and G2/M) by the regulation of miR-107, miR-145, miR-34, and of the miRNA clusters miR-15a/miR-16 and miR-192/miR-194/miR-215, able to target many cell cycle-related genes [49]. [score:6]
The miRNAs profile comparison between resting and activated B cells showed the up-regulation of 19 miRNA in activated B cells: mir-98, mir-106a, mir-20a, mir-17-5p, mir-20b, mir-16-2, mir-18a, mir-155, mir-21, mir-181d, mir-425-5p, mir-148a, mir-15b, mir-15a, mir-181b mir-181c, mir-181a, mir-130b, mir-148b (Table 3). [score:4]
Other miRNAs such as mir-155, mir-181b, mir-15a, mir-16, mir-15b, mir-34a, mir-9, mir-30, let-7a, mir-125b, mir-217 and mir-185 modulate the expression of pivotal genes and functions which contribute to the final B-cell maturation [6]. [score:3]
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99
[+] score: 12
miR-107 is enriched in neurons and recent studies indicate that numerous members of miR-15/107 family having the target sites in BACE1 gene including miR-15a, miR-15b, mR-16, miR-195, miR-103 as well as miR-107; all of these miRNAs are down-regulated in gray matter of AD patients (Wang et al., 2011). [score:6]
The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. [score:3]
Numerous miRNAs such as members of miR-15/107 family have ribonucleotide sequence similarity, and therefore have related target mRNAs (Finnerty et al., 2010). [score:3]
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100
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miR targeting of oncogene mRNA expression can act in its nature as a tumor suppressor (Figure 2); for example, miR-15a, which is downregulated in CLL, prostate cancer, and pituitary adenomas, targets anti-apoptotic BCL2 [23, 24]. [score:12]
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