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198 publications mentioning mmu-mir-15a (showing top 100)

Open access articles that are associated with the species Mus musculus 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: 183
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]
[1 to 20 of 89 sentences]
2
[+] score: 175
Other miRNAs from this paper: hsa-mir-15a, mmu-mir-150, hsa-mir-150
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]
[1 to 20 of 69 sentences]
3
[+] score: 139
Other miRNAs from this paper: hsa-mir-15a, hsa-mir-16-1, hsa-mir-16-2, 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: 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: 98
A second limitation is that our results are not able to fully clarify the nature of the upstream factors that up-regulate the expression of the ECM genes and down-regulate the expression of miR-29 and miR-15 family members. [score:11]
Our results suggest the existence of a related miRNA/mRNA network that could be involved in the shift of the metabolic program of the aorta from processes involved in development and extracellular matrix (ECM) protein synthesis in the neo samples to oxidative energy metabolism in the w6 samples, whereby there is a coordinate up-regulation of miR-29 and miR-15 family miRNAs and down-regulation of their ECM target genes including, prominently, elastin (Fig. 7). [score:10]
Genes with multiple miR-15 and miR-29 family MREs in coding sequence and 3′ UTR are down-regulated in the w6 aortaThese results motivated us to ask whether other genes with multiple miR-29 family MREs are also down-regulated in the w6 aorta. [score:7]
0016250.g007 Figure 7 U denotes upstream factors which tend to up-regulate ECM genes in the neonatal aorta and to suppress miR-29 and miR-15 family microRNAs. [score:6]
U denotes upstream factors which tend to up-regulate ECM genes in the neonatal aorta and to suppress miR-29 and miR-15 family microRNAs. [score:6]
We suggest that the high expression of miR-29 and the miR-15 family member in the adult aorta may be an important factor for the physiological suppression of the production of elastin in the adult organism. [score:5]
Identification of Differential Regulation of miR-15 and miR-29 family miRNAs and their Target mRNAs in Postnatal Aortic Development. [score:5]
An additional member of the miR-15 family, miR-15a, was up-regulated 4.1-fold in the w6 aortic specimens (Supplementary Table S2). [score:4]
Genes with multiple miR-15 and miR-29 family MREs in coding sequence and 3′ UTR are down-regulated in the w6 aorta. [score:4]
Five of the six miRNAs that were most up-regulated in the w6 aortas belonged to just two miRNA families, miR-29 and miR-15. [score:4]
Additionally, cardiac overexpression of miR-195 results in pathological cardiac growth and heart failure in transgenic mice [53], so that modulation of miR-15 miRNAs during development and maturation are unlikely to allow specific conclusions about the effect of miR-15 miRNAs on elastin metabolism. [score:4]
C Putative mo del of miR-15/miR-29 and mRNA target gene networks. [score:3]
In conclusion, we have shown that miR-29 and the miR-15 family members miR-195 and miR-497 are differentially regulated between the newborn and the six-week old murine aorta, and using in vitro assays we have demonstrated that they regulate elastin by means of multiple MREs in both the 3′ UTR and the CDS. [score:2]
The finding of a total of 14 MREs for miR-29 as well as 13 for the miR-15 miRNA miR-195 in the coding and 3′ UTR sequence of Eln is highly statistically significant (Fig. 6), and to our knowledge a similar finding has not been previously reported for any miRNA. [score:1]
0016250.g004 Figure 4In the cartoons of the mouse elastin gene (A) and the luciferase constructs (B,C) miR-29 MREs (UGGUGCU) are indicated by dashed lines, and miR-15 MREs (UGCUGCU) by arrows. [score:1]
The seed sequences of miR-15 miRNAs (AGCAGCA) and miR-29 family miRNAs (AGCACCA) differ by only one nucleotide (Fig. 3). [score:1]
In addition, Col1a2 has neither miR-15 nor miR-29 MREs in its 3′ UTR and was responsive to both miR mimics. [score:1]
miR-15 and miR-29 Overrepresentation in Eln. [score:1]
A limitation of our study is that a role for the miR-29 and miR-15 family MREs in the CDS of elastin and other matrix genes was not demonstrated in an in vivo mo del system. [score:1]
miR-29 and the miR-15 family members miR-195/miR-497 form three intergenic clusters in mouse chromosomes 1, 6, and 11.. [score:1]
MREs for miR-15 and miR-29 are highly overrepresented in the mRNA sequence of Eln We developed a simple statistical test for overrepresentation of MREs in mRNA sequences (see methods) and used it to analyze the counts of MREs for 373 miRNA families in the entire mRNA sequence of Eln. [score:1]
7-nucleotide matches for the MREs of miR-29 or miR-15 family miRNAs were counted in the elastin and type I collagen 1 and 2 genes of five mammalian species. [score:1]
Although Col1a1 has one miR-15 and one miR-29 MRE in its 3′ UTR, the great majority of MREs for these miRNAs are located in its CDS. [score:1]
Arrows mark the ten genes which contain at least five MREs for both miR-15 family and miR-29 family. [score:1]
revealed eleven additional 7–8mer binding sites for miR-29 in the coding sequence (CDS) of elastin (Fig. 4A, dashed lines), as well as eight MREs with perfect complementarity to the seed sequence of the miR-15 family members miR-195/miR-497 (Fig. 4A, arrows). [score:1]
In the rat, Col1a1 has 20 miR-29 MREs in its CDS and one in its 3′ UTR, and has 4 MREs for miR-15 family miRNAs in its CDS and one in its 3′ UTR; Col1a2 has 15 miR-29 MREs in its CDS and none in its 3′ UTR, and 7 miR-15 family MREs in its CDS; and Eln has 10 miR-29 MREs in its CDS and 3 in its 3′ UTR, and 9 MREs for miR-15 and none in the 3′ UTR. [score:1]
miR-29 showed the most highly significant enrichment (), and MREs for the miR-15 family showed the second most significant enrichment (). [score:1]
Eight of them have at least five MREs for miR-29, five have at least five MREs for miR-15, including three genes that additionally have at least five MREs for miR-29. [score:1]
Many of these genes also demonstrated multiple MREs for the miR-15 family (Supplementary Table S5). [score:1]
Computational analysis revealed eleven additional 7–8mer binding sites for miR-29 in the coding sequence (CDS) of elastin (Fig. 4A, dashed lines), as well as eight MREs with perfect complementarity to the seed sequence of the miR-15 family members miR-195/miR-497 (Fig. 4A, arrows). [score:1]
The construct on top with Eln exons 28 to 30 contains three miR-15 but no miR-29 MREs. [score:1]
In the cartoons of the mouse elastin gene (A) and the luciferase constructs (B,C) miR-29 MREs (UGGUGCU) are indicated by dashed lines, and miR-15 MREs (UGCUGCU) by arrows. [score:1]
The second construct additionally contained four miR-29 MREs, and was significantly responsive to both miRNA precursors, indicating a specific effect of miR-15 and miR-29 MREs in the CDS of murine Eln. [score:1]
miR-29 MREs are consistently overrepresented in mRNA sequences for elastin, and miR-15 family MREs are overrepresented in rat, cow, and dog but to a lesser degree in humans, suggesting species-specific differences (Supplementary Table S6). [score:1]
See also Supplementary Table S5 for counts of miR-15 and miR-29 family MREs. [score:1]
MREs for miR-15 and miR-29 are highly overrepresented in the mRNA sequence of Eln. [score:1]
Table S6miR-29 and miR-15 MREs are common in the mRNA sequences of many mammalian species throughout evolution. [score:1]
There are no MREs for miR-29 and miR-15 family miRNAs in the entire coding sequence of the firefly and renilla luciferase genes. [score:1]
The number of MREs for miR-29 and miR-15 family miRNAs in the rat genes is based on the sequences NM_012722 (Eln), NM_053304 (Col1a1), and NM_053356 (Col1a2). [score:1]
The high multiplicity of MREs for miR-15 and miR-29 family miRNAs is reminiscent of the VGVAPG repeating peptide in elastin, which can induce macrophage chemotaxis and other biological responses by interaction with the elastin -binding protein [48]– [50]. [score:1]
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6
[+] score: 69
Ischemia for 2 h without reperfusion induced upregulation of miR-21 expression that could still be detected after reperfusion for 1 and 7 d. In addition, miR-493 expression could be observed after ischemia and reperfusion for 4 h and 1 d but did not last for 7 d. When miRNA expression was compared in the muscle samples of C57BL/6 and Tlr4 [−/−]/ NF- κB [−/−] mice subjected to 2 h of ischemia and 1 d of reperfusion, only 3 miRNAs (miR-15a, miR-744, and miR-1196) showed significantly increased expression in C57BL/6 mice and decreased expression in Tlr4 [−/−]/ NF- κB [−/−] mice (Table 2). [score:13]
Among the dysregulated miRNAs, 3 TLR4/NF- κB-responsive miRNAs, miR-15a, miR-744, and miR-1196, were significantly upregulated in the skeletal muscles of C57BL/6 mice following IRI, but their expression notably decreased in similarly treated Tlr4 [−/−]/ NF- κB [−/−] mice. [score:7]
Three genes were regulated by at least 2 of these 3 upregulated miRNAs; that is, zinc finger BED domain containing 4 (Zbed4) was regulated by miR-15a, miR-744, and miRR-1196; leucine-rich repeat and sterile alpha motif containing 1 (Lrsam1), by miR-15a and miR-744; and the DEAD (Asp-Glu-Ala-Asp) box polypeptide 21 (Ddx21), by miR-744 and miR-1196. [score:6]
Among these 3 upregulated miRNAs, miR-15a showed increased expression in response to myocardial IRI [40], but association of miR-744 and miR-1196 with IRI has not been previously reported. [score:6]
In human, vascular endothelial growth factor-A and AKT-3 were validated as direct targets of miR-15a, and their protein levels were reduced in miR-15a -overexpressing circulating proangiogenic cells of healthy patients and those with critical limb ischemia [43]. [score:6]
miR-15a inhibits angiogenesis through direct inhibition of endogenous endothelial FGF2 and VEGF during hindlimb ischemia [42]. [score:6]
However, the exact role of miR-15a in angiogenesis after muscle IRI requires further experiments with miR-15a overexpression or inhibition for validation. [score:5]
Overexpression of miR-15a impaired survival and migration of healthy circulating proangiogenic cells; conversely, miR-15a inhibition improved the impaired migration of circulating proangiogenic cells in critical limb ischemia [43]. [score:5]
Transplantation of healthy circulating proangiogenic cells engineered to overexpress anti-miR-15a improves postischemic recovery in blood flow and muscular arteriole density in mice [43]. [score:3]
miRNA array analysis showed that the expression of miR-1196, but not miR-15a or miR-744, persisted till 7 d of reperfusion (Table 1). [score:3]
This study has profiled TLR4/NF- κB-responsive miRNAs (miR-15a, miR-744, and miR-1196) in thigh skeletal muscle isolated following IRI and identified their potential target genes by using prediction algorithms and RNA -binding protein immunoprecipitation microarray profiling of Ago2 immunoprecipitated complexes. [score:3]
The combined approach showed 5, 4, and 20 potential target genes for miR-15a, miR-744, and miR-1196, respectively, in the IRI muscle samples (Table 3). [score:3]
Microarray and qPCR results of five miRNA targets including miR-15a, miR-744, and miR-1196 in the experimental muscle of C57BL/6 mice after 2 h of ischemia and 1 d of reperfusion were in general agreement, with a Pearson correlation value of 0.912 (Supplementary File 2). [score:3]
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[+] score: 47
Overall, the results shown support the following cascade of events, miR-15 directly binds HNF1α mRNA to attenuate HNF1α expression and thus the inhibitory effect of HNF1α, resulting in transactivation of HBV Enhancer I, in turn causing the enhancement of HBV replication and expression of HBV antigens, including HBx protein, finally leading to the down-regulated expression of miR-15b. [score:13]
Wang Y. Jiang L. Ji X. Yang B. Zhang Y. Fu X. D. Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16–1 in hepatocytesJ. [score:7]
Ofir M. Hacohen D. Ginsberg D. MiR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F -induced proliferation by targeting cyclin EMol. [score:6]
G. Wu et al. reported that c-Myc mediated the HBx -induced repression of miR-15a/16 in HepG2 cells (32), while C. S. Wu et al. (56) presumed that regulation of miR-15b by HBx may also be mediated by HBx RNA as the mode of HBV regulation on miR-15a because miR-15a and miR-15b share most of the same sequence. [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 BCL2Proc. [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 activitiesNat. [score:3]
Finnerty J. R. Wang W. X. Hebert S. S. Wilfred B. R. Mao G. Nelson P. T. The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseasesJ. [score:3]
For miR-122 (53) and miR-15a (54, 55), HBV mRNA harboring complementary sites act as sponges to bind and sequester endogenous miRNA, indicating that the highly redundant HBV transcripts are involved in HBV -mediated miRNA suppression. [score:3]
HBsAg and HBeAg levels (Figure 1B), HBV RNA level and DNA copy number (Figure 1C) were all significantly higher in the miR-15 mimics group than in the scrambled control group. [score:1]
The miR-15/16 family is composed of miR-15a, miR-15b and miR-16. [score:1]
The miR-15b belongs to the miR-15/16 family of miRNAs. [score:1]
Besides miR-15b, all other nine mature miRNAs in miR-15/107 seed family (43) may also affect HNF1α because they all have the same seed sequence. [score:1]
Yue J. Tigyi G. Conservation of miR-15a/16–1 and miR-15b/16–2 clustersMamm. [score:1]
The miR-15a/16–1 and miR-15b/16–2 gene clusters are located on human chromosomes 13q and 3 (32). [score:1]
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[+] score: 44
It was reported that miR-15 family members were upregulated in infarct region of pigs [15] but downregulated in both border and infarct zone of mice [17] in response to myocardial infarction, while they were found to be up-regulated in the overloaded heart in multiple species [19]. [score:10]
We noted that miR-15 family members may be upregulated, downregulated or unchanged in response to various cardiac stresses (Supplementary Material, Figure S1). [score:7]
Although miR-15 family members share similar structure and some common targets, they can also exert distinct role in the pathogenesis of cardiovascular disease. [score:5]
Anti-miR chemistries suppressing miR-15 in mice were reported to reduce myocardial infarct size [15], while inhibition of either miR-15a or miR-16 enhanced post-ischemic neovascularization [19]. [score:5]
MiR-15 and miR-16 were reported to induce apoptosis by inhibiting Bcl-2 [18]. [score:3]
The miR-15 family members including miR-15a, miR-15b, miR-16, miR-195, miR-424, and miR-497, show 5′-end sequence similarity and many common targets [16, 17]. [score:3]
Similar to our findings on miR-497, Hullinger et al has demonstrated that miR-15b, also a member of miR-15 family, aggravates myocardial IR injury by targeting Bcl-2 [15]. [score:3]
The expression heterogeneity of miR-15 family members was also supported by previous studies. [score:3]
The regulation of miR-15 family is spatial, temporal and dynamic [15, 17]. [score:2]
It was reported miR-195 increases cardiac hypertrophy [27] and worsens systolic dysfunction in mice with MI [17], while miR-15b, another member of the same miR-15 family, was found to attenuate myocardial fibrosis and hypertrophy in pressure-overloaded mice [19]. [score:1]
Recent studies have shown that the miR-15 family can worsen or alleviate myocardial ischemia and heart failure [13– 15]. [score:1]
The expressions of other members of miR-15 family in cardiomyocytes or heart subjected to AR or MI or pressure overload induced by transverse aortic constriction were also investigated. [score:1]
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9
[+] score: 39
Further, p53 appears to regulate the expression of Dicer through its transcriptional target miRs, such as miR-192, 215, miR29a/b/c, miR-148, miR-15/16a, miR-206, and miR-103 [Table 2], suggesting that p53/p63/p73 could regulate the expression of dicer both at the transcriptional and the post-transcriptional level. [score:9]
Interestingly, p53 appears to inhibit the expression of hnRNP A1 through its target miRNA-15/16, suggesting that p53/p73/p63 could function as a negative regulator of the processing of the oncogenic miRNA-18a. [score:8]
Interestingly, both Drosha and DGCR8 appear to be targeted by p53-miR, miR-27, while both Dicer and TARBP2 appear to be targeted by p53-miRs, such as let-7, miR-103/107, and miR-15/16/195, suggesting a co-ordinated regulation of miRNA processing mediated by the p53-miRs. [score:6]
Remarkably, p53-miRs, such as miR-15, 16, and 29a/b/c, are predicted to inhibit the expression of P2P-R [Table S2], suggesting that there could be a feedback loop between p53/ΔN-p63 and P2P-R [Figure 4]. [score:5]
Among the p53-miRs that target the components of the miRNA processing complexes, miR-15/16/195, miR-103, miR-107, let-7, miR-124, miR-181, miR-148a/b, miR-30a/c, miR-27, miR-17, and miR-20 appear to target more than five components of the miRNA-processing pathway [Table 4, Table S3], suggesting the conserved nature of p53-miRs. [score:5]
Interestingly, miR-15/16/29 promoter contains p53/p63-REs, suggesting it could be a direct transcriptional target of p53/TA-p73/p63 (Boominathan, unpublished). [score:4]
MiRNAs, such as miR-34[a, b, c], miR-203, miR-29, let 7, miR-15, and miR-16, and their processing components have shown to be down regulated in multiple cancers. [score:2]
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10
[+] score: 34
This included seven (87.5%; miR-16-5p, miR-29b-3p, miR-29a-3p, miR-503-5p, miR-15a-5p, miR-155-5p, and miR-425-5p) that were significantly upregulated and one (12.5%; miR-880-3p) that was downregulated (>2 folds, P < 0.05). [score:7]
To determine whether the miRNAs dysregulate expression of their predicted target genes, we transfected 3 different types of miRNA mimics (hsa-miR-15a-5p mimic, hsa-miR-29a-3p mimic, and hsa-miR-29b-3p mimic) and 1 positive (hsa-miR-1 mimic) or negative control siRNA (AllStar negative control siRNA) into HepG2 cells. [score:6]
This study observed that expression of the miRNAs miR-155-5p, miR-425-5p, miR-15a-5p, miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p in the liver of Cmah -null mice may downregulate components of the insulin/PI3K-AKT signaling pathway in concert with other genes. [score:6]
Among them, miR-155-5p, miR-425-5P, miR-15a-5p, miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p were significantly upregulated in the liver and pancreas of Cmah -null mice. [score:4]
We next determined the effect of miR-15a on mRNA expression of Fasn, Col1a2, Col4a2, and Ccnd2 genes. [score:3]
Transfection of HepG2 cells with miR15a mimic significantly decreased the mRNA level of Col1a2, Col4a2, and Ccnd2, whereas Fasn mRNA expression was not changed (Figure 5(b)). [score:3]
As shown in Figure 4(b) miR-155-5p miR-15a-5p, and miR-425-5p in the case of insulin signaling and miR-29b-3p, miR-29a-3p, miR-16-5p, and miR-503-5p in the case of PI3K-AKT1-mTOR signaling were significantly dysregulated. [score:2]
The final concentrations of the transfectants (hsa-miR-15a-5p mimic, hsa-miR-29a-3p mimic, and hsa-miR-29b-3p mimic) and their respective controls (AllStar siRNA for negative control and hsa-miR-1 mimic for positive control) were either 10 nM (miRNA mimic) or 50 nM (siRNAs). [score:1]
Among them, we found two major signal pathways such as insulin signaling (miR-155-5p, miR-425-5p, and miR-15a-5p) and PI3K-AKT signaling (miR-503-5p, miR-16-5p, miR-29a-3p, and miR-29b-3p) pathways (Table 2). [score:1]
Hsa-miR-15a-5p mimic, hsa-miR-29a-3p mimic, hsa-miR-29b-3p mimic, hsa-miR-1 mimic, and AllStar negative control siRNA were purchased from Qiagen (Valencia, CA, USA). [score:1]
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11
[+] 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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12
[+] score: 28
Interestingly, this family of miRs was recently linked to the control of the post-natal mitotic arrest of cardiomyocytes [12], which seems to involve the up-regulation of several miR-15 family members, while miR-107 becomes down-regulated. [score:7]
The miR-15/107 family has been shown to co-regulate several mRNA targets that encode key proteins for distinct cellular functions, including metabolic regulation, cell cycle control, control of metastasis and epithelial mesenchymal transition and stem cell plasticity [5]. [score:5]
Thus, down regulation of miR-107 seems to be a distinctive feature of CSCs, implying a CSC specific regulatory profile for miR-15/107 target genes. [score:5]
To understand if the observed down-regulation of miR-107 may reflect a CSC specific fine-tuning of the pathways regulated by this group of miRs, we looked for the presence of other members of the miR-15/107 family in our dataset. [score:5]
Of the other two down-regulated miRs in CSCs, miR-302d has been described as embryonic stem cell specific in both mouse and humans [43], [44], whereas miR-107 belongs to the miR-15/107 family. [score:4]
D. miR-15/107 family expression levels in the cell populations characterized in this study. [score:1]
Plot displays normalized Ct values for each independent biological replicate sample of miR-15/107 family members present in the qPCR array. [score:1]
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13
[+] score: 25
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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14
[+] score: 24
Other miRNAs from this paper: mmu-mir-19b-2, mmu-mir-16-1, mmu-mir-330, mmu-mir-19b-1
The ability of GT and Q in combination with Doc to upregulate the expression of miR-15a and miR-330 and to balance miR-19b expression may partly contribute to the tumor inhibitory effect of the mixture in the present study. [score:10]
The downregulation of the tumor suppressor miR-15a and miR-330 has been wi dely found in prostate tumors compared to normal tissues particularly in more advanced tumors, associated with tumor cell survival, proliferation and invasion [34, 35]. [score:5]
The mixture significantly elevated the levels of tumor suppressor mir15a and mir330 in tumor tissues. [score:3]
The cluster of miR-15a/miR16-1 was reported to target Bcl-2, CCND1 (encoding cyclin D1) and WNT3A, leading to tumor cell growth arrest and apoptosis [34]. [score:3]
Both GT + Q and LD Doc alone demonstrated a non-significant trend to increase the expression of miR-15a compared to control, while their combination significantly elevated the level of miR-15a (Fig.   5). [score:2]
To investigate whether miRNAs are responsive to the combination treatment of GT, Q and Doc, we selected three candidate miRNAs that have been shown to be involved in prostate cancer, including two tumor suppressor miR-15a and miR-330 and an oncomiR miR-19b. [score:1]
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15
[+] score: 23
miR-15a overexpression leads to a decrease in the number, but an increase in the size, of murine adipocytes by inhibiting Delta-like 1 homolog expression [29]. [score:7]
As shown in the Venn diagram in Fig.   7, notably, 23 of the 28 upregulated miRNAs in DIO + LFD mice (mmu-miR-16, mmu-let-7i, mmu-miR-26a, mmu-miR-17, mmu-miR-107, mmu-miR-195, mmu-miR-20a, mmu-miR-25, mmu-miR-15b, mmu-miR-15a, mmu-let-7b, mmu-let-7a, mmu-let-7c, mmu-miR-103, mmu-let-7f, mmu-miR-106a, mmu-miR-106b, mmu-miR-93, mmu-miR-23b, mmu-miR-21, mmu-miR-30b, mmu-miR-221, and mmu-miR-19b) were downregulated in the DIO mice. [score:7]
Notably, 23 circulating miRNAs (mmu-miR-16, mmu-let-7i, mmu-miR-26a, mmu-miR-17, mmu-miR-107, mmu-miR-195, mmu-miR-20a, mmu-miR-25, mmu-miR-15b, mmu-miR-15a, mmu-let-7b, mmu-let-7a, mmu-let-7c, mmu-miR-103, mmu-let-7f, mmu-miR-106a, mmu-miR-106b, mmu-miR-93, mmu-miR-23b, mmu-miR-21, mmu-miR-30b, mmu-miR-221, and mmu-miR-19b) were significantly downregulated in DIO mice but upregulated in DIO + LFD mice. [score:7]
Some of the circulating miRNAs identified in this study have also been reported in the adipose tissue of DIO mice or implicated in adipogenic processes [11– 13], including Let-7, miR-103, miR-15, the miR-17-92 cluster (miR-17, miR-20a, and miR-92a), miR-21, miR-221, and miR-30b. [score:1]
In a study of miRNA libraries reconstructed from pre- and post-differentiated 3T3-L1 cells, it was noted that miR-15a may not be related to the actual differentiation process, but it may induce growth arrest and/or hormonal stimulation [30]. [score:1]
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16
[+] score: 23
mRNA targets that showed inversely correlated expression with miRNAs (Additional file 3) include previously validated miRNA/target pairs such as Mef2c with miR-223 [14], Bcl2 with miR-15 or miR-16 [38], Mybl2 with miR-29 or miR-30 family members [39], and Ezh2 with miR-26a [40]. [score:7]
Several miRNAs that were upregulated during granulopoiesis (miR-15a, miR-16 and miR-29) have previously been shown to be downregulated in acute myeloid leukemia [46, 47]. [score:7]
More recently, mouse-specific miR-709 was found to be enriched in the nucleus to target pri-miR-15a and pri-miR-16, thus regulating the expression of mature miR-15a and miR-16 [31]. [score:6]
In contrast to the previous finding in mouse liver, we did not observe an anti-correlation between the expression of nuclear miR-709 and cytoplasmic miR-15a/16 in myeloid cells. [score:3]
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17
[+] 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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18
[+] score: 21
Small RNA sequencing revealed several transcripts to be slightly regulated: miR-15 (log2 fold change 1.5), miR-383–5p (log2 fold change of 1.3) and miR-146b-5p (log2 fold change of 1.1) were top upregulated candidates, while Gm24706 (log2 fold change of 1.4), miR-7046–3p (log2 fold change of 1.1) and miR-203–5p (log2 fold change of 0.9) were top downregulated transcripts. [score:8]
Most highly downregulated candidates were Gm5878, aldehyde dehydrogenase 1 family member A3 and solute carrier family 14 (urea transporter), member 2. Small RNA sequencing revealed miR-15, miR-383-5p and miR-146b-5p as top upregulated candidates. [score:7]
Cimmino A miR-15 and miR-16 induce apoptosis by targeting BCL2Proc. [score:3]
Interestingly, miR-15 is described to play a role in apoptosis by targeting Bcl2 in chronic lymphocytic leukemia (CLL) [32] and mir-146b-5p was found to be induced in AKI and fibrosis [33]. [score:3]
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19
[+] score: 20
Other miRNAs from this paper: hsa-let-7a-2, hsa-let-7c, hsa-let-7e, hsa-mir-15a, 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-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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20
[+] 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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21
[+] score: 20
To our surprise, miR-15a and miR-126, two candidates miRNAs for targeting c-Myb 3′ UTR in differentiating cells, are also downregulated in a more metastatic alveolar form (ARMS) of rhabdomyosarcoma, tumors with myogenic features [25]. [score:6]
In [24] there is described that some quoted miRNAs were continuously upregulated during differentiation of C2C12 cells from D24 to D72 compared to GM values: miR-15a (from 0.92 times to 2.7 times), miR-126 (from 1.95 times to 2.75 times) and miR-200b (from 1.75 times to 2.73 times), these miRNAs could therefore play a role in extinguishing c-Myb expression. [score:5]
c-Myb activity is tightly regulated at different levels, including downregulation by several miRNAs: miR-150 [8], miR-15a [9], miR-34a [10], miR-126 [11], miR-200b, miR-200c and miR-429 [12] binding to its 3′ UTR. [score:5]
We therefore searched in the literature if some of miRNAs that have already been described to downregulate c-Myb via interacting with 3′ UTR, (miR-150, miR-15a, miR-34a, miR-126, miR-200b, miR-200c and miR-429), were activated during muscle differentiation. [score:4]
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22
[+] 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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23
[+] score: 17
Intriguingly, miR-15 is found most significant for its targets non-coherence, especially for signal transduction related functions in mouse development (Table S17) while target gene acvr2 is coherent to miR-15 consistent with that in [44]. [score:6]
Table S17 Ranksum test of non-coherent targets of miR-15 against non targets in the same GO category. [score:5]
In Xenopus embryonic development, miR-15 regulates Nodal signaling and acts at the crossroads of Nodal signaling and WNT signaling [44]. [score:3]
Comparing the enrichment of GO processes between developing lung and cerebellum, we found Metal ion transport and MAPKKK cascade are commonly significantly non-coherent to miR-15 and that Phosphorylation is commonly significantly coherent to miR-181 using picTar prediction (Table S16). [score:1]
MiR-15 has the greatest degree of multiplicity of 5′ UTR matches with synaptic transmission for reverse complementary seed sequences among the significant late miRs. [score:1]
Both these two categories are significantly non-coherent to miR-15. [score:1]
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24
[+] 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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25
[+] score: 16
miRNAs encoded by the miR-15a/16-1 locus (miR-15a and miR-16-1) function as tumor suppressors and are abundantly expressed in white blood cells, especially in lymphocytes [23]. [score:5]
Ingestion of wild type splenocytes slightly increases miR-15a level in miR-15a/16-1 KO blood but fails to increase lnk mRNA in lnk KO mouse blood. [score:1]
miR-15a). [score:1]
miR-15a level in blood was assessed by qRT-PCR. [score:1]
Figure 3Ingestion of wild type splenocytes slightly increases miR-15a level in miR-15a/16-1 KO blood but fails to increase lnk mRNA in lnk KO mouse bloodEach miR-15a/16-1 KO mouse was gavage fed with 20 million fresh splenocytes in 200 μl suspension from WT animals. [score:1]
To examine whether the mouse digestive system allows the increase of other dietary miRNAs in circulating blood, 20 million splenocytes from WT mice were used to orally feed each miR-15a/16-1 KO mouse. [score:1]
For lnk and miR-15a/16-1 experiments, spleens from WT mice were cut into small pieces and dispersed for making cell suspensions. [score:1]
Each miR-15a/16-1 KO mouse was gavage fed with 20 million fresh splenocytes in 200 μl suspension from WT animals. [score:1]
Ingestion of WT splenocytes slightly increases miR-15a level in miR-15a/16-1 KO blood but fails to increase lnk mRNA in lnk KO mouse bloodTo examine whether the mouse digestive system allows the increase of other dietary miRNAs in circulating blood, 20 million splenocytes from WT mice were used to orally feed each miR-15a/16-1 KO mouse. [score:1]
Ingestion of WT splenocytes slightly increases miR-15a level in miR-15a/16-1 KO blood but fails to increase lnk mRNA in lnk KO mouse blood. [score:1]
200 μl such splenocyte suspension per mouse was gavage-fed to the lnk or miR-15a/16-1 KO mice. [score:1]
lnk gene KO mice were kindly provided by Tony Pawson [24] (Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada) and maintained in our laboratory since 2012. miR-15a/16-1 KO mice were kindly provided by Dr. [score:1]
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26
[+] score: 15
We found a significant up-regulation of oncogenic miRNAs and a significant down-regulation of tumor-suppressing miRNAs, which included let-7, miR-17-92, miR-10b, miR-15, miR-16, miR-26, and miR-181. [score:9]
Of the 113 miRNAs with significantly aberrant expressions after RDX exposure, the expression levels of 10 miRNAs were significantly increased in both mouse liver and brain (p < 0.01): miR-99a, miR-30a, miR-30d, miR-30e, miR-22, miR-194, miR-195, miR-15a, miR-139-5p, and miR-101b. [score:5]
In this study, we found that many cancer-related miRNAs, such as let-7, miR-17-92, miR-10b, 125b, miR-146, miR-15, miR-200, and miR-16, were significantly affected by RDX exposure (Table 4). [score:1]
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27
[+] score: 15
MiR-15a and miR-16 have been known to act as a negative regulator of NF-κB activity by regulating IKKα expression, which contributes to the ability of miR-15 and niR-16 as a tumor suppressor. [score:7]
In fact, a study has reported that during monocyte-macrophage differentiation, expressions of miR-15a and miR-16 were decreased with higher expression of the IKKα [30]. [score:5]
For example, IKKα mRNA is a target for miR-15 and miR-16. [score:3]
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[+] 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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[+] 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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30
[+] score: 14
Other miRNAs from this paper: hsa-mir-15a, mmu-mir-15b, hsa-mir-15b
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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[+] score: 14
Deletion of the tumor suppressor miRNA cluster, encoding miR-15a and miR-16-1 led to a CLL like disease in mouse mo dels, albeit at around 18 months of age and only in ~30% of the involved mice (Aqeilan et al., 2010; Klein et al., 2010). [score:5]
Until recently, the chromosomal deletion of miR-15a/16 (chromosome 12p) and miR-146a (chromosome 5q) comprised the only two recurrent genetic abnormalities that can be traced as a direct cause for miRNA downregulation in the hematopoietic system and as noted below, in cancer pathogenesis. [score:5]
The classic examples include miR-15a and miR-16-1 loss in CLL and multiple myeloma, let-7 miRNA loss in lung and breast cancers (Garzon et al., 2009). [score:1]
Examples include miR-34a (lung adenocarcinoma), miR-145 and miR-33 (colon carcinoma) and miR-15 and 16-1 (colon carcinoma). [score:1]
miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. [score:1]
The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. [score:1]
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[+] score: 13
As shown in Table 2, up-regulated miRNAs in the spleen were mainly related with pro- and anti-apoptotic proteins, but those miRNAs that were down regulated were all involved in immune system regulation, including miR-15a (regulation of lymphoid development), miR-107 (regulation of macrophage adhesion) and miR-125a-5p (regulation of the inflammatory response and lipid uptake). [score:10]
miR-15a is known to be a regulator in lymphoid development [40]. [score:3]
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[+] score: 13
Dclk1 was the target of mmu-miR-15a-5p, Slit2 was the target of mmu-miR-322-5p, Ctgf and Notch2 were targets of mmu-miR-18a-5p, and Mgp was the target of mmu-miR-155-5p. [score:9]
Mmu-miR-322-5p, mmu-miR-20a-5p, mmu-miR-15a-5p, mmu-miR-503-3p, and mmu-miR-204-5p were decreased in expression in Sca1 [+]CD31 [−] cells. [score:3]
The miRNAs were mmu-miR-125b-5p, mmu-miR-34c-5p, mmu-miR-199b-5p, mmu-miR-379-5p, mmu-miR-127-3p, mmu-miR-322-5p, mmu-miR-20a-5p, mmu-miR-15a-5p, mmu-miR-503-3p, and mmu-miR-204-5p. [score:1]
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[+] score: 12
We observed moderate elevation of miR-15a, miR-15b and miR-16 expression levels, and great increase in miR-497∼195 expression in CD31 [hi]Emcn [hi] endothelial cells compared to CD31 [lo]Emcn [lo] endothelial cells (Supplementary Fig. 1a). [score:4]
The expression of miR-15a, miR-15b and miR-16 showed no significant difference between miR-497∼195 [−/−] and miR-497∼195 [lox/lox] controls indicating that genetic manipulation of miR-497∼195 in ECs has little effect on other members of the miR-15 family (Supplementary Fig. 2b). [score:3]
MiR-497 and miR-195 belong to miR-15 family, thus we also tested the expression of other members of the miR-15 family in bone marrow endothelial cells (BMECs). [score:3]
qRT-PCR revealed five folds higher of miR-497∼195 expression in Tg mice as compared with that in controls (Supplementary Fig. 4a) and no alterations in the transcription of miR-15a, miR-15b and miR-16 (Supplementary Fig. 4b). [score:2]
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[+] score: 11
In many tumors, there is either overexpression of so-called oncogenic miRNAs (e. g., miR-155, miR-17−5p and miR-21) [15, 16] or downregulation of tumor suppressor miRNAs (e. g., miR-34, miR-15a, miR-16−1 and let- 7) [17– 20]. [score:8]
Consequently miRNAs have been demonstrated to act either as oncogenes (e. g., miR-155, miR-17−5p and miR-21) [15, 16] or tumor suppressors (e. g., miR-34, miR-15a, miR-16−1 and let- 7) [17– 20]. [score:3]
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36
[+] score: 11
Increasing evidences have suggested that miRNAs are deregulated or upregulated in all types of cancers, acting either as tumor suppressors (e. g. miR-34, miR-15/16, let-7, miR 200 family) or as oncogenes (e. g. miR-155, miR-222/221, miR-17-5p, miR-21) [1], [3], [8], in which the miRNAs play key roles in important aspects of tumorigenesis, such as cancer initiation, differentiation, growth and progression [3], [5], [8], mainly by interfering with the expression of target genes involved in cell cycle, apoptosis, cell migration and invasion, angiogenesis. [score:11]
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[+] score: 11
Other miRNAs from this paper: hsa-mir-15a, mmu-mir-146a, hsa-mir-146a
Another interesting observation in the NZB/W mo del is the IFN induced expression of miR-15a in the spleens of treated mice; this is associated with downregulation of PAX5 and the emergence of autoantibodies and plasma cells. [score:6]
Since PAX5 is a negative regulator of miR-15a, the upregulation of miR-15a may be an early biomarker for IFN induction of plasma cells (35). [score:5]
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[+] score: 11
Altered expression of many miRNAs is seen in several tumor types: e. g. B-cell lymphomas (clustered miR-17) [2], [3], malignant lymphomas (miR-15a, miR-16-1; targeting BCL2) [4], glioblastoma tumors (miR-21up-regulation) [5], colorectal neoplasia (miR-143, miR-145 down-regulated) [6], lung cancer (miR-29) [7], and breast cancer (miR-10b) [8], with several more tumor types under analysis. [score:11]
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[+] score: 11
It should be noted that other microRNAs potentially regulating CCNE1 protein expression were also significantly changed, including down-regulation of miR-141, miR-16, miR-15a, miR-352, miR-15b and up-regulation of miR-518e, miR-29a, miR-192, and miR-29b, implicating a regulatory network fine-tuning the cell cycle checkpoints. [score:11]
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40
[+] score: 11
On the other hand, tumor suppressive miRNAs, such as let-7 and miR-15 families, downregulate a wide spectrum of positive regulators of the cell cycle machinery [55]. [score:7]
For instance, miR-15/16 family induces cell cycle arrest by simultaneously targeting multiple cyclins that regulate G [1]/S transition; these include CCND3, CCNE1 and CDK6 [25, 26]. [score:4]
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41
[+] score: 11
The miR-15 family, including the miR-15, 16, and 195 miRNAs, induce apoptosis by targeting BCL2 [49] and are direct transcriptional targets of E2F1 which is involved in cell cycle control [50]. [score:6]
Four differentially expressed miRNAs (miR-15a-5p, miR-92a-3p, miR-107, and miR-194-5p) were selected for verification by QPCR. [score:3]
In the present study, a strong correlation between the microarray and the qRT-PCR results was found for the miRNAs miR-15a-5p, miR-107, and miR-194-5p. [score:1]
The miRNAs miR-15a-5p (r = 0.92), miR-107 (r = 0.91), and miR-194-5p (r = 0.72) showed a strong correlation whereas the miR-92a-3p (r = −0.11) revealed no correlation. [score:1]
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42
[+] score: 11
Silencing PRDM14 reduced the expression of miRNAs upregulated in breast cancer tissues (e. g. miR-106a, miR-149, miR-18a, miR-221, miR-222, miR-224, miR-23a, miR-24, miR-27a/b, and miR-493) and increased expression of those that were downregulated (e. g. miR-15a, miR-150, miR-183, and miR-203). [score:11]
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[+] score: 11
Indeed, deletion or down-regulation of miR-15 and miR-16 in CLL is inversely correlated to BCL2 expression, and both miRNAs have been shown to negatively regulate BCL2 at a posttranscriptional level [17]. [score:7]
There is an emerging body of research to suggest that miRNAs play an important role in the pathology of haematological malignancies [23], first suggested with the deletion or down-regulation of miR-15 and miR-16 in a large proportion of chronic lymphocytic leukemia (CLL) cases [24]. [score:4]
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[+] score: 10
Other miRNAs from this paper: mmu-mir-138-2, mmu-mir-138-1
For instance, lncRNA Meg3 and cirRNA Igf1r could bind competitively with miRNA-15a-5p increasing target gene Inha, Acsl3, Kif21b, and Igfbp2 expressions. [score:5]
For instance, lncRNA Meg3 and cirRNA Igf1r were predicted to be ceRNAs of the miRNA miR-15a-5p, which targets the Inha, Acsl3, Kif21b, and Igfbp2 mRNAs. [score:3]
Further research on ceRNAs of miRNA-15a-3p and other associated functions are being carried out in our laboratory. [score:1]
Sixty lncRNAs (e. g., Meg3, Atp10b, Rian, Malat1), 29 circRNAs (e. g., Circular_Igf1r, Circular_Gas2, Circular_Cdy, Circular_Ccnb3), and 16 miRNAs (e. g., mmu-miR-424, mmu-miR-15a-5p, mmu-miR-138-5p, mmu-miR-15a-3p) have been included in the ceRNA network. [score:1]
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[+] score: 10
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-20a, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-93, hsa-mir-101-1, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-107, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-23b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-101a, mmu-mir-124-3, mmu-mir-125a, mmu-mir-130a, mmu-mir-9-2, mmu-mir-135a-1, mmu-mir-136, mmu-mir-138-2, mmu-mir-140, mmu-mir-144, mmu-mir-145a, mmu-mir-146a, mmu-mir-149, mmu-mir-152, mmu-mir-10b, mmu-mir-181a-2, mmu-mir-182, mmu-mir-183, mmu-mir-185, mmu-mir-24-1, mmu-mir-191, mmu-mir-193a, mmu-mir-195a, mmu-mir-200b, mmu-mir-204, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, 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-183, hsa-mir-204, hsa-mir-181a-1, hsa-mir-221, hsa-mir-222, hsa-mir-200b, mmu-mir-301a, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, mmu-mir-130b, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-23b, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-130a, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-138-2, hsa-mir-140, hsa-mir-144, 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-136, hsa-mir-138-1, hsa-mir-146a, hsa-mir-149, hsa-mir-185, hsa-mir-193a, hsa-mir-195, hsa-mir-320a, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-20a, mmu-mir-23a, mmu-mir-24-2, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-93, mmu-mir-34a, mmu-mir-330, mmu-mir-339, mmu-mir-340, mmu-mir-135b, mmu-mir-101b, hsa-mir-200c, hsa-mir-181b-2, mmu-mir-107, mmu-mir-10a, mmu-mir-17, mmu-mir-200c, mmu-mir-181a-1, mmu-mir-320, mmu-mir-26a-2, mmu-mir-221, mmu-mir-222, mmu-mir-29b-2, mmu-mir-135a-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-181c, mmu-mir-7a-1, mmu-mir-7a-2, mmu-mir-7b, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-130b, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-361, mmu-mir-361, hsa-mir-376a-1, mmu-mir-376a, hsa-mir-340, hsa-mir-330, hsa-mir-135b, hsa-mir-339, hsa-mir-335, mmu-mir-335, mmu-mir-181b-2, mmu-mir-376b, mmu-mir-434, mmu-mir-467a-1, hsa-mir-376b, hsa-mir-485, hsa-mir-146b, hsa-mir-193b, hsa-mir-181d, mmu-mir-485, mmu-mir-541, hsa-mir-376a-2, hsa-mir-320b-1, hsa-mir-320c-1, hsa-mir-320b-2, mmu-mir-301b, mmu-mir-674, mmu-mir-146b, mmu-mir-467b, mmu-mir-669c, mmu-mir-708, mmu-mir-676, mmu-mir-181d, mmu-mir-193b, mmu-mir-467c, mmu-mir-467d, hsa-mir-541, hsa-mir-708, hsa-mir-301b, mmu-mir-467e, mmu-mir-467f, mmu-mir-467g, mmu-mir-467h, hsa-mir-320d-1, hsa-mir-320c-2, hsa-mir-320d-2, mmu-mir-467a-2, mmu-mir-467a-3, mmu-mir-467a-4, mmu-mir-467a-5, mmu-mir-467a-6, mmu-mir-467a-7, mmu-mir-467a-8, mmu-mir-467a-9, mmu-mir-467a-10, hsa-mir-320e, hsa-mir-676, mmu-mir-101c, mmu-mir-195b, mmu-mir-145b, mmu-let-7j, mmu-mir-130c, mmu-mir-30f, mmu-let-7k, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
The miRNA families that change expression in both mouse and human were: let-7, miR-7, miR-15, miR-101, miR-140, miR-152 (all validated by qPCR, P < 0.05), as well as miR-17, miR-34, miR-135, miR-144, miR-146, miR-301, miR-339, miR-368 (qPCR not performed). [score:3]
The miRNA families that change expression in both mice and rats were: mir-7, mir-9, mir-10, mir-15, mir-17, mir-26, mir-29, mir-30, mir-101, mir-130, mir-181, mir-204, mir-339, mir-340, mir-368, mir-434, mir-467. [score:3]
Other differentially expressed miRNAs specific to the mouse mo del were also validated by qPCR, including miR-195 (member of the miR-15 family) and miR-541 family members. [score:3]
25E-0316mmu-miR-15a-5pmir-150.209.185.63E-052.24E-0320mmu-miR-195-5pmir-150.248.631.26E-044.01E-0353mmu-miR-15b-5pmir-150.156.854.15E-034.99E-0244mmu-miR-93-5pmir-170.166.981.73E-032.45E-0221mmu-miR-181d-5pmir-1810.248.471.51E-044.59E-0357mmu-miR-181a-5pmir-1810.209.815.96E-036.44E-0269mmu-miR-182-5pmir-1820.628.718.90E-038.21E-0262mmu-miR-183-5pmir-1830.668.386.90E-036. [score:1]
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[+] score: 10
[51] Loss of p53 in TCL1-tg/ p53 [−/−] crossed mice causes a decrease of miR15/16 together with an upregulation of MCL1 and the consequent development of a more severe CLL. [score:5]
5, 48, 49, 50 Subsequent studies, with the support of the TCL1-tg mouse mo del, disclosed an involvement of p53-miR15/16-MCL1 axis in the regulation of resistance. [score:2]
The first evidence for miRNAs involvement in human cancer was indeed from a study on CLL: 13q14.3 deletion, frequently observed in the patients, was shown to remove two microRNA genes, miR-15 and miR-16; their loss causes deregulation of BCL2. [score:2]
Recurrent cytogenetic aberrations include: deletion at 13q14.3 (55% of cases) is associated with an indolent form and loss of miR-15a and miR-16-1 genes; [5] deletions at 17p13 (7%) or 11q22-23 (18%) with consequent loss of TP53 at 17p, ATM and miR-34b/miR-34c at 11q are associated with a more aggressive form; 6, 7 trisomy 12 (16%) is associated with an intermediate form of CLL. [score:1]
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[+] score: 10
For example, miR-23 and miR-203 have been shown to enhance radiosensitivity by targeting IL8/Stat3 and IL8/AKT signalling pathway, respectively in nasopharyngeal carcinoma [24, 25]; miR-205 has been reported to function as a tumour radiosensitizer by inhibiting DNA repair pathway via down-regulation of ZEB1 and Ubc13 in breast cancer cells [26]; miR-15a/16 can enhance radiation sensitivity of NSCLC cells by targeting the TLR1/NF-κB signalling pathway [27]. [score:10]
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48
[+] score: 10
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-92a-1, hsa-mir-92a-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-15b, mmu-mir-23b, mmu-mir-27b, mmu-mir-130a, mmu-mir-133a-1, mmu-mir-140, mmu-mir-24-1, hsa-mir-196a-1, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, mmu-mir-206, hsa-mir-30c-2, hsa-mir-196a-2, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-200b, mmu-mir-301a, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-23b, hsa-mir-27b, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-140, hsa-mir-206, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-196a-1, mmu-mir-196a-2, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-24-2, mmu-mir-27a, mmu-mir-92a-2, hsa-mir-200c, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-17, mmu-mir-19a, mmu-mir-200c, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-19b-1, mmu-mir-92a-1, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-301a, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, hsa-mir-196b, mmu-mir-196b, dre-mir-196a-1, dre-mir-199-1, dre-mir-199-2, dre-mir-199-3, hsa-mir-18b, dre-let-7a-1, dre-let-7a-2, dre-let-7a-3, dre-let-7a-4, dre-let-7a-5, dre-let-7a-6, dre-let-7b, dre-let-7c-1, dre-let-7c-2, dre-let-7d-1, dre-let-7d-2, dre-let-7e, dre-let-7f, dre-let-7g-1, dre-let-7g-2, dre-let-7h, dre-let-7i, dre-mir-1-2, dre-mir-1-1, dre-mir-15a-1, dre-mir-15a-2, dre-mir-15b, dre-mir-17a-1, dre-mir-17a-2, dre-mir-18a, dre-mir-18b, dre-mir-18c, dre-mir-19a, dre-mir-20a, dre-mir-23b, dre-mir-24-4, dre-mir-24-2, dre-mir-24-3, dre-mir-24-1, dre-mir-27a, dre-mir-27b, dre-mir-27c, dre-mir-27d, dre-mir-27e, dre-mir-30c, dre-mir-92a-1, dre-mir-92a-2, dre-mir-92b, dre-mir-130a, dre-mir-133a-2, dre-mir-133a-1, dre-mir-133b, dre-mir-133c, dre-mir-140, dre-mir-196a-2, dre-mir-196b, dre-mir-200a, dre-mir-200b, dre-mir-200c, dre-mir-206-1, dre-mir-206-2, dre-mir-301a, dre-let-7j, hsa-mir-92b, mmu-mir-666, mmu-mir-18b, mmu-mir-92b, mmu-mir-1b, dre-mir-196c, dre-mir-196d, mmu-mir-3074-1, mmu-mir-3074-2, hsa-mir-3074, mmu-mir-133c, mmu-let-7j, mmu-let-7k, dre-mir-24b
miRNA Embryonic age Expression profile mir15a 48 and 72 hpf Midbrain, MHB, notochord mir15b 48 and 72 hpf Midbrain, neurocranium, notochord mir23b 30, 48, and 72 hpf Somites, lens, pharyngeal arches, notochord mir27b 48 and 72 hpf mir30c 48 and 72 hpf Brain, neurocranium, eye, heart mir130a 48 and 72 hpf Brain, gut tube, heart, eye mir133b 30, 48, and 72 hpf Notochord mir301a 48 and 72 hpf Forming cartilage Midbrain, neurocranium, eye, trigeminal ganglia Figure 5 Expression of mir23b in zebrafish embryos. [score:5]
miRNA Embryonic age Expression profile mir15a 48 and 72 hpf Midbrain, MHB, notochord mir15b 48 and 72 hpf Midbrain, neurocranium, notochord mir23b 30, 48, and 72 hpf Somites, lens, pharyngeal arches, notochord mir27b 48 and 72 hpf mir30c 48 and 72 hpf Brain, neurocranium, eye, heart mir130a 48 and 72 hpf Brain, gut tube, heart, eye mir133b 30, 48, and 72 hpf Notochord mir301a 48 and 72 hpf Forming cartilage Midbrain, neurocranium, eye, trigeminal ganglia Figure 5 Expression of mir23b in zebrafish embryos. [score:5]
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49
[+] score: 10
In advanced prostate cancer, for instance, miR-15a and miR-16 are significantly downregulated, whereas the expression of BCL2, CCND1 and WNT3A is concomitantly upregulated [37]. [score:9]
miR-16 belongs to the miR-15/miR-16 cluster that is located on the noncoding gene deleted in leukemia 2 (DLEU2) [36]. [score:1]
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50
[+] score: 9
Intriguingly, miR-15a and miR-15b are downregulated in AD brain and cerebrospinal fluid, respectively [25, 45, 46], providing clinical relevance for these observations. [score:4]
Moreover, miR-15 targets the proapoptotic protein Bcl-2, whose protein levels are increased in AD [47– 49]. [score:3]
2. Tau Phosphorylation Regulation by the miR-15 Family. [score:2]
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51
[+] score: 9
CI increases not only miR-15, miR-99, and miR-100 that target IL-6 and TNF, but also let-7g and miR-98 that target STAT3, whose activation transcribes iNOS [61– 64]. [score:5]
RI and CI also increase miR-15, miR-99, and miR-100, which target IL-6 and TNF. [score:3]
In the serum, IPA indicates that miR-125b alters p53, IL-12, and TNF; miR-29c alters IL-12 and IL-6; miR-15a alters VEGF and IL-6; and miR-148b alters PTEN (Fig 9). [score:1]
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52
[+] score: 9
A common genomic aberration in CLL leads to increased expression of anti-apoptotic protein BCL-2, which is negatively regulated by miR-15a and miR-16-1. The expression of these miRs is lost via deletion of a region on chromosome 13, 13q14.3 (59, 60). [score:6]
To mo del a common genetic alteration in the human disease, a transgenic mouse lacking the chromosomal region 13q14 encoding for DLEU-2, miR-15, and miR-16 were developed (67). [score:3]
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53
[+] score: 9
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-17, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-30a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-30b, mmu-mir-125b-2, mmu-mir-9-2, mmu-mir-150, mmu-mir-24-1, mmu-mir-204, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-204, hsa-mir-210, hsa-mir-221, hsa-mir-222, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-150, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-21a, mmu-mir-24-2, mmu-mir-27a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-326, mmu-mir-107, mmu-mir-17, mmu-mir-210, mmu-mir-221, mmu-mir-222, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, hsa-mir-30c-1, hsa-mir-30e, hsa-mir-378a, mmu-mir-378a, hsa-mir-326, ssc-mir-125b-2, ssc-mir-24-1, ssc-mir-326, ssc-mir-27a, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-103-1, ssc-mir-107, ssc-mir-204, ssc-mir-21, ssc-mir-30c-2, ssc-mir-9-1, ssc-mir-9-2, hsa-mir-378d-2, hsa-mir-103b-1, hsa-mir-103b-2, ssc-mir-15a, ssc-mir-17, ssc-mir-30b, ssc-mir-210, ssc-mir-221, ssc-mir-30a, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-378-1, ssc-mir-30d, ssc-mir-30e, ssc-mir-103-2, ssc-mir-27b, ssc-mir-24-2, ssc-mir-222, ssc-mir-125b-1, hsa-mir-378b, hsa-mir-378c, ssc-mir-30c-1, ssc-mir-378-2, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, ssc-let-7a-2, hsa-mir-378j, mmu-mir-21b, mmu-let-7j, mmu-mir-378c, mmu-mir-21c, mmu-mir-378d, mmu-mir-30f, ssc-let-7d, ssc-let-7f-2, ssc-mir-9-3, ssc-mir-150-1, ssc-mir-150-2, mmu-let-7k, ssc-mir-378b, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Cai et al. (2014) found that 18 miRNAs were differentially expressed between intact and castrated male pigs, including miR-15a, miR-21, miR-27, miR-30, and so on [23]; Bai et al. (2014) reported that 177 miRNAs had more than 2-fold differential expression between castrated and intact male pigs, including miR-21, miR-30, miR-27, miR-103, and so on [22]. [score:5]
We found 13 adipogenesis-promoting miRNAs (let-7、miR-9、miR-15a、miR-17、miR-21、miR-24、miR-30、miR-103、miR-107、miR-125b、miR-204、miR-210、and miR-378) target 860 lncRNA loci. [score:3]
We analyzed the relationship between the 343 identified lncRNAs with the 13 promoting adipogenesis miRNAs (let-7、miR-9、miR-15a、miR-17、miR-21、miR-24、miR-30、miR-103、miR-107、miR-125b、miR-204、miR-210、and miR-378) and five depressing adipogenesis miRNAs (miR-27, miR-150, miR-221, miR-222, and miR-326). [score:1]
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54
[+] score: 9
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]
Tang R. Li L. Zhu D. Hou D. Cao T. Gu H. Zhang J. Chen J. Zhang C. Y. Zen K. Mouse miRNA-709 directly regulates miRNA-15a/16-1 biogenesis at the posttranscriptional level in the nucleus: Evidence for a microRNA hierarchy system Cell Res. [score:3]
mir-709 was already described as a regulator of mir-15a/16 clusters at the post-transcriptional level in the nucleus of a mouse mo del [33]. [score:2]
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55
[+] score: 9
There was one significant difference between mir-15 and mir-221 expression: the KSHV -negative SLK cells transcribed significantly lower levels of mir-15. [score:3]
Loss of mir-221 precursor miRNA and gain of mir-15 precursor miRNA expression demarked the transition from merely immortal to fully tumorigenic cells. [score:3]
In a separate analysis of only the endothelial/KS sample and excluding SLK cells (data not shown), mir-15 levels correlated closely with KSHV latent mRNA and miRNA transcription and can thus be considered KSHV –regulated. [score:1]
We also identified specific KSHV and KS -associated pre-miRNAs, foremost among them mir-221, mir-140, mir-15a and mir-24. [score:1]
The mir-15 pre-miRNA is an example for miRNAs that exhibit the opposite pattern of transcription as mir-221. [score:1]
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56
[+] score: 8
Bandi N 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 cancerCancer Res. [score:5]
The reduced expression of microRNAs such as miR-15a and miR-21 has been noted in two common types of NSCLC [30]. [score:3]
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57
[+] score: 8
Other miRNAs from this paper: mmu-mir-15b, mmu-mir-155
Nevertheless, it has been shown that miR-15/16 controls NK maturation by directly regulating levels of the transcription factor MYB, since the overexpression of miR-15/16 or MYB deficiency in miR-15/16 -deficient NK cells rescues the maturation defect (74). [score:5]
More importantly, the opposing effect that miR-15/16 and miR-155 have on NK cell maturation highlights the pleiotropic effects of miRs and suggests that there is still much to learn about the role of miRs in NK cell biology, particularly about redundancies between miRs. [score:1]
Rather than NK cell survival, mIR-155 and miR15/16 appear to be essential for normal NK cell maturation, as NK cells lacking miR-15/16 are unable to fully mature into M2 NK cells (74), much like Dicer1 -deficient mice, while miR-155 -deficient NK cells undergo accelerated maturation (73). [score:1]
Although it remains unclear as to whether NK cell survival is dependent on specific miRs, miR-155 and miR-15/16 are unlikely candidates since mice that are deficient for either miR have normal NK cell numbers (73, 74). [score:1]
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58
[+] score: 8
miR-15a, miR-16, and miR-503 were reported to inhibit tumor angiogenesis by targeting VEGFA [15],[16]. [score:5]
FEBS J. 15 Sun CY, She XM, Qin Y, Chu ZB, Chen L et al. (2013) miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF. [score:3]
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59
[+] score: 8
Other miRNAs from this paper: mmu-mir-126a, mmu-mir-132, mmu-mir-126b
Down-regulation of miR-15a/b accelerates fibrotic remo delling in the Type 2 diabetic human and mouse heart. [score:4]
Moreover, early down-regulation of anti-fibrotic miR-15a and -15b in the myocardium of 12 week-old db/db mice facilitates adverse myocardial fibrosis that is only evident by 20 weeks of age (Rawal et al., 2017a). [score:4]
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60
[+] score: 8
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-27a, hsa-mir-30a, hsa-mir-31, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-127, mmu-mir-9-2, mmu-mir-141, mmu-mir-145a, mmu-mir-155, mmu-mir-10b, mmu-mir-24-1, mmu-mir-205, mmu-mir-206, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10b, hsa-mir-34a, hsa-mir-205, hsa-mir-221, mmu-mir-290a, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-141, hsa-mir-145, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-206, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-21a, mmu-mir-24-2, mmu-mir-27a, mmu-mir-31, mmu-mir-34a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-322, hsa-mir-200c, hsa-mir-155, mmu-mir-17, mmu-mir-25, mmu-mir-200c, mmu-mir-221, mmu-mir-29b-2, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, hsa-mir-106b, hsa-mir-30c-1, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-373, hsa-mir-20b, hsa-mir-520c, hsa-mir-503, mmu-mir-20b, mmu-mir-503, hsa-mir-103b-1, hsa-mir-103b-2, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-30f, mmu-let-7k, mmu-mir-126b, mmu-mir-290b, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
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]
One of the first discoveries that connected miRNAs and cell cycle regulation was the anti-proliferative potential of the miR-15a/16-1 family that target multiple cell cycle genes involved in cellular proliferation and growth arrest [132, 133, 134, 135]. [score:4]
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61
[+] score: 8
Other miRNAs from this paper: mmu-mir-15b
On the other hand, the analysis of the expression of miRNAs targeting GCNT3 showed that miR-15 family is significantly down-regulated by RE-2 (Table 3). [score:8]
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62
[+] score: 8
Other miRNAs from this paper: mmu-mir-16-1
Recent study suggested that one of the mechanisms was through up-regulation of MCL-1 expression via suppression of microRNA-15a/miR-16-1 [10]. [score:8]
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63
[+] score: 8
Other miRNAs from this paper: mmu-mir-15b, mmu-mir-21a, mmu-mir-17, mmu-mir-21b, mmu-mir-21c
Genesis 10 Li G, Miskimen KL, Wang Z, Xie XY, Brenzovich J, et al (2009) STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease. [score:5]
While multiple STAT5 regulated genes have been discovered [1], only a few microRNAs, among them miR 17–92 and miR-15/16 [9], [10] have been linked directly to STAT5. [score:3]
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64
[+] score: 8
Thus, for six miRNA families – mir-135, mir-205, mir-142-3p, mir-15/16, mir-218 and mir-24 - we obtained evidence for their functional relevance in the inner ear on two levels: (a) the miRNAs were differentially expressed between the two tissues; and (b) their predicted targets were differentially expressed in a manner consistent with the currently accepted mo del of miRNA regulation. [score:8]
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65
[+] score: 7
miR-15a and miR16-1 were deleted and/or down-regulated in ~ 70% of patients with chronic lymphocytic leukemia (29). [score:4]
miR-15a/16-1 induced apoptosis by inhibiting BCL-2 (30). [score:3]
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66
[+] score: 7
The loss of the miRNAs miR-15a and miR-16-1 in patients with the 13q deletion contributes to the pathogenesis of the disease [7], [8], and altered miR expression is associated with disease progression and poor prognosis [9]. [score:7]
[1 to 20 of 1 sentences]
67
[+] score: 7
Other miRNAs from this paper: mmu-mir-106a, mmu-mir-21a, mmu-mir-17, mmu-mir-21b, mmu-mir-21c
As Yin et al. demonstrated that the transcription factor KLF11 synergistically enhances PPARγ -based suppression of pro-apoptotic miR-15a expression in cerebrovascular endothelial cells [9], we hypothesized that IRF6’s co-repression of PPARγ -driven vasculoprotection may involve the regulation of endothelial cell apoptosis via a microRNA -based mechanism. [score:6]
Yin et al. ’s previous work has demonstrated that pioglitazone exerts its cerebrovascular protective effect through a miR-15a -associated mechanism [17]. [score:1]
[1 to 20 of 2 sentences]
68
[+] score: 7
miR-15a/16 inhibits CTLA-4 expression (Figure 1C), precluding optimal Treg -mediated inhibition of dendritic cell (DC) maturation (48, 66). [score:7]
[1 to 20 of 1 sentences]
69
[+] score: 7
A spectrum of miRNAs including miR-337-5p, miR-17-1, miR-15a, miR-491-5p, miR-339, miR-337-3p, miR-241, miR-19a were predicted to down regulate oncogenic targets like TGFβ, BCLXW, BCL-Xl, STATs, c-MYC and SMAD (as represented by red lines). [score:4]
For example, miR-337-5p, miR-17-1, miR-15a, miR-491-5p, miR-339, miR-337-3p, miR-241, miR-19a were found to modulate oncogenic targets including TGFβ, STATs, c-MYC and SMAD. [score:3]
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70
[+] score: 7
Previous studies have shown that CCND1 is the direct target of miR-186 [33] and miR-545 [34], while both CCND1 and CCND2 are directly targeted by miR-15a and miR-16 [35]. [score:7]
[1 to 20 of 1 sentences]
71
[+] score: 7
Notably, several large miRNA families (such as the miRNA-15, miRNA-30, and let-7 families) were upregulated in P10 cardiac ventricles, and miRNA-195 (a member of the miRNA-15 family) was shown to be the most highly upregulated miRNA. [score:7]
[1 to 20 of 1 sentences]
72
[+] score: 7
In addition to miR-27a and let-7b, the following miRNAs from the miRNA signature were considered to be tumor suppressors for DLBCL: miR-15a [29, 32, 43, 44], let-7c [20, 23], miR-24 [12], and miR-497 [9, 45]. [score:2]
Since miRNAs can have different aliases, the 10 miRNAs (Fig 1) are identified as the following for the rest of this manuscript: let-7 = let-7b, let-7a-5p = let-7c, miR-10 = miR-10b, miR-130 = miR-130a, miR-155 = miR-155, miR-27 = miR27a, miR-24-3p = miR-24, miR-17 = miR-18a, miR-15 = miR-15a, and miR-16-5p = miR-497. [score:1]
This miRNA signature consists of 10 miRNAs: miR-130, miR-27, miR-17, miR-10, miR-155, let-7a-5p, let-7, miR-24-3p, miR-15, and miR-16-5p. [score:1]
This key circulating miRNA signature consists of ten miRNAs (let-7c, let-7b, miR-15a, miR-18a, miR-27a, miR-155, miR-24, miR-130a, miR-10b, and miR-497), which were responsible for DLBCL initiation and was present prior to the formation of visible tumor. [score:1]
Five out of the ten miRNAs (let-7c, miR-15a, miR-18a, miR-24, and miR-130a) showed an increased amount of circulating miRNA with age for both Smurf2 [T/T] and wild-type mice (Fig 4). [score:1]
More specifically, impact of miRNA on lymphomas was initially underestimated with only a handful of miRNAs, including miR-155 [52, 53] and a miR-16 and miR-15 combination [54], first thought to be the key players in B cell lymphomas. [score:1]
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73
[+] score: 7
Among the 10 most upregulated miRNAs (Supplementary Table 2), miR-16-5p, miR-23b-3p, let-7a-5p, miR-15a-5p, miR-17-5p and miR-93 were identified as the candidate regulators of PDCD4. [score:5]
As a result, luciferase activity was markedly reduced in cells transfected with pre-miR-23b-3p, pre-miR-17-5p or pre-miR-93, while pre-miR-16-5p, pre-let-7a-5p and pre-miR-15a-5p have no influence on the luciferase activity (Supplementary Fig. 1B). [score:1]
The resulting plasmid was transfected into the human gastric carcinoma cell line AGS along with pre-miRNAs of miR-16-5p, miR-23b-3p, let-7a-5p, miR-15a-5p, miR-17-5p and miR-93. [score:1]
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74
[+] score: 6
Clustered miRNAs and homologous miRNAs had various expression levels (even involved in larger expression divergence), but they always showed consistent dysregulation patterns (For example, mir-15b cluster and mir-193b cluster; mir-15 family) although the fold change may differ. [score:6]
[1 to 20 of 1 sentences]
75
[+] score: 6
miR-709 was recently described as a tumor-suppressor miRNA targeting Myc, Akt and Ras, which participates in the regulation of apoptosis through the miR-15a/miR-16-1 pathway [80], [81]. [score:6]
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76
[+] score: 6
Oncogenic miRs are frequently over-expressed in cancer tissues, including miR-21, miR-17-92, miR-155 and miR-372, while miRs such as miR-34 and the let-7 family miR-15a and miR-16-1 are considered as tumor suppressors and their expression is often reduced in cancer tissues [27]. [score:6]
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77
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Our previous data also indicated that miR-15a/16-1 inhibited the expression of WT1 probably through an indirect mechanism in leukemic cells [52]. [score:6]
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78
[+] score: 6
It would be interesting to determine whether ADAMTS-4 may induce mechanisms previously described to downregulate neurotrophic factor production, for instance, by modulating the nuclear translocation of transcription factors such as the histone deacetylase HDAC6 (negative regulator) [35], CREB (cAMP response element -binding protein) or NF-κB (nuclear factor kappa B) (positive regulators) [36– 38], and/or by modulating micro -RNAs (miR) production such as miR-15a, miR-132, miR-134, miR-221 or Let-7 miR [39– 41]. [score:6]
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79
[+] score: 6
Bandi et al. documented that cell cycle arrest induced by miR-15a and miR-16 depended on the expression of Rb [9]. [score:3]
The miR-15a and miR-16 cluster was also demonstrated as having more than one target [9, 10, 49]. [score:3]
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80
[+] score: 6
By combining transcriptome profiling, in situ hybridization and bioinformatics the authors zoomed in on six miRNAs (miR-15a, miR-18a, miR-30b, miR-99a, miR-182, and miR-199a) showing different spatio-temporal expression in new born mouse cochlea and vestibule. [score:3]
By using bioinformatics tool the authors also identified Slc12a2, Cldn12 and Bdnf as potential targets for miR-15a. [score:3]
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81
[+] score: 6
Postnatal inhibition of miR-15 family prolonged the proliferative capacity of neonatal CM [12]. [score:3]
Consistent with this, Hippo/Yap pathway components 9, 10, the transcription factor Meis1 [11], and a series of microRNA including members of the miR-15 family [12], miR-199a, miR-590 [13], miR-17-92 cluster [14], miR-99/10, and Let-7a/c [15] have been separately implicated in the regulation of CM proliferation. [score:2]
Porrello ER MiR-15 family regulates postnatal mitotic arrest of cardiomyocytesCirc. [score:1]
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82
[+] score: 6
Vascular endothelial cell-specific microRNA-15a directly targets FGF2 and VEGF to inhibit angiogenesis [18]. [score:6]
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83
[+] score: 6
Interestingly, many moRNA-deriving, cancer -associated hairpins are also expressed in oocytes such as mir-17-92 cluster, miR-20, miR-21, miR-15a/16 and miR-103 [50] whereas miR-421 from mir-374b-421 cluster has been reported to be up-regulated in ovarian teratomas [60]. [score:6]
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84
[+] score: 6
Other miRNAs from this paper: mmu-mir-21a, mmu-mir-31, mmu-mir-21b, mmu-mir-21c
B to D) Plots of fold-change (to control) of RT-PCR data showing similar expression levels of mir-15a (B), mir-21 (C) and mir-31 (D; P14 control kidneys: 5 samples, 4 replicates each; P14 mutant kidneys: 6 samples, 4 replicates each). [score:3]
No differences were found by real-time quantitative PCR in a set of 3 microRNA's previously linked to cystic disease (mir15a, mir21 and mir31 [20], [22]; Figure 3). [score:3]
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85
[+] score: 6
Importantly, also, miR-497 and miR-15b, which target the same seed region of miR-16, were found among the top candidates (cluster #1, Table  2), and the other miRNAs belonging to the same family (miR-195, miR-15a, and miR-424), even if less efficiently, all showed an inhibitory effect on A549 cells (0.902, 0.837, and 0.834 normalized A549 cell number, respectively). [score:5]
This is the case, for example, of miR-16 which, together with miR-15, was the first miRNA described to be deleted in cancer, specifically in chronic lymphocytic leukemia (CLL) cells [14]. [score:1]
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86
[+] score: 5
Two members of the miR-15a/16 cluster, miR-15a and miR-15b, were also down-regulated in the activated blastocysts. [score:4]
These include the miR-17∼92 (miR-17-5p, -18, -19b, -20), 15a/16 (miR-15a, -15b), and 290–295 (miR-290, -294, -295) clusters. [score:1]
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87
[+] score: 5
For instance, members of the let-7 miRNA family can negatively regulate all three members of the RAS oncogene family [27], and miR-15a/miR-16-1 can target and regulate BCL2 in B-cell CLL cells [25]. [score:5]
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88
[+] score: 5
We also determined that the expression of Mlycd (malonyl-CoA decarboxylase) can be suppressed by mmu-miR-15a and mmu-miR-351. [score:5]
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89
[+] score: 5
In particular miR-23b, miR-199a, and miR-15a displayed increased expression during early AVC development and characterization of target genes suggests that they are involved in regulating epithelial-mesenchymal transition (EMT) signaling pathways [106]. [score:5]
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90
[+] score: 5
Other miRNAs from this paper: mmu-mir-16-1, mmu-mir-23a, mmu-mir-486a, mmu-mir-486b
The induction of HbF can be obtained by using low molecular weight drugs causing the induction of the γ-globin gene (6– 8, 14– 17), artificial promoters (18, 19), decoy molecules targeting transcription factors involved in the transcriptional repression of γ-globin genes (MYB, KLF-1 and BCL-11A) (20, 21), or microRNAs targeting mRNAs coding for these repressors (data are available for microRNAs miR-15a, miR-16-1, miR-486-3p and miR-23a/27a) (22– 24). [score:5]
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91
[+] score: 5
Conversely, there are miRs having the negative role in regulation of cell proliferation and are often down-regulated in cancer cells, such as let-7c, miR-10b, miR-15a, miR-31, miR-34, miR-145, miR-223 [7]. [score:5]
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92
[+] score: 5
Moreover, microarray profiling of mRNA expression in BMMs after DOTAP -mediated LNA/DNA AMO transfection (for miR-19a-3p, miR-15a-5p and miR-34a-5p) did not result in a significant de-repression of genes targeted by these miRNAs according to specific hexamer enrichment analyses with DIANA-mirExtra (42) (data not shown). [score:5]
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93
[+] score: 5
Furthermore, let-7, miR-15a, miR-31, miR-34, miR-205 and others were demonstrated to suppress Ras, Myc, Bcl2, Notch, E2F1 or CyclinD1 [14], suggesting a tumor-suppressive activity for these miRNAs. [score:5]
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94
[+] score: 5
Other miRNAs from this paper: hsa-mir-15a, dme-mir-982, dme-mir-252
The gene of interest at 13q14 may be RB1 (retinoblastoma tumour suppressor protein), or one of the miRNAs at this locus which are under-expressed in CLL and MM (miR-15a/16). [score:5]
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95
[+] score: 5
miRNAs can act as tumor suppressors (e. g. miR-15a and miR-16-1 [4]), oncogenes (e. g. miR-155 [5], [6] and miR-21 [7], [8], [9], [10]) and as promoters (e. g. miR-10b, miR-182 and miR-29a [11], [12], [13]) or suppressors (e. g. miR-335 and miR-126 [14]) of metastasis. [score:5]
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96
[+] score: 5
Regulation of lymphoid development, apoptosis, Toll-like receptor signaling pathway and nucleotide excision repair was modified by miR-15 and miR-155. [score:3]
mRNAs of IL-6 and TAB2 was down regulated by increased mmu-miR-142-3p and mmu-miR-15, while mmu-miR-152 and mRNA of CaMK II was both increased in allografts compared with syngrafts. [score:1]
Mmu-miR-15 family was associated with apoptosis, lysine degradation, calcium signaling pathway, Toll-like receptor signaling pathway, p53 signaling pathway and multiple pathways related with melanoma, prostate cancer, small cell lung cancer, colorectal cancer, basal cell carcinoma. [score:1]
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97
[+] score: 5
Other miRNAs from this paper: mmu-mir-107
The expression of β-amyloid cleavage enzyme 1 (BACE-1), one of the key enzymes to produce Aβ, is regulated by several miRNAs including miR-15a and miR-107 44 48. [score:4]
Interestingly, age-related neurodegeneration shown in the cortex of the Dicer c KO mouse is caused by specific loss function of miR-15a but not global miRNAs, as miR-15a affects tau phosphorylation 37. [score:1]
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98
[+] score: 5
Many studies have demonstrated that miRNA expression profiles are subject to change in different cells when stimulated by LPS via TLR-signaling pathways, including miR-146a, miR-155, miR-132, miR-15a/16, miR-27a and miR-532-5p [19, 20, 21, 22, 23]. [score:3]
Moon H. G. Yang J. Zheng Y. Jin Y. miR-15a/16 regulates macrophage phagocytosis after bacterial infection J. Immunol. [score:2]
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99
[+] score: 5
Other miRNAs from this paper: mmu-mir-15b
The cell cycle arrest has also been linked with the up-regulation of multiple members of the miR-15 family of microRNA, that regulate a number of cell cycle genes [7]. [score:5]
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100
[+] score: 4
For example, miR-15 and miR-16, which are deleted or down-regulated in the majority of B-CLL patients, can modulate genes involved in proliferation and survival pathways. [score:4]
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