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49 publications mentioning mmu-mir-503

Open access articles that are associated with the species Mus musculus and mention the gene name mir-503. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

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[+] score: 337
Furthermore, over -expression of miR-503 and knockdown of PI3K p85 can down-regulate the expression of Snail, which confirms that miR-503 regulates EMT via the regulation of the transcription factor Snail. [score:11]
The aforementioned studies have shown that the expression of miR-503 is down-regulated in the silica -treated HBE cells and A549 cells (Fig.   4e,f and Supplementary Fig.   1d,e), thus we wonder whether the expression of miR-503 is regulated by lncRNA. [score:9]
In addition, we confirmed that ectopic expression of miR-503 via mimic transfection could partly reverse the morphological changes of HBE cells (Supplementary Fig.   1j) and suppressed the expression of p-PI3K p85, PI3K p85, vimentin and α-SMA, and correspondingly enhanced the expression of E-cadherin at the protein level (Fig.   4g and Supplementary Fig.   1k). [score:9]
Furthermore, knockdown of MALAT1 released miR-503 and inhibited the expression of its target gene PI3K p85 thus alleviating the process of EMT. [score:8]
Having verified the expression of miR-503 was down-regulated in the mouse lung tissues of silica -induced pulmonary fibrosis, then we explored whether raising the expression of miR-503 in vivo alleviates the process of EMT and influences the pathological process of silicosis. [score:8]
Increased miR-503 attenuates the EMT in vivoHaving verified the expression of miR-503 was down-regulated in the mouse lung tissues of silica -induced pulmonary fibrosis, then we explored whether raising the expression of miR-503 in vivo alleviates the process of EMT and influences the pathological process of silicosis. [score:8]
In addition, the over expression of miR-503 could also suppress p-Akt expression both in vivo and in vitro, which all suggest that miR-503 limits the development of EMT via PI3K/Akt signaling pathway. [score:8]
Consistently, the up-regulation of miR-503 increased the protein expression level of E-cadherin and decreased the expression levels of vimentin and α-SMA, thus alleviating the process of EMT (Fig.   2d). [score:8]
The results showed that the expression of lncRNA MALAT1 was significantly up-regulated in the silica -treated group compared to the control one (Fig.   6b), which is negatively correlated with miR-503 expression. [score:7]
Li et al. [42] suggested that the expression of miR-503 is up-regulated in the adenocarcinoma. [score:6]
Although we have demonstrated that the expression of miR-503 is down-regulated in silica -induced pulmonary fibrotic tissues and HBE cells, the mechanisms for the alterations of miR-503 are still obscure. [score:6]
The expression of miR-503 is down-regulated in the lung tissues of mice with silica -induced pulmonary fibrosis. [score:6]
In silica -treated HBE and A549 cell lines, the protein expression levels of p-PI3K p85 and PI3K p85 increased (Fig.   4c and d and Supplementary Fig.   1d and e), and the miR-503 levels were decreased significantly (Fig.   4e and f and Supplementary Fig.   1h and i), which showed the inverse correlation with PI3K p85 expressions. [score:5]
Furthermore, miR-503 overexpression can inhibit EMT, slowing down the progression of pulmonary fibrosis. [score:5]
So we predicted the target genes by the bioinformatics tools and found that PI3K p85 is a target of miR-503. [score:5]
Based on these findings, we concluded that miR-503 suppresses EMT by targeting PI3K/Akt/mTOR/Snail pathway in silica -induced pulmonary fibrosis. [score:5]
Silica treatment resulted in the enhanced expression of lncRNA MALAT1, which competitively binding to miR-503 and depressed its expression. [score:5]
On the contrary, overexpression of miR-503 repressed the protein expression of p-Akt, p-mTOR and Snail in vivo (Fig.   5d) and in vitro (Fig.   5e and Supplementary Fig.   2a). [score:5]
These data showed that the expression of miR-503 appears to be disease-specific or cell-type specific. [score:5]
The results revealed that inhibition of lncRNA MALAT1 could significantly increase the expression of miR-503 in these two cell lines (Fig.   6f and Supplementary Fig.   3c). [score:5]
In this study, we have identified that PI3K p85 is highly expressed in silica -induced lung fibrotic tissues, HBE cells, A549 cells, which is consistent with the negative expression of miR-503. [score:5]
Therefore, we use TargetScan bioinformatics software to predict the target genes of miR-503. [score:5]
It concentrated on the EMT-suppressive effects of miR-503 on the silica -induced pulmonary fibrosis via the classical PI3K/Akt/Snail signaling pathway, and the lncRNA MALAT1 serves as a molecular sponge to competitively decrease the expression of miR-503. [score:5]
Interestingly, overexpression of PI3K p85 largely counteracted the inhibitory effects of miR-503 mimic (Fig.   4i and Supplementary Fig.   1m). [score:5]
Conversely, the cells treated with silica result in the enhanced expression of lncRNA MALAT1, which competitively binds to miR-503 and depresses its expression. [score:5]
Our rescue experiment also showed that co-transfection with pcDNA3.1-PI3K p85 and miR-503 mimic restored the protein expression levels of p-Akt, p-mTOR and Snail which were inhibited by miR-503 mimic (Fig.   5g and Supplementary Fig.   2c). [score:5]
While accumulated evidence indicated that the expression of miR-503 varies in different organs and diseases. [score:5]
Zhou et al. [23] identified a potential epigenetic mechanism for the explanation of the down-regulation of miR-503 in HepG2 and LO2 cells. [score:4]
And up-regulated miR-503 in a mouse mo del also reduced the protein levels of p-PI3K p85 and PI3K p85 (Fig.   3c). [score:4]
Moreover, Yang et al. [27] reported that PI3K p85 is a direct target of miR-503 in non-small cell lung cancer. [score:4]
For the wild type with PI3K p85 reporter, over -expression of miR-503 significantly reduced its relative luciferase activity compared to group transfected with non-target miRNA mimic control, whereas this effect was abolished in the case of the mutant reporter in which the miR-503 binding site was mutated (Fig.   3d and Supplementary Fig.   1b). [score:4]
Our previous microarray analysis showed miR-503 is down-regulated in the lung fibrotic tissue which suggested miR-503 may play an important role in the process of pulmonary fibrosis. [score:4]
It means the expression of miR-503 could be possibly regulated by the modulation of methylation of the CpG islands. [score:4]
All these results strongly suggest that PI3K p85 can be targeted by miR-503 directly. [score:4]
Taken together, our results indicated that miR-503 alleviates the process of EMT by down -regulating the expression of PI3K p85. [score:4]
In present study, we have identified PI3K p85 is a target gene of miR-503, and a number of studies have demonstrated that PI3K p85 can be regulated by some other miRNAs. [score:4]
Taken together, these results indicated that miR-503 is able to alleviate the development and pathological process of mouse pulmonary fibrosis in vivo via the EMT-suppressive effects. [score:4]
MiR-503 binds to the 3′-UTR region of PI3K p85 and represses its levels, thus inhibiting the expression of the downstream molecules, p-Akt, p-mTOR and Snail, and ultimately leading to alleviation of EMT. [score:4]
It was also proved that miR-503 overexpression increased E-cadherin expression and reduced vimentin in fibrotic lung tissues by using immunohistochemistry assays (Fig.   2e). [score:4]
To validate the expression level of miR-503 in this re-established mo del, qRT-PCR analysis was performed and displayed markedly decreased expression of miR-503, about five-fold changes, in the day 28 group as compared with the control group (Fig.   1c). [score:4]
The miR-503 overexpression mouse lung fibrosis mo del was conducted by intratracheal instillation of 200 nmol/kg miR-503 agomir (RiboBio Co, Ltd, Guangzhou, China) after silica instillation. [score:3]
All these results indicated that miR-503 is significantly down-regulated in the fibrotic mice lung tissues, but whether miR-503 influences the pathological process and development of the pulmonary fibrosis needs further investigation. [score:3]
Two CpG enriched islands were found near the translational start site of miR-503. [score:3]
Figure 1The expression of miR-503 is decreased in mouse lung tissues of silica -induced pulmonary fibrosis. [score:3]
It was found that PI3K p85 might be the functional potential target of miR-503 (Fig.   3a). [score:3]
The results showed down-regulation of miR-503 was found in the silica group compared with the control group, but elevated when treated with miR-503 agomir (Fig.   2b). [score:3]
The results obtained here have preliminarily illustrated the target gene of miR-503, while the downstream molecular signaling mechanisms need further research. [score:3]
Some studies revealed that the expression of miR-503 is increased in several kinds of cancers 41– 44. [score:3]
For example, Long et al. reported that miR-503 inhibits cell proliferation in human breast cancer [22]. [score:3]
Therefore, we examined whether miR-503 could inhibit EMT through PI3K/Akt/mTOR/Snail signaling pathway. [score:3]
However, on the contrary, some other studies reported the declined expression of miR-503 in cervical cancer [19], non-small cell lung cancer (NSCLC) [45] and hepatocellular carcinoma(HCC) [46]. [score:3]
To further investigate whether MALAT1 is a functional target of miR-503, the relative expression of lncRNA MALAT1 in silica -treated HBE cells was detected by qRT-PCR. [score:3]
Peng et al. identified that miR-503 inhibits cell growth and EMT in gastric cancer [24]. [score:3]
We overexpressed PI3K p85 by the co-transfection of pcDNA3.1-PI3K p85 plasmid with miR-503 mimic. [score:3]
The miR-503 expression levels were normalized to U6 (interval reference) and the lncRNA MALAT1 expression levels were normalized to GAPDH (interval reference) and calculated via 2 [−ΔΔCt] method. [score:3]
With the help of several bioinformatics software, we found that lncRNA MALAT1 might be the potential target of miR-503. [score:3]
The predict software (Starbase v2.0 and RegRNA 2.0) was used to identify the potential target lncRNA of miR-503 and found a putative complementary sequence for miR-503 in lncRNA MALAT1 at position 6623–6650 (Fig.   6a). [score:3]
Figure 7 The signaling pathway for miR-503 playing its EMT-suppressive role in silica -induced pulmonary fibrosis. [score:3]
The miR-503 expression was performed using SYBR Green methods (TaKaRa Bio Inc, Japan) by qRT-PCR (ABI7900 real-time PCR instrument). [score:3]
But the molecular mechanisms underlying the EMT-suppressive effects of miR-503 are still unclear. [score:3]
And on day 7, 14, 21 after the molding, 120nmol/kg miR-503 agomir were given to the miR-503 over expression group via tail vein injection. [score:3]
Having identified PI3K p85 is the target gene of miR-503, we were also wondering which signaling pathway is the key point in alleviating EMT in pulmonary fibrosis. [score:3]
After we have confirmed lncRNA MALAT1 could act as a sponge of miR-503, and miR-503 could influence EMT through PI3K/Akt/mTOR/Snail signaling pathway, it is need to test whether lncRNA MALAT1 regulates the process of EMT via the miR-503-PI3K/Akt/mTOR/Snail signaling pathway. [score:2]
Our previous miRNA microarray data have shown that the expression of miR-503 is decreased in mouse lung tissues of the silica group compared to the control group. [score:2]
We have identified that the expression levels of miR-503 are significantly decreased in the tissues of silica -induced pulmonary fibrosis and two cell lines (HBE and A549) treated with silica compared with their control groups. [score:2]
MiR-503 blocks the process of EMT via targeting PI3K p85. [score:2]
Our previous data revealed that the relative expression of miR-503 is reduced in the lung tissues of the silica group compared to the control group by microarray analysis. [score:2]
Figure 6LncRNA MALAT1 promotes EMT via binding to miR-503 directly. [score:2]
Based on our findings, a functional mo del was proposed to integrate miR-503 with downstream PI3K/Akt/mTOR/Snail signaling and upstream endogenous ‘sponge’ lncRNA MALAT1 regulation network (Fig.   7). [score:2]
However, fewer studies have concentrated on the regulation of miR-503 in the pathological process of lung fibrosis, particularly silicosis. [score:2]
LncRNA MALAT1 promotes EMT via binding to miR-503 directly. [score:2]
Taken together, it appears that lncRNA MALAT1 is able to bind to miR-503 directly. [score:2]
To verify whether miR-503 is capable of regulating PI3K p85 via the binding sites in its 3′-UTR, we constructed the 3′-UTR containing the predicted miR-503 binding site downstream of the firefly luciferase coding region in the psi-CHECK2-REPORT luciferase vector. [score:2]
Previous microarray study of mouse lung fibrosis showed that the expression of miR-503 on day 28 after silica treatment was decreased about three-fold changes compared with the control group (Supplementary Fig.   1a). [score:2]
, Ltd, Shanghai, China) and was co -transfected with miR-503 mimic into HBE and A549 cells for the rescue experiment. [score:1]
To our knowledge, this is the first report showed miR-503 could be sponged by lncRNA MALAT1. [score:1]
Furthermore, was applied to validate whether miR-503 could bind to lncRNA MALAT1. [score:1]
Moreover, Zhao et al. [43] revealed that the increase of miR-503 is associated with tumorigenesis of retinoblastoma. [score:1]
And then we confirmed that MALAT1 could bind to miR-503 directly by performing and dual-luciferase reporter gene assay. [score:1]
In addition, miR-503 has been reported to exert diverse biological functions in several kinds of cancer, such as hepatocellular carcinoma (HCC), cervical cancer, prostate cancer, etc. [score:1]
HBE or A549 cells were cultured in 24-well plates and transfected with 400 ng of either firefly luciferase reporter plasmids (pGL3-MALAT1-wt-3′-UTR; pGL3-MALAT1-mut-3′-UTR) together with 25 ng renilla luciferase construct (pRL-SV40), or 300ng of psiCHECK2-PIK3R1-wt-3′-UTR or psiCHECK2-PIK3R1- mut-3′-UTR combined with 50 nM miR-503 or miR-NC mimic using Reagent (RiboBio Co, Ltd, Guangzhou, China) according to the manufacturer’s protocol. [score:1]
The C57BL/6 mice were co -transfected 200 nmol/kg either miR-503 or miR-NC agomir with 50 mg/kg silica suspension via intratracheal instillation, and the mice were injected with 120 nmol/kg miR-503 or miR-NC agomir via the tail vein on day 7, 14 and 21. [score:1]
Transfection of 50 nM miR-503 mimic (RiboBio Co, Ltd, Guangzhou, China) and PI3K p85 siRNA (RiboBio Co, Ltd, Guangzhou, China) were performed the day before the treatment of silica suspension following the manufacturer’s protocol. [score:1]
Zhou et al. discussed the role of miR-503 in tumor angiogenesis and growth [23]. [score:1]
To confirm the therapeutic importance of miRNAs in silica -induced pulmonary fibrosis, our previous work have revealed that miR-486-5p and miR-489 play important anti-fibrotic roles in silica -induced pulmonary fibrosis 15, 16. miR-503, located on the chromosome Xq26.3, is an intragenic miRNA, and belongs to the miR-16 family [17]. [score:1]
When miR-503 was silenced, PI3K p85 binding to miR-503 was released and thereby activated the downstream molecules, thus causing intensified process of EMT. [score:1]
Therefore, a critical issue for better understanding is that whether there are some lncRNAs that could sponge miR-503. [score:1]
Biotinylated miR-503 (bio-miR-503) and miR-NC were incubated with the extracted RNA of HBE cells (10 μl of the RNA samples were reserved for input) to pull down lncRNA MALAT1. [score:1]
We cloned sequences containing the binding region of miR-503 in PI3K p85 mRNA and lncRNA MALAT1 and their mutated version were cloned into the psiCHECK2 vector or pGL3-control vector (Generay Biotech Co. [score:1]
To confirm our assumption, the mo del was conducted by dripping miR-503 agomir or miR-NC intratracheally following the instillation of silica at day 0, and then miR-503 agomir or miR-NC was injected via the tail vein on day 7, 14, and 21 after silica treatment. [score:1]
A significant decrease in relative luciferase activity was observed when the pGL3-MALAT1-wt-3′-UTR vector was co -transfected with the miR-503 mimic but not with the miRNA mimic control (Fig.   6d and Supplementary Fig.   3a). [score:1]
When miR-503 is silenced, PI3K p85 bounding to miR-503 is released and thereby activates the downstream molecules, thus leading intensified process of EMT. [score:1]
These data suggest that lncRNA MALAT1 could affect the process of EMT in silica -induced pulmonary fibrosis via miR-503-PI3K/Akt/mTOR/Snail signaling pathway. [score:1]
The correlation between miR-503 and PI3K p85 was further determined by the rescue experiment in both cell lines. [score:1]
Increased miR-503 attenuates the EMT in vivo. [score:1]
Figure 2Increased miR-503 attenuates EMT in vivo. [score:1]
From the study above, we can easily come to the conclusion that miR-503 plays a pivotal role in the process of EMT, thus limiting mouse lung fibrosis. [score:1]
The abundance of MALAT1 also provides great possibility to be a well-sponge platform for many kinds of miRNAs, not only miR-503. [score:1]
The results indicated that miR-503 might be a potentially vital miRNA for the therapy of silicosis. [score:1]
The luciferase reporter vectors together with the miR-503 mimic or miRNA mimic control were transfected into the HBE and A549 cells. [score:1]
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Moreover, transfer of endothelial MPs carrying miR-503 into pericytes reduced the expression of EFNB2 and VEGFA, whereas use of ROCK or NF-κB inhibitors has prevented the downregulation of the two miR-503 target genes (Fig. 7d). [score:10]
Lastly, p75 [NTR] overexpression or HG treatment in ECs induced a significant upregulation in luciferase activity of the reporter construct containing NF-κB -binding site within miR-503 promoter sequence. [score:6]
Overexpression of miR-503 (Supplementary Fig. 7B) decreased luciferase activity for each of the putative target genes, whereas mutation of the putative miR-503 -binding site within EFNB2 or VEGFA prevented miR-503 -induced reduction in luciferase activity (Fig. 6a,b). [score:6]
Furthermore, using a coculture system described above, we have demonstrated that treatment with Eptifibatide prevented the transfer of miR-503 through MPs from ECs into pericytes (Fig. 7f), preventing the downregulation of target genes, VEGFA and EFNB2 by miR-503 (Fig. 7f). [score:6]
The Targetscan 6.2 algorithm 32 predicted EFNB2 and VEGFA to be the direct targets of miR-503. [score:6]
The p75 [NTR] receptor regulates miR-503 expressionWe have previously reported minimal or no expression of p75 [NTR] in cultured human umbilical vein ECs (HUVECs), human microvascular ECs (HMVECs) under basal conditions and in the capillaries of limb muscles of healthy mice 11 12. [score:6]
This resulted in an increased expression of miR-503, miR-30-c2*, miR-183* and miR-198, with miR-503 being the most upregulated (Fig. 1c). [score:6]
To this end, miR-503 was overexpressed in the presence of EFNB2 or VEGFA cDNA, which lacked parts of the 3′UTR sequence (ΔEFNB2 and ΔVEGFA) containing the binding sites for the miR-503 (and therefore could not be targeted by miR-503). [score:5]
To better clarify the link between miR-503 and p75 [NTR], we analysed the functional effect of miR-503 inhibition in the p75 [NTR] -overexpressing HUVECs. [score:5]
Finally, the analysis of expression of CDC25A and CCNE1, previously identified target genes of miR-503 (ref. [score:5]
Mutation of a putative NF-κB -binding site prevented this upregulation of luciferase activity under the above conditions, thus showing that binding of NF-κB results in miR-503 transcription (Fig. 3e). [score:5]
Overexpression of p75 [NTR] further induced the expression of miR-503 precursor (pri-miR-503; Fig. 1d). [score:5]
To investigate whether miR-503 directly regulates VEGFA, and EFNB2 expression, portions of the 3′UTR of these potentials target genes were inserted downstream of a luciferase open reading frame (pLUC). [score:5]
We have initially identified VEGFA and EFNB2 as target genes of miR-503, and both of these targets are critical for EC–pericyte crosstalk. [score:5]
Moreover, miR-503 overexpression reduced the target gene mRNA (Supplementary Fig. 7C) and protein levels (Fig. 6c), and the secretion of VEGFA in cell medium (Fig. 6d). [score:5]
Taken together, the above evidence suggests that regulation of NF-κB has a strong impact on post-ischaemic vascularization in diabetic mice via the regulation of miR-503 expression. [score:5]
miR-503 regulates EFNB2 and VEGFA expression in pericytes. [score:4]
The p75 [NTR] receptor regulates miR-503 expression. [score:4]
In addition, the expression of miR-503 increased in HUVECs exposed to HG, with this response being prevented on knockdown of p75 [NTR] by short interfering RNA (Fig. 1e and Supplementary Fig. 3A,B). [score:4]
In conclusion, our data demonstrate a novel mechanism in diabetic ischaemia, involving coordinated expression of p75 [NTR] and regulation of miR-503 in ECs, and thus leading to impaired function of pericytes following uptake of the endothelial MPs carrying miR-503. [score:4]
p75 [NTR] regulates miR-503 expression. [score:4]
Here we have further explored and established the mechanisms that regulate miR-503 expression through p75 [NTR] activation of NF-κB; associated them with the negative effects diabetes induces on vascular cells. [score:4]
Overall, we propose that miR-503 upregulation within the ECs affects the pericyte functionality and in vivo coverage, which correlates with the increased vascular permeability in a diabetic ischaemic mouse mo del. [score:4]
To further validate the role of NF-κB in regulating miR-503 transcription in response to HG or p75 [NTR] overexpression, we used a loss-of-function approach. [score:4]
These results confirmed target gene regulation by miR-503, as previously published in the diabetic mouse mo del of limb ischaemia 10. [score:4]
We provide mechanistic evidence that NF-κB plays a primary role in regulating miR-503 transcription in ECs, exposed to HG or overexpressing p75 [NTR]. [score:4]
Expression of mature miR-503 in MPs isolated by centrifugation from (a) the supernatant of HUVECs transduced with Ad. [score:3]
To this end, we also found that condition that mimics diabetes and ischaemia in vitro (HG in low-growth-factor medium) increased the expression of miR-503 within MPs (Fig. 5a). [score:3]
miR-503 relative expression in pericytes was analysed using qPCR at 24 and 48 h after the start of coculture; * P<0.05 versus Ad. [score:3]
Accordingly, both targets were predicted to contain a single conserved binding sequence for miR-503 in their 3′UTRs (Supplementary Fig. 7A). [score:3]
In addition, miR-503 was present in the MPs from the plasma of diabetic ischaemic mice and non-diabetic ischaemic mice following adenovirus -mediated overexpression of p75 [NTR] (Fig. 5b). [score:3]
Then, we investigated whether endothelial MPs containing miR-503 could transfer miR-503 from ECs into pericytes and thus reduce the expression of miR-503 target genes in the recipient cells. [score:3]
In this coculture system, green -labelled endothelial MPs were transferred from the p75 [NTR]-HUVECs into pericytes (Supplementary Fig. 9B) and increased expression of miR-503 was detected in the pericytes (Fig. 7b). [score:3]
This could be prevented by local inhibition of miR-503 (Fig. 8d). [score:3]
p75 increased miR-503 expression in non-diabetic WT, with this response being blunted by simultaneous injection of Ad. [score:3]
miR-503 targets VEGFA and EFNB2 in pericytes. [score:3]
In vivo regulation of miR-503 by p75 [NTR]We previously demonstrated that diabetic p75 [NTR] knockout mice (p75 KO), with surgically induced limb ischaemia, show improved post-ischaemic angiogenesis and blood flow recovery in comparison with the diabetic wild-type (WT) mice 19. [score:3]
In ECs extracted from ischaemic limbs of diabetic mice, the pri-miR-503 and mature miR-503 are more expressed in comparison with non-diabetic muscle (Fig. 8a), whereas diabetes and ischaemia did not increase the transcription of pri-miR-503 in the pericytes (Fig. 8b). [score:3]
Inhibition of miR-503 was achieved by using adenovirus- decoy. [score:3]
dnIKK2 reduced the pri-miR-503 and mature miR-503 expression, which were previously increased by Ad. [score:3]
The miR-503 expression was increased in the ischaemic muscles of diabetic WT mice, but not in diabetic p75 KO mice (Fig. 2a). [score:3]
Nonetheless, significant increase of expression of the mature miR-503 is observed in the pericytes under diabetic ischaemia (Fig. 8b), thus suggesting that mature miR-503 was likely to be acquired in a paracrine manner and not produced by the pericytes. [score:3]
dnIKK2 or treated with Y27632 or HA-1077 and miR-503 expression was analysed in pericytes (bottom compartment) after 48 h from the treatment; (d) in the same experimental conditions, expression of EFNB2 and VEGFA was measured; * P<0.05 versus Ad. [score:3]
dnIKK2 on vascularization were abolished by the simultaneous overexpression of miR-503 (by adenovirus carrying miR-503; Ad. [score:3]
Microparticles carrying miR-503 are secreted from the diabetic ECs and can be transferred into neighbouring pericytes to subsequently modulate vessel permeability and angiogenesis through miR-503 target genes, VEGFA and EFNB2. [score:3]
Now, we provide new evidence that MPs carrying miR-503 are secreted from diabetic ECs and can transfer miR-503 into the neighbouring pericytes, thus modulating gene expression and their biological phenotype. [score:3]
EFNB2 and VEGFA are miR-503 target genes. [score:3]
As noted before, p75 [NTR] overexpression induced the release of MPs carrying miR-503 in HUVECs (Fig. 5a). [score:3]
To clone EFNB2 or VEGFA, cDNAs, which lacked parts of the 3′UTR sequence and could not be targeted by miR-503 (EFNA2Δ or VEGFAΔ), EFNA2 (NCBI accession: NM_004093) and VEGFA cDNA (NCBI accession: NM_001025366), were excised from pCMV6-XL4 (Origene) using NotI/XbaI or NotI/SmaI, respectively and cloned in pcDNA3.1 using standard techniques. [score:3]
Lipofectamine RNAiMAX (Invitrogen) was used to transfect HUVECs, HEK293T or pericytes with pre-miR-503, pre-miR-control (50 nM final concentration) or with short interfering RNA targeting p75 [NTR], EFNB2 or VEGFA, according to the manufacturer's instructions. [score:3]
In particular, we asked whether a dominant -negative form of IkB kinase 2 (dnIKK2) 25, a kinase that is an upstream activator of NF-κB, interferes with the expression of miR-503. [score:3]
dnIKK2 dramatically reduced miR-503 expression in the ischaemic limb muscles of diabetic mice (Fig. 4b). [score:3]
Then, our study extends these findings by establishing that endothelial MPs carrying miR-503 interfere with EFNB2 and VEGFA expression in pericytes, further blocking post-ischaemic angiogenesis and vascular integrity under diabetes. [score:3]
Consistently, the inhibition of ROCK (by Y27632 or HA-1077) or NF-κB (dnIKK2), previously shown to decrease the release of MPs (Fig. 5d), has reduced the transfer of miR-503 into pericytes exposed to the MPs (Fig. 7c), also suggesting that this process is mediated by actively formed endothelial MPs. [score:3]
Overexpression of miR-503 reduced the proliferative and migratory capacities of pericytes (Fig. 6e,f). [score:3]
We additionally show the first evidence of the release and trafficking of endothelial MPs from ECs into pericytes, thus MP mediated the transfer of miR-503 during the diabetes -induced vascular disease. [score:3]
Following p75 [NTR] overexpression, the release of MPs carrying miR-503 from the cultured ECs increased (Fig. 5a). [score:3]
NF-κB p65 binds miR-503 promoter and regulates its transcription. [score:2]
To our knowledge, this is the very first example of a direct involvement of miR-503 signalling in the endothelial–pericyte crosstalk under diabetic ischaemia. [score:2]
Under basal conditions, pericytes express miR-503, although in a lower amount compared with ECs. [score:2]
p75 [NTR] -dependent activation of NF-κB regulates miR-503 transcription in hyperglycemic ECs and the release of miR-503 in the extracellular compartment within microparticles. [score:2]
In vivo regulation of miR-503 by p75 [NTR]. [score:2]
Vectors in which five nucleotide mutations were inserted in the 3′UTR sequences (VEGFA: 293–299; EFNB2: 1,126–1,132) complementary to the miR-503 ‘seed' sequence were prepared using the GeneTailor kit (Invitrogen). [score:2]
NF-κB activation is sufficient to control the transcriptional regulation of miR-503 and its release into MPs. [score:2]
How to cite this article: Caporali, A. et al. p75 [NTR] -dependent activation of NF-κB regulates microRNA-503 transcription and pericyte–endothelial crosstalk in diabetes after limb ischaemia. [score:2]
Our study provides the first insights into the mechanisms of transcriptional regulation of miR-503 in ECs by diabetes. [score:2]
Moreover, in our in vivo experiment, we detected only the mature form of miR-503 in the pericytes, which might be reconciled with a direct transfer of mature miR-503 from the endothelial MPs into pericytes. [score:2]
Direct incubation of pericytes with the endothelial MPs carrying miR-503 increased the intracellular levels of miR-503 in a concentration -dependent manner (Supplementary Fig. 9A). [score:2]
Slides were then incubated with TSA-plus fluorescein isothiocyanate for 10 min at RT to detect miR-503. [score:1]
Moreover, we have demonstrated that miR-503 can be transferred via endothelial MPs to produce a negative effect in the neighbouring pericytes. [score:1]
A triple staining was performed using a miR-503 probe, isolectin-B4 and NG2. [score:1]
In vivo NF-κB -dependent transcription of miR-503. [score:1]
Finally, we employed in situ hybridization to further confirm the localization of miR-503 in ECs and pericytes in the limb muscles of diabetic ischaemic mice (Supplementary Fig. 11). [score:1]
The discovery of an endothelial MP -mediated delivery of miR-503 into pericytes raises intriguing possibilities to better understand the mechanisms behind various mo dels of vascular cell-to-cell communications. [score:1]
25) and miR-503 are produced and used as described in ref. [score:1]
For the detection of miR-503 in mouse hindlimb muscle, sections were rehydrated in histoclear and graded concentrations of ethanol. [score:1]
MPs transport miR-503 from ECs into pericytes. [score:1]
Mechanism of MP-miR-503 release in endothelial cells. [score:1]
Accordingly, we detected an enrichment of H3K4me3 at the TSS of the miR-503 promoter in ECs infected with Ad. [score:1]
dnIKK2, and qPCR was carried out to measure the expression of pri-miR-503 and mature miR-503; ** P<0.01 versus Ad. [score:1]
We thus performed sequence analysis of the human miR-503 hypothetical promoter at chromosome X (5,000-bp region spanning the transcription starting site (TSS) in the genomic location ChrX:133,681,808 (ref. [score:1]
On the basis of our in vitro findings we additionally explored whether transfer of miR-503 from ECs into pericytes could repress EFNB2 and VEGFA in vivo. [score:1]
Our data show that transcription of pri-miR-503 is not increased in the pericytes under ischaemic condition in diabetic mice. [score:1]
miR-503 (Ad. [score:1]
Mechanism of MPs-miR-503 release from ECs. [score:1]
Previously, we defined neurotrophin receptor p75 [NTR] and miR-503 as independent negative modulators of EC function and diabetes -induced post-ischaemic reparative neovascularization 10 11. [score:1]
Moreover, the activation of NF-κB determines the release of miR-503 within the endothelial MPs, which can be found in the extracellular compartment in vitro and in the systemic circulation of diabetic ischaemic mice. [score:1]
P75 [NTR] mediates nuclear translocation of the NF-κB p65 subunit to bind the promoter of miR-503 and induce transcription of miR-503. [score:1]
The in vivo transfer of miR-503 between ECs and pericytesOn the basis of our in vitro findings we additionally explored whether transfer of miR-503 from ECs into pericytes could repress EFNB2 and VEGFA in vivo. [score:1]
Thus, the last 2,834 bps of EFNA2 3′UTR or 1,705 bps of VEGFA 3′UTR, encompassing miR-503 -binding sites, were deleted. [score:1]
However, treatment with HG in low-growth-factor medium did not increase miR-503 transcription (pri-miR-503 levels) or the levels of mature miR-503 in pericytes (Fig. 7a). [score:1]
miR-503; Fig. 4c–e and Supplementary Fig. 5B,C). [score:1]
miR-503 (n=6 per group). [score:1]
miR-503 or Ad. [score:1]
Therefore, we evaluated the impact of local miR-503 inhibition (by Ad. [score:1]
In vivo transfer of miR-503 during diabetes and ischaemia. [score:1]
In line with this, we tested whether NF-κB could also mediate transcription of miR-503 in response to increased p75 [NTR]. [score:1]
Endogenous peroxidases were blocked by incubation with 3% H [2]O [2] in H [2]O. Then, slides were incubated with hybridization buffer (50% formamide, 4 × SSC, 2.5 × Denhadrt's solution, 2.5 mg ml [−1] salmon DNA, 0.6 mg ml [−1] yeast tRNA, 0.025% SDS and 0.1% blocking reagent) at 60 °C for 1 h followed by a 60-°C overnight incubation with 40 nM miR-503 or scramble miRCURY LNA Detection probe, 5′-DIG labelled (Exiqon) in the same buffer. [score:1]
The in vivo transfer of miR-503 between ECs and pericytes. [score:1]
NF-κB p65 -dependent transactivation of miR-503. [score:1]
Relative expression of pri-miR-503 and mature miR-503 was measured in (a) endothelial cells and in (b) pericytes. [score:1]
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[+] score: 276
Ultimately, to explore whether there is direct inhibition of miR-503 on SMAD7, the SMAD7 3′-UTR segment was cloned into an miRNA target reporter clone with firefly luciferase gene located upstream of the SMAD7 3′-UTR, and the target sites at SMAD7 3′-UTR predicted with TargetScan were then mutated with the QuickChange Lightning site-directed mutagenesis kit (Agilent Technologies) (Fig. 4 G). [score:11]
A possible explanation is that miR-503 could be up-regulated by the same machinery that up-regulates SMAD7 and could serve as a limiting factor to fine-tune its up-regulation. [score:10]
After obtaining the list of predicted targets, further screening was performed to select targets related to TGFβ1-signaling pathway, given the importance of TGFβ1 in SMC differentiation and its role in regulating miR-503 expression. [score:8]
In MSC to SMC differentiation, upon stimulation of TGFβ1, miR-503 is up-regulated in a SMAD4 -dependent pathway and directly targets SMAD7, which is a negative regulator of the TGFβ1 SMAD -dependent signaling pathway, to promote SMC differentiation. [score:8]
Thus far, we established that the up-regulation of miR-503 and the down-regulation of miR-222-5p both regulate MSC to SMC differentiation. [score:8]
Consistent with the microRNA array results, the up-regulation of miR-503-5p and the down-regulation of miR-222-5p were time -dependent (Fig. 3 A). [score:7]
Taken together, we showed that miR-503 is transcriptionally up-regulated upon TGFβ1 treatment through a SMAD4 -dependent pathway and subsequently targets SMAD7, which is a negative regulator of SMAD -dependent signaling. [score:7]
During SMC differentiation, miR-222-5p down-regulation might work together with miR-503 up-regulation. [score:7]
It was established in our study that miR-503 targets SMAD7 to promote MSC to SMC differentiation, and miR-222-5p targets ROCK2 to inhibit the differentiation process. [score:7]
SMAD7 is a direct target of miR-503 and miR-503 is transcriptionally up-regulated through SMAD4 -dependent pathway. [score:7]
It was revealed that miR-503 co-transfection in HEK293 cells could inhibit the relative luciferase activity in plasmid reporter with SMAD7 3′-UTR compared with miRNA control in plasmid reporter with SMAD7 3′-UTR, and the inhibition was abolished if the miR-503 target site on the 3′-UTR segment was mutated (Fig. 4 H). [score:6]
The postulation that downstream targets of miR-222-5p may also regulate miR-503 expression would merit further examination. [score:6]
); miRNA inhibitor negative control (199006-001, Exiqon); miR-503 inhibitor (4100899-001, Exiqon); siRNA negative control (AM4611, Life Technologies, Inc. [score:5]
Furthermore, the expression of miR-503 could be inhibited by miR-222-5p. [score:5]
H, protein expression and quantification after miR-503 inhibitor treatment for 3 days in αMEM with 1% FBS and 5 ng/ml TGFβ1 were analyzed. [score:5]
F, TaqMan microRNA assay showed significant down-regulation of miR-503 after inhibitor treatment for 1 day. [score:5]
The expression level of miR-503-3p fluctuated, which compromised the stability of the expression. [score:5]
Furthermore, the mechanistic study implied that miR-503 mimics or miR-222-5p inhibitors carry the potential to improve the performance of these vascular grafts through enhancing SMC differentiation from MSCs while avoiding possible off-target effects from the use of TGFβ1. [score:5]
Figure 4. miR-503 directly targets SMAD7 in regulating SMC differentiation. [score:5]
Although they target different pathways regulating SMC differentiation, whether miR-503 and miR-222-5p directly interact with each other merited further examination. [score:5]
This suggested that miR-222-5p could affect the expression of miR-503, but miR-503 does not interfere with the expression of miR-222-5p. [score:5]
To explore the potential targets of miR-503, algorithm -based bioinformatic prediction, literature review, and in vitro examination of gene expression were conducted. [score:5]
Zhou R., Gong A. Y., Chen D., Miller R. E., Eischeid A. N., and Chen X. M. (2013) Histone deacetylases and NF-κB signaling coordinate expression of CX3CL1 in epithelial cells in response to microbial challenge by suppressing miR-424 and miR-503. [score:5]
*, p < 0.05; **, p < 0.01, and ***, p < 0.001. mim ctrl, miRNA mimic negative control; mim 503, miR-503 mimic; inhi ctrl, miRNA inhibitor negative control; inhi 503, miR-503 inhibitor. [score:5]
More importantly, the level of SMAD7 upon miR-503 mimic treatment showed significant down-regulation by Q-PCR (Fig. 4 C). [score:4]
As demonstrated earlier, SMAD7 and miR-503 are both transcriptionally up-regulated by TGFβ1. [score:4]
In our study, miR-503 directly targets SMAD7 by binding to its 3′-UTR segment. [score:4]
Among the up-regulated miRNAs, we identified the miR-15 family, including the stem-loop forms of miR-503 and miR-424, miR-503 mature strand miR-503-5p, and the miR-503 star strand miR-503-3p (Table 1). [score:4]
Figure 5. miR-503 is transcriptionally up-regulated through SMAD4 -dependent pathway. [score:4]
These results implied that SMAD4 plays a key role in TGFβ1 -mediated up-regulation of miR-503. [score:4]
Interestingly, SMAD7 is also up-regulated in a SMAD4 -dependent pathway suggesting that miR-503 might serve as a self-limiting factor for the SMAD4 -dependent induction of SMAD7 (Fig. S3). [score:4]
Interestingly, miR-503 was significantly down-regulated when SMAD4 was depleted in cells with TGFβ1, although its level was not affected if the medium did not contain TGFβ1 (Fig. 5 C). [score:4]
G, alignment of miR-503 and the 3′-UTR of SMAD7 gene showed the postulated target -binding sites (red) and induced mutations (blue). [score:4]
miR-222-5p mimic transfection resulted in miR-503 down-regulation. [score:4]
D, Q-PCR showed the mRNA level up-regulation of SMC-specific markers after miR-503 mimic treatment for 3 days in αMEM with 1% FBS. [score:4]
D, representative picture of and analysis from three independent experiments showed the down-regulation of SMAD7 at the protein level after treatment with miR-503 mimics in αMEM with 1% FBS for 3 days. [score:4]
Previous studies related to the upstream regulation of miR-503 transcription have described peroxisome proliferator-activated receptor γ and nuclear factor κ–light-chain enhancer of activated B cells (NF-κB) as direct regulators (38 – 40). [score:4]
By establishing SMAD7 as a direct target of miR-503, we present miR-503 as a new component of the TGFβ1-signaling pathway. [score:4]
H, co-transfection of miR-503 mimics and reporter with WT SMAD7 3′-UTR segment showed reduced relative luciferase activity as compared with vector with empty plasmid, whereas mutation of target -binding sites recovered the reduction. [score:3]
Genome browsing in the UCSC genome sequence database (21) implied that the 3′-UTR of SMAD7 contain a “GCTGCTA” sequence that may be a target site for miR-503. [score:3]
E, protein expression and quantification after miR-503 mimic treatment for 3 days in αMEM with 1% FBS were analyzed. [score:3]
However, 24 h after transfection of the miR-222-5p mimic in MSCs, the level of miR-503 was significantly down-regulated as shown by TaqMan microRNA assay (Fig. 8 E). [score:3]
The inhibition of SMAD7 by miR-503 provides a further level of complexity in the already complex TGFβ1-related signaling pathway. [score:3]
Transfection of miR-503 mimics in MSCs in medium with 1% FBS promoted SMC differentiation with increased expression of SMC markers, including calponin, SM22, αSMA, and SMMHC at the mRNA level after 3 days as shown by Q-PCR (Fig. 3 D). [score:3]
This is the first time that miR-503 has been shown to target SMAD7, thereby influencing the SMC differentiation process. [score:3]
G, level of SMC-specific markers was detected with Q-PCR after miR-503 inhibitor treatment for 3 days in αMEM with 1% FBS and 5 ng/ml TGFβ1. [score:3]
To explore the role of miR-503 in MSC differentiation toward SMCs, miRNA mimics and inhibitors were used to perform the gain-of-function and loss-of-function analysis of miR-503. [score:3]
The transfection efficiency was confirmed 24 h after transfection as shown by a more than 100-fold increase of miR-503 expression in MSCs transfected with the miR-503 mimics (Fig. 3 C). [score:3]
C, TaqMan microRNA assay showed significant up-regulation of miR-503 after mimic treatment for 1 day in αMEM with 1% FBS. [score:3]
The implication from our in vitro study is that miR-503 mimics and miR-222-5p inhibitors may have the potential to augment the performance of vascular grafts by promoting the differentiation of stem cells toward SMCs. [score:3]
Loss-of-function effects of miR-503 were demonstrated by the transfection of miR-503 inhibitors in the cells. [score:3]
Finally, miRNA-centered mechanisms involved in the differentiation process into SMCs were elucidated with the identification of novel regulatory miRNAs (miR-503-5p and miR-222-5p). [score:2]
E, level of miR-503 was inhibited by miR-222-5p mimic treatment after 1 day as shown with TaqMan microRNA assay. [score:2]
Caporali A., Meloni M., Nailor A., Mitić T., Shantikumar S., Riu F., Sala-Newby G. B., Rose L., Besnier M., Katare R., Voellenkle C., Verkade P., Martelli F., Madeddu P., and Emanueli C. (2015) p75(NTR) -dependent activation of NF-κB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia. [score:2]
The lack of complementary sequence between miR-503 and miR-222-5p suggests that they are unlikely to directly bind to each other (data not shown). [score:2]
We then performed chromatin immunoprecipitation (ChIP) experiments to detect SMAD4 binding, and three sets of primers were used to target the promoter region of miR-503. [score:2]
Next, the level of miR-503 was examined after SMAD4 knockdown. [score:2]
We also showed that miR-503 was regulated by miR-222-5p. [score:2]
For this reason, miR-503-3p was not included in further experiments, and miR-503 was used to refer to miR-503-5p in the rest of the paper. [score:1]
); miR-503 mimic (4464066 MC10378, Life Technologies, Inc. [score:1]
One day after transfection, the level of miR-503 was significantly decreased (Fig. 3 F). [score:1]
In this study, SMAD4 enriches at the promoter region of miR-503 after TGFβ1 treatment. [score:1]
In addition, promotion of SMC differentiation was also observed in human adipose tissue-derived MSCs (Fig. S2, A and B) and mouse adipose tissue-derived MSCs (Fig. S2, C–E), which is demonstrated by the induction of SMC markers with miR-503 mimic treatment at the mRNA and protein level. [score:1]
*, p < 0.05, and ***, p < 0.001. mim ctrl, miRNA mimic negative control; mim 503, miR-503 mimic; ctrl, plasmid without SMAD7 3′-UTR; wt, plasmid bearing WT SMAD7 3′-UTR. [score:1]
*, p < 0.05; **, p < 0.01; and ***, p < 0.001. mim ctrl, miRNA mimic negative control; mim 503, miR-503 mimic; si ctrl, siRNA negative control; si SMAD7, siRNA SMAD7; ctrl, plasmid negative control; wt, plasmid bearing WT SMAD7 3′-UTR. [score:1]
Importantly, miR-503 could also promote SMC differentiation in other types of MSCs, suggesting its universal effect among MSCs. [score:1]
Q-PCR was performed for the enrichment of SMAD4 at the promoter region of miR-503. [score:1]
Enrichment of SMAD4 at the promoter region of miR-503 was confirmed, and at the same time SMAD4 was not enriched at the promoter region of GAPDH, which served as a negative control (Fig. 5 D). [score:1]
On the contrary, 24 h after transfection of miR-503 mimic in MSCs, the level of miR-222-5p was not affected (Fig. 8 F). [score:1]
Interaction of miR-503 and miR-222-5p. [score:1]
Moreover, we showed that SMAD4 is enriched at the promoter region of miR-503 upon TGFβ1 treatment. [score:1]
miR-503 promotes MSC to SMC differentiation. [score:1]
The miR-503 family participates in a number of pathophysiological pathways (35). [score:1]
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[+] score: 156
Previous work has demonstrated that upregulation of miR-503 leads to inhibition of tumor angiogenesis through regulation of FGF2 and VEGFA [39], while downregulation of miR-503 in ECs has been suggested to lead to improved angiogenesis in diabetes mellitus [40]. [score:10]
Overexpression of miR-424 and miR-503 led to significant decrease in both the mRNA and protein expression of CD40, whereas inhibition of miR-424 and miR-503 using anti-miRs led to CD40 upregulation (Fig.   2a,b, Sup. [score:10]
In conclusion, we demonstrate that downregulation of miR-424 and miR-503 and subsequent upregulation of CD40 is associated with inflammation -induced angiogenesis. [score:7]
Furthermore, the demonstration that PPARγ directly regulates miR-424 and miR-503 expression identifies novel transcriptional targets of this pleiotropic gene that may in part explain its vaso-protective effects. [score:7]
Figure 1Pro-inflammatory stimuli upregulate CD40 and reduce miR-424 and miR-503 expression in HUVECs. [score:6]
The finding that miR-424 and miR-503 directly regulate CD40 led us to further investigate the effect of miR-424 and miR-503 overexpression on the regulation of pro-inflammatory stimuli -induced CD40 expression. [score:6]
Furthermore, we found that PPARγ is a direct transcriptional activator of miR-424 and miR-503, and its activation by pioglitazone leads to suppression of CD40 expression and LPS -induced angiogenesis in a miR-424 and miR-503 dependent manner. [score:6]
Our findings demonstrate that miR-424 and miR-503 can inhibit pro-inflammatory -induced angiogenesis through direct targeting of CD40. [score:6]
In addition, a previous study has suggested indirect regulation of miR-424/503 expression by PPARγ via its induction of the G protein coupled receptor ligand apelin, which positively regulates miR-424 and miR-503 [33]. [score:6]
We found abrogation of the effect of miR-424 and miR-503 overexpression by concurrent CD40 expression (Fig.   3g,h). [score:5]
We found both the pri-forms and the mature forms of miR-424 and miR-503 were significantly downregulated by PPARγ knockdown (Fig.   5b). [score:5]
Combined, these results show that miR-424 and miR-503 directly regulate CD40 expression. [score:5]
We demonstrate that endothelial CD40 expression is closely regulated by two microRNAs (miRNAs), miR-424 and miR-503, and this regulatory mechanism becomes disrupted by inflammatory stimuli. [score:5]
We next determined whether miR-424 and miR-503 regulate CD40 expression via binding directly to the 3′UTR. [score:5]
Pro-inflammatory stimuli induce CD40 and inhibit miR-424 and miR-503 expression in ECs. [score:5]
In addition, we conducted sprouting bead angiogenesis assays, and found significant inhibition of LPS induced EC sprouting in cells that overexpress miR-424 and miR-503 (Fig.   3f). [score:4]
In our current study, we examined the role of miR-424 and miR-503 in vascular inflammation and found that they control a key molecular mechanism involved in regulation of CD40 expression. [score:4]
Taken together, the studies to date suggest a context dependent role for miR-424 and miR-503 in ECs, and further studies are needed to fully elucidate the role of these highly-regulated miRNAs in endothelial function in health and disease. [score:4]
PPARγ regulates miR-424 and miR-503 expression. [score:4]
CD40 is directly targeted by miR-424 and miR-503. [score:4]
Taken together, these results demonstrate that PPARγ is a key factor that controls miR-424 and miR-503 expression in response to endothelial inflammation. [score:3]
Moreover, overexpression of miR-424 and miR-503 significantly reduced LPS -induced EC migration and tube formation (Fig.   3d,e). [score:3]
To determine the molecular mechanism underlying the effect of PPARγ on pro-inflammatory stimuli -induced angiogenesis, we first examined the effect of pioglitazone, a PPARγ agonist, on miR-424 and miR-503 expression. [score:3]
org), we found that miR-424 and miR-503, which have highly conserved seed sequences, were predicted to bind to the 3′ untranslated region (UTR) of CD40 (Fig.   1d). [score:3]
Moreover, stimulation of HUVECs with either LPS or TNFα led to significant decrease in both the mRNA and protein levels of PPARγ, suggesting that decreased PPARγ expression in ECs may be a key mechanism by which miR-424 and miR-503 levels are decreased in response to inflammatory stimuli (Fig.   5h–k). [score:3]
Transfection of HUVECs with miR-424 and miR-503 mimics prior to treatment with LPS or TNFα led to significantly decreased CD40 protein expression (Fig.   3c). [score:3]
Figure 2CD40 is regulated by miR-424 and miR-503 directly. [score:3]
The miR-424 and miR-503 transcription unit is highly expressed in ECs and is known to be a key factor in maintaining homeostasis of these cells 28– 32. [score:3]
We next tested whether pro-inflammatory stimuli can affect endothelial miR-424 and miR-503 expression. [score:3]
We found significant decrease in both the immature pri-forms and the mature forms of miR-424 and miR-503 in response to either LPS or TNFα stimulation, suggesting that these miRs are transcriptionally suppressed in the context of endothelial response to inflammation (Fig.   1e,f). [score:3]
We next investigated whether LPS and TNFα regulate miR-424 and miR-503 expression in a PPARγ dependent manner. [score:2]
Co-transfection of the wildtype CD40 3′UTR reporter construct with miR-424 and miR-503 mimics significantly reduced the reporter activity, while reporter activity in cells transfected with mutagenized CD40 3′UTR of two different types (mutant #1 and mutant #2) was unchanged by concurrent transfection with miR-424 and miR-503 mimics (Figs  1d and 2c). [score:1]
Moreover, we demonstrate enhanced angiogenic response to inflammatory stimuli in mice with endothelial specific deletion of miR-322 (miR-424 ortholog) and miR-503. [score:1]
Mice with loxP sites surrounding the microRNA cluster 24 (which includes miR-322, miR-503, and miR-351) were crossed to mice with a tamoxifen inducible Cdh5 Cre driver (Cdh5-CreERT2) (Sup. [score:1]
Overall, these findings provide key in vivo genetic evidence supporting the downstream role of miR-424 and miR-503 in determining endothelial response to inflammatory stimuli. [score:1]
MiRNA quantitative reverse‐transcriptase PCR (qRT‐PCR) was performed using TaqMan Universal Master Mix II, no UNG (Life Technologies) and MiR-424 and miR-503 were detected with Taqman probes (Life Technologies). [score:1]
Mice with endothelial-specific deletion of miR-322 and miR-503 demonstrate increased angiogenesis in response to LPS. [score:1]
Indeed, we found that treatment of HUVECs with pioglitazone resulted in a significant increase in miR-424 and miR-503 levels (Fig.   4a). [score:1]
Lastly, we investigated whether CD40 overexpression could rescue miR-424 and miR-503 effects on EC tube formation and migration. [score:1]
HeLa cells were transfected with the luciferase reporter constructs and either miR-424, miR-503 mimics or negative control miRNAs using lipofectamine 2000 (Invitrogen). [score:1]
In addition, we found that miR-424 and miR-503 levels were restored by pioglitazone when treated in conjunction with LPS (Fig.   4b). [score:1]
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[+] score: 116
Other miRNAs from this paper: mmu-mir-16-1, mmu-mir-16-2, mmu-mir-505
miR-424 overexpression mimicked the effect of T3 inhibiting growth in suspension, while depletion of either miR-424 or miR-503 reversed T3 -dependent inhibition (Figure 4C). [score:7]
On the other hand, transfection with miRNA inhibitors, which caused a strong reduction of miR-424 or miR-503 levels (Figure 3C), reversed the inhibitory effect of T3 on CHK1, WEE1, CDC25, c-MYB or E2EF, while CDK6 or CCND2 levels remained low (Figure 3D). [score:5]
Influence of miR-424 expression and miR-424 and miR-503 depletion on the effect of T3 on target proteins. [score:5]
Interestingly, expression of the target proteins of miR-424 and miR-503 was also decreased in T3 -treated breast cancer cells. [score:5]
miR-424 and miR-503 are predicted to target many mRNAs (microRNA and TargetScan), some of them already validated [31, 37, 41]. [score:5]
Expression of miR-424 and miR-503 was, however, undetectable in parental and TRb -expressing HepG2 cells both in the absence and presence of T3 (Suppl. [score:5]
Furthermore, T3 arrested hepatocarcinoma cells in G1 and the knockdown of miR-424 and miR-503 reversed this effect, underscoring the important role of these miRNAs in the inhibition of cell proliferation. [score:4]
Depletion of miR-424 or miR-503 strongly inhibited the effects of T3, and combined knockdown of both miRNAs abolished T3 -dependent increase in G1 and reduction of S-phase. [score:4]
Since miR-424 and miR-503 down-regulate proteins with an important role in cell proliferation, we analyzed their effect on the cell cycle of SK-TRb cells. [score:4]
Conversely, miR-424 or miR-503 depletion increased wound closure and, when used in combination, reversed the inhibitory effect of T3 (Figure 5B). [score:3]
Transfection of miR-424 also reduced growth in suspension of HepG2-TRb cells that do not express miR-424 or miR-503 (Suppl. [score:3]
Among them, the miR-16 family regulates cell proliferation [26- 28] and miR-503, a miR-16 family member, might be a master regulator of the cell cycle [29]. [score:3]
Depletion of miR-424 and miR-503 reduces the inhibitory effect of T3 on cellular invasion. [score:3]
Besides affecting tumor cell proliferation and increasing sensitivity to DNA damaging agents, elevated levels of miR-424 and miR-503 are required for the inhibitory effect of the hormone on cell migration and invasion. [score:3]
In this work we show that miR-424 and miR-503 are transcriptionally induced by T3 in hepatocarcinoma and breast cancer cells expressing TRb, and demonstrate that this induction appears to play an important role in the anti-proliferative and anti-invasive actions of the hormone both in cultured cells and in vivo. [score:3]
T3 induces expression of miR424 and miR503 in breast cancer cells. [score:3]
In miRNA microarrays we found that miR-424 and miR-503 levels were higher (2.32- and 2.99-fold, respectively) in T3 -treated SK-hep1 cells expressing TRb (SK- TRb) than in untreated cells. [score:3]
As shown in Figure 9, miR-424 and miR-503 expression was reduced in the tumors developed in hypothyroid mice, correlating with their increased invasive properties. [score:3]
In addition, miR-424 and/or miR-503 depletion increased cellular invasion and reduced the inhibition by T3 (Figure 8F). [score:3]
Reduced miR-424 and miR-503 expression in tumor xenografts developed in hypothyroid mice. [score:3]
To further test the functional relevance of miR424 and miR-503 induction by T3, we conducted experiments of gain and loss of function of the miRNAs and evaluated the expression of the different targets by western blotting. [score:3]
This is consistent with the previous report that miR-503 was down-regulated in the highly metastatic hepatocarcinoma cell line HCCLM3 when compared with MHCC97-L cells with a lower metastatic potential [39]. [score:3]
Furthermore, depletion of miR-424, miR-503, or both, increased cellular invasion and reduced noticeably the inhibitory effect of T3. [score:3]
Anti-miR Inhibitor for miR-424, miR-503 and the Anti-miR Negative Control#1 were purchased from Ambion (Cat. [score:3]
To analyze whether thyroidal status could also alter miRNA expression in the tumors, we next compared miR-424 and miR-503 levels in xenografts formed by inoculation of SK-TRb and MDA-TRb cells into euthyroid and hypothyroid mice. [score:2]
The increased transcription of miR-424 and miR-503 is relevant for the regulation of most of these proteins by the hormone. [score:2]
Therefore we next determined if miR-424 and miR-503 could also regulate this process. [score:2]
Hypothyroidism reduces miR-424 and miR-503 levels in xenografts. [score:1]
Euthyroid and hypothyroid nude mice were injected with SK-TRb (A) and MDA-TRb cells (B), and the levels of miR-424 and miR-503 were determined 8 weeks later in the tumors. [score:1]
T3 induces transcriptional activation of miR-424 and miR-503. [score:1]
Invasion was then performed for 16 h in the presence and absence of the hormone and the cells that passed through the filter were counted (F) Similar experiment in cells transfected with a negative control anti-miRNA, anti-miR-424, anti-miR-503 or both. [score:1]
The thyroid hormone -dependent increase of miR-424 and miR-503 appears to modulate tumor growth and progression in multiple ways. [score:1]
Additionally, miR-424 and miR-503 depletion restored the ability of T3 -treated hepatocarcinoma and breast cancer cells to growth in suspension under rocking conditions. [score:1]
The functional role of miR-424 and miR-503 induction by T3 in MDA-TRb cells was also examined. [score:1]
miR-424 and miR-503 levels were analyzed in the tumors 8 weeks after inoculation. [score:1]
The anti-tumorigenic actions of miR-424 and miR-503 could be related to their effect on the cell cycle. [score:1]
Thus, miR-424 and miR-503 induction is also involved in this action of T3 in SK-TRb cells. [score:1]
Taken together our results show that binding of T3 to the TRb receptor induces transcription of miR-424 and miR-503. [score:1]
miR-503 is an intragenic miRNA clustered with miR-424, other miR-16 family member, and both are produced as a polycistronic message [30]. [score:1]
In addition, miR-424 and miR-503 are involved in cancer cell migration and invasion [38, 39], and are reduced in human hepatocarcinoma tumors [40]. [score:1]
Representative images are shown at the left and quantifications at the right panel (B) Similar experiment in cells transfected with a negative control anti-miRNA, anti-miR-424, anti-miR-503 or both. [score:1]
Therefore, induction of miR-424 and miR-503 by T3 is not restricted to hepatocarcinoma cells. [score:1]
Therefore, we next examined the effect of miR-424 and miR-503 on growth of SK-TRb cells in suspension under rocking conditions. [score:1]
T3 increased the level of both pri-miRNAs and stimulated the activity of the proximal promoter of miR-424/miR-503 in SK-TRb cells, indicating that the hormone induces transcription of the polycistronic message that encodes both miRNAs. [score:1]
T3 increased the levels of pri-miRNA-424 and pri-miRNA-503 in SK- TRb cells (Figure 1B), suggesting that the hormone induces transcription of the miRNAs precursor. [score:1]
T3 induces transcription of miR424 and miR503 in hepatocarcinoma cells. [score:1]
Figure 9Euthyroid and hypothyroid nude mice were injected with SK-TRb (A) and MDA-TRb cells (B), and the levels of miR-424 and miR-503 were determined 8 weeks later in the tumors. [score:1]
was abolished by T3 and was restored after depletion of miR-424, miR-503, or both (Figure 8D). [score:1]
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6
[+] score: 66
Other miRNAs from this paper: mmu-mir-30a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-132, mmu-mir-134, mmu-mir-135a-1, mmu-mir-138-2, mmu-mir-142a, mmu-mir-150, mmu-mir-154, mmu-mir-182, mmu-mir-183, mmu-mir-24-1, mmu-mir-194-1, mmu-mir-200b, mmu-mir-122, mmu-mir-296, mmu-mir-21a, mmu-mir-27a, mmu-mir-92a-2, mmu-mir-96, rno-mir-322-1, mmu-mir-322, rno-mir-330, mmu-mir-330, rno-mir-339, mmu-mir-339, rno-mir-342, mmu-mir-342, rno-mir-135b, mmu-mir-135b, mmu-mir-19a, mmu-mir-100, mmu-mir-139, mmu-mir-212, mmu-mir-181a-1, mmu-mir-214, mmu-mir-224, mmu-mir-135a-2, mmu-mir-92a-1, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-125b-1, mmu-mir-194-2, mmu-mir-377, mmu-mir-383, mmu-mir-181b-2, rno-mir-19a, rno-mir-21, rno-mir-24-1, rno-mir-27a, rno-mir-30a, rno-mir-92a-1, rno-mir-92a-2, rno-mir-96, rno-mir-100, rno-mir-101a, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-132, rno-mir-134, rno-mir-135a, rno-mir-138-2, rno-mir-138-1, rno-mir-139, rno-mir-142, rno-mir-150, rno-mir-154, rno-mir-181b-1, rno-mir-181b-2, rno-mir-183, rno-mir-194-1, rno-mir-194-2, rno-mir-200b, rno-mir-212, rno-mir-181a-1, rno-mir-214, rno-mir-296, mmu-mir-376b, mmu-mir-370, mmu-mir-433, rno-mir-433, mmu-mir-466a, rno-mir-383, rno-mir-224, mmu-mir-483, rno-mir-483, rno-mir-370, rno-mir-377, mmu-mir-542, rno-mir-542-1, mmu-mir-494, mmu-mir-20b, rno-mir-494, rno-mir-376b, rno-mir-20b, rno-mir-503-1, mmu-mir-1224, mmu-mir-551b, mmu-mir-672, mmu-mir-455, mmu-mir-490, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-504, mmu-mir-466d, mmu-mir-872, mmu-mir-877, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-872, rno-mir-877, rno-mir-182, rno-mir-455, rno-mir-672, mmu-mir-466l, mmu-mir-466i, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-466j, rno-mir-551b, rno-mir-490, rno-mir-1224, rno-mir-504, mmu-mir-466m, mmu-mir-466o, mmu-mir-466c-2, mmu-mir-466b-4, mmu-mir-466b-5, mmu-mir-466b-6, mmu-mir-466b-7, mmu-mir-466p, mmu-mir-466n, mmu-mir-466b-8, rno-mir-466d, mmu-mir-466q, mmu-mir-21b, mmu-mir-21c, mmu-mir-142b, mmu-mir-466c-3, rno-mir-322-2, rno-mir-503-2, rno-mir-466b-3, rno-mir-466b-4, rno-mir-542-2, rno-mir-542-3
The expression levels of miR-183, miR-96, and miR-182 were most highly up-regulated, whereas miR-122, miR-503, and miR-139-3p exhibited the greatest down-regulation as a result of 17α-E2 treatment. [score:9]
The expression levels of miR-183 (4.61-fold), miR-96 (4.56-fold), and miR-182 (4.29-fold) were most highly up-regulated, whereas miR-122 (9.79-fold), miR-503 (5.88-fold), and miR-139-3p (1.94-fold) showed the greatest down-regulation as a result of 17α-E2 treatment. [score:9]
ACTH up-regulated the expression of miRNA-212, miRNA-182, miRNA-183, miRNA-132, and miRNA-96 and down-regulated the levels of miRNA-466b, miRNA-214, miRNA-503, and miRNA-27a. [score:9]
The levels of miR-212, miRNA-183, miRNA-182, miRNA-132, miRNA-370, miRNA-377, and miRNA-96 were up-regulated, whereas miR-125b, miRNA-200b, miR-122, miRNA-466b, miR-138, miRNA-214, miRNA-503 and miRNA27a were down-regulated in response to 17α-E2 treatment. [score:7]
Real-time quantitative PCR measurements confirmed that the expression of miR-212, miRNA-183, miRNA-182, miRNA-132, miRNA-370, miRNA-377 and miRNA-96 was up-regulated and that of miRNA-122, miRNA-200b, miRNA-466b, miRNA-138, miRNA-214, miRNA-503 and miRNA-27a down-regulated in adrenals from 17α-E2 treated rats. [score:7]
qRT-PCR measurements confirmed that the expression of miR-212, miRNA-183, miRNA-182, miRNA-132, miRNA-370, miRNA-377 and miRNA-96 was up-regulated and that of miRNA-122, miRNA-200b, miRNA-466b, miRNA-138, miRNA-214, miRNA-503 and miRNA-27a down-regulated in adrenals from 17α-E2 treated rats (Fig. 3 ). [score:7]
Real-time PCR (qRT-PCR) measurements demonstrated that ACTH treatment upregulated the expression of miRNA-212, miRNA-183, miRNA-182, miRNA-132 and miRNA-96, while down -regulating the expression of miRNA-466b, miRNA-214, miRNA-503 and miRNA-27a. [score:7]
For example, miRNA-503, miRNA-224 and miRNA-383 are expressed almost exclusively in mouse granulosa cells and oocytes [68], [72], whereas a large number of miRNAs are differentially expressed in bovine ovarian cortex, cumulus cells and corpus luteum [60]. [score:5]
Significant ACTH -induced down-regulation of miRNA-466b, miRNA-214, miRNA-503 and miRNA-27a was also observed (Fig. 3 ). [score:4]
Quantitative RT-PCR (qRT-PCR) validation of miRNA-212, miRNA-200b, miRNA-183, miRNA-122, miRNA-19a, miRNA-466b, miRNA-182, miRNA-132, miRNA-138, miRNA-370, miRNA-96, miRNA-503, miRNA-27a and miRNA-214 levels in control, ACTH-, 17α-E2 or DEX -treated adrenals in vivo. [score:1]
0078040.g003 Figure 3Quantitative RT-PCR (qRT-PCR) validation of miRNA-212, miRNA-200b, miRNA-183, miRNA-122, miRNA-19a, miRNA-466b, miRNA-182, miRNA-132, miRNA-138, miRNA-370, miRNA-96, miRNA-503, miRNA-27a and miRNA-214 levels in control, ACTH-, 17α-E2 or DEX -treated adrenals in vivo. [score:1]
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7
[+] score: 22
In contrary, it has been reported that miR-322-5p and miR-503 were induced during myogenesis and promoted cdk2 inhibition by down -regulating Cdc25A, the phosphatase responsible for removing inhibitory phosphorylation of cdk2 [60]. [score:6]
Finally, clustering genes which were down-regulated in later myoblast differentiation were enriched for miR-335-3p, -206-3p, -322-3p, -322-5p, -351-5p, and miR-503-5p targets (Fig 3D and S4D Table) which were associated with, for example, nuclear factor like 2, breast cancer 1 and 2 (early onset), tumor protein p53, cell division cycle 25C (S5G Table). [score:6]
In addition to that, some genes such as Wee1, Chek1, Cdc6, Ccna2, and Ccnd1 were associated with several enriched pathways (S2A Table) and were predicted to be targeted by several inversely regulated miRNAs including foremost miR-322-5p, miR-206, and miR-503. [score:4]
Thus, miR-322-3p and miR-503-5p targeted a similar spectrum of pathways in skeletal muscle differentiation. [score:3]
MiR-503-5p revealed targets such as cyclins, ataxia telangiectasia and Rad3 related (Atr), cell division cycle, and cancer-related genes, as well as Tp53 (S6G Table). [score:2]
S6 TableEnrichment analysis of signal transduction pathway associations of (A) miR-206-3p, (B) miR-322-3p, (C) miR-322-5p, (D) miR-335-3p, (E) miR-335-5p, (F) miR-351-5p, (G) miR-503-5p, (H) miR-133a-3p/miR-133b-3p, (I) miR-155-5p. [score:1]
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8
[+] score: 20
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]
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]
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]
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]
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9
[+] score: 17
Furthermore, miR-503, whose expression is down-regulated by hypoxia through HIF1α, also targets FGF2 and VEGFA for inhibiting tumor angiogenesis and growth [30]. [score:10]
In contrast, miR-361-5p, alone with other microRNAs known to target VEGF directly, including miR-34a, miR-503 and miR-24, were dysregulated in CAD-EPCs (Fig. 2). [score:5]
Deregulation of microRNA-503 contributes to diabetes mellitus -induced impairment of endothelial function [31]. [score:2]
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10
[+] score: 12
The fact that in ultra-deep sequencing the number of sequence reads and the upregulation factors were both at the borderline may have prevented the robust detection of miR-503*-regulation by qRT-PCR. [score:5]
In comparison, mmu-miR-503* could be detected, however, we could not confirm regulation. [score:2]
Interestingly, four of those miRNAs, namely mmu-miR-351, mmu-miR-503, mmu-miR-503*, and mmu-miR-542-5p are located in a genomic cluster within 5 kb on the mouse X-chromosome. [score:1]
To provide comparability among the quantification of the different miRNAs we did not modify the recommended protocol of the commercial detection kit in order to achieve detection of mmu-miR-503. [score:1]
Using a commercial kit, mmu-miR-503 was not detected by qRT-PCR analysis. [score:1]
The relative expression levels of mmu-miR-503, mmu-miR-503*, mmu-miR-351 and mmu-miR-542-5p was determined in a stem-loop based quantitative real-time PCR (qRT-PCR) assay (TaqMan MicroRNA Assay, Applied Biosystems) according to the supplier's instructions. [score:1]
Four of those miRNAs, namely mmu-miR-351, mmu-miR-503, mmu-miR-503*, and mmu-miR-542-5p, are clustered in a miRNA dense region on the mouse X-chromosome. [score:1]
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11
[+] score: 12
Additionally, several miRNAs that are known to exhibit tumour suppressive functions, like miR-30a-5p, miR-31, miR-335, miR-382 and miR-503, were downregulated in the p53R172H cells upon reprograming to iPS cells. [score:6]
Furthermore, a high number of miRNAs that were downregulated in p53 compromised iPS cells convey tumour suppressive functions, that is, miR-30a-5p, [55] miR-31, 56, 57 miR-335, [58] miR-382 [59] and miR-503. [score:6]
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12
[+] score: 11
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-18a, hsa-mir-22, hsa-mir-29a, hsa-mir-30a, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-124-3, mmu-mir-126a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-146a, mmu-mir-200b, mmu-mir-203, mmu-mir-204, mmu-mir-205, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-203a, hsa-mir-204, hsa-mir-205, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-221, hsa-mir-222, hsa-mir-200b, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-30b, hsa-mir-124-1, hsa-mir-124-2, hsa-mir-124-3, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-146a, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-148a, 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-22, mmu-mir-29a, mmu-mir-29c, mmu-mir-93, mmu-mir-34a, hsa-mir-200c, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-10a, mmu-mir-100, mmu-mir-200c, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-221, mmu-mir-222, mmu-mir-29b-2, mmu-mir-124-1, mmu-mir-124-2, mmu-mir-9-1, mmu-mir-9-3, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-375, mmu-mir-375, hsa-mir-335, mmu-mir-335, mmu-mir-133a-2, hsa-mir-424, hsa-mir-193b, hsa-mir-512-1, hsa-mir-512-2, hsa-mir-515-1, hsa-mir-515-2, hsa-mir-518f, hsa-mir-518b, hsa-mir-517a, hsa-mir-519d, hsa-mir-516b-2, hsa-mir-516b-1, hsa-mir-517c, hsa-mir-519a-1, hsa-mir-516a-1, hsa-mir-516a-2, hsa-mir-519a-2, hsa-mir-503, hsa-mir-642a, mmu-mir-190b, mmu-mir-193b, hsa-mir-190b, mmu-mir-1b, hsa-mir-203b, mmu-let-7j, mmu-mir-30f, mmu-let-7k, mmu-mir-126b, mmu-mir-9b-2, mmu-mir-124b, mmu-mir-9b-1, mmu-mir-9b-3
The top negatively correlated (conserved) mouse miRNAs include miR-30a/d (targets Runx2) [57], miR-148a (targets Met/Snail) [58], miR-503 (targets Bcl-2 and Igf1r, implicated in involution) [59], miR-203 (targets the transcription factor p63) [60] and miR-34a (targets Dll1 and CD44, important for stem cell activity) [61, 62]. [score:11]
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[+] score: 11
In turn, we used miRNA coexpression data as a trait for the coexpressed protein modules and found that the protein modules that best correlated to the EoC trait were negatively correlated with down-regulated miR-3091-3p, miR-503-5p, 346-3p, miR-2861 in CTX (Figure 2G) and also negatively correlated with down-regulated let-7a-2-3p, miR-763, miR-1958, miR-697 (among others) in MB (Figure 2H). [score:11]
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[+] score: 10
We built regression mo dels for these two miRNAs and found that these two loci accounted for 44 % and 37 % of variation in miR-322 and miR-503 expression, respectively. [score:3]
The trans-eQTL locus shared by miR-322 and miR-503 was also weakly associated with the expression of miR-351 and miR-497 (p [adjusted] < 0.1). [score:3]
The predicted structure of pre-miR-342 with the addition of the in del (rs261236356) is shown at right Seven other miRNAs had local eQTL: miR-146b, miR-181d, miR-187, miR-203, miR-221, miR-322, and miR-503. [score:1]
The predicted structure of pre-miR-342 with the addition of the in del (rs261236356) is shown at rightSeven other miRNAs had local eQTL: miR-146b, miR-181d, miR-187, miR-203, miR-221, miR-322, and miR-503. [score:1]
For example, miR-322 and miR-503 each had one local eQTL (on Chr X) and one trans-eQTL on Chr 11. [score:1]
Pairwise Pearson Correlation Values Among miR-322, miR-252, miR-497, and miR-503. [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-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-20a, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-93, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-23b, mmu-mir-27b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-125a, mmu-mir-9-2, mmu-mir-133a-1, mmu-mir-136, mmu-mir-138-2, mmu-mir-181a-2, mmu-mir-24-1, mmu-mir-191, hsa-mir-196a-1, hsa-mir-148a, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-122, mmu-mir-143, mmu-mir-30e, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-196a-2, hsa-mir-181a-1, mmu-mir-296, mmu-mir-298, mmu-mir-34c, mmu-let-7d, mmu-mir-130b, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-138-2, hsa-mir-143, 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, mmu-mir-19b-2, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-148a, mmu-mir-196a-1, mmu-mir-196a-2, 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-21a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-29c, mmu-mir-27a, mmu-mir-92a-2, mmu-mir-93, mmu-mir-34a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-330, mmu-mir-346, hsa-mir-1-1, mmu-mir-1a-2, mmu-mir-107, mmu-mir-17, mmu-mir-19a, mmu-mir-100, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-19b-1, mmu-mir-92a-1, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-138-1, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-34c, hsa-mir-296, hsa-mir-130b, hsa-mir-30e, hsa-mir-375, hsa-mir-381, mmu-mir-375, mmu-mir-381, hsa-mir-330, mmu-mir-133a-2, hsa-mir-346, hsa-mir-196b, mmu-mir-196b, hsa-mir-18b, hsa-mir-20b, hsa-mir-146b, hsa-mir-519d, hsa-mir-501, hsa-mir-503, mmu-mir-20b, hsa-mir-92b, mmu-mir-146b, mmu-mir-669c, mmu-mir-501, mmu-mir-718, mmu-mir-18b, mmu-mir-92b, hsa-mir-298, mmu-mir-1b, hsa-mir-103b-1, hsa-mir-103b-2, hsa-mir-718, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-30f, mmu-let-7k, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Ortega et al., however, show miR-503 as the most down-regulated miRNA during differentiation of human adipocytes [14], while in our murine data set miR-503 was upregulated during both primary brown and white adipocyte differentiation. [score:7]
The discrepancy with respect to mir-503 regulation may relate to differential regulation between man and mouse, or differences in the differentiation protocols applied. [score:3]
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[+] score: 10
Other miRNAs from this paper: mmu-mir-144, mmu-mir-322, mmu-mir-451a, mmu-mir-451b
As the KO allele carries a LacZ expression cassette upstream of the coding sequence of miR-322 and miR-503 (“knockout first”), β-galactosidase serves as the reporter of miR-322 and miR-503 expression. [score:6]
The male Mirc24 [tm1Mtm]/ Mmjax mice were mated with the female Tg(Sox2-Cre) mice to generate female heterozygous knockout mice (miR-322/503 [-/+]) of miR-322 and miR-503 (Fig 1). [score:2]
Mirc24 [tm1Mtm]/ Mmjax, the “knockout first” mouse strain of miR-322 and miR-503, was obtained from the Jackson Laboratory (Stock No: 017513) [12]. [score:2]
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[+] score: 8
Among those miRNAs showing increased expression in the HF fed offspring, histone 4 H4 is a common target for 5 different miRNAs (miR-503*, miR-770-3p, miR-369-3p, miR-197 and miR-667, Fig. 1). [score:5]
Histone 4 H4 are predicted targets for 5 miRNAs (miR-503*, miR-770-3p, miR-369-3p, miR-197 and miR-667) showing increased levels in maternal HF fed offspring. [score:3]
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[+] score: 8
The qRT-PCR data for let7c2 and mir503 are less dramatic than the other microRNA 5′ leaders, suggesting that the respective pri-miRNAs are more abundant than the 5′ leaders produced by Drosha, either due to less frequent Drosha processing for these miRNAs, or instability of the 5′ leaders of these miRNAs despite knockdown of mMtr4. [score:2]
We used the same RNA samples used to generate the data, and focused on mir322, mir503, let7b, let7c2 and mir138-1. qRT-PCR analysis of miRNA 5′ leader sequences was analyzed relative to qRT-PCR that spans the junction between the 5′ leader and the pre-miRNA (as depicted by representative amplicons 1 and 2 in Fig. 6A ). [score:1]
Adenylated transcripts associated with the mir322 host gene accumulate in the mMtr4KDThe above analyses identified two significant peaks of adenylation on chromosome X corresponding to a full length non-coding cDNA (RIKEN-C43009B03RIK) containing a miRNA cluster (mir322-mir503-mir351). [score:1]
In the case of mir322, the 3′ fragment will contain two additional microRNAs, mir503 and mir351, which may subsequently influence the fate of that fragment (discussed below). [score:1]
The above analyses identified two significant peaks of adenylation on chromosome X corresponding to a full length non-coding cDNA (RIKEN-C43009B03RIK) containing a miRNA cluster (mir322-mir503-mir351). [score:1]
The top diagram shows the mir322 - mir503 mir351 cluster and associated RIKEN transcripts on chromosome X. Note that the chromosomal orientation has been reversed such that the mm9 chromosomal coordinates are in decreasing order from left to right because the transcripts are on the minus strand. [score:1]
Although we cannot completely rule out that the mir322-mir503-mir351 cluster is more actively transcribed upon mMTR4 depletion, even a 2-fold increase would seem too small to explain the large, 67-fold increase in adenylated mir322 5′ leader by a mechanism of increased transcription alone. [score:1]
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[+] score: 7
Among the downregulated miRNAs, miRNA-503 and miR-31 were recently found to impair EC function, as well as restorative angiogenesis processes [13, 31]. [score:4]
miR-221 and miR-222 and miR-503 were also found to inhibit EC morphogenesis [8, 13]. [score:3]
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[+] score: 6
The top 5 miRNAs, which were highly expressed in IEC-6 cells, were miR-320, miR-494, miR-503, miR-185 and miR-206. [score:3]
In agreement with other reports, several miRNAs, including miR-320, miR-494, miR-503, and members of the let-7 family, were highly expressed in IEC-6 cells, giving strong hybridization signals on the miRNA arrays. [score:3]
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[+] score: 6
Moreover, downregulation of the MicroRNAs MiR-424 and MiR503 was shown to upregulate Rictor, which promotes colon cancer progression [34]. [score:6]
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[+] score: 6
Other miRNAs from this paper: mmu-mir-199a-1, mmu-mir-148a, mmu-mir-199a-2
Interestingly, IKKβ is the target of miR148a, miR503, and miR199a, 45, 46, 47 which are upregulated microRNAs in vascular calcification. [score:6]
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[+] score: 5
miRNA RQ Validated target genes Biological process Role in disease miR-31-3p 4.5 RhoA Proliferation and migration Cancer 53 miR-691 3.4 No data No data No data miR-700-3p 3.1 No data No data No data miR-29a-5p 3.1 No data No data Cancer 54 miR-501-3p 3 Gria1 Neuro-transmision No data 55 miR-338-3p* 2.7 Aatk, Atp5g1, CoxIV Axonal guidance, apoptosis, mitochondrial function Cancer, neurodegeneration 42, 56 miR-139-3p 2.7 MMP11 Extracellular matrix organization Cancer 57 miR-34a-5p* 2.5 Bcl-2, Notch1, Map2k1, Sirt1 Apoptosis, mitochondrial function, oxidative stress response Cancer, Alzheimer, cardiomyopathy 29, 30, 34, 43, 44 miR-335-3p 2.1 Ank3 No data No data 58 miR-1949 1.7 Rb1 Cell cycle control Cancer 59 miR-326-3p 0.5 Bcl-xl, Notch1/2 Apoptosis, proliferation Cancer 60, 61 miR-671-5p 0.3 Smarcb1 Proliferation Cancer 62 miR-503-3p 0.2 No data No data No data miR-350* 0.2 p38, Jnk Apoptosis Cardiac hypertrophy 32 [*]miRNAs selected for further studies. [score:5]
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[+] score: 5
miR-15a, miR-16, and miR-503 were reported to inhibit tumor angiogenesis by targeting VEGFA [15],[16]. [score:5]
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25
[+] score: 5
Thus, in different stages of the lung development, Prdx6 may show different functions which are mainly determined by mmu-mir-503 and mmu-mir-19a, respectively. [score:2]
MiRNA overlap (Figure 5(c))We have found that there are five miRNAs participated in both the early and late stages: mmu-mir-200a, mmu-mir-200b, mmu-mir-135b, mmu-mir-494 and mmu-mir-503. [score:1]
Gene Prdx6 is involved in one circuit in the early stage (IRF1~mmu-mir-503~Prdx6), while involved in the other two circuits containing the same miRNA (MYC~mmu-mir-19a~Prdx6, IRF1~mmu-mir-19a~Prdx6) in the late stage. [score:1]
We have found that there are five miRNAs participated in both the early and late stages: mmu-mir-200a, mmu-mir-200b, mmu-mir-135b, mmu-mir-494 and mmu-mir-503. [score:1]
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[+] score: 5
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-15a, 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, 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
Another study showed that miR-322/424 and miR-503 are upregulated during myogenesis and these miRNAs promote cell cycle arrest at G1 phase by down -regulating Cdc25A [144]. [score:5]
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[+] score: 5
For example, Ccnd1 is targeted by miR-138, but it is also targeted by miR-34a, miR-16, miR-195, miR-153, miR-503 and many other microRNAs [50]. [score:5]
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[+] score: 5
A previous study showed that miR-322/424 and miR-503 can promote cell differentiation by enhancing cell cycle arrest through the inhibition of cell cycle regulator Cdc25A [32]. [score:4]
MiR-148a, miR-206 and miR-214 have been shown to be similar to miR-322/424 and miR-503 [12, 33, 34]. [score:1]
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[+] score: 4
For OFSCs, the expression levels of hsa-miR-28-5p, hsa-miR-503 and hsa-miR-769-5p (transcripts per million < 1,000) were too low to act as a regulator for immunomodulation. [score:4]
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[+] score: 4
We found that compared to medium, moDCs stimulated with B0213 showed significantly increased expression of hsa-miR-132-3p, hsa-miR-144-3p, hsa-miR-147a, hsa-miR-155-5p, hsa-miR-503-3p, and hsa-miR-99b-5p and a decreased expression hsa-miR-222-3p (Fig.   3c). [score:4]
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[+] score: 4
Thus, p73, by increasing the expression of Ago-1/2, it could increase the processing of miRNAs, such as let-7 (HMGA2; lin-28; EGFR; Kras; c-myc; Bcl-xL), miR-134 (Nanog; LRH1; Oct-4; Collagenase-3; Stromelysin), miR-130b (ERK2; Fosl1; TGFβR1; ERα; Tcf-4; Collagenase-3; Ago4; Dicer; p63), miR-214 (EZH2; CTNNB1), miR-449a (CDK6; SirT1; HDAC1; E2F-1), miR-503 (CCND1; Fosl1), miR-181d (ERK2; TGFβR1; Tcl-1; ERα; AID; Bcl-2) and miR-379 (lin-28) [Figure 2] [31], [32]. [score:3]
The C-terminal NHL domain of TRIM-32 forms complex with Ago1, and thereby promotes the efficiency of processing of a number of miRNAs [Figure 2], including let-7, miR-134, miR-130, miR-214, 449, 379, 181, and miR-503 [31]. [score:1]
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[+] score: 4
Other miRNAs from this paper: hsa-let-7c, hsa-let-7d, hsa-mir-16-1, hsa-mir-21, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-28, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-99a, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-99a, mmu-mir-101a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-128-1, mmu-mir-9-2, mmu-mir-142a, mmu-mir-144, mmu-mir-145a, mmu-mir-151, mmu-mir-152, mmu-mir-185, mmu-mir-186, mmu-mir-24-1, mmu-mir-203, mmu-mir-205, hsa-mir-148a, hsa-mir-34a, hsa-mir-203a, hsa-mir-205, hsa-mir-210, hsa-mir-221, mmu-mir-301a, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-125b-1, hsa-mir-128-1, hsa-mir-142, hsa-mir-144, hsa-mir-145, hsa-mir-152, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125b-2, hsa-mir-126, hsa-mir-185, hsa-mir-186, mmu-mir-148a, mmu-mir-200a, mmu-let-7c-1, mmu-let-7c-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-21a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-31, mmu-mir-34a, mmu-mir-148b, mmu-mir-339, mmu-mir-101b, mmu-mir-28a, mmu-mir-210, mmu-mir-221, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, mmu-mir-128-2, hsa-mir-128-2, hsa-mir-200a, hsa-mir-101-2, hsa-mir-301a, hsa-mir-151a, hsa-mir-148b, hsa-mir-339, hsa-mir-335, mmu-mir-335, hsa-mir-449a, mmu-mir-449a, hsa-mir-450a-1, mmu-mir-450a-1, hsa-mir-486-1, hsa-mir-146b, hsa-mir-450a-2, hsa-mir-503, mmu-mir-486a, mmu-mir-542, mmu-mir-450a-2, hsa-mir-542, hsa-mir-151b, mmu-mir-301b, mmu-mir-146b, mmu-mir-708, hsa-mir-708, hsa-mir-301b, hsa-mir-1246, hsa-mir-1277, hsa-mir-1307, hsa-mir-2115, mmu-mir-486b, mmu-mir-28c, mmu-mir-101c, mmu-mir-28b, hsa-mir-203b, hsa-mir-5680, hsa-mir-5681a, mmu-mir-145b, mmu-mir-21b, mmu-mir-21c, hsa-mir-486-2, mmu-mir-126b, mmu-mir-142b, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Of the down-regulated miRNAs, 24 miRNAs showed a >5-fold decrease, including four miRNAs, i. e. miR-205, miR-503, miR-708 and miR-2115*, which were undetectable in the metastatic line. [score:4]
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33
[+] score: 4
Zhou B MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growthCancer Lett. [score:4]
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34
[+] score: 4
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-21, hsa-mir-23a, hsa-mir-30a, hsa-mir-98, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-30a, mmu-mir-30b, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-9-2, mmu-mir-132, mmu-mir-133a-1, mmu-mir-135a-1, mmu-mir-150, mmu-mir-155, mmu-mir-204, mmu-mir-205, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-34a, hsa-mir-204, hsa-mir-205, hsa-mir-217, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-150, mmu-mir-19b-2, 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-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-21a, mmu-mir-23a, mmu-mir-34a, mmu-mir-98, mmu-mir-322, mmu-mir-338, hsa-mir-155, mmu-mir-17, mmu-mir-19a, mmu-mir-135a-2, mmu-mir-19b-1, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-125b-1, mmu-mir-217, hsa-mir-30c-1, hsa-mir-34b, hsa-mir-34c, hsa-mir-30e, hsa-mir-338, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, hsa-mir-18b, hsa-mir-503, mmu-mir-541, mmu-mir-744, mmu-mir-18b, hsa-mir-541, hsa-mir-744, mmu-mir-133c, mmu-mir-21b, mmu-let-7j, mmu-mir-21c, mmu-mir-30f, mmu-let-7k, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
After repeated osteo-induction (2w+), miR-30d and miR-30c were induced, and the expression levels of miR-503, miR-322 and miR-125b-3p were the most powerfully repressed (Fig. 4B, E). [score:3]
miR-30d and miR150 as well as other miRNAs were induced by long-term culture for 2 weeks in the absence of differentiation stimulus, while miR-503 and miR-744 were reduced by the long-term culture (Fig. 4C, F). [score:1]
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[+] score: 4
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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36
[+] score: 3
Another study showed that miR-503, a miRNA that is repressed in endometriosis, induces apoptosis and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells [38]. [score:3]
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[+] score: 3
[58] Several VEGFA-/FGF2 -targeting miRNAs have been described in different cancers, including miR-503 in prostate cancer, [59] miR-497 in hepatocellular carcinoma [60] and miR-185 in clear cell renal cell carcinoma. [score:3]
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38
[+] score: 3
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-16-1, hsa-mir-17, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-23a, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-100, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-16-2, mmu-mir-23b, mmu-mir-27b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-127, mmu-mir-128-1, mmu-mir-132, mmu-mir-133a-1, mmu-mir-188, mmu-mir-194-1, mmu-mir-195a, mmu-mir-199a-1, hsa-mir-199a-1, mmu-mir-200b, mmu-mir-205, mmu-mir-206, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-122, mmu-mir-30e, hsa-mir-199a-2, hsa-mir-199b, hsa-mir-205, hsa-mir-211, hsa-mir-212, hsa-mir-214, hsa-mir-217, hsa-mir-200b, hsa-mir-23b, hsa-mir-27b, hsa-mir-30b, hsa-mir-122, hsa-mir-128-1, hsa-mir-132, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-127, hsa-mir-138-1, hsa-mir-188, hsa-mir-194-1, hsa-mir-195, hsa-mir-206, mmu-mir-19b-2, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-23a, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-27a, mmu-mir-31, mmu-mir-351, hsa-mir-200c, mmu-mir-17, mmu-mir-19a, mmu-mir-100, mmu-mir-200c, mmu-mir-212, mmu-mir-214, mmu-mir-26a-2, mmu-mir-211, mmu-mir-29b-2, mmu-mir-199a-2, mmu-mir-199b, mmu-mir-19b-1, mmu-mir-138-1, mmu-mir-128-2, hsa-mir-128-2, mmu-mir-217, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-30e, hsa-mir-26a-2, hsa-mir-379, mmu-mir-379, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-412, mmu-mir-431, hsa-mir-431, hsa-mir-451a, mmu-mir-451a, mmu-mir-467a-1, hsa-mir-412, hsa-mir-485, hsa-mir-487a, hsa-mir-491, hsa-mir-503, hsa-mir-504, mmu-mir-485, hsa-mir-487b, mmu-mir-487b, hsa-mir-556, hsa-mir-584, mmu-mir-665, mmu-mir-669a-1, mmu-mir-674, mmu-mir-690, mmu-mir-669a-2, mmu-mir-669a-3, mmu-mir-669c, mmu-mir-696, mmu-mir-491, mmu-mir-504, hsa-mir-665, mmu-mir-467e, mmu-mir-669k, mmu-mir-669f, hsa-mir-664a, mmu-mir-1896, mmu-mir-1894, mmu-mir-1943, mmu-mir-1983, mmu-mir-1839, mmu-mir-3064, mmu-mir-3072, mmu-mir-467a-2, mmu-mir-669a-4, mmu-mir-669a-5, mmu-mir-467a-3, mmu-mir-669a-6, mmu-mir-467a-4, mmu-mir-669a-7, mmu-mir-467a-5, mmu-mir-467a-6, mmu-mir-669a-8, mmu-mir-669a-9, mmu-mir-467a-7, mmu-mir-467a-8, mmu-mir-669a-10, mmu-mir-467a-9, mmu-mir-669a-11, mmu-mir-467a-10, mmu-mir-669a-12, mmu-mir-3473a, hsa-mir-23c, hsa-mir-4436a, hsa-mir-4454, mmu-mir-3473b, hsa-mir-4681, hsa-mir-3064, hsa-mir-4436b-1, hsa-mir-4790, hsa-mir-4804, hsa-mir-548ap, mmu-mir-3473c, mmu-mir-5110, mmu-mir-3473d, mmu-mir-5128, hsa-mir-4436b-2, mmu-mir-195b, mmu-mir-133c, mmu-mir-30f, mmu-mir-3473e, hsa-mir-6825, hsa-mir-6888, mmu-mir-6967-1, mmu-mir-3473f, mmu-mir-3473g, mmu-mir-6967-2, mmu-mir-3473h
The analysis showed miRNAs that were related to ER stress pathway (let-7f, miR-351, miR-127, miR-133a, miR-195, miR-214 and miR-503), suggesting CASP3, CASP7, XBP1, ATF6 and ATF4 as possible target genes for these miRNAs (Table 4). [score:3]
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[+] score: 3
Hepatitis C virus nonstructural 5A protein (HCV-NS5A) inhibits hepatocyte apoptosis through the NF-kappab/miR-503/bcl-2 pathway. [score:3]
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40
[+] score: 2
The proposed microRNAs that are regulated through the processing machinary include let-7, miR-200c, miR-143, miR-107, miR-16, miR-145, miR-134, miR-449a, miR-503, and miR-21 [16]. [score:2]
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41
[+] score: 2
Caporali A Deregulation of microRNA-503 contributes to diabetes mellitus -induced impairment of endothelial function and reparative angiogenesis after limb ischemiaCirculation. [score:2]
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42
[+] score: 2
MicroRNAs, such as hsa-miR-503, hsa-miR-205, and hsa-miR-200b, have been shown to be dysregulated in endometrioid endometrial carcinoma (EEC) [1, 2]. [score:2]
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43
[+] score: 2
For example, miR-503 was among the most induced miRNAs between the zygote and 2-cell stages of development; between the 2-cell and 4-cell stages, it was among the most repressed (Fig. 4c–d). [score:2]
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44
[+] score: 2
This network analysis predicated several novel regulators, which includes TASP1, TOB1, C1orf61, AIF1, ROCK1, TFF2 and miR503-5p that may be acting on the 13-day-old heart. [score:2]
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[+] score: 1
miR-107, together with miR-15a/b, miR-16, miR-103, miR-195, miR-424, miR-497, miR-503, and miR-646, belongs to the miR-15-107 group. [score:1]
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46
[+] score: 1
mir-351 is potentially part of a miRNA cluster with mir-503 and mir-322 lying within 2 kb upstream, with numerous ESTs mapped in this region supporting this possibility. [score:1]
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47
[+] score: 1
Other miRNAs from this paper: hsa-mir-424, hsa-mir-503, rno-mir-503-1, rno-mir-503-2
An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. [score:1]
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48
[+] score: 1
49), miR-503 (ref. [score:1]
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49
[+] score: 1
More than 40 microRNAs in the Uup group were shared by the above pathways, while miR-503, miR-122, miR-495, and miR-382 were exclusively involved in the focal adhesion pathway, and miR-150, miR-411, miR-146a/b exclusively participated in the MAPK pathway (S4 Table). [score:1]
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