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16 publications mentioning hsa-mir-524

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-524. 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: 448
On the other hand, direct suppression of TP53INP1 expression by miR-524-5p also leads to the p53 ablation, which in turn causes downregulation of a cascade of p53 -targeted genes involved in the cell cycle arrest and apoptosis, but upregulates expression of pluripotency genes. [score:16]
Nevertheless, the upregulated miR-524-5p level in WJ0706 was sufficient to downregulate the expression of its target genes including TP53INP1, ZEB2, and SMAD4 (Fig.   6a). [score:11]
Taken together, our results demonstrated involvement of miR-524-5p in events relevant to reprogramming, namely promotion of cell proliferation, suppression of oxidant -induced apoptosis, and upregulation of pluripotency -associated genes via targeting and downregulation of the TP53INP1 transcript in the p53 signaling pathway. [score:11]
miR-524-5p -induced TP53INP1 downregulation enhanced cell proliferation, suppressed apoptosis, and upregulated the expression of pluripotency genes, all of which are critical early events of the reprogramming process. [score:11]
Taken together, luciferase assays confirmed that miR-524-5p directly targets TP53INP1 to downregulate TP53INP1 expression, and that the miRNA and target gene may have co-evolved late in the evolution of the primate. [score:10]
The expression of the predicted EMT-related target genes, including TGFβR1, SMAD2, SMAD3, SMAD4, ZEB1, ZEB2, and TWIST1, was determined by RT-PCR, which showed that only ZEB2 and SMAD4 expression were downregulated 48 h post-transfection with the miR-524-5p mimic (data not shown). [score:10]
Via targeting TP53INP1, ZEB2, and SMAD4, miR-524-5p contributes to the early stage of inducing pluripotency by promoting cell proliferation, inhibiting apoptosis, upregulating expression of pluripotency genes, and enhancing MET. [score:10]
The data clearly showed that both overexpression of miR-524-5p and TP53INP1 knockdown upregulated the expression of all four pluripotency genes tested in the transfected cells (Fig.   5f). [score:9]
In this scheme, miR-524-5p suppresses SMAD4 and ZEB2 resulting in upregulation of the MET marker E-cadherin via the TGFβ pathway or by direct suppression of E-cadherin, respectively. [score:9]
Similar to siRNA -mediated TP53INP1 suppression, forced overexpression of miR-524-5p significantly downregulated TP53INP1 at both the mRNA and protein levels compared with the mock control (Fig.   3c and d), further confirming a reverse relationship between miR-524-5p and TP53INP1 expression. [score:9]
Furthermore, miR-524-5p was shown to target and downregulate expression of the EMT-related genes ZEB2 and SMAD4 and, hence, promoting MET, which is also an essential initial event of reprogramming [2, 3]. [score:8]
By targeting TP53INP1, miR-524-5p was shown to enhance proliferation and suppress apoptosis (Fig.   5a–d), both of which are early crucial events for reprogrammable cells to enter subsequent phases of activation or upregulation of pluripotency genes in the progression of the reprogramming process [2, 3]. [score:8]
Interestingly, our previous study has shown that miR-524-5p was abundantly expressed in iPSCs whereas miR-524-5p expression was undetected or detected at very low levels in MSC cell lines [7], suggesting an inverse correlation between the expression of miR-524-5p and TP53INP1 and negative regulation of TP53INP1 by miR-524-5p. [score:8]
Hence, the results support that miR-524-5p negatively regulates TP53INP1, which in turn regulates p53, to upregulate expression of pluripotency genes. [score:8]
The data further suggested that miR-524-5p regulated TP53INP1 expression probably via downregulation of the TP53INP1 transcript. [score:7]
Furthermore, we also observed in this study the lack of inverse correlation in expression levels between miR-524-5p and TP53INP1 in some cell lines, suggesting that besides regulation by miR-524-5p, TP53INP1 expression is likely regulated by other factors, notably by different transcription factors. [score:7]
The putative target, TP53INP1, showed an inverse expression relationship with miR-524-5p; direct TP53INP1 targeting was confirmed in luciferase assays. [score:7]
Furthermore, p53, a pro-apoptotic, antiproliferative, and antioxidant regulator, is indirectly regulated by miR-524-5p through targeting TP53INP1 and HIPK2 (Fig.   2). [score:6]
Hence, it may be speculated that the miR-524-5p/TP53INP1 -induced upregulated expression of pluripotency genes observed in this study may be a consequence of TP53INP1 -induced p53 repression. [score:6]
Thus, these data suggested negative regulation of expression of ZEB2 and SMAD4 by miR-524-5p, which was confirmed by demonstration of direct miRNA targeting in luciferase assays (Fig.   6c and d). [score:6]
Overexpression of miR-524-5p downregulated TP53INP1 mRNA levels as anticipated, as did the transfection of siTP53INP1. [score:6]
The results indicated that miR-524-5p was undetectable in WJ0706 cells (Fig.   5a, left panel, the mock control), whereas the expression level was upregulated to about 10,000 copies/cell 48 h post-transfection of the miR-524-5p mimic (Fig.   5a, left panel, 524-5p mimic). [score:6]
miR-524-5p was also shown in this work to upregulate the expression of pluripotency genes Oct4, Nanog, Sox2, and Rex1 (Fig.   5f). [score:6]
Compared to transfection with the negative control mimic, forced expression of miR-524-5p significantly inhibited endogenous mRNA expression of ZEB2 and SMAD4 by almost 40% and 30%, respectively (Fig.   6a). [score:6]
miR-524-5p downregulation of endogenous expression of ZEB2 and SMAD4 was confirmed in quantitative real-time RT-PCR and Western blot analysis (Fig.   6a and b). [score:6]
In the scheme, miR-524-5p promotes reprogramming by downregulating TP53INP1 to mediate processes associated with cell cycle, apoptosis, and expression of pluripotency genes, which are essential for the early stage of reprogramming. [score:6]
Taken together, the results confirmed that miR-524-5p targeted and repressed the expression of the EMT -associated genes ZEB2 and SMAD4, which may have a direct bearing on the initial phase of establishing pluripotency. [score:6]
Hence, we hypothesized that miR-524-5p may also enhance MET by targeting the EMT -associated genes that were predicted to be targeted by miR-524-5p. [score:5]
We previously showed in miRNA microarray and miRNA copy number analyses that miR-524-5p was expressed abundantly in pluripotent stem cells, including ESCs and iPSCs, whereas miR-524-5p expression was undetected or detected at low levels in the MSC cell lines from which the iPSCs were derived [7]. [score:5]
The observation of the lack of inverse correlation between miR-524-5p and TP53INP1 in some cell lines suggests that, besides regulation by miR-524-5p, other factors are involved in regulating TP53INP1 expression, particularly in cancer cells (see ). [score:5]
EMT epithelial-to-mesenchymal transition, iPSC induced pluripotent stem cell, ROS reactive oxygen species In this work, we have provided experimental evidence to support that the C19MC miR-524-5p targets TP53INP1 to enhance cell proliferation and to suppress apoptosis, which are critical events in the early phase of cellular reprogramming. [score:5]
a, b Effects of miR-524-5p overexpression on the expression of the EMT-related genes. [score:5]
ESCs and placenta, which comprehensively express all the C19MC miRNAs and, therefore, miR-524-5p [7], also expressed TP53INP1, and in higher levels in ESCs. [score:5]
Our data also show that miR-524-5p targets the EMT -associated SMAD4 and ZEB2 genes to suppress MET, which is also a crucial step in initiating reprogramming. [score:5]
PI cells, also expressed various levels of miR-524-5p [7], but correlation could not be made between the TP53INP1 and miR-524-5p expression levels. [score:5]
TP53INP1 was also identified as a miR-524-5p target that mediated enhanced cell proliferation and suppressed apoptosis, both of which are relevant to the early stage of reprogramming, establishing the contribution of a C19MC miRNA as an enhancer for cellular reprogramming. [score:5]
c, d Effects of miR-524-5p overexpression on TP53INP1 expression. [score:5]
In this study, miR-524-5p was found to promote MET by inhibiting the expression of the EMT-related genes SMAD4 and ZEB2 (Fig.   6), which may thereby be associated with enhancing the reprogramming process. [score:5]
In the top panel, alignment of miR-524-5p with the putative target site 2 (boxed and in bold letters) in the 3’-UTR of the TP53INP1 transcript (see text) is shown, so are the mutations (in italics and underlined) in the luciferase construct Mut2. [score:4]
TP53INP1 is a direct target of miR-524-5p. [score:4]
Similarly, miR-302/367 and miR-200 play a crucial role in iPSC generation by targeting EMT-related genes TGFβR2 and ZEB1/ZEB2, respectively [12, 14], echoing our finding of miR-524-5p regulation of ZEB2. [score:4]
The results indicated that transfection of the miR-524-5p mimic suppressed the damaging effects of H [2]O [2] -induced oxidative stress on cell viability, and the protection was likely via TP53INP1 since TP53INP1 knockdown also resulted in similar protection effects (Fig.   5d). [score:4]
miR-524-5p promotes MET required for initiating reprogramming by downregulating EMT-related genes. [score:4]
b Upregulated miR-524-5p levels in OSKM/mir-524 co-transduced relative to OSKM-transduced HFF-1 cells. [score:4]
Besides p53, miR-524-5p was also predicted to target a member of the Rb family, RB1, an event that regulates the cell cycle by enhancing G1 to S transition and proliferation. [score:4]
Fig. 4Direct TP53INP1 targeting by and possible co-evolution with miR-524-5p. [score:4]
miR-524-5p also promoted mesenchymal-to-epithelial transition (MET), a required initial event of reprogramming, by directly targeting the epithelial-to-mesenchymal transition (EMT)-related genes, ZEB2 and SMAD4. [score:4]
Hence, miR-524-5p enhances cell proliferation which may partially be due to TP53INP1 downregulation. [score:4]
Fig. 2Predicted miR-524-5p -targeted genes regulate the G1 to S transition phase of the cell cycle. [score:4]
miR-524-5p, a C19MC member, is highly homologous to the reprogramming miR-520d-5p; we also reported that miR-524-5p was expressed in iPSCs but not mesenchymal stem cells (MSCs). [score:3]
C19MC miR-524-5p Reprogramming efficiency Cell proliferation Apoptosis Pluripotency genes MET TP53INP1 ZEB2 SMAD4 Differentiated somatic cells can be reprogrammed into a pluripotent state by forced expression of a defined set of transcription factors, typically Oct4, Sox2, Klf4, and c-Myc (OSKM), to become induced pluripotent stem cells (iPSCs) [1]. [score:3]
We report here that miR-524-5p, a C19MC member, was able to enhance OSKM -driven somatic reprogramming probably by promoting MET via targeting the EMT -associated genes ZEB2 and SMAD4. [score:3]
Co -expressing the miR-524 precursor with OSKM resulted in a two-fold significant increase in the number of AP- and Nanog -positive ESC-like colonies, indicating a role for miR-524-5p in reprogramming. [score:3]
Since a Wharton’s Jelly MSC 0706 (WJ0706) cell line was used in subsequent experiments, the endogenous expression levels of both miR-524-5p and TP53INP1 in WJ0706 cells were first determined based on transcript copy number and RT-PCR, respectively (Fig.   5a). [score:3]
On the other hand, luciferase construct of target site 2, designated as WT2, when co -transfected with the miR-524-5p mimic resulted in a reduction to ~ 40% of luciferase activity relative to that in the control cells transfected with the blank vector (Fig.   4c). [score:3]
Putative miR-524-5p target genes are shown in yellow boxes Repression of the PI3K/PKB/Akt/mTOR and TGFβ pathways, such as PTEN, p21/CDK1NA, TGFβR1, and SMAD2/3/4, has been reported to promote self-renewal and proliferation by blocking the G1 to S transition boundary of the cell cycle [13, 28– 30]. [score:3]
Fig. 3Inverse relationship between expression of miR-524-5p and TP53INP1. [score:3]
A miR-524-5p mimic was transfected into HCT-15 cells for 48 h before the cells were harvested for 40 cycles of real-time RT-PCR (c) or Western blot analysis (d) to determine TP53INP1 expression. [score:3]
Putative miR-524-5p target genes are shown in yellow boxes Repression of the PI3K/PKB/Akt/mTOR and TGFβ pathways, such as PTEN, p21/CDK1NA, TGFβR1, and SMAD2/3/4, has been reported to promote self-renewal and proliferation by blocking the G1 to S transition boundary of the cell cycle [13, 28– 30]. [score:3]
Based on the earlier bioinformatics analysis [7], eight predicted G1-to-S transition-related genes, namely TGFβR1, Smad2/3/4, Rb1, PTEN, HIPK2, and TP53INP1, were identified to be targeted by miR-524-5p (Fig.   2). [score:3]
ASC adipose-derived stem cell, ESC embryonic stem cell, iPSC induced pluripotent stem cell, MSC mesenchymal stem cell, NC negative control When HCT-15 cells were transfected with a miR-524-5p mimic to achieve a ~ 16-fold upregulation of the miR-524-5p level 48 h post-transfection (Fig.   3b), the TP53INP1 mRNA and protein levels were assayed in qRT-PCR and Western blots (Fig.   3c and d). [score:3]
Bioinformatics analysis of miRNA-524-5p and predicted target mRNA interactions. [score:3]
The long 4521-bp 3’-UTR of the TP53INP1 transcript (NM_033285) encompasses four putative miR-524-5p -targeted sites, each with a six- to seven-nucleotide seed sequence alignment with the TP53INP1 sequence at nucleotide (nt) positions 1461–1466, nt 3397–3403, nt 5450–5455, and nt 5530–5536 of the transcript (Fig.   4b). [score:3]
Furthermore, miR-524-5p also enhances MET, a required process for initial reprogramming, by targeting the EMT-related genes ZEB2 and SMAD4. [score:3]
Echoing possible co-evolution of miR-524-5p and TP53INP1 suggested above, the active target site 2 also showed identical sequences between the two primate genes, but not with other mammalian orthologs (Fig.   4d). [score:3]
b Efficient transfection and overexpression of the miR-524-5p mimic in HCT-15 cells. [score:3]
To test this hypothesis, a miR-524-5p mimic was first transiently transfected into WJ0706 cells, which do not express miR-524-5p, and the mimic transfection resulted in an increase of the miR-524-5p to ~ 10,000 copies/cell 48 h post-transfection (see above and Fig.   5a, left panel). [score:3]
ASC adipose-derived stem cell, ESC embryonic stem cell, iPSC induced pluripotent stem cell, MSC mesenchymal stem cell, NC negative control When HCT-15 cells were transfected with a miR-524-5p mimic to achieve a ~ 16-fold upregulation of the miR-524-5p level 48 h post-transfection (Fig.   3b), the TP53INP1 mRNA and protein levels were assayed in qRT-PCR and Western blots (Fig.   3c and d). [score:3]
On the other hand, the endogenous TP53INP1 transcript level was high in WJ0706 (Fig.   5a, right panel, mock control); however, the TP53INP1 transcript level was reduced 48 h post-transfection of the miR-524-5p mimic (Fig.   5a, right panel), which also echoed the miR-524-5p -suppressed TP53INP1 transcript and protein levels in HCT-15 cells (Fig.   3c and d; see also Fig.   6b, left most panel below). [score:3]
The miR-302/367 cluster enhances reprogramming efficiency by increasing cell division rate [13] and suppressing apoptosis [39], as well as promoting epigenetic reactivation of pluripotency genes [40], as shown here for miR-524-5p. [score:3]
It was also noted that the transfected miR-524-5p expression level in WJ0706 was lower than that in HCT-15 (Fig.   3b), suggesting different efficiencies in transient miRNA transfection of cancer and stem cells. [score:3]
Fig. 1Overexpression of mir-524 precursor promotes OKSM -driven iPSC generation at the early stage of induction. [score:3]
The transition from the initiation to the maturation phase of the reprogramming process is also highlighted by upregulation of pluripotency -associated genes, including Oct4, Nanog, Sox2, and Rex1 [2, 3], which were assayed in miR-524-5p mimic- and siTP53INP1 -transfected cells (Fig.   5f). [score:3]
miR-524-5p regulates processes relevant to reprogramming. [score:2]
c Experimental validation of miR-524-5p targeting TP53INP1 in luciferase assays. [score:2]
The result showed ~ 40% significant reduction of nucleosome production in the miR-524-5p- or siTP53INP1 -transfected cells compared to the mock control, further indicative of miR-524-5p suppression of apoptosis via TP53INP1. [score:2]
b– f The miR-524-5p mimic -transfected WJ0706 cells were subjected to assays to determine cell proliferation (b, c), cell viability (d), apoptosis after oxidative stress induced with 200 μM H [2]O [2] (e), and expression of selected pluripotency genes (f). [score:2]
c, d Experimental validation of miR-524-5p targeting of ZEB2 and SMAD4 in luciferase assays. [score:2]
Before (mock) or after transfection of a miR-524-5p mimic, WJ0706 cells were harvested 48 h post-transfection for analysis; miR-524-5p copy number was determined by Taqman qRT-PCR (left panel); TP53INP1 transcript level was determined by direct RT-PCR (right panel). [score:2]
Contribution of miR-524-5p to cell proliferation and apoptosis was examined by cell counts, BrdU, MTT, and cell death assays, and pluripotency gene expression by real-time PCR. [score:2]
Fig. 7A proposed scheme of miR-524-5p regulation of the early stage of the reprogramming process [2, 3]. [score:2]
Since cell cycle, more critically the G1-to-S transition phase, is an important feature of the regulation of stem cell self-renewal [13, 27] we focused in this work on determining possible functions of miR-524-5p in relation to the G1-S phase of the cell cycle. [score:2]
Next, to examine whether miR-524-5p expression influences the cell proliferation rate, WJ0706 cells were transfected with the miR-524-5p mimic and in vitro cell proliferation assays were performed. [score:2]
In short, TP53INP1 is subjected to both positive and negative regulation by a battery of transcription factors and miRNAs, including miR-524-5p as shown in this work. [score:2]
Taken together, a scheme is proposed here to summarize the involvement of miR-524-5p in the reprogramming process via interactions with TP53INP1, ZEB2, and SMAD4, and the subsequent regulation of the p53 circuitry (Fig.   7). [score:2]
In each of the three independent experiments, the total number of ESC-like and AP [+]Nanog [+] colonies observed varied between three to six in the triplicate wells of the 12-well plate transduced with OSKM alone, or OSKM with the blank vector CD511, and from seven to twelve colonies on OSKM/mir-524 transduction (Table  1). [score:1]
The protein levels of ZEB2 and SMAD4 were also diminished by miR-524-5p mimic (Fig.   6b). [score:1]
Our bioinformatics analysis revealed identical seed sequence and high degree of sequence homology between miR-524-5p and miR-520d-5p (Fig.   1a). [score:1]
In the reprogramming of somatic cells, miRNAs are more likely to act as co-factors by enhancing the reprogramming process, as shown with miR-524-5p in this work, rather than acting in solo to exert their effects. [score:1]
WJ0706 cells were transfected with miRNA mimic miR-524-5p, miRNA NC, or TP53INP1 siRNA (siTP53INP1). [score:1]
miRNA-524-5p enhances reprogramming. [score:1]
In the OSKM/mir-524 co-transduction, and in the ESC-like colonies formed (see below), the miR-524-5p level was determined to be double that of the endogenous miR-524-5p levels of ~ 11.9 × 10 [4] copies/cell (data not shown) found in colonies of the OSKM-transduced cells (Fig.   1b). [score:1]
The miR-524-5p -transfected cells also showed ~ 50% significantly higher BrdU incorporation compared to the mock control as in the experiment with TP53INP1 knockdown by siRNA transfection, which also significantly increased BrdU incorporation by 40% (Fig.   5c). [score:1]
The effects of miR-524-5p on oxidative stress -induced apoptosis was further determined by ELISA quantification of the histone -associated DNA fragments in mono- and oligonucleosomes produced during nuclear DNA denaturation of apoptotic cells (Fig.   5e). [score:1]
HFF-1 cells were transduced with pCDH-mir-524 together with the Dox-inducible lentiviral vectors each carrying the human cDNAs encoding one of the four transcription factors OCT4, SOX2, c-MYC, and KLF4 (OSKM), and a constitutively active lentivirus transducing the reverse tetracycline transactivator FUW-m2rtTA (see ). [score:1]
a High degree of sequence homology (bold letters) between miR-524-5p and miR-520d-5p. [score:1]
To investigate the relationship between miR-524-5p and TP53INP1, endogenous TP53INP1 expression in MSC and iPSC lines was first established by RT-PCR (Fig.   3a). [score:1]
This study aimed to elucidate possible contributions of miR-524-5p to the reprogramming process. [score:1]
The ZEB2 or SMAD4 3’-UTR construct was individually transfected into HCT-15 cells alone, or in the presence of miR-524-5p mimic or a NC, which resulted in 40% and 35% reduction of luciferase activity, respectively, when co -transfected with the miR-524-5p mimic (Fig.   6d). [score:1]
A miR-524-5p mimic was transfected to WJ0706 cells for 48 h before the cells were harvested for analysis. [score:1]
However, miR-524-5p was effective in enhancing the OSKM factor -driven reprogramming process. [score:1]
Since both C19MC members including miR-520d-5p and miR-524-5p are highly homologous in sequences and share the same seed sequence (Fig.   1a), the two miRNAs may share similar biological functions. [score:1]
Hence, we hypothesized that miR-524-5p may also play an important role in reprogramming in iPSCs. [score:1]
A miR-524-5p precursor was introduced into human fibroblast HFF-1 in the presence of OSKM, and the relative number of embryonic stem cell (ESC)-like colonies that stained positively with alkaline phosphatase (AP) and Nanog were quantified to determine reprogramming efficiency. [score:1]
It was first noted that miR-524-5p alone was unable to reprogram the normal fibroblast cells tested (data not shown). [score:1]
MirVana miR-524-5p mimic (Cat. [score:1]
The HFF-1 cells were seeded in six-well plates and transduced with individual lentiviruses carrying human m2rtTA, OCT4, SOX2, KLF4, or C-MYC, with or without the miR-524 precursor (System Biosciences, Mountain View, CA, USA). [score:1]
The miR-524-5p miRNA sequence is shown in blue above the TP53IPN1 sequences. [score:1]
The copy number of miR-524-5p was determined as previously described [7]. [score:1]
Furthermore, miR-524-5p shares 19/20 nucleotides with miR-520d-5p (Fig.   1a), suggesting identical biological functions for both miRNAs. [score:1]
The data thus support the notion that miR-524 enhanced OKSM -induced reprogramming of HFF-1 fibroblast cells. [score:1]
a Endogenous transcript levels of miR-524-5p and TP53INP1 in WJ0706 cells. [score:1]
A miR-524-5p mimic was transfected to MSCs to investigate the effects of miR-524-5p on TP53INP1, ZEB2, and SMAD4 expression by real-time polymerase chain reaction (PCR) and Western blot. [score:1]
Interestingly, the TP53INP1 gene may have co-evolved late with the primate-specific miR-524-5p. [score:1]
PCR products of fragments covering the predicted miR-524-5p binding sites in the 3’-UTR of the TP53INP1, ZEB2, and SMAD4 transcripts were cloned at the 3’-end of firefly luciferase gene in the dual reporter vector pmirGLO (GenBank accession FJ376737; Promega, Madison, WI, USA) at the SacI and XbaI restriction sites. [score:1]
Based on the predicted miR-524-5p binding sites (red vertical lines) in the 3’-UTRs of the ZEB2 and SMAD4 transcripts, a 3’-UTR luciferase construct of each gene was generated (boxed) (c). [score:1]
A validated miR-524-5p mimic, or mimic negative control (NC; Ambion), was used in co-transfection with the luciferase wild-type or mutant constructs. [score:1]
In brief, a synthetic mature miR-524-5p oligonucleotide (Integrated DNA Technologies IDT, Coralville, IA, USA) was serially diluted 10-fold to final concentrations between 200 nM and 0.02 pM. [score:1]
Keeping in mind that miR-524-5p belongs to the primate-specific C19MC cluster, the observation may hint at primate-specific co-evolution of the miR-524-5p and TP53INP1 gene sequences. [score:1]
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[+] score: 174
Multivariate Cox regression analysis revealed that miR-524-5p expression, Ki-67 expression and total resection were correlated independently with overall survival when considering gender, KPS score, IDH1 mutation, EGFR expression and PCNA expression (P < 0.3, univariate cox regression analysis). [score:10]
showed that EZH2 expression was down-regulated in glioma cells over -expressing miR-524-5p or miR-324-5p (Figure 3A). [score:8]
As shown in Supplementary Table 1, high expression of miR-524-5p was significantly associated with IDH1 mutation, PCNA expression, but not associated with MGMT promoter methylation. [score:6]
In melanoma cells, miR-524-5p directly interacts with the 3’-untranslated regions of both BRAF and ERK2 to inhibit MAPK/ERK signaling, cell proliferation, and cell migration [23]. [score:6]
We characterize two candidates, miR-524-5p and miR-324-5p, which bind to EZH2 3’UTR to down-regulate EZH2 expression, thereby suppressing glioma cell proliferation. [score:6]
Furthermore, immunohistochemistry assay showed the decreased expression of EZH2 and increased expression of p21 and DKK1 after overexpression of miR-324-5p or miR-524-5p, which were consistent with the in vitro results (Supplementary Figure 1). [score:6]
Of these miRNAs, miR-524-5p and miR-324-5p confered poor prognosis for glioma patients and inhibited glioma cell proliferation by targeting EZH2. [score:5]
Overexpression of miR-524-5p inhibits glioma cell growth in vitro and in vivo. [score:5]
MiR-524-5p and miR-324-5p exhibit a strong tumor-suppressive effect by targeting EZH2. [score:5]
Overexpression of miR-524-5p or miR-324-5p inhibits tumor growth in vitro. [score:5]
Another study has shown that miR-524-5p behaves as a tumor suppressor by negatively targeting Jagged-1 and Hes-1 in gliomas [24]. [score:5]
These data indicate that miR-524-5p or miR-324-5p directly modulated EZH2 expression by binding to the respective 3′UTR. [score:4]
Figure 2Overexpression of miR-524-5p or miR-324-5p inhibits tumor growth in vitro (A) Cells were treated with miR-524-5p or miR-324-5p mimics, and subjected to MTT assay. [score:4]
EZH2 is a direct target of miR-524-5p and miR-324-5p. [score:4]
We found that high expression of miR-524-5p, high KPS score and total resection were statistically associated with overall survival, while IDH1 mutation and MGMT promoter methylation were not associated with overall survival (Table 1). [score:4]
Overexpression of miR-524-5p significantly inhibited glioma cell proliferation in U87 and U251 cells by MTT assay (Figure 2A). [score:4]
Here, we found miR-524-5p is down-regulated in glioma tissues and associated with tumor grade. [score:4]
Taken together, these findings demonstrate that both miR-524-5p and miR-324-5p inhibited glioma malignant progression in vivo. [score:3]
Low expression of miR-524-5p in GBM is determined to be a strong and independent predictor of short overall survival. [score:3]
MiR-524-5p and miR-324-5p target EZH2. [score:3]
Expression of EZH2 overrides miR-524-5p and miR-324-5p function. [score:3]
Accumulating data have been validated that miR-524-5p is a key tumor suppressors in several human cancers. [score:3]
These data indicate that miR-524-5p and miR-324-5p overexpression correlates with a significantly better survival outcome. [score:3]
Further we check miR-524-5p and miR-324-5p expression in 158 glioma tissues. [score:3]
And EZH2 overexpression could reverse miR-524-5p role in TMZ chemosensitivity. [score:3]
MiR-524-5p and miR-324-5p suppress tumor growth in an intracranial xenograft mo del. [score:3]
The MTT assay showed that upregulation of miR-524-5p significantly reduced the viability of U87 and U251 cells after TMZ treatment (Figure 5A). [score:3]
Further a combined index of miR-524-5p and EZH2 expressions better reflects prognosis of glioma patients. [score:3]
Importantly, restoring EZH2 expression could override miR-524-5p and miR-324-5p function in glioma cells. [score:3]
Therefore, we conclude that classification combining miR-524-5p and EZH2 expression represents a more precise biological property and prognosis. [score:3]
Having demonstrated the profound effects of miR-524-5p and miR-324-5p on tumor suppression, we sought to examine the importance of EZH2 in miR-524-5p and miR-324-5p mediated cell proliferation. [score:3]
The samples expressing lower level of miR-524-5p were associated with decreased survival relative to those with higher level in all gliomas (P < 0.0001) and high grade gliomas (grade III and grade IV) (P = 0.0020) (Figure 1C). [score:3]
U87 cells were transfected with lentivirus overexpressing miR-524-5p or miR-324-5p and ontaining a luciferase reporter in vitro for 2 days. [score:3]
Lentivirus overexpressing miR-524-5p and ontaining a luciferase reporter were obtained from genechem (Shanghai, China). [score:3]
These suggest that EZH2 is a critical target of miR-524-5p and miR-324-5p involved in glioma cell proliferation. [score:3]
MiR-524-5p could be used to sub-classify gliomas in combination with EZH2 expression. [score:2]
As shown in Figure 6A, when miR-524-5p was overexpressed, the intracranial tumor significantly decreased compared with the corresponding control group (P < 0.01). [score:2]
MiR-524-5p suppresses tumor growth in an intracranial xenograft mo del. [score:2]
Moreover, GBM demonstrated a significant decrease in miR-524-5p expression compared with that observed in low grade gliomas (P < 0.0001) and anaplastic gliomas (grade III) (P = 0.0227). [score:2]
Over all, these findings suggest that EZH2 specific miRNAs miR-524-5p and miR-324-5p may play an important role in glioma development. [score:2]
Critical role of miR-524-5p and miR-324-5p in glioma cell proliferation. [score:1]
Among them, two miRNAs (miR-524-5p and miR-324-5p), were predicted to bind to EZH2 3’UTR. [score:1]
The level of miR-524-5p was significant lower in high grade gliomas than in low grade gliomas (P < 0.0001) (Figure 1D). [score:1]
In addition, we created pGL3-WT-EZH2-3′UTR and pGL3-MUT-EZH2-3′UTR plasmids for miR-524-5p or miR-324-5p, respectively. [score:1]
Cox regression analyses of miR-524-5p expression and pathologic characteristics in relation to overall survival in GBM. [score:1]
Figure 4 (A) of lysates from cells transfected by miR-524-5p or miR-324-5p mimics alone, or in combination with EZH2 cDNA probed with EZH2 antibody. [score:1]
These suggested that miR-524-5p and miR-324-5p may modulate TMZ resistance in glioma cells. [score:1]
Patients with low levels of miR-524-5p or miR-324-5p had a significantly worse outcome. [score:1]
EZH2 is crucial for miR-524-5p and miR-324-5p signaling in glioma. [score:1]
MiR-524-5p and miR-324-5p increase TMZ chemosensitivity in glioma. [score:1]
EZH2 reduction elevated DKK1 and p21 were elevated when cells were treated by si-EZH2, miR-524-5p and miR-324-5p mimics, as shown in Figure 5B. [score:1]
Thus, we explore whether miR-524-5p and miR-324-5p play key roles in TMZ resistance. [score:1]
MiR-524-5p and miR-324-5p increases TMZ chemosensitivity in glioma. [score:1]
Figure 3 (A) of lysates from cells transfected by miR-524-5p or miR-324-5p mimics probed with EZH2 antibody. [score:1]
Further, miR-524-5p was an independent prognostic factor in GBM patients. [score:1]
High EZH2 and low miR-524-5p in glioma patients was associated with the longest OS (median OS = 460.6 days; logrank test, P < 0.0001). [score:1]
MiR-524-5p and miR-324-5p were identified as key EZH2 specific miRNAs. [score:1]
As shown in Figure 6C, GBM patients with low EZH2 and high miR-524-5p had the longest OS, whereas GBM patients with high EZH2 and low miR-524-5p had the shortest (median OS = 529.6 vs. [score:1]
We transfected miR-524-5p mimics or miR-324-5p mimics together with and without EZH2 plasmid lacking 3′UTR into glioma cells (Figure 4A). [score:1]
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3
[+] score: 97
Other miRNAs from this paper: hsa-mir-494, hsa-mir-500a, hsa-mir-298, hsa-mir-500b
The inferred chondrogenic network implies that mir-524-5p is able to target SOX9 mRNA, thereby inhibiting expression of SOX9 and its target genes (COL2A1, ACAN, COL10A1). [score:9]
The relative expression of SOX9 decreased when mir-524-5p was overexpressed and the control virus (PM_40) remained comparable to the relative expression of the positive control (TGFB1+BMP2). [score:7]
Since miR-524-5p expression is suppressed by the TGF-beta1+BMP2 stimulus, SOX9 expression increases and leads to activation of the differentiation markers COL2A1, ACAN and COL10A1. [score:7]
As seen in the final mo del, the input stimulus (TGF-beta1+BMP2) inhibits the expression of 3 miRNAs (miR-494, miR-524-5p, miR-298) and activates miR-500, which is in turn suppressed by TRPS1. [score:7]
SOX9, the main regulatory factor in chondrogenesis [41], is inhibited by miR-524-5p, a finding which is supported by a predicted miRNA target site (Table 1). [score:6]
Expression data of the validation experiments which investigated the impact of miR-524-5p overexpression on the expression level of SOX9, COL2A1, COL10A1 and ACAN. [score:5]
Therefore, primary chondrogenesis might be under control of miR-524-5p through the modulation of the expression of SOX9 and its target genes. [score:5]
Furthermore, we found expression of miR-524-5p to be differently regulated during osteogenic and adipogenic hMSC differentiation (Additional file 3). [score:4]
By analysing the inferred network, we identified a previously unknown regulatory effect of miR-524-5p on the expression of the transcription factor SOX9 and the chondrogenic marker genes COL2A1, ACAN and COL10A1. [score:4]
In our mo del, its expression is regulated by the stimulus as well as by miR-494 and miR-524-5p. [score:4]
In conclusion, experimental validation showed that lentiviral based overexpression experiments of mir-524-5p in differentiating hMSCs resulted in a significant inhibition of several chondrogenic marker genes compared to either non -transfected hMSCs or transfected with a control lentivirus. [score:4]
The downregulation of miR-524-5p provides an interesting explanation about how chondrogenic differentiation might be modulated on the level of post-transcriptional mRNA interference. [score:4]
Time series of miR-524-5p expression. [score:3]
Click here for file Time series of miR-524-5p expression. [score:3]
The results showed that mir-524-5p overexpression decreases the relative expression of all measured marker genes. [score:3]
Therefore, we performed overexpression experiments of mir-524-5p in hMSCs to validate if chondrogenesis is impaired in this case. [score:3]
Time series of miR-524-5p expression after chondrogenic, osteogenic and adipogenic stimulation of human mesenchymal stem cells. [score:3]
Analysis of the network resulted in hypotheses and additional experiments which verified mo del predictions by showing that miR-524-5p can affect the expression of the central transcription factor gene SOX9 and differentiation marker genes. [score:3]
Those include untreated cells (Incomplete), TGF-beta1+BMP2 -treated cells (TGFB1+BMP2), lentiviral based miR-524-5p overexpression with three different concentrations (Mir-524_20, Mir-524_40, Mir-524_80) and negative control experiments (Jnk RNAi_20, Jnk RNAi_40, Jnk RNAi_80, PM_40). [score:3]
Four miRNAs (miR-524-5p, miR-494, miR-298 and miR-500) were found to be potentially involved in the regulation of chondrogenesis. [score:2]
This indicates that the repression of miR-524-5p activity may be relevant for lineage specificity during hMSC differentiation. [score:1]
Nodes represent either a miRNA (miR-524-5p, miR-494, miR-298, miR-500), a transcription factor gene (SOX9, MEF2C, TRPS1, SATB2) or a chondrogenic marker gene (COL2A1, COL10A1, ACAN). [score:1]
In addition, hMSCs were transfected with mir-524-5p lentivirus and the empty pMIRNA backbone (PM_40) vector lentivirus (as negative control) and, subsequently, cells were allowed to differentiate for 14 days prior RNA qPCR analysis. [score:1]
Then, cells were transfected using lentivirus containing either the empty pMIRNA backbone vector (control) or pMIRNA vector with mir-524-5p premature DNA sequences (purchased from System Biosciences). [score:1]
In summary, the applied multi-step selection procedure resulted in a set of 11 network components, including 4 miRNAs (miR-524-5p, miR-494, miR-298 and miR-500), 4 transcription factor genes (SOX9, TRPS1, MEF2C and SATB2) and 3 chondrogenic marker genes coding for components of the extracellular matrix (COL2A1, ACAN and COL10A1). [score:1]
The interaction with miR-494 is underpinned by prior knowledge (blue connection in Figure 4), but surprisingly there is also a predicted binding site for miR-524-5p within the TRPS1 mRNA. [score:1]
Previous studies have reported that miR-524-5p is active in glioma cells and interacts with two components of the Notch signalling pathway [45]. [score:1]
For this, hMSCs were transfected with lentivirus harbouring the mir-524-5p coding sequence, while a non-related murine Jnk RNAi lentivirus was used as a negative control. [score:1]
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4
[+] score: 66
Finally, miR-524-5p and miR-582-3p (down-regulated in sALS; Table  2 and Additional file 1: Table S1) induced an up-regulatory effect on the NFL 3′UTR-L (p < 0.001), and NFL 3′UTR-S (p < 0.001), -M (p < 0.001) and –L (p < 0.01; Figure  2), respectively. [score:7]
This reduced expression of miRNAs that can up-regulate NFL (such as miR-524-5p and miR582-3p) further supports our previous observations that NFL mRNA is selectively decreased in ALS. [score:6]
In our studies, we observed that two miRNAs whose expression levels were down-regulated in sALS (miR-524-5p and miR-582-3p) induced an increase of the reporter linked to the NFL mRNA 3′UTR. [score:6]
It is interesting that miR-146a*, miR-524-5p and miR-582-3p sites in the NFL mRNA 3′UTR are not conserved across species and all of them showed consistent results making them prime candidates for the down-regulation of NFL mRNA expression in the SC in ALS. [score:6]
All of our results demonstrate that a pool of three functionally relevant miRNAs capable of interacting with NFL mRNA 3′UTR, miR-146a*, miR-524-5p and miR-582-3p, are dysregulated in sALS, suggesting their participation in the regulation of NFL mRNA expression in mammalian cells. [score:5]
MiR-146a*, miR-524-5p and miR-582-3p directly regulate NFL expression. [score:5]
In fact, two mutations within any of the three MREs analyzed (miR-146a*, miR-524-5p and miR-582-3p) further destabilized target recognition, yielding less favorable ΔGs (Figure  4B). [score:4]
Our results demonstrate that three miRNAs that are dysregulated in sALS (miR-146a*, miR-524-5p and miR-582-3p) are capable of interacting with NFL mRNA 3′UTR in a manner that is consistent with the suppressed steady state mRNA levels observed in spinal motor neurons in ALS. [score:4]
Figure 3 MiR-146a*, miR-524-5p and miR-582-3p regulate the expression of NFL mRNA 3′UTR. [score:4]
Figure 4 Mutations in the recognition elements of miR-146a*, miR-524-5p and miR-582-3p reveal a direct regulation of the miRNA on luciferase transcripts coupled to the NFL 3′UTR. [score:4]
Our data demonstrate that miR-146a*, miR-524-5p and miR-582-3p are able to directly regulate the NFL 3′UTR (Figure  4C). [score:3]
Therefore, miR-146a*, miR-524-5p and miR-582-3p showed consistent results in the reporter gene assay and the relative quantitative RT-PCR, making them prime candidates for the negative regulation of NFL mRNA expression in the SC in ALS. [score:3]
In addition, 7 miRNAs were expressed in controls and not in sALS [miR-624 (p < 0.001); miR-520e, miR-524-5p, miR-548a-5p, miR-606, miR-612, miR-647(p < 0.05)] (Table  2). [score:3]
To study whether the regulatory effect of miR-146a*, miR-524-5p and miR-582-3p on the NFL 3′UTR was direct or indirect, we developed 3′UTR mutants of each MRE to test them with the reporter gene assay. [score:3]
Our data suggest a potential role of miR-146a*, miR-524-5p and miR-582-3p in the selective decrease of NFL mRNA observed in ALS that could contribute to the etiology of neurofilamentous aggregates and the pathology of ALS. [score:1]
showed that miR-146a* was able to decrease the level of firefly luciferase mRNA fused with NFL 3′UTR-M (p < 0.01; Figure  3), while miR-524-5p and 582-3p were able to increase the level of luciferase mRNA coupled to NFL 3′UTR-L (p < 0.01) and NFL 3′UTR-S (p < 0.001), -M (p < 0.001) and –L (p < 0.001), respectively (Figure  3). [score:1]
It is important to note that some miRNAs have MREs within the three NFL 3′UTRs reported, -S, -M and –L (e. g. miR-23a), others within NFL 3′UTR-M and –L (e. g. miR-146a*) and one miRNA has a single recognition element within the NFL 3′UTR-L (miR-524-5p; Table  5, Figure  1B). [score:1]
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5
[+] score: 26
Each scatter spot representing average normalized expression level of miRNA in three repeats of each treatment; (b) 13 miRNAs exhibiting aberrant expression in Jurkat cells cultured with TNF-α (20 ng/mL) for 7 days; (c) decreased expression of miR-139-3p, miR-204, miR-760, miR-524-5p, miR-136, miR-548d-3p, miR-214, miR-383, and miR-887 in RA T cells miRNA, compared with normal T cells. [score:6]
The expression levels of 12 miRNAs, including miR-139-3p, miR-204, miR-760, miR-432, miR-524-5p, miR-136, miR-548d-3p, miR-206, miR-214, miR-383, miR-224, and miR-887 were significantly lower, whereas the expression level of miR-146a was significantly higher, in Jurkat cells after being cultured with TNF-α for 7 days (fold change > 4, p < 0.05, Fig.   1b). [score:5]
Initially, our studies showed that among the expression of T cell miRNAs affected by TNF-α in Jurkat cells, the expression levels of miR-139-3p, miR-204, miR-760, miR-383, miR-524-5p, miR-136, miR-548d-3p, and miR-214 were significantly decreased in RA T cells. [score:5]
In addition, it is of interest to note that the expression level of miR-524-5p was increased in T cells from patients with systemic lupus erythematosus [37], but decreased in those from patients with RA. [score:3]
Decreased expression of miR-139-3p, miR-204, miR-760, miR-524-5p, miR-136, miR-548d-3p, miR-214, miR-383, and miR-887 were noted in RA T cells. [score:3]
The fold changes of expression levels for these miRNAs were 0.42-fold for miR-139-3p, 0.43-fold for miR-204, 0.13-fold for miR-760, 0.32-fold for miR-524-5p, 0.45-fold for miR-136, 0.19-fold for miR-548d-3p, 0.37-fold for miR-214;0.36-fold for miR-383, and 0.14-fold for miR-887, compared with controls. [score:2]
The expression of miR-139-3p, miR-204, miR-760, miR-524-5p, miR-136, miR-548d-3p, miR-214, miR-383, and miR-887 was found to be significantly lower in RA T cells (p < 0.05), compared with controls (Fig.   1c). [score:2]
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6
[+] score: 14
Eight miRNAs (miR-183, miR-193a-5p, miR-222, miR-516b, miR-524-5p, miR-601, and miR-629, 99b) were upregulated and five miRNAs (miR-124, miR-32, miR-574-5p, miR-744, and miR-96) were downregulated. [score:7]
miR-184, miR-524-5p, miR-629, and miR-766 were upregulated, while miR-124, miR-222, miR-32, miR-744, and miR-765 were downregulated [28]. [score:7]
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7
[+] score: 13
We have shown the top TFs and its related diseases for rhesus inter-species in Table  5. Besides these, mml-miR-338-5p, mml-miR-218, mml-miR-495, mml-miR-203, mml-miR-590-3p, mml-miR-596, mml-miR-548p, and mml-miR-524-5p have connection with “an auto immune disease like SIV” [52], Huntintong’s Disease [53], Age mediated skeletal muscle contamination [54], Enhances Coxsackievirus B3 replication [55], Neuro inflammation Disorder [56], Schizophernia [57], monkey hippocampus effected [58], and Amyotrophic lateral sclerosis [59], respectively. [score:7]
For example, a TF namely ZNF423 is connected with Joubart’s Syndrome in human, and TF namely SP1 is associated with “Disrupt in early Huntington’s disease” in human, whereas hsa-miR-34c-5p is responsible for Bipolar disorder and Schizophenia in human, and miR-524-5p is associated with Amyotrophic lateral sclerosis in human. [score:3]
Following that, miR-19b, miR-19a, miR-520d-5p, miR-524-5p, miR-519b-5p, miR-519a, miR-519c-3p, miR-495, miR-944 and miR-664 regulate 121, 119, 130, 130, 109, 109, 109, 102, 138, 123 genes, respectively. [score:2]
, miR-524-5p and miR-495) are known (i. e., known to both human and rhesus), and remaining eight miRs (viz. [score:1]
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8
[+] score: 9
We previously demonstrated that the expression of five microRNAs (miR-181d, miR-518b, miR-524-5p, miR-566 and miR-1227) were correlated with the survival of glioblastoma patients [12]. [score:3]
Additionally, we demonstrated that the expression profile of miR-566 as well as that of four other miRNAs (miR-181d, miR-518b, miR-524-5p and miR-1227) correlated with the prognosis of glioblastoma patients [12]. [score:3]
We previously identified a group of microRNAs (miR-21, miR-23b, miR-27b and miR-524-5p) that regulate proliferation, invasion and apoptosis in glioma [8- 11]. [score:2]
Previous studies have clarified the functions of the miR-181 family, miR-518b, miR-524-5p and miR-1227. [score:1]
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9
[+] score: 9
Furthermore, expression of the Group B miR-524-5p, and all three Group C miRNAs was detected in CRL-1790, which was derived from normal fetal colon epithelium (Fig.   1c). [score:3]
To obtain further supporting evidences on selective activation, expression of eight miRNAs spanning the C19MC cluster (Fig.   1a), but with different genomic structures, was selected for further experimentally verification; amongst the selected miRNAs, miR-512-3p is transcribed by the two miR-512-1 and-512-2 genes located at the 5’-end of the C19MC miRNA gene cluster; miR-520c-3p, -519b-3p and -520f-3p are single miRNA genes located between previously proposed exons; miR-524-5p and -517a-3p are two of three miRNA genes mapped on intron 18 and miR520d-5p and -520g-3p are two of four miRNAs mapped on intron 20 (Fig.   1a) [24]. [score:3]
Notably, the miR-524-5p and -517a-3p and the miR520d-5p and -520g-3p couples are flanked by two proposed exons but belong to different expression groups B and C (Fig.   1a). [score:3]
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10
[+] score: 8
MiR-524-5p was shown to directly bind to the 3′-UTR of both BRAF and ERK2 and to suppress the expression of these proteins in melanoma cells [100]. [score:5]
Because BRAF and ERK2 are main components of the RAS-MAPK pathway, the decreased expression of miR-524-5p in melanomas could mediate tumor proliferation and cell migration in melanomas. [score:3]
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11
[+] score: 7
Liu et al. revealed that miR-524-5p could inhibit cell migration and tumor proliferation and suppressed their activities in melanoma by targeting MAPK1 and BRAF through MAPK/ERK signaling pathway [44]. [score:7]
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12
[+] score: 5
Results showed that miR-323b-5p, miR-221-3p, miR-524-5p, and miR-188-3p were underexpressed in albuminuric relative to nonalbuminuric patients, while miR-214-3p, miR-92b-5p, hsa-miR-765, hsa-miR-429, miR-373-5p, miR-1913, and miR-638 were overexpressed [71]. [score:5]
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13
[+] score: 3
Among these miRNAs, miR-518b, miR-518c, miR-519b, miR-519c, miR-520a, miR-520c, miR-520e, miR-520g, and miR-524* are over-expressed in undifferentiated hES cells [24, 26, 29]. [score:3]
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14
[+] score: 2
Several miRNA were reported as regulators of BRAF in different cancers such as miR-524-5p in melanoma, miR-143 and miR-145 in CRC [42, 43]. [score:2]
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15
[+] score: 1
In a small-scale analysis, others found that a group of miRNAs that are altered by hypoxia in trophoblasts (miR-27a, miR-30d, miR-141, miR-200c, miR-424, miR-205 and miR-451, miR-491, miR-517a, miR-518b, miR-518e, and miR-524) is elevated in FGR pregnancies (n = 14 FGR versus n = 14 controls) [47]. [score:1]
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16
[+] score: 1
Top 10 miRNAs [d] : miR-335-3p, miR-26a-2-3p, miR-181d-5p, miR-509-5p, miR-524-5p, miR-137, miR-26a-1-3p, miR-595, miR-580-3p, miR-130a-3p EV: extracellular vesicles [a]miRNAs in bold type were also found within the top 20 miRNAs of the current experiment [b]miRNA names are converted to miRBase version 21.0 annotation version 16.0 [c]miRNA names converted from unspecified earlier version [d]miRNA names converted from miRBase version 13.0. [score:1]
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