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13 publications mentioning hsa-mir-4728

Open access articles that are associated with the species Homo sapiens and mention the gene name mir-4728. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 180
Top 250 down regulated genes from a microarray experiment of miR-4728-3p overexpression were filtered for IS and CS target sites respectively. [score:6]
F. Distribution of duplex energies of 3' UTRs containing IS target sites comparing genes down regulated by miR-4728-3p overexpression (t-statistics of <-4, TRUE) with unaffected genes (t-statistics ≥4, FALSE). [score:6]
The vectors were transfected into the miR-4728-3p expressing, HER2+/ER+ cell line BT-474, to test if endogenously expressed miRNAs could use the IS and regulate the reporter. [score:6]
To study its function, we transfected miR-4728-3p mimics into MCF 10A, a normal-like breast epithelial cell line normally not expressing mir-4728, and analyzed global effects on gene expression using microarrays. [score:5]
Furthermore, this anti-correlation is more pronounced among HER2+ tumors, which is probably the consequence of miR-4728-3p reaching the concentration levels required for target suppression. [score:5]
Conventional bioinformatic predictions using TargetScan and DIANA micro-T [31] failed to detect any miR-4728-3p CS target sites in ESR1 and deep sequencing of HER2+ BC tumors showed no evidence of 5′-end truncated isomiRs (Fig. 1C), so we searched our AGO-CLIP data for support for an IS-ESR1 interaction. [score:5]
But while down regulation of genes carrying canonical seed (CS) 2–8 target sites was the most prominent feature in the miR-1 control experiment (Figure S1 in File S1, middle panel), CS matches were only the third most enriched word for miR-4728-3p. [score:4]
Figure 1F shows the distribution of duplex energies of 3′ UTRs with IS 6-mer matches comparing down regulated genes with those carrying IS matches but unaffected by miR-4728-3p overexpression. [score:4]
To investigate the regulation of ESR1 by the miR-4728-3p IS target site experimentally, we cloned a fragment of the ESR1 3' UTR containing the target region downstream of a Firefly luciferase reporter gene. [score:4]
To exclude that the observed down regulation of ESR1 proceeds through these pathways rather than by miR-4728-3p -mediated repression, we assessed total HER2 expression as well as levels of activated pMAPK1 and pAKT in our experiments. [score:4]
These results support the existence of a functional internal seed region at positions 6–12 and suggest that miR-4728-3p is a bimodal miRNA that may alternate between seed regions 2–8 and 6–12 to specifically down regulate different target gene sets. [score:4]
Here, miR-4728-3p down-regulates ESR1 to around 70% (Fig. 4F). [score:4]
We furthermore demonstrate that miR-4728-3p down regulates expression of ESR1 through an internal seed interaction. [score:4]
Here we show that HER2 amplification may lead to ESR1 down-regulation through the IS activity of miR-4728-3p and that miR-4728-3p is even more anti-correlated to ESR1 than is HER2 in our sample set. [score:4]
We also examined the nature of miR-4728-3p target gene interactions among the down regulated genes detected by microarrays. [score:4]
Repression of WT ESR1 construct by endogenous miR-4728-3p (left) is alleviated by an antisense oligo (AS) against endogenous miRNA (right) but not by a non -targeting control (middle). [score:3]
Sequencing reads of mir-4728 in cell lines with endogenous expression (BT-474, JIMT1 and SKBR3), mimic -transfected MCF 10A (Mimic) and tumors are given to the right as percentages of total miR-4728-3p reads. [score:3]
When examining the reported miR-30a overexpression data [28] (GEO accession #GSE29921) we found that the strongest signal corresponded to the IS match at positions 6–12 (Fig. 3), demonstrating that the functionality of the IS region is not exclusive for miR-4728-3p. [score:3]
A. SylArray enrichment landscape plots for 6-, 7- and 8-mer words (from top to bottom) for ranked genes from a microarray experiment of miR-4728-3p overexpression in MCF 10A. [score:3]
IS targeting is not restricted to miR-4728-3p. [score:3]
The main isoform of miR-4728-3p is 24-26nt long and interacts with its targets through an internal seed. [score:3]
By investigating the effects of miR-4728-3p on global expression data we found that it functions as a bimodal miRNA, controlling different target gene sets depending on the region used for interaction; involving either a canonical seed in positions 2–8 or nt 6–12 of the miRNA. [score:3]
To exclude the need of extensive compensatory base-paring outside the IS, we predicted the thermodynamic stability of hybrid formation between miR-4728-3p and its targets using RNAduplex [23]. [score:3]
IGV view (Integrative Genomics Viewer) showing the enrichment of AGO-CLIP sequencing reads in miR-4728-3p transfected vs non -transfected control around the IS target site on the 3′UTR of the Ubiquitin carboxyl-terminal hydrolase 1 (USP1) gene. [score:3]
Calibrated Normalized Relative Quantity (CNRQ) of miR-4728-3p (left) and HER2 (right) is plotted against expression levels of ESR1. [score:3]
These results show that the regulation of ESR1 does not proceed through an indirect effect on these pathways and confirm that a miR-4728-3p IS interaction functionally connects the two major BC biomarkers. [score:3]
To confirm the physical interaction between IS and target mRNA, we applied AGO-CLIP to MCF 10A cells transfected with miR-4728-3p mimic and matched controls. [score:3]
0097200.g001 Figure 1 A. SylArray enrichment landscape plots for 6-, 7- and 8-mer words (from top to bottom) for ranked genes from a microarray experiment of miR-4728-3p overexpression in MCF 10A. [score:3]
In lieu of applying routine target prediction algorithms, we then performed a motif search on microarray data from six biological replicates 32 hours after transfection of miR-4728-3p and controls including miR-1. We identified over-represented stretches of consecutive bases (“words”) in the 3' untranslated regions (UTRs) of genes from ranked gene lists and calculated the statistical significance of their enrichment using SylArray [22]. [score:3]
Although sufficient to affect ESR1, miR-4728-3p activity exerts a limited effect on expression levels of estrogen responsive genes in our experimental set up (data not shown). [score:3]
We have shown that miR-4728-3p can use positions 6-12 instead of the canonical 2-8 seed sequence for interaction with its targets. [score:3]
We used TargetScan Custom 5.2 [12] and submitted the 7-mer miR-4728-3p IS as seed sequence. [score:3]
In accordance with these results, blocking endogenous miR-4728-3p with antisense 2′-O-methyl oligonucleotides in HER2+/ER+ BT-474 and HER2+/ER- HCC1954 cells (both endogenously expressing miR-4728-3p, see Fig. S4 in File S1) resulted in an increase of ESR1 protein levels (Fig. 4E and 4F). [score:3]
This clinically very relevant interaction would have passed undetected if current rules for miRNA function had been applied for miR-4728-3p target prediction. [score:3]
The two main isoforms of ESR1 (47 and 66 kDa), plotted as percentage of control signal of matching size, are down regulated upon transfection of miR-4728-3p mimics. [score:2]
This suggests that while miR-4728-3p activity alone may not result in tamoxifen resistance, it adds an additional layer of regulation to the highly complex interplay of ESR1 and HER2 in BC. [score:2]
We show here that endogenous miR-4728-3p regulates ESR1 and that the long isoforms responsible for this IS interaction are the most common isomiRs found in HER2+ BC cell lines. [score:2]
Total amounts of HER2, pMAPK1 and pAKT1 mostly remain unchanged at this time point (Fig. 4D and 4E, left) and any observed changes rather indicated a slight decrease in MAPK1 upon miR-4728-3p up regulation. [score:2]
B. Luciferase assay in BT-474 with ESR1 3′UTR constructs carrying either wild type target site of miR-4728-3p internal seed (WT) or mutated internal seed site (MUT). [score:2]
miR-4728-3p IS regulates ESR1. [score:2]
miR-4728-3p is encoded within one of the most important BC oncogenes, so we wanted to evaluate the clinical relevance of target gene regulation by the IS. [score:2]
miR-4728-3p IS regulation connects the HER2 and ESR1 pathways. [score:2]
Anti-correlation of HER2 and ESR1 could not be confirmed in our small sample set (Spearman rho −0.149, p = 0.541) but, interestingly, anti-correlation was evident between miR-4728-3p and ESR1 (Spearman rho −0.495, p = 0.033) (Fig. 4A), hinting at the possibility of transcription independent of its host gene or a specific regulated processing. [score:2]
ESR1 isoform of 47 kDa is up regulated under miR-4728-3p blocking. [score:2]
Western blotting showed that overexpression of miR-4728-3p in Her2-/ER+ MCF7 cells decreased ESR1 protein compared to transfection with a negative control (Fig. 4C). [score:2]
ESR1 is up regulated when blocking endogenous miR-4728-3p with AS-oligonucleotides, while pMAPK and pAKT remain largely unchanged. [score:2]
0097200.g004 Figure 4 A. qRT-PCR analysis of ESR1 and HER2 transcripts and miR-4728-3p among a panel of 38 breast cancer tumors (19 HER2+, 19 HER2-). [score:1]
Total RNA from miR-4728-3p transfected and untransfected MCF10A cells was prepared with TriZol reagent (Life Technologies) according to the manufacturer's instructions. [score:1]
Reads mapping to miR-4728-3p were analyzed in the processing from the 5′ end. [score:1]
C. Alignment of small RNA sequencing reads to miR-4728-3p genomic context. [score:1]
Indeed, we recently identified mir-4728 [7], a microRNA (miRNA) encoded in intron 24 of the HER2 gene. [score:1]
A total of 777 regions were associated with either CS (nt 2–7, n = 449) or IS (nt 6–11, n = 328) miR-4728-3p binding. [score:1]
To prove that this repression is associated with miR-4728-3p, we blocked the endogenous miR-4728-3p with 2′-O-methyl antisense oligonucleotides which released the repression of the ESR1 3' UTR as expected (Fig. 4B, right). [score:1]
D. MCF7 cells were transfected with indicated concentrations of miR-4728-3p mimic. [score:1]
All miRNA mimics were purchased from Qiagen; the customized mimics corresponding to the mature sequence of miR-4728-3p (25 nt) and a 25 nt control. [score:1]
IS usage beyond miR-4728-3p. [score:1]
We speculated that a truncated miR-4728-3p, shortened by four nt at its 5' end, would convert positions 6–12 into a canonical nt 2–8 seed. [score:1]
We therefore measured the expression of miR-4728-3p, HER2 and ESR1 in a set of 19 Her2- and 19 Her2+ breast tumors by qPCR. [score:1]
A. qRT-PCR analysis of ESR1 and HER2 transcripts and miR-4728-3p among a panel of 38 breast cancer tumors (19 HER2+, 19 HER2-). [score:1]
To further clarify this point, we analyzed the distribution of sequenced miR-4728-3p 5′-ends obtained by crosslinking immunoprecipitation from AGO2 complexes (AGO-CLIP) in MCF 10A cells transfected with miR-4728-3p mimics. [score:1]
The most common miR-4728-3p isomiRs in HER2+ cells are 24-26 nt in length with the longest isomiR ending in a non-templated U, probably the product of post-transcriptional uridylation [35]. [score:1]
We therefore concluded that the IS enrichment detected by SylArray was not caused by CS matches of a truncated miR-4728-3p mimic. [score:1]
This sequence has no complementarity to any CS deposited in miRBase 20, suggesting the use of an alternative seed for miR-4728-3p. [score:1]
In our previous work we showed that the dominant mature form of mir-4728 is the one derived from the 3' arm of the precursor; miR-4728-3p [7]. [score:1]
To exclude this possibility we performed a northern blot analysis with total RNA extracted from miR-4728-3p mimic transfected cells (Fig. 1B). [score:1]
Blots were hybridized with [32]P-labeled miR-4728-3p probe for 16 hours in 7% SDS, 200 mM Na [2]HPO [4] (pH 7.2), 1 mM EDTA and 1x Denhardt's solution at 40°C. [score:1]
B. Northern blot of total RNA from cells A) untransfected and B) transfected with miR-4728-3p mimics with a radiolabeled miR-4728-3p probe. [score:1]
With this in mind, we decided to study miR-4728-3p function without applying prior knowledge of the interaction mode or requirements for evolutionary conservation. [score:1]
The two main 5′ isomiRs detected for miR-4728-3p were between 24–25 nt long and displayed the canonical 5′ end or a second one shortened by one base (Fig. 1C). [score:1]
In fact, a cumulative distribution function of signals from array probes detecting 3′ UTRs carrying only CS matches (n = 1752), only IS matches (n = 1078) or both (n = 307) shows that the two seeds act independently of one another and that IS sites are sufficient for miR-4728-3p -guided repression (Fig. 1D). [score:1]
Repression of ESR1 3′UTR by miR-4728-3p indicates a new mechanism for cross-talk between the HER2 and estrogen pathways. [score:1]
Regardless of these speculations, the proven IS activity of miR-4728-3p may have interesting clinical implications. [score:1]
Thermodynamic stability of hybrid formation between targets and miR-4728-3p was calculated using RNAduplex from the Vienna package. [score:1]
Aligning the IS regions of miR-4728-3p and other miRNAs from published data failed to identify a clear IS consensus sequence. [score:1]
Control lane shows signal from synthetic miR-4728-3p RNA and the ethidium bromide staining in the lower panel shows tRNA bands as loading control. [score:1]
We checked the correct 5′-end processing of miR-4728-3p in these cells by deep sequencing of RNAs co-immunoprecipitated with AGO2 (Fig. 1C). [score:1]
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2
[+] score: 141
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-mir-21, hsa-mir-122
GSEA of predicted target genes for miR-21-5p from TargetScan in the microarray data also confirmed significant enrichment of targets among upregulated genes in SK-BR-3 upon blocking of miR-4728-3p at 48 and 96 h (FDR = 0.0014 and 0.0011, respectively, see Supplementary Fig. S4). [score:10]
TargetScan lists one predicted target site for miR-4728-3p in the PAPD5 3′ untranslated region (UTR), suggesting a putative direct link, although repeated assays failed to show consistent functionality for this target site (data not shown). [score:9]
This analysis showed significant enrichment of TargetScan-predicted miR-4728-3p targets among upregulated genes at both time points in SK-BR-3 (FDR < 0.001 and 0.035, respectively, see Supplementary Fig. S2b), again confirming the experimental approach. [score:8]
Since mir-4728 is lowly expressed in most tissues and amplification or overexpression of HER2 increase the cellular concentration above a functional threshold 8, inhibition of mir-4728 and the mir-4728/PAPD5/miR-21-5p circuit could act as an anti-HER2 cancer therapy that is selectively active in HER -positive cancer cells. [score:7]
Although differential expression was more modest in BT-474, we observed a clear trend of PAPD5 upregulation upon miR-4728-3p blocking (Fig. 1b). [score:6]
Blocking miR-4728-3p leads to downregulation of miR-21-5p and inhibition of cell proliferation. [score:6]
These results indicate that this pro-proliferative process is restricted to HER2 -positive cells where miR-4728-3p expression is up-regulated. [score:6]
Blocking miR-4728-3p does not interfere with expression of HER2 and overexpression of full-length HER2 or a truncated, intracellular form (p95) increases transcription of mir-21. [score:5]
Since mir-4728 has been suggested to regulate factors downstream of HER2 9, we wanted to test if HER2 signalling could control PAPD5 and thus cause the observed downregulation of miR-21-5p upon blocking of miR-4728-3p. [score:5]
We also demonstrate that inhibition of miR-4728-3p results in a significant decrease in cell proliferation, implying that this miRNA contributes to the oncogenic activity of the HER2 locus by sustaining proliferation through inhibition of miR-21-5p degradation. [score:5]
This regulatory circuit establishes a new oncogenic role for the HER2 locus through the intronically encoded miRNA mir-4728 that is not currently being targeted by any anti-HER2 therapy. [score:4]
Upregulation of PAPD5 in HER2 -positive breast cancer cell lines treated with miR-4728-3p ASO was confirmed by real-time qRT-PCR for both time points with a doubling of mRNA abundance 48 hours after ASO transfection in SK-BR-3 (Fig. 1a). [score:4]
We found that neither miR-21-3p nor any of the pri- or pre-miRNA fragments were affected by blocking miR-4728-3p and that the observed downregulation was specific for mature miR-21-5p (Supplementary Fig. S3b). [score:4]
Resting mouse T cells display increased adenylation and degradation of miR-21-5p in low molecular weight protein fractions inactive in regulation of gene expression and a mo del summarizing the oncogenic circuit linking HER2, miR-4728-3p and mir-21. [score:4]
Blocking miR-4728-3p upregulates PAPD5, which mediates degradation of miR-21-5p. [score:4]
We reasoned that if miR-4728-3p acts in concert with HER2 to increase the level of miR-21-5p, the latter should be up-regulated in HER2-like tumours compared to other breast cancer subtypes, while the adenylation and degradation ratios should decrease. [score:3]
To confirm that the observed effect on PAPD5 was mediated by miR-4728-3p we repeated the ASO treatment in HeLa cells that do not express mir-4728 and PAPD5 levels remained unchanged (Supplementary Fig. S3a). [score:3]
Moreover, this shows that the PAPD5 -mediated trimming pathway is independent of HER2 receptor signalling, suggesting that the pro-proliferative action of miR-4728-3p on HER2 -positive cells cannot be targeted by anti-HER2 drugs. [score:3]
To verify the action of this treatment we cloned a 3′ untranslated region (UTR) with perfect complementarity to miR-4728-3p downstream of a firefly luciferase gene in a reporter vector. [score:3]
The effect of co -targeting mir-4728 on alleviating some of these issues as well as blocking its pro-proliferative action would be interesting to study. [score:3]
Expression of PAPD5 mRNA increased at both 48 and 96 h after blocking of miR-4728-3p by transfection of a 2′- O-methyl -modified antisense oligonucleotide in the HER2 -positive breast cancer cell lines SK-BR-3 (a) and BT-474 (b). [score:3]
This effect was not observed in HER2 -negative MCF10A cells that do not express mir-4728 (Supplementary Fig. S5). [score:3]
As expected, transfection of this vector showed that the presence of a miR-4728-3p target site in the 3′ UTR reduced luciferase activity through the action of endogenous miR-4728-3p and that co-transfection with miR-4728-3p ASO reverted this repression (Supplementary Fig. S2a). [score:3]
miR-4728-3p controls miR-21-5p expression and cell proliferation independently of HER2 receptor signalling. [score:3]
Here we show that regulation of miR-21-5p by this pathway is controlled by the HER2-encoded miRNA mir-4728. [score:2]
In summary, the HER2 growth factor receptor induces a signalling cascade that increases transcription of mir-21, while miR-4728-3p blocks PAPD5, a negative regulator of miR-21-5p stability. [score:2]
The number of differentially expressed genes was considerably smaller in BT-474 compared to SK-BR-3 upon miR-4728-3p ASO treatment (125 and 412 genes at 48 h, respectively; cut-off log [2] fold change ± 0.5 and adjusted P < 0.05). [score:2]
For luciferase assays, two DNA oligonucleotides corresponding to a perfectly complementary target site for miR-4728-3p were phosphorylated, annealed and ligated between the SacI and SalI sites of the pmirGLO plasmid (Promega). [score:2]
This confirms a role for miR-4728-3p in the regulation of miR-21-5p through the PAPD5/PARN pathway. [score:2]
miR-4728-3p activity in HER2 -positive cells regulates PAPD5. [score:2]
We first assessed miR-21-5p levels independently of isoform by real-time qRT-PCR in SK-BR-3 cells and total miR-21-5p levels were reduced when blocking miR-4728-3p (Fig. 1c). [score:1]
In a previous study 6, we observed that miR-4728-3p was the main mature product of the HER2-encoded mir-4728 precursor. [score:1]
We therefore focused on miR-4728-3p and selected two HER2 -positive breast cancer cell lines, SK-BR-3 and BT-474, to block miRNA function by transfecting 2′- O-methyl -modified antisense oligonucleotides (ASOs). [score:1]
MicroRNA-4728 is a 5′ tailed half-mirtron with its 3′ end coinciding with the 5′ splice site of the HER2 exon 24 (NM_004448.3). [score:1]
The transfected cDNA clones produce the respective HER2 variant, but not the intronically encoded miR-4728-3p, allowing us to functionally separate the effects of miRNA and host gene. [score:1]
Interestingly, STAT3 mRNA levels increased upon blocking of miR-4728-3p in our experiments. [score:1]
We reasoned that if miR-4728-3p affected PAPD5/PARN tailing-and-trimming, this should only change the levels of miR-21-5p while miR-21-3p and other parts of the primary mir-21 transcript should remain unchanged. [score:1]
Regardless of whether it occurs exclusively through miR-21-5p, our work uncovered an oncogenic role for miR-4728-3p in sustaining proliferative signalling in a pathway that is independent of the HER2 receptor. [score:1]
To test this idea we transfected miR-4728-3p ASOs in SK-BR-3 cells again, but this time in combination with trastuzumab. [score:1]
Real-time qRT-PCR analysis showed that HER2 mRNA levels remained unchanged upon miR-4728-3p ASO treatment in the two cell lines (Fig. 2a,b). [score:1]
Since mir-4728 piggybacks transcription of HER2 and, as shown above, the two genes work together in an orchestrated manner, blocking HER2 signalling exclusively could unbalance some functions of mir-4728. [score:1]
Furthermore, a western blot for HER2 showed that also protein levels were unaffected by miR-4728-3p ASO treatment (Fig. 2c,d). [score:1]
HER2 mRNA levels remained constant upon treatment of SK-BR-3 (a) and BT-474 (b) cells with the miR-4728-3p antisense oligonucleotide. [score:1]
As shown in Fig. 1f,g, blocking miR-4728-3p resulted in a significant decrease in proliferation rate in both cell types. [score:1]
How to cite this article: Newie, I. et al. HER2-encoded miR-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5. [score:1]
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3
[+] score: 31
Other miRNAs from this paper: hsa-mir-4429, hsa-mir-4492
As an empirical example, we identified PADI2 as a novel risk gene of RA that could be a potential therapeutic target, as well as the miRNA that suppresses PADI2 protein expression (miR-4728-5p) 2 30. [score:7]
miR-4728-5p suppresses PADI2 protein expression, a novel RA risk gene as a potential therapeutic target. [score:7]
As an empirical example, we focused on PADI2 at 1p36 pointed by multiple miRNAs (miR-4492 at 11q23 and miR-4728-5p at 17q12) in the context of the RA GWAS, as inhibition of this drug target gene is considered to be promising for treatment of autoimmune diseases 33. [score:6]
We functionally confirmed that miR-4728-5p suppresses PADI2 protein expression levels through direct binding to the 3′ UTR region. [score:6]
We note that the RA risk SNPs in these loci were not located on the seed or target sequences of miR-4728-5p. [score:3]
Luciferase reporter plasmids and 10 nmol/L of miRNAs (miR-Negative Control [NC], miR-4429 or miR-4728-5p; Thermo Fisher Scientific, Waltham, MA) were co -transfected in HeLa cells using Lipofectamine 2000 (Thermo Fisher Scientific) according to the manufacturer’s instrument. [score:1]
MiR-4728-5p was located in the previously reported RA risk loci at 17q12 (Supplementary Figure 5), while cis-eQTL effects of the regional SNPs on miR-4728-5p was not publicly available. [score:1]
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4
[+] score: 19
Differential expression of RNAseq data identified 12 miR with changes in relative expression during follicular trachoma, of which 9 were confirmed as differentially expressed by qPCR (miR-155, miR-150, miR-142, miR-181b, miR-181a, miR-342, miR-132, miR-4728 and miR-184). [score:7]
MiR-184 and miR-4728 were down-regulated in TF independently of Ct infection. [score:4]
MiR-184 and miR-4728 were down-regulated during follicular trachoma in the absence of Ct. [score:4]
We found that miR-184 and miR-4728-3p were down-regulated in follicular trachoma irrespective of Ct infection. [score:4]
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5
[+] score: 15
Focusing on the miRNAs able to target different genes at the same time, we evidenced that the genes are targeted by twelve following miRNAs: hsa-miR24-3p, hsa-miR-6778-5p, hsa-miR-6514-3p, hsa-miR-5010-5p, hsa-miR-23a-5p, hsa-miR-25-5p, hsa-miR-6792-5p, hsa-miR-6866-5p, hsa-miR-4728-5p, hsa-miR-6825-5p, hsa-miR-6803-3p, hsa-miR-6794-5p (Table 2 and Figure 4). [score:5]
Hsa-miR-4728-5p is a negative regulator of MAPK correlated with a negative overall survival in breast cancer [112] and was found as a tumour suppressor in the ulcerative colitis associated with colon cancer [113]. [score:4]
Pekow J. Hutchison A. L. Meckel K. Harrington K. Deng Z. Talasila N. Rubin D. T. Hanauer S. B. Hurst R. Umanskiy K. miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis -associated Colorectal Neoplasia Through Regulation of Focal Adhesion SignalingInflamm. [score:4]
Schmitt D. C. Madeira da Silva L. Zhang W. Liu Z. Arora R. Lim S. Schuler A. M. McClellan S. Andrews J. F. Kahn A. G. ErbB2-intronic MicroRNA-4728: A novel tumor suppressor and antagonist of oncogenic MAPK signalingCell Death Dis. [score:2]
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6
[+] score: 14
Only two of the differentially expressed miRNAs in our study are directly processed by the spliceosome (miR-3605-5p and miR-4728-5p), and we found an intergenic miRNA (let-7i-5p) to be significantly downregulated in the SF3B1 mutated samples. [score:7]
Except for one mirtron (miR-4728-5p) all of these miRNAs were intragenic canonical miRNAs transcribed in the same direction as their host genes and downregulated in the mutated samples. [score:5]
Only five miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, miR-335-5p, and miR-4728-5p) were differentially expressed in SRSF2 mutated compared to wild-type MDS samples. [score:2]
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7
[+] score: 7
It has been only observed in patients with myelodysplastic syndrome that SF3B1 and SRFS2 mutations are associated with a downregulated expression of miRNAs derived from the putative 5′-tailed mirtrons hsa-miR-3605-5p and hsa-miR-4728-5p, respectively [5]. [score:7]
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8
[+] score: 6
MiRNA subtypes, including miR-548d-3p, miR-559, miR-125a, miR-125b, miR-205, miR-155 and miR-4728, target ERBB2 and are downregulated in cancers [17– 20]. [score:6]
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9
[+] score: 4
Nineteen of the downregulated miRNAs in chronic patients were found to be associated with carcinogenesis in various organs and tissues, such as miR-1207 [40], miR-3162-5p [41, 42], miR-3196 [43, 44], miR-371b-5p [45], miR-574-5p [46, 47], miR-1225-5p [48], miR-4485 [49], miR-572 [50], miR-4299 [51], miR-3679-5p [52], miR-3940-5p [53], miR-638 [54, 55], miR-1202 [56], miR-5787 [57], miR-1973 [58], miR-4532 [59], miR-1275 [60], miR-4728-5p [61], and miR-1915-3p [62]. [score:4]
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10
[+] score: 2
All these information are exemplified for the oncogene ERBB2 containing mir-4728 (Figure 2). [score:1]
Figure 2. A summary of the main information presented in miRIAD for the coding gene ERBB2 and its intragenic mir-4728. [score:1]
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11
[+] score: 1
[6] Although miR-101 has been linked to MKP-1, many other miRNAs have been associated with various components of immune response, [6] suggesting that other miRNAs also might be related to MKP-1. Both miR-4728 and miR-564 have been shown to be an antagonist of MAPK signaling in breast cancer. [score:1]
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[+] score: 1
This motif is a perfect seed match for ten human miRNAs; miR-7106-5p, miR-6883-5p, miR-6799-5p, miR-6785-5p, miR-4728-5p, miR-6887-5p, miR-6885-5p, miR-6799-5p, miR-328-5p and miR-149*. [score:1]
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[+] score: 1
hsa-miR-2355-3p2.000.001622hsa-miR-133b4.300.009926hsa-miR-451a2.200.0108517hsa-miR-4664-3p4.310.000228hsa-miR-130b-3p2.300.0462722hsa-miR-44314.350.003682hsa-miR-486-5p2.320.002088hsa-miR-4804-3p4.360.000235hsa-miR-361-5p2.330.04722Xhsa-miR-18b-3p4.620.00191Xhsa-miR-3156-3p2.500.0072910hsa-miR-675-3p4.680.0002811hsa-miR-4728-3p2.670.0002917hsa-miR-550b-3p4.720.013827hsa-miR-3191-5p2.670.0002019hsa-miR-551a4.750. [score:1]
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