Correction to: A functional polymorphism in the promoter of miR-17-92 cluster is associated with decreased risk of ischemic stroke.
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ABSTRACT:
SUBMITTER: Huang H
PROVIDER: S-EPMC6886212 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Correction to: A functional polymorphism in the promoter of miR-17-92 cluster is associated with decreased risk of ischemic stroke.
Huang Huatuo H Wei Guijiang G Wang Chunfang C Lu Yulan Y Liu Chunhong C Wang Rong R Shi Xiang X Yang Jun J Wei Yesheng Y
BMC medical genomics 20191202 1
Following publication of the original article [1], it was reported that during the production process, Fig. 3b was omitted from the final article. ...[more]
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Project description:BACKGROUND:The microRNA-17-92 (miR-17-92) cluster is one of the most extensively studied miRNA clusters. Abnormal expression of the cluster has been found to play important role in different kinds of human diseases, including ischemic stroke (IS). The aim of our study was to investigate the association between three polymorphisms (rs1491034, rs9301654 and rs982873) in the promoter of the miR-17-92 cluster and risk of IS. METHODS:Three hundred and ninety-eight patients with IS and 397 control subjects were included. The genotypes of the three polymorphisms were determined by Snapshot SNP genotyping assay. Relative expression of the cluster in peripheral blood mononuclear cells (PBMCs) of cases and controls were examined by quantitative real-time PCR. RESULTS:Significant association between rs9301654 polymorphism and risk of IS were observed basing on genotype, model and allele analyses (GA vs. AA: adjusted OR?=?0.63, 95% CI: 0.41~0.97, P?=?0.037; GG vs. AA: adjusted OR?=?0.23, 95% CI: 0.07~0.78, P?=?0.018; GA?+?GG vs. AA: adjusted OR?=?0.57, 95% CI: 0.38~0.87, P?=?0.009; GA?+?AA vs. GG: adjusted OR?=?0.27, 95% CI: 0.08~0.89, P?=?0.032; G vs. A: adjusted OR?=?0.58, 95% CI: 0.40~0.83). Haplotype analysis showed that TGC and TGT haplotypes were associated with decreased risk of IS (OR?=?0.59, 95% CI: 0.40~0.87, P?=?0.007 for TGC haplotype; OR?=?0.21, 95% CI: 0.06~0.75, P?=?0.009 for TGT haplotype). Importantly, we found the expression of miR-17-5p was significant higher while miR-19a-3p was significant lower in patient with IS compared with the control group (P?<?0.01), and patients with rs9301654GG or GA genotype displayed lower level of miR-19a-3p compared with the AA genotype (P?<?0.01). CONCLUSIONS:Our findings indicated that rs9301654 polymorphism in the promoter of miR-17-92 cluster may be associated with susceptibility of IS in the Chinese population. However, we found that rs9301654 polymorphism and its respective gene expression did not demonstrate consistent association with IS in the Chinese population. Further studies such as gene-gene interaction are warranted to reveal the role of miR-19a and its regulatory genes in the etiology of IS.
| S-EPMC6839137 | biostudies-literature
Project description:MiR-17-92 cluster is an oncogenic miRNA cluster that is implicated in several cancers, although its role in hepatocarcinogenesis has not been clearly defined. In this study, we show that the miR-17-92 cluster is highly expressed in human hepatocellular carcinoma (HCC) tissues compared to the non-tumorous liver tissues by RT-PCR and in situ hybridization analyses. Increased miR-17-92 cluster expression in HCC tissues was further confirmed by analysis of the RNA-sequencing data of 319 patients available from the Cancer Genome Atlas (TCGA) Data Portal (https://tcga-data.nci.nih.gov/tcga/). To create an animal model that resembles enhanced miR-17-92 in the liver, we developed liver-specific miR-17-92 transgenic mice and the animals were treated with the hepatic carcinogen, diethylnitrosamine (DEN). We observed that the liver-specific miR-17-92 transgenic mice showed significantly increased hepatocellular cancer development compared to the matched wild-type control mice. Forced overexpression of the miR-17-92 cluster in cultured human hepatocellular cancer cells enhanced tumor cell proliferation, colony formation and invasiveness in vitro, whereas inhibition of the miR-17-92 cluster reduced tumor cell growth. By analyzing the miRNA and mRNA sequencing data from the 312 hepatocellular cancer patients available from the TCGA database, we observed that the expression levels of the miR-17-92 cluster members and host gene in the tumor tissues are negatively correlated with several target genes, including CREBL2, PRRG1, NTN4. Our findings demonstrate an important role of the miR-17-92 cluster in hepatocarcinogenesis and suggest the possibility of targeting this pivotal miRNA cluster for potential therapy.
| S-EPMC4794620 | biostudies-literature
Project description:miR-17-92 cluster is identified as a potential oncogenic miRNA. The aim of this study was to investigate the association of polymorphisms in the promoter region of miR-17-92 cluster with the risk of colorectal cancer (CRC). Three polymorphisms (i.e., rs9588884, rs982873 and rs1813389) in the promoter of miR-17-92 were analyzed among 874 cases and 1132 controls using a TaqMan allelic discrimination assay or a polymerase chain reaction-restriction fragment length polymorphism method. Relative expression of miR-17-92 was examined among CRC tumors and noncancerous tissues using quantitative reverse transcription-PCR. Transcriptional activities were measured using dual-luciferase reporter assay. We found a significantly reduced CRC risk with the rs9588884 (GG vs. CC: adjusted OR = 0.46, 95% CI, 0.35-0.62; dominant model: adjusted OR = 0.72, 95% CI, 0.59-0.86; recessive model: adjusted OR = 0.53, 95% CI, 0.40-0.69) and the rs982873 (CC vs. TT: adjusted OR = 0.60, 95%CI, 0.46-0.80; recessive model: adjusted OR = 0.62, 95% CI, 0.49-0.80). Haplotype analysis showed that the GCG haplotype had a decreased risk for CRC compared to the CTA haplotype (adjusted OR = 0.67, 95% CI, 0.57-0.79). The rs9588884 GG displayed a lower level of miR-20a and the rs982873 CC displayed a lower level of miR-17. Additionally, the rare allele of rs9588884 G and the rs982873 C revealed a reduced luciferase activity. These findings indicate that the rs9588884 GG and the rs982873 CC in the promoter of miR-17-92 may protect against CRC, possibly by decreasing transcriptional activity and eventually resulting in lower levels of miR-20a and miR-17.
| S-EPMC5669908 | biostudies-literature
Project description:Enterovirus 71 (EV71), the etiological agent of hand-foot-and-mouth disease, has become an increasing public health challenge worldwide. Accumulating evidence suggests that mammalian microRNAs (miRNAs), a class of non-coding RNAs of 18 to 24 nucleotides (nt) with important regulatory roles in cellular processes, participate in host antiviral defense and studies have suggested roles of miRNAs in EV71 replication and pathogenesis. In the current study, we reported that the expression of hsa-miR-17∼92 cluster was significantly downregulated during EV71 infection. Overexpression of hsa-miR-17∼92 inhibited, while inhibition of endogenous hsa-miR-17∼92 facilitated EV71 replication. We identified two sequences located at nt 3024 to 3038 and nt 2838 to 2862 of the EV71 (strain FY0805) genome as potential targets for hsa-miR-17-5p and miR-19a/b, respectively, which were validated by luciferase reporter assays and Western blot. Meanwhile, we identified DNA methylation as a novel mechanism of hsa-miR-17∼92 regulatory roles. The methylation of the miR-17-92 promoter was significantly increased (50%) upon EV71 infection, which appeared to be caused by the increased expression of DNMT3B but not DNMT1 and DNMT3A. Furthermore, we demonstrated that the members of miR-17-92 cluster were decreased in the sera of EV71 infected patients, suggesting the clinical implication and the potential therapeutic application of miR-17-92.
| S-EPMC6447709 | biostudies-literature
Project description:Background and purposeMultipotent mesenchymal stromal cell (MSC) harvested exosomes are hypothesized as the major paracrine effectors of MSCs. In vitro, the miR-17-92 cluster promotes oligodendrogenesis, neurogenesis, and axonal outgrowth. We, therefore, investigated whether the miR-17-92 cluster-enriched exosomes harvested from MSCs transfected with an miR-17-92 cluster plasmid enhance neurological recovery compared with control MSC-derived exosomes.MethodsRats subjected to 2 hours of transient middle cerebral artery occlusion were intravenously administered miR-17-92 cluster-enriched exosomes, control MSC exosomes, or liposomes and were euthanized 28 days post-middle cerebral artery occlusion. Histochemistry, immunohistochemistry, and Golgi-Cox staining were used to assess dendritic, axonal, synaptic, and myelin remodeling. Expression of phosphatase and tensin homolog and activation of its downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β in the peri-infarct region were measured by means of Western blots.ResultsCompared with the liposome treatment, both exosome treatment groups exhibited significant improvement of functional recovery, but miR-17-92 cluster-enriched exosome treatment had significantly more robust effects on improvement of neurological function and enhancements of oligodendrogenesis, neurogenesis, and neurite remodeling/neuronal dendrite plasticity in the ischemic boundary zone (IBZ) than the control MSC exosome treatment. Moreover, miR-17-92 cluster-enriched exosome treatment substantially inhibited phosphatase and tensin homolog, a validated miR-17-92 cluster target gene, and subsequently increased the phosphorylation of phosphatase and tensin homolog downstream proteins, protein kinase B, mechanistic target of rapamycin, and glycogen synthase kinase 3β compared with control MSC exosome treatment.ConclusionsOur data suggest that treatment of stroke with tailored exosomes enriched with the miR-17-92 cluster increases neural plasticity and functional recovery after stroke, possibly via targeting phosphatase and tensin homolog to activate the PI3K/protein kinase B/mechanistic target of rapamycin/glycogen synthase kinase 3β signaling pathway.
| S-EPMC5330787 | biostudies-literature
Project description:Medulloblastoma, originating in the cerebellum, is the most common malignant brain tumor in children. Medulloblastoma consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH medulloblastomas exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared with granule progenitors and postmitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting locked nucleic acid (LNA)-modified anti-miR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH medulloblastomas. We found that tumor cells (medulloblastoma cells) passively took up 8-mer LNA-anti-miRs and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by anti-miR-17 and anti-miR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of anti-miR-17 and anti-miR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-anti-miRs might be considered for the treatment of SHH medulloblastomas.
| S-EPMC3857104 | biostudies-literature
Project description:Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors.
| S-EPMC4981532 | biostudies-literature
Project description:The expression of miR-143/miR-145 was up-regulated in ischemic stroke (IS), which may be used as biomarkers and/or therapeutic targets for IS. We aimed to investigate the association of rs4705342 and rs4705343 polymorphisms in the promoter of miR-143/145 with risk of IS. The study population comprised 445 patients with IS and 518 controls. The rs4705342 genotype was analyzed by using a TaqMan Assay and the rs4705343 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. Relative expression of miR-143/miR-145 was measured by quantitative real-time PCR. We found that the rs4705342 was associated with a decreased risk of IS (TC vs. TT: adjusted OR?=?0.74, 95% CI, 0.57-0.97; CC vs. TT: adjusted OR?=?0.53, 95% CI, 0.34-0.83). Haplotype analysis showed that the TC haplotype was associated with an increased risk of IS risk (OR?=?1.33, 95% CI, 1.01-1.75), whereas the CT haplotype was associated with a decreased risk of IS risk (OR?=?0.68, 95% CI, 0.50-0.92). Importantly, patients carrying the rs4705342TC/CC genotypes had a lower level of miR-145 (P?=?0.03). We found for the first time that the rs4705342 CC was a protective factor for IS, probably by reducing the level of miR-145.
| S-EPMC5052611 | biostudies-literature
Project description:MicroRNA (miRNA) biogenesis is tightly regulated to maintain distinct miRNA expression patterns. Almost half of mammalian miRNAs are generated from miRNA clusters, but this process is not well understood. We show here that Serine-arginine rich splicing factor 3 (SRSF3) controls the processing of miR-17-92 cluster miRNAs in pluripotent and cancer cells. SRSF3 binding to multiple CNNC motifs downstream of Drosha cleavage sites within miR-17-92 is required for efficient processing of the cluster. SRSF3 depletion specifically compromises the processing of two paralog miRNAs, miR-17 and miR-20a. In addition to SRSF3 binding to the CNNC sites, the SRSF3 RS-domain is essential for miR-17-92 processing. SHAPE-MaP probing demonstrates that SRSF3 binding disrupts local and distant base pairing, resulting in global changes in miR-17-92 RNA structure. Our data suggest a model where SRSF3 binding, and potentially its RS-domain interactions, may facilitate an RNA structure that promotes miR-17-92 processing. SRSF3-mediated increase in miR-17/20a levels inhibits the cell cycle inhibitor p21, promoting self-renewal in normal and cancer cells. The SRSF3-miR-17-92-p21 pathway operates in colorectal cancer, linking SRSF3-mediated pri-miRNA processing and cancer pathogenesis.
| S-SCDT-10_15252-EMBR_202256021 | biostudies-other
Project description:The loss and damage of podocytes is an early feature of diabetic nephropathy (DN). The miR-17?92 cluster was dysregulated in diabetic and polycystic kidney disease patients, but its role in DN is unclear. Hence, an in vitro study on the high glucose- (HG-) treated mouse podocytes (MPC5) was designed to elucidate the effect of miR-17?92 cluster downregulation on cell viability, apoptosis, inflammation, fibrosis, and podocyte function. The results suggested that the miR-17?92 cluster members miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a were upregulated in the renal biopsy tissue of DN patients and HG-treated MPC5. The downregulation of the miR-17?92 cluster effectively suppressed the cell apoptosis, inflammation, fibrosis, and podocyte dysfunction in HG-stimulated MPC5 cells. The bioinformatics analysis and rescue experiments showed that ABCA1 (ATP-binding cassette transporter A1) is an effector of the miR-17~92 cluster. Silence of ABCA1 inhibited the protective effect of the miR-17?92 cluster downregulation on podocyte damage. In summary, this research indicated that the downregulation of the miR-17?92 cluster ameliorates HG-induced podocyte damage via targeting ABCA1.
| S-EPMC7391105 | biostudies-literature