Dataset Information

Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Sun R

PROVIDER: S-EPMC5669908 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer.

Sun Ruifen R Liang Yundan Y Yuan Fang F Nie Xinwen X Sun Hong H Wang Yanyun Y Yu Tao T Gao Linbo L Zhang Lin L

Oncotarget 20170731 47

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 expr ...[more]

PMID: 29137282

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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.

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.

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Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer.

Publications

Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer.

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