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A polymorphism at the microRNA binding site in the 3' untranslated region of RYR3 is associated with outcome in hepatocellular carcinoma.

ABSTRACT: OBJECTIVE:MicroRNAs can bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with the translation of targeting genes, thereby regulating cell differentiation, apoptosis, and tumorigenesis. In this study, three microRNA binding site single nucleotide polymorphisms (SNPs) located in the 3' UTR of RYR3 (rs1044129), C14orf101 (rs4901706), and KIAA0423 (rs1053667) were genotyped to assess their relationships with the risks and outcomes of hepatocellular carcinoma (HCC). METHODS:The SNPs were genotyped with the ligation detection reaction method. Renilla luciferase reporter assays were used to measure the binding affinity between microRNA 367 and RYR3. Survival curves were calculated using the Kaplan-Meier method, and comparisons between the curves were made using the log-rank test. Multivariate survival analysis was performed using a Cox proportional hazards model. RESULTS:It was found that rs1044129 at the 3' UTR of RYR3 was related to postoperative survival in HCC, with the AA type associated with longer survival times as per the log-rank test. After adjusting with the Cox model, rs104419 was identified as an independent predictor of HCC survival (relative risk: 1.812; 95% confidence interval: 1.026-3.201; P=0.041). Luciferase analysis also indicated the different binding affinities between the SNPs of rs1044129 and microRNA 367. CONCLUSION:The SNP in the microRNA binding site of RYR3 can be used as a valuable biomarker when predicting HCC outcomes.

SUBMITTER: Peng C

PROVIDER: S-EPMC4539090 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A polymorphism at the microRNA binding site in the 3' untranslated region of RYR3 is associated with outcome in hepatocellular carcinoma.

Peng Chenxing C Guo Zhanjun Z Wu Xiaoyan X Zhang Xiao-Lan XL

OncoTargets and therapy 20150810

<h4>Objective</h4>MicroRNAs can bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with the translation of targeting genes, thereby regulating cell differentiation, apoptosis, and tumorigenesis. In this study, three microRNA binding site single nucleotide polymorphisms (SNPs) located in the 3' UTR of RYR3 (rs1044129), C14orf101 (rs4901706), and KIAA0423 (rs1053667) were genotyped to assess their relationships with the risks and outcomes of hepatocellular carcinoma ...[more]

PMID: 26309413

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Project description:The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3' untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3' UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3' UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3' UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment.

Dataset Information

A polymorphism at the microRNA binding site in the 3' untranslated region of RYR3 is associated with outcome in hepatocellular carcinoma.

Publications

A polymorphism at the microRNA binding site in the 3' untranslated region of RYR3 is associated with outcome in hepatocellular carcinoma.

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