title: Genetic polymorphism at miR-181a binding site contributes to gastric cancer susceptibility.
abstract: Recent evidences show that genetic polymorphisms falling in miRNA binding sites can alter the strength of miRNA binding and disturb miRNA-mediated posttranscriptional regulation. Our study aimed to investigate the role of single-nucleotide polymorphisms (SNPs) in putative miRNA binding sites in gastric cancer (GC). Based on microarray and quantitative reverse transcription PCR analyses, we found that miR-181a was significantly upregulated in GC tissues. Bioinformatics survey was used to explore SNPs within miR-181a binding sites. Three SNPs were genotyped in a case-control study (500 cases and 502 controls). The T allele genotypes (rs12537CT and TT) of MTMR3 were found associated with significantly increased GC risk [adjusted odds ratio 1.72, 95% confidence interval (CI) 1.36-2.16, P = 3.99×10(-5)] and poor overall survival [hazard ratio (HR) 1.38, 95% CI 1.03-1.83, P = 0.029], although they were not an independent prognostic factor in multivariate Cox regression analysis (HR 1.28, 95% CI 0.95-1.72, P = 0.11). We further demonstrated that the rs12537CT genotype carriers had lower MTMR3 mRNA expression levels than CC genotype carriers in GC tissues (P = 0.013), whereas no significant difference in miR-181a expression levels was found (P = 0.135). Luciferase assay revealed that miR-181a directly targeted MTMR3, and its suppressive effect was enhanced when the rs12537C allele was substituted by T variant, although the difference was not significant (P = 0.055). Our study suggested that rs12537 is associated with susceptibility and prognosis of GC in southern Han Chinese, and miR-181a and its target gene MTMR3 play important roles in GC.
authors.affiliation: Department of Gastroenterology, Guangzhou Key Laboratory of Digestive Disease, Guangzhou First Municipal People's Hospital, Guangzhou Medical University,  Guangzhou 510180, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Nie
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Li
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Du
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.forename: Yuyuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C444436:MTMR3 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor