title: Association of a genetic variation in a miR-191 binding site in MDM4 with risk of esophageal squamous cell carcinoma.
abstract: As an oncoprotein, MDM4 plays a key part in P53 tumor suppressor pathway through negatively regulating P53 function. It has been reported that an rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets consisted of 1128 ESCC cases and 1150 controls from two regions of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The impact of the polymorphism on MDM4 expression was examined with esophagus tissues. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased ESCC risk compared with the AA genotype in both case-control sets (Jinan set: OR = 0.54, 95% CI = 0.35-0.82, P = 0.004; Huaian set: OR = 0.68, 95% CI = 0.45-0.99, P = 0.049). Stratified analyses revealed that a multiplicative interaction between rs4245739 and smoking or drinking was evident (Gene-smoking: P(interactioin) = 0.022; gene-drinking: P(interactioin) = 0.032). After detecting In vivo MDM4 mRNA expression, we found that the rs4245739 AC and CC genotype carriers had significantly decreased MDM4 expression in normal esophagus tissues compared with AA genotype carriers, indicating a consistent genotype-phenotype correlation. Our results elucidate that the MDM4 rs4245739 polymorphism contributes to susceptibility of ESCC and support the hypothesis that genetic variants, interrupting miRNA-mediated gene regulation, may modify cancer risk.
authors.affiliation: Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China.
authors.forename: Liqing
authors.initials: L
authors.lastname: Zhou
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Li
authors.forename: Changchun
authors.initials: C
authors.lastname: Zhou
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Tang
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Helou
authors.initials: H
authors.lastname: Li
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Yuan
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; C546177:MIRN191 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger