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.
Highlights
Esophageal squamous cell carcinoma (ESCC) is one of the most common and fatal cancers in the word, showing a relatively high morbidity in Asian, especially in China [1]
We found that carriers of the rs4245739 AC and CC genotypes had a 0.65-fold decreased risk to develop ESCC compared to the AA genotype carriers (Trend test, P = 1.661024) (Table 2)
Because tobacco smoking and alcohol drinking are predisposing factors for ESCC, we investigated whether a gene– environment interaction existed between the MDM4 rs4245739 polymorphism and these risk factors (Table 3)
Summary
Esophageal squamous cell carcinoma (ESCC) is one of the most common and fatal cancers in the word, showing a relatively high morbidity in Asian, especially in China [1]. Recent progresses on genome-wide association studies (GWAS) underscore the direct genetic contribution of single nucleotide polymorphisms (SNPs) to ESCC risk, as well as the genetic contribution to ESCC through interaction with the abovementioned environmental causes [4,5,6,7,8,9]. MDM2, a key regulator of P53 tumor suppressor pathway, can directly bind to P53 protein, inhibit its activity and lead to its degradation via the ubiquitination pathway [14,15]. As the structurally homologous protein of MDM2, MDM4 is a negative regulator of P53 and cooperates with MDM2 to inhibit P53 activity in cellular response to DNA damage [16,17]. Spontaneous tumorigenesis in transgenetic mice overexpressing MDM4 did show that MDM4 is a bona fide oncogene in vivo cooperating with P53 [19]
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