MDM2 and its functional polymorphism SNP309 contribute to the development of esophageal carcinoma

Abstract

Background: Overexpression of the murine double minute 2 (MDM2) has been explored in many tumors with high proliferation and anti-apoptosis ability.However, the role of MDM2 and its functional single nucleotide polymorphism (SNP) rs2279744 (also known as SNP309) in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods:We performed a genotype study of blood samples in 360 ESCC patients and 360 healthy control individuals to determine the risk of various rs2279744 in ESCC. To further evaluate the role of rs2279744 in regulating MDM2 expression, we performed an allele-specific reporter assay and investigated whether the SNPcontaining sequences functioned as an active enhancer. To examine the functional role of MDM2 on esophageal cancer cell lines, we carried out an MTS assay and flow cytometry analysis.Results: From the genotyping study, we found that GG genotype of SNP309 significantly increased the risk of ESCC in an additive model [odds ratio (OR) = 2.55, 95% confidence interval (CI) = 1.66-3.89, p = 1.50 × 10 -5 ) and in a recessive model (OR = 2.44, 95% CI = 1.69-3.51, p = 1.60 × 10 -8 ). Furthermore, the G allele was significantly associated with a higher risk of ESCC (OR = 1.56, 95% CI = 1.26-1.92, p = 2.81 × 10 -5 ). In multivariate logistic regression analysis, the GG genotype had increased the occurrence of ESCC by 2.39-fold (95% CI = 1.48-3.8). Compared to the T allele, the variant G allele had significantly higher luciferase activity on the promoter of MDM2 in both cell lines. By transfecting the gene to ESCC lines, we showed that overexpression of MDM2 significantly promote cell proliferation and anti-apoptosis. Conclusions:The MDM2 promoter SNP309 is a risk factor for esophageal cancer.MDM2 promotes the proliferation and anti-apoptosis of ESCC.

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

“…MDM2 contribution to SCC tumorigenesis seems to be particularly relevant in ESCCs patients where MDM2-positive lesions show a shorter overall survival [48,49]. In addition, a promoter polymorphism (SNP309) that enhances the binding affinity of the Sp1 transcription factor and results in elevated levels of MDM2 protein is a risk factor to ESCC and is associated with poorly differentiated and advanced forms of this type of cancer [50].…”