Functional Haplotypes in the Promoter of Matrix Metalloproteinase-2 Predict Risk of the Occurrence and Metastasis of Esophageal Cancer

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Abstract
Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer development and aggression. Our previous studies revealed a strong association between the MMP-2 −1306C/T polymorphism and risk of several cancers. A novel −735C/T polymorphism in MMP-2 promoter has been identified but the function is undefined. This study examined our hypothesis that these two polymorphisms might have functional relevance and impact on risk of esophageal squamous cell carcinoma in the context of haplotype. Genotypes and haplotypes were analyzed in 527 cases and 777 controls and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The function of the polymorphisms was examined by electrophoretic mobility shift assays, luciferase gene expression assays, and reverse transcriptase-PCR analyses. It was found that the −735C→T transition disrupts an Sp1 site and displays a lower promoter activity. The C-1306–C-735 haplotype had 7-fold increased luciferase expression and 3.7-fold increased MMP-2 mRNA levels in esophageal tissues compared with the T-1306–T-735 haplotype. A case-control analysis revealed a 1.52-fold (95% CI = 1.17–1.96) or 1.30-fold (95% CI = 1.04–1.63) excess risk of developing esophageal squamous cell carcinoma for the −1306CC or −735CC genotype carriers compared with noncarriers, respectively. A greater association was observed between elevated risk of developing esophageal squamous cell carcinoma and C-1306 or C-735 allele containing haplotypes, with the risk being highest for the C-1306–C-735 haplotype compared with the T-1306–T-735 haplotype (OR = 6.53; 95% CI = 2.78–15.33). The C-1306–C-735 haplotype was also associated with increased risk for distant metastasis of esophageal squamous cell carcinoma (OR = 3.34; 95% CI = 1.16–9.63). These findings suggest that the C-1306–C-735 haplotype in the MMP-2 promoter contributes to risk of the occurrence and metastasis of esophageal squamous cell carcinoma by increasing expression of MMP-2.