Association Between Single Nucleotide Polymorphisms In The Matrix Metalloproteinase-2 Promoter And Risk Of Development And Metastasis Of Lung Cancer And Esophageal Cancer

Matrix metalloproteinase-2 (MMP-2) plays an important role in several steps of cancer development. The expression of MMP-2 is regulated by transcriptional factors including AP-2 and Sp1. It has been shown that sequence variation in the promoter is an important factor affecting gene transcription. Several single nucleotide polymorphisms (SNPs) have been identified in the MMP2 promoter. However, the biological significance of these SNPs is not all known. This study was to explore the functions of -735C→T, alone and in combination with -1306C→T, and to examine the association between these SNPs and risk of development and metastasis of lung cancer and esophageal cancer.To examine the functional significance of these SNPs in vitro and in vivo, luciferase report gene assay, electrophoretic mobility shift assay, and reverse transcriptase-PCR analysis were performed. The results showed that the -735C/T polymorphism locates within a consensus sequence of Spl binding site, and the C→T transition disrupts the binding of Spl, thus causing lower promoter activity of the T allele. The C_-1306-C_-735 haplotype-containing promoter drove 7-fold increased luciferase gene expression compared with that driven by the T_-1306-T_-735 haplotype-containing promoter. Subjects with the -1306CC genotype or C_-1306-C_-735 haplotype had 5- or 3.7-fold increased MMP2 mRNA levels in their esophageal tissues compared with those with the other genotypes or haplotypes.Because of functional significance of these two SNPs, we therefore conducted a case-control study to examine the hypothesis that they might be associated with risk of development and metastasis of lung cancer and esophageal cancer. On the basis of analysis of 770 lung cancer cases and 527 esophageal cancer cases and 777 controls, we observed a significant association between these two MMP2 polymorphisms and the...