Association of MMP7 −181A→G Promoter Polymorphism with Gastric Cancer Risk

• Published in: The Journal of biological chemistry Vol. 290; no. 23; pp. 14391 - 14406
• Main Authors: Kesh, Kousik, Subramanian, Lakshmi, Ghosh, Nillu, Gupta, Vinayak, Gupta, Arnab, Bhattacharya, Samir, Mahapatra, Nitish R., Swarnakar, Snehasikta
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.06.2015
• Subjects: association study; cAMP response element-binding protein (CREB); gastric cancer; MMP7; nicotine; promoter; single-nucleotide polymorphism (SNP); transcription factor; transcription factor; nicotine; cAMP response element-binding protein (CREB); MMP7; gastric cancer; association study; promoter; single-nucleotide polymorphism (SNP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.630129

Elevated expression of matrix metalloproteinase7 (MMP7) has been demonstrated to play a pivotal role in cancer invasion. The −181A→G (rs11568818) polymorphism in the MMP7 promoter modulates gene expression and possibly affects cancer progression. Here, we evaluated the impact of −181A→G polymorphism on MMP7 promoter activity and its association with gastric cancer risk in eastern Indian case-control cohorts (n = 520). The GG genotype as compared with the AA genotype was predisposed (p = 0.02; odds ratio = 1.9, 95% confidence interval = 1.1–3.3) to gastric cancer risk. Stratification analysis showed that tobacco addiction enhanced gastric cancer risk in GG subjects when compared with AA subjects (p = 0.03, odds ratio = 2.46, and 95% confidence interval = 1.07–5.68). Meta-analysis revealed that tobacco enhanced the risk for cancer more markedly in AG and GG carriers. Activity and expression of MMP7 were significantly higher in GG than in AA carriers. In support, MMP7 promoter-reporter assays showed greater transcriptional activity toward A to G transition under basal/nicotine-induced/cAMP-response element-binding protein (CREB) overexpressed conditions in gastric adenocarcinoma cells. Moreover, nicotine (a major component of tobacco) treatment significantly up-regulated MMP7 expression due to enhanced CREB phosphorylation followed by its nuclear translocation in gastric adenocarcinoma cells. Furthermore, chromatin immunoprecipitation experiments revealed higher binding of phosphorylated CREB with the −181G than the −181A allele. Altogether, specific binding of phosphorylated CREB to the G allele-carrying promoter enhances MMP7 gene expression that is further augmented by nicotine due to increased CREB phosphorylation and thereby increases the risk for gastric cancer. Background: Effect of tobacco carcinogen nicotine on MMP7 transcription and gastric cancer risk remains unknown. Results: Preferential binding of pCREB, induced by nicotine, to G-allele promoter enhanced the transcription and thus aggravated gastric cancer risk. Conclusion: Nicotine shows an additive effect over MMP7 GG genotype toward gastric cancer risk. Significance: These findings may help in the clinical management of gastric cancer.