Association of MMP7-181A/G promoter polymorphism with gastric cancer risk: Influence of nicotine in differential allele-specific transcription via increased phosphorylation of CREB [Gene Regulation]

April 6th, 2015 by Kesh, K., Subramanian, L., Ghosh, N., Gupta, V., Gupta, A., Bhattacharya, S., Mahapatra, N. R., Swarnakar, S.

Elevated expression of matrix metalloproteinase7 (MMP7) has been demonstrated to play a pivotal role in cancer invasion. The −181A/G (rs11568818) polymorphism in MMP7 promoter modulates gene expression and plausibly affects cancer progression. Here, we evaluated the impact of −181A/G polymorphism in MMP7 promoter activity and its association with gastric cancer risk in eastern Indian case-control cohorts (n=520). The GG genotype as compared to the AA genotype was predisposed (p=0.02; OR=1.9, 95% CI=1.1-3.3) to gastric cancer risk. Stratification analysis showed that tobacco addiction enhanced gastric cancer risk in GG in comparison to AA genotype (p=0.03, OR=2.46, 95% CI=1.07-5.68). Meta-analysis revealed that tobacco enhanced the risk for cancer more pronouncedly in AG and GG carriers. Activity and expression of MMP7 were significantly higher in the GG than AA carriers. In support, MMP7 promoter-reporter assays showed greater transcriptional activity towards A to G transition under basal/nicotine-induced/CREB-over-expressed conditions in gastric adenocarcinoma cells (AGS). Moreover, nicotine, a major component of tobacco, treatment significantly up-regulated MMP7 expression due to enhanced CREB phosphorylation followed by its nuclear translocation in AGS cells. Furthermore, chromatin immunoprecipitation experiments revealed higher binding of phosporylated CREB with the −181G than −181A allele. Altogether, specific binding of phosphorylated CREB to 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.
  • Posted in Journal of Biological Chemistry, Publications
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