title: Association of MMP7 -181A→G Promoter Polymorphism with Gastric Cancer Risk: INFLUENCE OF NICOTINE IN DIFFERENTIAL ALLELE-SPECIFIC TRANSCRIPTION VIA INCREASED PHOSPHORYLATION OF cAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB).
abstract: 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.
authors.affiliation: From the Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata 700032.
authors.forename: Kousik
authors.initials: K
authors.lastname: Kesh
authors.affiliation: the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, and.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Subramanian
authors.affiliation: From the Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata 700032.
authors.forename: Nillu
authors.initials: N
authors.lastname: Ghosh
authors.affiliation: the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, and.
authors.forename: Vinayak
authors.initials: V
authors.lastname: Gupta
authors.affiliation: the Saroj Gupta Cancer Center and Research Institute, Kolkata 700104, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Gupta
authors.affiliation: the Saroj Gupta Cancer Center and Research Institute, Kolkata 700104, India.
authors.forename: Samir
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: the Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, and.
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
authors.affiliation: From the Drug Development Diagnostic and Biotechnology Division, Indian Institute of Chemical Biology, Kolkata 700032, snehasiktas@hotmail.com.
authors.forename: Snehasikta
authors.initials: S
authors.lastname: Swarnakar
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D002273:Carcinogens / Q000378:metabolism; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D009538:Nicotine; D020783:Matrix Metalloproteinase 7
keywords: MMP7; association study; cAMP response element-binding protein (CREB); gastric cancer; nicotine; promoter; single-nucleotide polymorphism (SNP); transcription factor
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