Interaction of Cyclooxygenase-2 Variants and Smoking in Pancreatic Cancer: A Possible Role of Nucleophosmin

Background & Aims: Overexpression of cyclooxygentsase-2 (COX-2) is implicated in cancer development. This study examined the functional relevance of genetic polymorphisms in the COX-2 promoter and evaluated their associations with susceptibility to pancreatic cancer. Methods: Genotypes and haplotypes of COX-2 -765G/C, -1195G/A, and -1290A/G were analyzed in 393 pancreatic cancer patients and 786 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression. The function of the -765G→C polymorphism was examined by a set of biochemical assays. Results: The -1195AA or -765GC genotype carriers had a 1.34-fold (95% CI: 1.12-1.60) or 1.63-fold (95% CI: 1.25-2.10) excess risk for developing pancreatic cancer. These 2 variants showed a cooperative effect in context of haplotype, with the ORs for the A_-1195-C_-765-containing haplotypes being significantly greater than those for the G_-1195-G_-765-containing haplotypes. The -765C allele and smoking displayed a multiplicative joint effect, with an OR of 3.72 (95% CI: 1.70-8.14) for heavy smokers carrying the -765GC genotype. Biochemical assays suggest that the -765G→C change creates a binding site for nucleophosmin (NPM) and phosphorylated NPM (p-NPM), which acts as a transcriptional inhibitor. Cigarette smoke remarkably increased COX-2 promoter activity, and this effect was more pronounced for the -765C allele compared with the -765G allele. Cigarette smoke reduced nuclear p-NPM levels, which was reversely associated with COX-2 expression. Conclusions: Functional COX-2 polymorphisms are associated with susceptibility to pancreatic cancer and tobacco smoke specifically increases -765C promoter activity, which might be mediated by p-NPM.