Interaction of cyclooxygenase-2 variants and smoking in pancreatic cancer: a possible role of nucleophosmin

Gastroenterology. 2009 May;136(5):1659-68. doi: 10.1053/j.gastro.2009.01.071.

Abstract

Background & aims: Overexpression of cyclooxygenase-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / metabolism
  • Electrophoretic Mobility Shift Assay
  • Female
  • Gene Frequency
  • Gene Transfer Techniques
  • Genes, Reporter
  • Genetic Predisposition to Disease*
  • Genotype
  • Haplotypes
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Male
  • Middle Aged
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / metabolism*
  • Pancreatic Neoplasms / etiology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Smoking / adverse effects*
  • Transcription, Genetic

Substances

  • Neoplasm Proteins
  • Nuclear Proteins
  • nucleophosmin
  • Luciferases
  • Cyclooxygenase 2