Interaction of Cyclooxygenase-2 Variants and Smoking in Pancreatic Cancer: A Possible Role of Nucleophosmin
Received 27 May 2008; accepted 29 January 2009. published online 11 February 2009.
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.
⁎Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
‡Department of Abdominal Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
§Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Reprint requests Address requests for reprints to: Dongxin Lin, MD, Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing 100021, China. fax: (86) 10-6772 2460
Ping Zhao, MD, Department of Abdominal Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing 100021, China. fax: (86) 10-6778 7079
Conflicts of interest The authors disclose no conflicts.
Funding Supported by the National Natural Science Foundation grant 30471957 and the State Key Basic Research Program grant 2004CB518701.
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