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Volume 136, Issue 5 , Pages 1659-1668, May 2009

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

Dan Zhao
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Dongkui Xu
- Department of Abdominal Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Xuemei Zhang
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Li Wang
- Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Wen Tan
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Yongli Guo
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Dianke Yu
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
Hui Li
- Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Ping Zhao
- Department of Abdominal Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China
- Ping Zhao, MD, Department of Abdominal Surgery, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing 100021, China. fax: (86) 10-6778 7079
Dongxin Lin
- Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, 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

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.

Abbreviations used in this paper: COX-2, cyclooxygenase-2, CSC, cigarette smoke condensate, NPM, nucleophosmin, p-NPM, phosphorylated NPM, SNPs, single nucleotide polymorphisms