Interaction of cyclooxygenase-2 variants and smoking in pancreatic cancer: a possible role of nucleophosmin.
OBJECTIVE
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.
Zhao
Dan
D
Department of Etiology and Carcinogenesis, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing.
Xu
Dongkui
D
Zhang
Xuemei
X
Wang
Li
L
Tan
Wen
W
Guo
Yongli
Y
Yu
Dianke
D
Li
Hui
H
Zhao
Ping
P
Lin
Dongxin
D
D000368:Aged; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012907:Smoking / Q000009:adverse effects*; D014158:Transcription, Genetic
C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D008156:Luciferases; D051546:Cyclooxygenase 2