Data from Up-regulation of Inflammatory Signalings by Areca Nut Extract and Role of <i>Cyclooxygenase-2</i> −1195G>A Polymorphism Reveal Risk of Oral Cancer

Abstract

<div>Abstract<p>Because the mRNA expression of <i>cyclooxygenase-2</i> (<i>COX-2</i>) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of <i>COX-2</i> and its upstream effectors in three oral epithelial carcinoma cell lines (KB, SAS, and Ca9-22) by using areca nut extract (ANE) and saliva-reacted ANE (sANE). A case-control study of 377 oral squamous cell carcinoma (OSCC) patients and 442 controls was conducted to evaluate the gene-environment interaction between <i>COX-2</i> promoter polymorphisms and substance use of alcohol, betel quid, and cigarettes (ABC) in risk of OSCC. The heterogeneous characteristics of the oral site and the <i>COX-2</i> −1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB≫Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the <i>COX-2</i> up-regulation might be mostly elicited from alternative nuclear factor-κB activation. In the case-control study, betel chewing [adjusted odds ratios (aOR), 42.2] posed a much higher risk of OSCC than alcohol drinking and cigarette smoking (aORs, 2.4 and 1.8, respectively), whereas the <i>COX-2</i> −1195A/A homozygote presented a potential genetic risk (OR, 1.55). The strongest joint effect for OSCC was seen in betel chewers with −1195A/A homozygote (aOR, 79.44). In the non–betel chewing group, the −1195A/G and A/A genotypes together with the combined use of alcohol and cigarettes increased risk to 15.1-fold and 32.1-fold, respectively, compared with the G/G genotype without substance use. Taken together, these findings illustrate a valuable insight into the potential role of the <i>COX-2</i> promoter region in contributing to the development of betel-related OSCC, including ANE/sANE–induced transcriptional effects and enhanced joint effects of <i>COX-2</i> −1195A allele with substance use of ABC. [Cancer Res 2008;68(20):8489–98]</p></div>