This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chiang, S.-L. Articles by Ko, Y.-C. Search for Related Content PubMed PubMed Citation Articles by Chiang, S.-L. Articles by Ko, Y.-C.

Up-regulation of Inflammatory Signalings by Areca Nut Extract and Role of Cyclooxygenase-2 –1195G>A Polymorphism Reveal Risk of Oral Cancer

¹ Graduate Institute of Medicine, ² Department of Public Health, Faculty of Medicine, College of Medicine, ³ Graduate Institute of Public Health, College of Health Science, ⁴ Graduate Institute of Oral Health Sciences, College of Dental Medicine, ⁵ Center of Excellence for Environmental Medicine, ⁶ Department of Otorhinolaryngology, ⁷ Division of Oral and Maxillofacial Surgery, Department of Dentistry, ⁸ Division of Gastroenterology, Department of Internal Medicine, Chung-Ho Memorial Hospital, Kaohsiung Medical University; ⁹ Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung, Taiwan; and ¹⁰ School of Medicine, University of Western Australia, Perth, Australia

Requests for reprints: Ying-Chin Ko, Division of Environmental Health and Occupational Medicine, National Health Research Institutes, No. 100 Shih-Chuan 1st Road, Kaohsiung 807, Taiwan, Phone: 886-7-311-4418; Fax: 886-7-316-2725; E-mail: ycko{at}nhri.org.tw.

Key Words: areca nut • inflammatory signaling • gene expression • COX-2 promoter • oral cancer • substance use • gene-environment interaction

Because the mRNA expression of cyclooxygenase-2 (COX-2) is up-regulated by arecoline in human gingival fibroblasts, as shown in our previous study, we further investigated the mRNA expression level of COX-2 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 COX-2 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 COX-2 –1195G>A polymorphism in these cell lines showed diverse inflammatory response (KB>>Ca9-22>SAS) after 24-hour ANE/sANE treatments, and the COX-2 up-regulation might be mostly elicited from alternative nuclear factor-B 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 COX-2 –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 COX-2 promoter region in contributing to the development of betel-related OSCC, including ANE/sANE–induced transcriptional effects and enhanced joint effects of COX-2 –1195A allele with substance use of ABC. [Cancer Res 2008;68(20):8489–98]