Up-regulation of inflammatory signalings by areca nut extract and role of cyclooxygenase-2 -1195G>a polymorphism reveal risk of oral cancer.

Abstract

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-kappaB 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.

• Authors: Shang-Lun Chiang, Ping-Ho Chen, Chien-Hung Lee, Albert Min-Shan Ko, Ka-Wo Lee, Ying-Chu Lin, Pei-Shan Ho, Hung-Pin Tu, Deng-Chyang Wu, Tien-Yu Shieh, Ying-Chin Ko
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 20 Pg. 8489-98 (Oct 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18922923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• GDF15 protein, human
• Growth Differentiation Factor 15
• NF-kappa B
• Plant Extracts
• Cyclooxygenase 2
• PTGS2 protein, human

Topics

• Adult
• Aged
• Alcohol Drinking
• Areca (toxicity)
• Carcinoma, Squamous Cell (etiology, genetics)
• Case-Control Studies
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclooxygenase 2 (genetics)
• Cytokines (genetics)
• Gene Expression Regulation (drug effects)
• Genotype
• Growth Differentiation Factor 15
• Humans
• Middle Aged
• Mouth Neoplasms (etiology, genetics)
• NF-kappa B (physiology)
• Plant Extracts (toxicity)
• Polymorphism, Genetic
• Promoter Regions, Genetic
• Risk Factors
• Signal Transduction (drug effects)
• Smoking (adverse effects)
• Up-Regulation