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.
Highlights
Oral cavity cancer is the eighth most common cancer in men worldwide, with an age-standardized incidence rate (ASIR) of 6.7Note: Supplementary data for this article are available at Cancer Research Online.I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0823 per 100,000 men, and occurs in south central Asia [1]
After a series of areca nut extract (ANE)/ saliva-reacted ANE (sANE) treatments for 24 hours, sANE decreased cell viability in a dose-dependent manner (Ptrend < 0.05 or Ptrend < 0.01) in all cell lines, whereas ANE significantly decreased the viability of KB and
The higher cytotoxic www.aacrjournals.org effects at cell morphologic changes and mRNA expression level were observed in sANE treatments
Summary
Oral cavity cancer is the eighth most common cancer in men worldwide, with an age-standardized incidence rate (ASIR) of 6.7Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).I2008 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-08-0823 per 100,000 men, and occurs in south central Asia [1]. Oral cavity cancer is the eighth most common cancer in men worldwide, with an age-standardized incidence rate (ASIR) of 6.7. In Taiwan, the ASIR of oral cancer was almost 27 per 100,000 men in 2000, which ranks highly in the world [2]. The standardized death rate of oral cavity cancer increased between 1986 and 2006. Oral squamous cell carcinoma (OSCC) accounts for >90% of oral cancer and can develop from oral precancerous lesions (OPL), such as leukoplakia and erythroplakia. It is well documented that the prevalent habit of betel chewing is a serious public health concern and an independent environmental risk in developing oral cancer in Taiwan [4,5,6]
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