| Summary: | 碩士 === 國立臺灣大學 === 臨床牙醫學研究所 === 96 === Betel quid (BQ) chewing is a common oral habit in Southeast Asian contries. There are about six hundred million BQ chewers in the world. The evidence of BQ chewing as one of the major risk factors leading to leukoplakia, oral submucous fibrosis, oral cancer and esophagus cancers have been well published. The BQ chewers may swallow saliva completely and therefore the severe toxic effects of BQ may occurs at sites other than the oral cavity. The animal studies have demonstrated that the betel quid components causes hepatotoxicity and the genotoxic effects of hepatocytes. In addition, transcriptional factors AP-1 and NF-κB has strong correlation with liver carcinogenesis and can be activated by X protein of the HBV. Recently, the epidemiology reports have shown that the habitual BQ chewing is an independent risk factors of hepatocellular carcinoma (HCC) and may have an addiditve effect with HBV infection. The HBsAg carrier rate in general population of Taiwan is one of the highest in the world. In our study, we like to investigate the AP-1 and NF-κB molecular mechanisms combine with HBV factors for the association of BQ components with the development of HCC. By using the luciferase assay, we found that the AN extract (ANE) 800 μg/ml and Arecoline (ACO) 0.8 mM induced AP-1 binding site activation mainly through Ras/Raf/MEK/ERK pathways. At the same ANE concentrations, NF-κB binding sites were activated mainly through PKC and MEK/ ERK pathways, but not the Ras pathways. In the presence of HBx protein, ANE-induced AP-1 and NF-κB is synergistically activated and with MEK/ERK pathways involvement. Compare with ANE, ACO-induced AP-1 and NF-κB activation in the presence of HBx protein only reach to the additive effects. At the mRNA level, some HCC invasiveness markers were induced by ANE (tPA, PAI-1 and IL-6 ) or ACO (N-Cadherin, VCAM-1). At the protein level, ANE alone or combine with HBx both induced IL-6 expression. However, the protein expression of IL-8 was only found in ANE or ACO stimulation in the presence of HBx. In conclusion, BQ components activate AP-1 and NF-κB transcriptional factors and induced the HCC invasiveness markers expression at the mRNA and protein level. ANE combine with HBV synergistically induced AP-1 and NF-κB activation. We provide the possible molecular mechanism of betel nuts chewing and combine with viral factors in the development of HCC. Our clinical implication is betel but chewing in HBsAg carriers may increase the risk of HCC development.
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