Molecular epidemiological study on the pathogenesis of cholangiocarcinoma caused by infection with liver flukes in Thailand

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Infection with the liver fluke Opisthorchis viverrini (OV) is a major risk factor of cholangiocarcinoma especially in north-eastern region of Thailand. Chronic inflammation mediated by infection is an important factor causing cancer. Reactive nitrogen species are generated under inflammatory conditions, and react with guanine to form 8-nitroguanine, a mutagenic nitrative DNA lesion, which may contribute to infection-related carcinogenesis. We produced specific anti-8-nitroguanine antibody, and we firstly demonstrated that 8-nitroguanine was formed in bile duct epithelium of OV-infected hamsters in association with carcinogenesis (BBRC 2003, Nitric Oxide 2004, Carcinogenesis 2004). An antihelminthic drug almost completely diminished iNOS-dependent DNA damage in bile duct epithelium (Int.J.Cancer in press). We carried out a molecular epidemiological study in patients with intrahepatic cholangiocarcinoma. It is noteworthy that 8-nitroguanine formation in surgical specimens of cholangiocar … More cinoma patients was significantly correlated with tumor invasion, suggesting that DNA damage participates in not only initiation and promotion but also tumor progression (World J.Gastroenterol. 2005). We demonstrated that OV antigen induced inflammatory responses via TLR2-dependent pathway in a macrophage cell line (Int.J.Parasitol. 2005). Our international molecular epidemiological study has provided an insight into molecular mechanisms of a wide variety of inflammation-related carcinogenesis. We also investigated DNA damage in patients with various infectious diseases. 8-Nitroguanine was formed in patients with Helicobacter pylori-induced gastritis (BBRC 2004), chronic hepatitis C (J.Hepatol. 2005) and oral premalignant lesions (Cancer Sci. 2005, Nitric Oxide 2006). We showed that 8-nitroguanine was formed in colon epithelium of the mouse model of inflammatory bowel diseases (Cancer Sci. 2005). In these studies, we found that 8-nitroguanine is formed at the sites of carcinogenesis regardless of etiology, and proposed the possibility that 8-nitroguanine could be a promising biomarker to evaluate the risk and prognosis of inflammation-related carcinogenesis. Less