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

感染肝吸虫是胆管癌的主要危险因素，特别是在泰国东北部地区。感染介导的慢性炎症是致癌的重要因素。活性氮物种是在炎症条件下产生的，并与鸟嘌呤反应形成8-硝基鸟嘌呤，这是一种突变的硝化DNA损伤，可能有助于感染相关的癌症发生。我们制备了特异性的抗8-硝基鸟嘌呤抗体，并首次证明了8-硝基鸟嘌呤在OV感染的仓鼠胆管上皮细胞中形成与致癌相关(BBRC 2003，NO 2004，Carcinations2004)。一种抗蠕虫药物几乎完全减少了胆管上皮细胞中iNOS依赖的DNA损伤(Int.J.Cancer in Press)。我们对肝内胆管细胞癌患者进行了分子流行病学研究。值得注意的是，胆管瘤…手术标本中8-硝基鸟嘌呤的形成更多的癌症患者与肿瘤的侵袭性显著相关，这表明DNA损伤不仅参与了肿瘤的启动和促进，而且还参与了肿瘤的进展(World J.2005)。我们证明了OV抗原通过TLR2依赖的途径在巨噬细胞系(Int.J.Parasitol)中诱导炎症反应。2005)。我们的国际分子流行病学研究为各种炎症相关致癌的分子机制提供了洞察力。我们还调查了各种传染病患者的DNA损伤情况。8-硝基鸟氨酸是在幽门螺杆菌引起的胃炎(BBRC 2004)、慢性丙型肝炎(J。2005)和口腔癌前病变(癌症科学。2005年，一氧化氮2006年)。我们发现8-硝基鸟嘌呤在炎症性肠病小鼠模型的结肠上皮细胞中形成。2005)。在这些研究中，我们发现8-硝基鸟嘌呤无论病因如何，都是在致癌部位形成的，并提出了8-硝基鸟嘌呤有可能成为评估炎症相关癌变风险和预后的一种有前途的生物标志物。较少

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