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

泰国肝吸虫感染所致胆管癌发病机制的分子流行病学研究

• 批准号: 15406027
• 负责人: KAWANISHI Shosuke
• 金额: $ 8.58万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15406027/
• 关键词: Opisthorchis viverrini; cholangiocarcinoma; 8-nitroguanine; infection; inflammation; reactive nitrogen species; inducible NO synthase; carcinogenesis; 8-oxodG; 8-nitroG; NO; ニトロチロシン; ヒストン

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

感染肝吸虫后睾吸虫（OV）是胆管癌的主要危险因素，特别是在泰国东北部地区。由感染介导的慢性炎症是导致癌症的重要因素。活性氮在炎症条件下产生，并与鸟嘌呤反应形成8-硝基鸟嘌呤，这是一种致突变的硝化DNA损伤，可能有助于感染相关的致癌作用。我们制备了特异性抗8-硝基鸟嘌呤抗体，并首次证明了在OV感染仓鼠的胆管上皮中形成的8-硝基鸟嘌呤与致癌作用相关（BBRC 2003，Nitric Oxide 2004，Carcinogenesis 2004）。一种抗蠕虫药物几乎完全减少了胆管上皮中iNOS依赖性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，胆管癌手术标本中8-硝基鸟嘌呤的形成 ...更多信息 在癌症患者中，DNA损伤与肿瘤侵袭显著相关，这表明DNA损伤不仅参与肿瘤的起始和促进，而且参与肿瘤的进展（World J.Gastroenterol. 2005年）。我们证明了OV抗原在巨噬细胞系中通过TLR2依赖性途径诱导炎症反应（Int.J.Parasitol. 2005年）。我们的国际分子流行病学研究提供了一个深入了解各种炎症相关的致癌分子机制。我们还研究了各种感染性疾病患者的DNA损伤。8-在幽门螺杆菌诱导的胃炎（BBRC 2004）、慢性丙型肝炎（J.Hepatol. 2005）和口腔癌前病变（Cancer Sci. 2005，Nitric Oxide 2006）。我们表明，8-硝基鸟嘌呤在炎症性肠病小鼠模型的结肠上皮中形成（Cancer Sci. 2005年）。在这些研究中，我们发现，无论病因如何，8-硝基鸟嘌呤都在致癌部位形成，并提出了8-硝基鸟嘌呤可能成为评估炎症相关致癌风险和预后的有前途的生物标志物的可能性。少

项目成果

Radical production and DNA damage induced by carcinogenic 4-hydrazinobenzoic acid, an ingredient of mushroom Agaricus bisporus,

致癌性 4-肼基苯甲酸（双孢蘑菇的一种成分）引起的自由基产生和 DNA 损伤，

• 发表时间: 2006
• 期刊: Free Radic. Res. 40(1):
• 作者: Oikawa;S
• 通讯作者: S

Mechanism of site-specific DNA damage induced by ozone

• DOI: 10.1016/j.mrgentox.2005.04.004
• 发表时间: 2005-08-01
• 期刊: MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS
• 影响因子: 1.9
• 作者: Ito, K;Inoue, S;Kawanishi, S
• 通讯作者: Kawanishi, S

Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxide

• DOI: 10.1016/j.lfs.2004.05.040
• 发表时间: 2005-02-11
• 期刊: LIFE SCIENCES
• 影响因子: 6.1
• 作者: Mizutani, H;Tada-Oikawa, S;Kawanishi, S
• 通讯作者: Kawanishi, S

DNA damage by ethylbenzenehydro-peroxide formed from carcinogenic ethylbenzene by sunlight irradiation

致癌乙苯在阳光照射下形成氢过氧化乙苯对 DNA 的损伤

• 发表时间: 2003
• 期刊: Biochem.Biophys.Res.Commun. 304
• 作者: Toda;C.;Uchida;T.;Midorikawa;K.;Murata;M.;Hiraku;Y.;Okamoto;Y.;Ueda;K.;Kojima;N.;Kawanishi;S.
• 通讯作者: S.

Accumulation of 8-nitroguanine in human gastric epithelium induced by Helicobacter pylori infection

• DOI: 10.1016/j.bbrc.2004.04.193
• 发表时间: 2004-06-25
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ma, N;Adachi, Y;Kawanishi, S
• 通讯作者: Kawanishi, S