Nitrative and oxidative DNA damage in intrahepatic cholangiocarcinoma patients in relation to tumor invasion

作     者：Somchai Pinlaor Banchob Sripa Ning Ma Yusuke Hiraku Puangrat Yongvanit Sopit Wongkham Chawalit Pairojkul Vajarabhongsa Bhudhisawasdi Shinji Oikawa Mariko Murata Reiji Semba Shosuke Kawanishi 

作者机构：Department of Parasitology Department of Pathology Department of Anatomy Department of Environmental and Molecular Medicine Department of Biochemistry Department of Surgery 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2005年第11卷第30期

页      面：4644-4649页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Supported by the Khon Kaen University Research Fund in Thailand Grants-in-Aid for Scientific Research from the Ministry of Education  Science  Sports and Culture of Japan 

主　　题：8-Nitroguanine 8-Oxo-7,8-dihydro-2'-deoxyguanosine Hypoxia-inducible factor-1α Cholangiocarcinoma Tumor invasion 

摘      要：AIM： Nitrative and oxidative DNA damage such as 8-nitroguanine and 8-oxo-7,8-dihydro-2＇-deoxyguanosine （8-oxodG） formation has been implicated in initiation and/ or promotion of inflammation-mediated carcinogenesis. The aim of this study is to clarify whether these DNA lesions participate in the progression of intrahepatic cholangiocarcinoma. METHODS： We investigated the relation of the formation of 8-nitroguanine and 8-oxodG and the expression of hypoxia-inducible factor-1α （HIF-1α） with tumor invasion in 37 patients with intra-hepatic cholangiocarcinoma. RESULTS： Immunohistochemical analyses revealed that 8-nitroguanine and 8-oxodG formation occurred to a much greater extent in cancerous tissues than in non-cancerous tissues. HIF-1α could be detected in cancerous tissues in all patients, suggesting low oxygen tension in the tumors. HIF-1α expression was correlated with inducible niltric oxide synthase （iNOS） expression （r = 0.369 and P = 0.025） and 8-oxodG formation （r = 0.398 and P = 0.015）. Double immunofluorescence study revealed that iNOS and HIF-1α co-localized in cancerous tissues. Notably, the formation of 8-oxodG was correlated significantly with lymphatic invasion （r = 0.386 and P = 0.018）. Moreover, 8- nitroguanine and 8-oxodG in non-cancerous tissues were associated significantly with neural invasion （P = 0.042 and P = 0.026, respectively）. These results suggest that reciprocal activation between HIF-1α and iNOS mediates persistent DNA damage, which induces tumor invasiveness via mutations, resulting in poor prognosis. CONCLUSION： The formation of 8-nitroguanine and 8-oxodG plays an important role in multiple steps of genetic changes leading to tumor progression, including invasiveness.