Liver Cancer
Copyright ©The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2005; 11(30): 4644-4649
Published online Aug 14, 2005. doi: 10.3748/wjg.v11.i30.4644
Nitrative and oxidative DNA damage in intrahepatic cholangiocarcinoma patients in relation to tumor invasion
Somchai Pinlaor, Banchob Sripa, Ning Ma, Yusuke Hiraku, Puangrat Yongvanit, Sopit Wongkham, Chawalit Pairojkul, Vajarabhongsa Bhudhisawasdi, Shinji Oikawa, Mariko Murata, Reiji Semba, Shosuke Kawanishi
Somchai Pinlaor, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Banchob Sripa, Chawalit Pairojkul, Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Puangrat Yongvanit, Sopit Wongkham, Department of Bioch-emistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Vajarabhongsa Bhudhisawasdi, Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Somchai Pinlaor, Banchob Sripa, Puangrat Yongvanit, Sopit Wongkham, Chawalit Pairojkul, Vajarabhongsa Bhudhisawasdi, Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Ning Ma, Reiji Semba, Department of Anatomy, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
Somchai Pinlaor, Yusuke Hiraku, Shinji Oikawa, Mariko Murata, Shosuke Kawanishi, Department of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan
Author contributions: All authors contributed equally to the work.
Supported by the Khon Kaen University Research Fund in Thailand and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan
Correspondence to: Professor Shosuke Kawanishi, Department of Environmental and Molecular Medicine, Mie University School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan. kawanisi@doc.medic.mie-u.ac.jp
Telephone: +81-59-231-5011 Fax: +81-59-231-5011
Received: October 9, 2004
Revised: November 23, 2004
Accepted: December 1, 2004
Published online: August 14, 2005
Abstract

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 nitric 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.

Keywords: 8-Nitroguanine, 8-Oxo-7,8-dihydro-2’-deoxyg-uanosine, Hypoxia-inducible factor-1α, Cholangiocarcinoma, Tumor invasion