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

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-1alpha (HIF-1alpha) 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-1alpha could be detected in cancerous tissues in all patients, suggesting low oxygen tension in the tumors. HIF-1alpha 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-1alpha 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-1alpha 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.

• Authors: Somchai Pinlaor, Banchob Sripa, Ning Ma, Yusuke Hiraku, Puangrat Yongvanit, Sopit Wongkham, Chawalit Pairojkul, Vajarabhongsa Bhudhisawasdi, Shinji Oikawa, Mariko Murata, Reiji Semba, Shosuke Kawanishi
• Journal: World journal of gastroenterology (World J Gastroenterol) Vol. 11 Issue 30 Pg. 4644-9 (Aug 14 2005) ISSN: 1007-9327 [Print] United States
• PMID: 16094703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 8-nitroguanine
• DNA, Neoplasm
• DNA-Binding Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• Transcription Factors
• Guanine
• 8-Hydroxy-2'-Deoxyguanosine
• NOS2 protein, human
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Adult
• Case-Control Studies
• Cholangiocarcinoma (metabolism, pathology)
• DNA Damage
• DNA, Neoplasm (chemistry, metabolism)
• DNA-Binding Proteins (metabolism)
• Deoxyguanosine (analogs & derivatives, biosynthesis)
• Female
• Guanine (analogs & derivatives, biosynthesis)
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Liver Neoplasms (metabolism, pathology)
• Male
• Middle Aged
• Neoplasm Invasiveness
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Nuclear Proteins (metabolism)
• Transcription Factors (metabolism)