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


CONCLUSIONS
The formation of 8-nitroguanine and 8-oxodG plays an important role in multiple steps of genetic changes leading to tumor progression, including invasiveness.
Pinlaor
Somchai
S
Department of Parasitology, Khon Kaen University, Thailand.
Sripa
Banchob
B
Ma
Ning
N
Hiraku
Yusuke
Y
Yongvanit
Puangrat
P
Wongkham
Sopit
S
Pairojkul
Chawalit
C
Bhudhisawasdi
Vajarabhongsa
V
Oikawa
Shinji
S
Murata
Mariko
M
Semba
Reiji
R
Kawanishi
Shosuke
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D016022:Case-Control Studies; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C095838:8-nitroguanine; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D006147:Guanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D003849:Deoxyguanosine