Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma.
BACKGROUND
This study evaluated the relationship between inflammation, intra-hepatic oxidative stress, oxidative DNA damage and the progression of liver carcinogenesis in hepatitis C virus (HCV)-infected humans.


METHODS
Non-cancerous liver tissues were collected from 30 patients with an HCV-associated solitary hepatocellular carcinoma (HCC) who received curative tumor removal. After surgery, the patients were followed at monthly intervals at the outpatient clinic. Distribution of the inflammatory cells (CD68+), the number of 8-hydroxydeoxyguanosine (8-OHdG) DNA adducts and 4-hydroxynonenal (HNE) protein adducts and the expression of apurinic/apyrimidinic endonuclease (APE) were determined by immunohistochemical analysis in serial liver sections from tumor-free parenchyma at the surgical margin around the tumor.


RESULTS
Significant positive correlations were observed between the number of CD68+ cells, the amount of HNE protein adducts, and the number of 8-OHdG adducts in liver tissue of patients with HCC and HCV. The cumulative disease-free survival was significantly shorter in patients with the highest percentage of 8-OHdG-positive hepatocytes. Using a Cox proportional hazard model, 8-OHdG, HNE and CD68 were determined to be good biomarkers for predicting disease-free survival in patients with HCC and HCV.


CONCLUSIONS
These results support the hypothesis that HCV-induced inflammation causes oxidative DNA damage and promotes hepatocarcinogenesis which directly affects the clinical outcome. Since patients with greater intra-hepatic oxidative stress had a higher incidence of HCC recurrence, we suggest that oxidative stress biomarkers could potentially be used as a useful clinical diagnostic tool to predict the duration of disease-free survival in patients with HCV-associated HCC.
Maki
Akira
A
Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, North Carolina 27599, USA.
Kono
Hiroshi
H
Gupta
Mayetri
M
Asakawa
Masami
M
Suzuki
Tetsuya
T
Matsuda
Masanori
M
Fujii
Hideki
H
Rusyn
Ivan
I
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000447:Aldehydes / Q000032:analysis; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018736:DNA Adducts; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000472:pathogenicity*; D006498:Hepatectomy; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015227:Lipid Peroxidation; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000209:etiology; D018384:Oxidative Stress; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D015996:Survival Rate; D033921:Vesicular Transport Proteins / Q000378:metabolism; D000097382:CD68 Molecule
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase; D000447:Aldehydes; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D018736:DNA Adducts; D003849:Deoxyguanosine; D008840:Microfilament Proteins; D017382:Reactive Oxygen Species; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C027576:4-hydroxy-2-nonenal