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Predictive Power of Biomarkers of Oxidative Stress and Inflammation in Patients with Hepatitis C Virus-Associated Hepatocellular Carcinoma

¹ 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
² First Department of Surgery, Yamanashi University, Tamaho, Nakakoma, Yamanashi Prefecture, Japan
³ Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

Correspondence: Address correspondence and reprint requests to: Ivan Rusyn; E-mail: iir{at}unc.edu

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.

Key Words: Hepatocellular carcinoma • Hepatitis C virus • Oxidative stress • Disease • free survival