Oxidative Stress Induce1, N~6-ethenodeoxyadenosine Adduct Formation Contributes To Hepatocarcinogenesis

Introduction:Oxidative stress has been linked to an increased risk of diverse malignant tumors. There is a large body of evidence indicating that oxidative stress play a common patho-genetic role in different agents-mediated hepatocarcinogenesis, including Hepatitis B virus (HBV), Hepatitis C virus (HCV), alcohol, non-alcoholic steatohepatitis (NASH). Many studies have found oxidative stress-derived1, N6-ethenodeo-xyadenosine (ε-dA) may act as a driving force towards hepatocellular carcinoma (HCC) in cancer-prone liver diseases.Objective:1. Evaluate the status of oxidative stress in HCC and surrounding non-tumor liver tissue;2. Determine the occurrence of ε-dAin these tissues;3. Assess a correlation exists between the formation of ε-dA and p53protein expression in HCC tissue;4. Determine if the formation of ε-dA was associated with liver inflammatory activity and fibrosis development.Methods:Oxidative stress-related parameters include total antioxidant capacity (T-AOC), total superoxide dismutase (SOD) activity, glutathione (GSH) and maleic dialdehyde (MDA) were examined in tumor and adjacent non-tumor liver tissues of32patients with HCC. ε-dA, p53protein and proliferating cell nuclear antigen (PCNA) were immunohistochemic-ally investigated in control liver, adjacent non-tumor liver and HCC tissues.Results:The total antioxidant capacity (T-AOC) and total superoxide dismutases (SOD) activity of HCC tissues were lower than those of adjacent non-tumor liver tissues (p<0.05vs. p<0.001), but the level of GSH and MDA were not different between HCC and adjacent non-tumor liver tissues. The prevalence of ε-dA in HCC (47.6±20.6%) was significantly higher than in control (7.9±7.5%,p<0.0001) and in adjacent non-tumor liver tissues (29.4±15.8%,p<0.001). The level of T-AOC, total SOD activity and ε-dA was correlated with the differentiation of HCC. Furthermore, a significant correlation between the positive rate of ε-dAand p53protein was observed in HCC tissues (r=0.5162,p<0.01). The positive rate of PCNA in HCC (47.6±10.9%) was significantly higher than in control (25.8±7.7%,p<0.0001) and in adjacent non-tumor liver tissues (34.1±8.2%,p＜0.0001). In addition, there was a possible link between the formation of ε-dA and chronic inflammation and fibrosis in non-tumor liver tissues.Conclusions:Oxidative stress induce ε-dA excessive formation, the elevated accumulation of ε-dA partially contributes to the p53protein over-expression and excessive cell proliferation, eventually initiating hepatocarcinogenesis. ε-dA lesion may be gradual accumulation in chronic liver diseases, it may play a driving role towards hepatocarcinogenesis in cancer-prone chronic liver diseases.