Oxidative stress and hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. There are two major challenges for HCC, the first being that early detection is generally not applicable, and secondly, it is usually fatal within several months after diagnosis. HCC is an inflammation-induced cancer. It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation, generating excess oxidative stress, together with aldehydes which can react with DNA bases to form promutagenic DNA adducts. In this review, the evidence between oxidative stress and liver carcinogenesis is summarized. We focused on the potential of using DNA adducts as oxidative stress biomarkers for liver carcinogenesis.

Detection of a lipid peroxidation-induced DNA adduct across liver disease stages

Background:Oxidative stress and chronic inflammation can increase cellular levels of reactive oxygen species and lipid peroxidation(LPO)when associated with the pathogenesis of hepatocellular carcinoma(HCC),which can develop following the progression of steatosis,fibrosis and cirrhosis.Using a monoclonal antibody for cyclicγ-hydroxy-1,N2-propanodeoxyguanosine(γ-OHPdG),a promutagenic DNA adduct formed endogenously by LPO,we examined its formation across liver disease stages to understand it's potential role in HCC development.Methods:Formalin-fixed paraffin embedded(FFPE)liver tissue samples from 49 patients representing normal,steatosis,fibrosis,cirrhosis and HCC were stained forγ-OHPdG and 8-hydroxydeoxyguanosine(8-oxo-dG),an oxidative damage biomarker.Quantification of immunohistochemical(IHC)staining was performed using histological scoring of intensity and distribution.Using primary human hepatocytes(HH)and a stellate cell(SC)co-culture,immunocytochemical staining ofγ-OHPdG and Nile Red was performed to determine if the formation ofγ-OHPdG was consistent between the clinical sample disease stages and the in vitro steatotic and fibrotic conditions.Results:γ-OHPdG levels varied significantly between the stages of normal and steatosis,steatosis and fibrosis,and steatosis and cirrhosis(P≤0.005).There was a trend,although not significant,of increased levels ofγ-OHPdG in HCC compared to the other groups.A strong correlation was observed(Pearson's,R2=0.85)between levels ofγ-OHPdG and 8-oxo-dG across the disease spectrum.The increase ofγ-OHPdG in steatosis and decrease in fibrosis was a pattern confirmed in an in vitro model using primary HH co-cultured with human SCs.Conclusions:γ-OHPdG was detected in FFPE liver tissues of patients with different stages of liver disease and in vitro studies,demonstrating that its formation is consistent with LPO in early stages of liver disease and suggesting that it may be a source of mutagenic DNA damage in liver disease progression.