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

Hepatobiliary Surgery and Nutrition 2018年第2期7卷 85-97页

作者： Heidi Coia Ning Ma Aiwu Ruth He Bhaskar Kallakury Deborah LBerry eva permaul Kepher HMakambi Ying Fu Fung-Lung Chung Department of Biochemistry&Molecular Biology Georgetown University Medical CenterWashingtonDCUSA Department of Oncology Bioinformaticsand BiomathematicsGeorgetown UniversityWashingtonDCUSA Department of Pathology Lombardi Comprehensive Cancer CenterBioinformaticsand BiomathematicsGeorgetown UniversityWashingtonDCUSA Department of Biostatistics Bioinformaticsand BiomathematicsGeorgetown UniversityWashingtonDCUSA

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 *** 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 ***: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 *** of immunohistochemical(IHC)staining was performed using histological scoring of intensity and *** 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 ***: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 *** 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 ***: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

关键词： γ-hydroxy-1 N2-propanodeoxyguanosine(γ-OHPdG) steatosis fibrosis cirrhosis hepatocellular carcinoma(HCC)

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