1. Prevention of Lipid Peroxidation-derived Cyclic DNA Adduct and Mutation in High-Fat Diet-induced Hepatocarcinogenesis by Theaphenon E.
- Author
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Coia H, Ma N, Hou Y, Dyba MD, Fu Y, Cruz MI, Benitez C, Graham GT, McCutcheon JN, Zheng YL, Sun B, Kallakury BV, Ma J, Fang HB, Berry DL, Muralidaran V, and Chung FL
- Subjects
- Animals, Carcinogenesis drug effects, Carcinogenesis genetics, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular pathology, Diet, High-Fat adverse effects, Drug Screening Assays, Antitumor, Incidence, Liver drug effects, Liver pathology, Liver Neoplasms, Experimental epidemiology, Liver Neoplasms, Experimental etiology, Liver Neoplasms, Experimental pathology, Male, Mice, Mice, Inbred C57BL, Mutation Rate, Obesity complications, Obesity etiology, Obesity pathology, Plant Extracts chemistry, Polyphenols administration & dosage, Tea chemistry, Exome Sequencing, Carcinoma, Hepatocellular prevention & control, DNA Adducts drug effects, Lipid Peroxidation drug effects, Liver Neoplasms, Experimental prevention & control, Plant Extracts administration & dosage
- Abstract
Obesity is associated with cancer risk and its link with liver cancer is particularly strong. Obesity causes non-alcoholic fatty liver disease (NAFLD) that could progress to hepatocellular carcinoma (HCC). Chronic inflammation likely plays a key role. We carried out a bioassay in the high-fat diet (HFD)-fed C57BL/6J mice to provide insight into the mechanisms of obesity-related HCC by studying γ-OHPdG, a mutagenic DNA adduct derived from lipid peroxidation. In an 80-week bioassay, mice received a low-fat diet (LFD), high-fat diet (HFD), and HFD with 2% Theaphenon E (TE) (HFD+TE). HFD mice developed a 42% incidence of HCC and LFD mice a 16%. Remarkably, TE, a standardized green tea extract formulation, completely blocked HCC in HFD mice with a 0% incidence. γ-OHPdG measured in the hepatic DNA of mice fed HFD and HFD+TE showed its levels increased during the early stages of NAFLD in HFD mice and the increases were significantly suppressed by TE, correlating with the tumor data. Whole-exome sequencing showed an increased mutation load in the liver tumors of HFD mice with G>A and G>T as the predominant mutations, consistent with the report that γ-OHPdG induces G>A and G>T. Furthermore, the mutation loads were significantly reduced in HFD+TE mice, particularly G>T, the most common mutation in human HCC. These results demonstrate in a relevant model of obesity-induced HCC that γ-OHPdG formation during fatty liver disease may be an initiating event for accumulated mutations that leads to HCC and this process can be effectively inhibited by TE. Cancer Prev Res; 11(10); 665-76. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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