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.
Highlights
Hepatocellular carcinoma (HCC) is responsible for nearly 700,000 deaths each year worldwide [1]
We hypothesize that fatty livers caused by high-fat diet (HFD) are www.aacrjournals.org challenged with increased lipid peroxidation (LPO) and, raised the levels of g-OHPdG, a LPO-derived mutagenic DNA adduct, leading to higher mutation loads that set the stage for HCC development and that this process can be prevented by Theaphenon E (TE), a standardized green tea extract formulation
We focused on g-OHPdG as a mutagenic bulky adduct derived from LPO [18]. g-OHPdG induces primarily G>T and G>A mutations and it preferentially binds at the mutation hotspots of human p53 gene and it is implicated in human cancers [19,20,21]
Summary
Hepatocellular carcinoma (HCC) is responsible for nearly 700,000 deaths each year worldwide [1]. Obesity, which causes nonalcoholic fatty liver disease (NAFLD), is strongly linked to HCC and is the fastest growing risk factor for liver cancer in the United States as 40% of its population is obese and 30% suffers from NAFLD [4,5,6]. Challenged with increased LPO and, raised the levels of g-OHPdG, a LPO-derived mutagenic DNA adduct, leading to higher mutation loads that set the stage for HCC development and that this process can be prevented by Theaphenon E (TE), a standardized green tea extract formulation. Fatty livers increase inflammation and oxidative DNA damage [11] and may progress to fibrosis and cirrhosis due to liver damage caused by LPO and ROS [12].
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