Abstract 5751: Dietary cholesterol promotes steatohepatitis-related hepatocellular carcinoma by inducing aberrant gene expression in metabolism and mutations in calcium signaling

Background and Aims: Dietary cholesterol and nonalcoholic steatohepatitis (NASH) are risk factors for hepatocellular carcinoma (HCC), but their molecular mechanisms are undefined. Methods: We investigated the effects of cholesterol on NASH and HCC in diethylnitrosamine-injected mice fed high-fat diets with or without high cholesterol. mRNA microarray and whole-exome sequencing analyses were applied for expressional and genetic aberrations. Identified molecular changes were validated in 37 human NASH-HCCs. Results: Whereas non-cholesterol-fed mice developed simple steatosis, high-cholesterol-fed mice developed NASH, with inflammatory, metabolic and oncogenic genes upregulated in NASH versus steatosis. In cholesterol-induced NASH, HCCs were larger and more numerous than in non-cholesterol-induced steatosis. Although similar numbers of differentially expressed genes were identified between NASH- and steatosis-HCCs, more pathways were found to be uniquely affected in NASH-HCCs, including calcium signaling, insulin signaling, cell adhesion, and axon guidance. In addition, significantly more nonsynonymous somatic mutations occurred in NASH-HCCs (335±84/sample) than steatosis-HCCs (43±13/sample) (P Conclusions: Dietary cholesterol causes NASH by dysregulating genes involved in inflammation and metabolism, and promotes NASH-HCC by inducing oncogenic expression and mutations. We identified novel aberrant gene expression, mutations and core oncogenic pathways that contribute to cholesterol-associated NASH-HCC in mice that are relevant to human NASH-HCC. Citation Format: Qiaoyi Jessie Liang, Narcissus Teoh, Lixia Xu, Geoffrey Farrell, Jun Yu. Dietary cholesterol promotes steatohepatitis-related hepatocellular carcinoma by inducing aberrant gene expression in metabolism and mutations in calcium signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5751.