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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5751-5751
• Main Authors: Liang, Qiaoyi Jessie, Teoh, Narcissus, Xu, Lixia, Farrell, Geoffrey, Yu, Jun
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-5751

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