ena-STUDY-THE CHINESE UNIVERSITY OF HONG KONG-15-08-2017-11:56:08:292-298
Dietary cholesterol promotes steatohepatitis-related hepatocellular carcinoma by inducing aberrant genomic expression and mutations
Background & 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 up-regulation of inflammatory, metabolic and oncogenic genes, versus simple steatosis. In cholesterol-induced NASH, HCCs (at 8 months) were larger and more numerous than in non-cholesterol-induced steatosis (tumor index high versus no cholesterol, P <0.0001). Aberrantly expressed genes in NASH-HCCs (but not steatosis-HCCs) were enriched in pathways of calcium signaling, insulin signaling, cell adhesion molecules (CAMs) and axon guidance. Twelve aberrantly expressed genes in murine NASH-HCC were significantly dysregulated in human NASH-HCC, including ALCAM, DDIT3, MAP3K6, PAK1, ALDH18A1 and SQLE. In addition, significantly more non-synonymous somatic mutations occurred in NASH-HCCs (335±83.9/sample) than steatosis-HCCs (43±13/sample) (P<0.05), and 80 recurrent mutations were found in NASH-HCCs. Mutations in NASH-HCCs were in calcium and insulin signaling pathways, CAMs, axon guidance and metabolic pathways. Integrated analysis of gene expression and mutations revealed pathways of calcium signaling, insulin signaling, CAMs, axon guidance and metabolism in experimental NASH-HCCs. Among the recurrently mutated genes, 21 were validated in human NASH-HCCs, including MTOR, SDK1, RYR1, RYR2 and CACNA1H.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 and HCC.
Background & 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 up-regulation of inflammatory, metabolic and oncogenic genes, versus simple steatosis. In cholesterol-induced NASH, HCCs (at 8 months) were larger and more numerous than in non-cholesterol-induced steatosis (tumor index high versus no cholesterol, P <0.0001). Aberrantly expressed genes in NASH-HCCs (but not steatosis-HCCs) were enriched in pathways of calcium signaling, insulin signaling, cell adhesion molecules (CAMs) and axon guidance. Twelve aberrantly expressed genes in murine NASH-HCC were significantly dysregulated in human NASH-HCC, including ALCAM, DDIT3, MAP3K6, PAK1, ALDH18A1 and SQLE. In addition, significantly more non-synonymous somatic mutations occurred in NASH-HCCs (335±83.9/sample) than steatosis-HCCs (43±13/sample) (P<0.05), and 80 recurrent mutations were found in NASH-HCCs. Mutations in NASH-HCCs were in calcium and insulin signaling pathways, CAMs, axon guidance and metabolic pathways. Integrated analysis of gene expression and mutations revealed pathways of calcium signaling, insulin signaling, CAMs, axon guidance and metabolism in experimental NASH-HCCs. Among the recurrently mutated genes, 21 were validated in human NASH-HCCs, including MTOR, SDK1, RYR1, RYR2 and CACNA1H.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 and HCC.