Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1α

Cancer Lett. 2019 Feb 1;442:40-52. doi: 10.1016/j.canlet.2018.10.024. Epub 2018 Oct 26.

Abstract

Aberrant activation of the RAS cascade ubiquitously occurs in human hepatocellular carcinomas (HCC), regardless of rare mutations of RAS. However, the association between the Ras cascade and hepatic steatosis during hepatocarcinogenesis remains under-investigated. Here, the variation in the constitutive activity of Ras signaling and HCC incidence was found in a nonalcoholic fatty liver disease (NAFLD)-HCC mouse model, and Ras activity was induced by hepatic steatosis. Even in hepatocyte-specific expression of KrasG12D (Alb-Cre/KrasG12D, Krashep) mice, mutagenic activation of Ras signaling was still significantly enhanced by NAFLD, with downregulation of negative regulators. Interestingly, hepatic steatosis could be alleviated by persistent activation of Ras, whereas Ras accelerated DNA damage and HCC progression through Carnitine palmitoyltransferase 1A (CPT1α). A close correlation between active Ras and CPT1α was also shown in clinical steatosis peri-tumor tissues of HCC samples and experimental models. CPT1α inhibitor etomoxir (ETO) largely ameliorated active Ras-drived HCC. These findings can provide a novel link between steatosis and Ras activity in liver cancer.

Keywords: CPT1α; DNA damage; Hepatic steatosis; Hepatocarcinogenesis; Ras activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / prevention & control
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism*
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA Damage
  • Diet, High-Fat*
  • Diethylnitrosamine
  • Disease Progression
  • Enzyme Inhibitors / pharmacology
  • Epoxy Compounds / pharmacology
  • Fatty Liver / etiology
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipid Metabolism
  • Liver / drug effects
  • Liver / enzymology*
  • Liver / pathology
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / enzymology*
  • Liver Neoplasms, Experimental / pathology
  • Liver Neoplasms, Experimental / prevention & control
  • Mice, Transgenic
  • Oxidative Stress
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Signal Transduction
  • Time Factors

Substances

  • Enzyme Inhibitors
  • Epoxy Compounds
  • Diethylnitrosamine
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • Proto-Oncogene Proteins p21(ras)
  • etomoxir