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

An Xu; Bibo Wang; Jing Fu; Wenhao Qin; Ting Yu; Zhishi Yang; Qingjun Lu; Jingyi Chen; Yao Chen; Hongyang Wang

doi:10.1016/j.canlet.2018.10.024

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.

Authors

An Xu¹, Bibo Wang², Jing Fu¹, Wenhao Qin³, Ting Yu⁴, Zhishi Yang³, Qingjun Lu⁵, Jingyi Chen¹, Yao Chen⁶, Hongyang Wang⁷

Affiliations

¹ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
² International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
³ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
⁴ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Fuling Central Hospital of Chongqing City, Chongqing, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China. Electronic address: chyyn2003@163.com.
⁷ International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; Fuling Central Hospital of Chongqing City, Chongqing, China. Electronic address: hywangk@vip.sina.com.

PMID: 30401637
DOI: 10.1016/j.canlet.2018.10.024

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 Kras^G12D (Alb-Cre/Kras^G12D, Kras^hep) 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