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

Xu A¹, Wang B², Fu J¹, Qin W³, Yu T⁴, Yang Z³, Lu Q⁵, Chen J¹, Chen Y⁶, Wang H⁷.

Author information

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

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.

Copyright © 2018. Published by Elsevier B.V.

KEYWORDS:

CPT1α; DNA damage; Hepatic steatosis; Hepatocarcinogenesis; Ras activation