| First Author | Xu A | Year | 2019 |
| Journal | Cancer Lett | Volume | 442 |
| Pages | 40-52 | PubMed ID | 30401637 |
| Mgi Jnum | J:268440 | Mgi Id | MGI:6271832 |
| Doi | 10.1016/j.canlet.2018.10.024 | Citation | Xu A, et al. (2019) Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1alpha. Cancer Lett 442:40-52 |
| abstractText | 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 (CPT1alpha). A close correlation between active Ras and CPT1alpha was also shown in clinical steatosis peri-tumor tissues of HCC samples and experimental models. CPT1alpha inhibitor etomoxir (ETO) largely ameliorated active Ras-drived HCC. These findings can provide a novel link between steatosis and Ras activity in liver cancer. |
