International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
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.
Cancer Lett. 2019 Feb 1;442:40-52. doi: 10.1016/j.canlet.2018.10.024. Epub 2018 Oct 26.
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 (Alb-Cre/Kras, Kras) 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.
RAS 级联的异常激活在人类肝细胞癌 (HCC) 中普遍发生，而不管 RAS 的罕见突变如何。然而，Ras 级联在肝癌发生过程中与肝脂肪变性之间的关联仍未得到充分研究。在这里，在非酒精性脂肪性肝病 (NAFLD)-HCC 小鼠模型中发现了 Ras 信号传导的组成性活性和 HCC 发生率的变化，并且肝脂肪变性诱导了 Ras 活性。即使在肝细胞特异性表达 Kras（Alb-Cre/Kras，Kras）的小鼠中，Ras 信号传导的诱变激活仍然被 NAFLD 显著增强，同时负调节因子下调。有趣的是，持续激活 Ras 可以减轻肝脂肪变性，而 Ras 通过肉毒碱棕榈酰基转移酶 1A (CPT1α) 加速 DNA 损伤和 HCC 进展。在 HCC 样本和实验模型的临床脂肪变性肿瘤周围组织中也显示出活性 Ras 与 CPT1α 之间的密切相关性。CPT1α 抑制剂 etomoxir (ETO) 可显著改善活性 Ras 驱动的 HCC。这些发现可以为脂肪变性和肝癌中的 Ras 活性之间提供新的联系。
