Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1α
Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1α
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饮食诱导的肝脂肪变性通过 CPT1α 激活 Ras 促进肝癌发生
DOI：
10.1016/j.canlet.2018.10.024
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发表时间：
2019
期刊：
影响因子：
9.7
通讯作者：
王红阳
中科院分区：
文献类型：
--
作者：
徐安;王碧波;付静;秦文昊;余挺;杨知时;卢青军;陈静怡;陈瑶;王红阳
RAS级联的异常激活普遍发生在人肝细胞癌（HCC）中，无论RAS的罕见突变如何。然而，在肝癌发生过程中Ras级联和肝脂肪变性之间的关联仍然研究不足。在此，在非酒精性脂肪性肝病（NAFLD）-HCC小鼠模型中发现Ras信号传导的组成性活性和HCC发病率的变化，并且Ras活性由肝脂肪变性诱导。即使在肝细胞特异性表达的KrasG 12 D（Alb-Cre/KrasG 12 D，Krashep）小鼠中，NAFLD仍显著增强Ras信号转导的诱变激活，并下调负调节因子。有趣的是，Ras的持续激活可以减轻肝脂肪变性，而Ras通过肉毒碱棕榈酰转移酶1A（CPT 1 α）加速DNA损伤和HCC进展。在肝癌组织和实验模型中，活性Ras与CPT 1 α之间也存在密切的相关性。CPT 1 α抑制剂依托莫西（ETO）可显著改善活性Ras驱动的HCC。这些发现可以提供肝癌中脂肪变性与Ras活性之间的新联系。
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.