mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans
mTOR Activation in Liver Tumors Is Associated with Metabolic Syndrome and Non-Alcoholic Steatohepatitis in Both Mouse Models and Humans
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DOI：
10.3390/cancers10120465
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发表时间：
2018-12-01
期刊：
影响因子：
5.2
通讯作者：
Wanibuchi, Hideki
中科院分区：
文献类型：
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作者：
Okuno, Takahiro;Kakehashi, Anna;Wanibuchi, Hideki
非酒精性脂肪性肝炎（NASH）可导致肝纤维化和肝硬化，在某些情况下最终进展为肝细胞癌（HCC）。已经提出各种因素参与NASH的发展。考虑到许多可能的促成因素，我们假设从NASH进展为HCC的机制可能因风险因素而异。在本研究中，我们应用了两种NASH-HCC小鼠模型，并对小鼠肝肿瘤进行了组织病理学和蛋白质组学分析。此外，为了比较小鼠和人类NASH-HCC进展的机制，我们通过免疫组织化学研究了具有代谢综合征和NASH背景的人类HCC以及与肝炎病毒感染相关的HCC。利用蛋白质组学分析证明，在具有代谢综合征特征的小鼠（TSOD小鼠）的肝肿瘤中，与雷帕霉素（mTOR）通路的哺乳动物靶相关的上游调节物被改变。免疫组织化学分析显示，TSOD小鼠的肝脏肿瘤和人类代谢综合征病例的肝癌中mTOR呈特征性磷酸化。这些结果表明，与其他病因的肝肿瘤不同，mTOR通路在代谢综合征和NASH肝肿瘤中特征性活化。
Non-alcoholic steatohepatitis (NASH) can cause liver fibrosis and cirrhosis, with final progression to hepatocellular carcinoma (HCC) in some cases. Various factors have been suggested to be involved in the development of NASH. Considering the many possible contributing factors, we postulated that mechanisms of progression from NASH to HCC could differ depending on the risk factors. In the present study, we applied two mouse models of NASH-HCC and performed histopathological and proteome analyses of mouse liver tumors. Furthermore, to compare the mechanisms of NASH-HCC progression in mice and humans, we investigated HCCs in humans with a background of metabolic syndrome and NASH, as well as HCCs associated with hepatitis virus infection by immunohistochemistry. It was demonstrated that upstream regulators associated with the mammalian target of rapamycin (mTOR) pathway were altered in liver tumors of mice with metabolic syndrome characteristics (TSOD mice) using proteome analysis. Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans. These results indicated that the mTOR pathway is characteristically activated in liver tumors with metabolic syndrome and NASH, unlike liver tumors with other etiologies.