JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
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JCAD 通过抑制 LATS2 激酶活性促进非酒精性脂肪性肝炎进展为肝癌
DOI：
10.1158/0008-5472.can-17-0229
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发表时间：
2017-10-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Jian
中科院分区：
文献类型：
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作者：
Ye, Juan;Li, Tian-Sheng;Wu, Jian
非酒精性脂肪性肝炎相关肝细胞癌（NASH-HCC）是一种发病率迅速上升的恶性肿瘤。然而，在脂肪变性微环境中驱动HCC发展的机制尚不清楚。在这里，我们报道肥胖相关蛋白JCAD在人类NASH-HCC标本中的表达水平明显高于癌周标本。在多种肝癌细胞系中证实了JCAD的高表达。肝癌细胞中JCAD的过度表达促进了肿瘤的生长和增殖，而JCAD的沉默则产生相反的效果。JCAD与肿瘤抑制激酶LATS2的激酶结构域相互作用，LATS2是Hippo信号通路的核心成分。JCAD过表达抑制LATS2磷酸化该通路中YAP的能力，进而上调CCND1和GLI2，促进肝癌细胞增殖。JCAD是由肝细胞脂肪酸超载诱导的，在nash -癌前病变小鼠模型中高表达，其中磷酸化-YAP与YAP的比例降低。在人类NASH-HCC标本中，JCAD表达和YAP磷酸化模式与小鼠模型相似。我们的研究结果阐明了JCAD的新作用及其在NASH向HCC转变过程中Hippo信号级联中的关键相互作用，对这种情况下的治疗发展具有潜在的意义。(c) 2017 aacr。
Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting. (C) 2017 AACR.