CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.
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DOI：
10.1038/onc.2016.400
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发表时间：
2017-04-27
期刊：
影响因子：
8
通讯作者：
Huang W
中科院分区：
文献类型：
--
作者：
Meng Z;Ma X;Du J;Wang X;He M;Gu Y;Zhang J;Han W;Fang Z;Gan X;Van Ness C;Fu X;Schones DE;Xu R;Huang W
肝细胞癌（HCC）是目前仍缺乏有效治疗的最致命的癌症之一。激酶信号转导失调经常被报道是HCC的原因之一。在这项研究中，我们使用生物信息学的方法来确定激酶，调节基因表达的变化，在人类肝癌和两个小鼠肝癌模型。我们确定了钙/钙调蛋白依赖性蛋白激酶II γ亚型（CAMK 2 γ）在肝癌发生中的作用。与野生型对照组相比，CAMK 2 γ−/−小鼠显示出严重增强的化学诱导的肝癌发生。从机制上讲，CAMK 2 γ缺失增强了雷帕霉素复合物1（mTORC 1）的机制靶点的肝脏激活，导致肝细胞过度增殖。雷帕霉素对mTORC 1的抑制有效地减弱了CAMK 2 γ−/−肝脏中肝细胞的代偿性增殖。我们进一步证明了CAMK 2 γ通过抑制IRS 1/AKT信号传导抑制生长因子或胰岛素诱导的mTORC 1活化。总之，我们的研究结果揭示了一种新的机制，CAMK 2 γ拮抗mTORC 1激活在肝癌发生过程中。
Hepatocellular carcinoma (HCC) is one of the most deadly cancers that still lacks effective treatments. Dysregulation of kinase signaling has frequently been reported to contribute to HCC. In this study, we used bioinformatic approaches to identify kinases that regulate gene expression changes in human HCCs and two murine HCC models. We identified a role for calcium/calmodulin-dependent protein kinases II gamma isoform (CAMK2γ) in hepatocarcinogenesis. CAMK2γ−/− mice displayed severely enhanced chemical-induced hepatocarcinogenesis compared with wild-type controls. Mechanistically, CAMK2γ deletion potentiates hepatic activation of mechanistic target of rapamycin complex 1 (mTORC1), which results in hyperproliferation of hepatocytes. Inhibition of mTORC1 by rapamycin effectively attenuats the compensatory proliferation of hepatocytes in CAMK2γ−/− livers. We further demonstrated that CAMK2γ suppressed growth factor- or insulin-induced mTORC1 activation by inhibiting IRS1/AKT signaling. Taken together, our results reveal a novel mechanism by which CAMK2γ antagonizes mTORC1 activation during hepatocarcinogenesis.