You Xiahong, Dou Longyu, Tan Mingjia, Xiong Xiufang, Sun Yi
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China.
Cancer Center of Zhejiang University, Hangzhou 310029, China.
Life Med. 2024 May 23;3(3):lnae023. doi: 10.1093/lifemedi/lnae023. eCollection 2024 Jun.
SHOC2 is a scaffold protein that activates the RAS-MAPK signal. Our recent study showed that SHOC2 is also a negative regulator of the mTORC1 signal in lung cancer cells. Whether and how SHOC2 differentially regulates the RAS-MAPK vs. the mTORC1 signals in liver cancer remains unknown. Here, we showed that is overexpressed in human liver cancer tissues, and SHOC2 overexpression promotes the growth and survival of liver cancer cells via activation of the RAS-MAPK signal, although the mTORC1 signal is inactivated. knockdown suppresses the growth of liver cancer cells mainly through inactivating the RAS-MAPK signal. Thus, in the cell culture models, SHOC2 regulation of growth is dependent of the RAS-MAPK but not the mTORC1 signal. Interestingly, in a mouse liver cancer model induced by diethylnitrosamine (DEN)-high-fat diet (HFD), hepatocyte-specific deletion inactivates the Ras-Mapk signal but has no effect in liver tumorigenesis. However, in the loss-induced liver cancer model, deletion further activates mTorc1 without affecting the Ras-Mapk signal and promotes liver tumorigenesis. Collectively, it appears that SHOC2 could act as either an oncogene (via activating the MAPK signal) or a tumor suppressor (via inactivating the mTORC1 signal) in the manner dependent of the dominancy of the MAPK vs. mTORC1 signals.
SHOC2是一种激活RAS-MAPK信号的支架蛋白。我们最近的研究表明，SHOC2在肺癌细胞中也是mTORC1信号的负调节因子。SHOC2在肝癌中是否以及如何差异调节RAS-MAPK与mTORC1信号仍不清楚。在这里，我们表明SHOC2在人类肝癌组织中过表达，并且SHOC2过表达通过激活RAS-MAPK信号促进肝癌细胞的生长和存活，尽管mTORC1信号被灭活。SHOC2敲低主要通过使RAS-MAPK信号失活来抑制肝癌细胞的生长。因此，在细胞培养模型中，SHOC2对生长的调节依赖于RAS-MAPK而不是mTORC1信号。有趣的是，在由二乙基亚硝胺（DEN）-高脂饮食（HFD）诱导的小鼠肝癌模型中，肝细胞特异性SHOC2缺失使Ras-Mapk信号失活，但对肝肿瘤发生没有影响。然而，在SHOC2缺失诱导的肝癌模型中，SHOC2缺失进一步激活mTorc1而不影响Ras-Mapk信号并促进肝肿瘤发生。总体而言，SHOC2似乎可以以依赖于MAPK与mTORC1信号优势的方式充当癌基因（通过激活MAPK信号）或肿瘤抑制因子（通过使mTORC1信号失活）。
