Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A.
Aberrant amino acid signaling promotes growth and metastasis of hepatocellular carcinomas through Rab1A-dependent activation of mTORC1 by Rab1A.
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DOI：
10.18632/oncotarget.5175
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发表时间：
2015-08-28
期刊：
影响因子：
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通讯作者：
Zheng XF
中科院分区：
文献类型：
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作者：
Xu BH;Li XX;Yang Y;Zhang MY;Rao HL;Wang HY;Zheng XF
mTORC1是细胞生长和增殖的主要调控因子，是一种公认的抗癌药物靶点。异常mTORC1信号在肝细胞癌（HCC）中很常见，但其潜在机制尚不清楚。Rab1A是一种新发现的mTORC1激活因子，介导Rag GTPases的替代氨基酸（AA）信号分支。由于肝脏是营养感知和代谢稳态的生理中枢，我们研究了Rab1A在HCC中的可能作用。我们发现Rab1A在HCC中经常过表达，从而增强了AA-mTORC1信号的过度活跃，促进了肝癌在体外和体内的恶性生长和转移。此外，Rab1A异常表达与预后不良密切相关。引人注目的是，异常Rab1A过表达导致雷帕霉素敏感性增加，这表明在HCC中，不适当的AA信号激活是一种癌症驱动事件。我们的研究结果进一步表明Rab1A是肝癌预后和个体化mtorc1靶向治疗的有价值的生物标志物。
mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo. Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer.