MEK1 signaling promotes self-renewal and tumorigenicity of liver cancer stem cells via maintaining SIRT1 protein stabilization.
MEK1 signaling promotes self-renewal and tumorigenicity of liver cancer stem cells via maintaining SIRT1 protein stabilization.
复制标题
MEK1信号通过维持SIRT1蛋白稳定促进肝癌干细胞的自我更新和致瘤性
DOI：
10.18632/oncotarget.7972
复制
发表时间：
2016-04-12
期刊：
影响因子：
--
通讯作者：
Qian C
中科院分区：
文献类型：
--
作者：
Cheng J;Liu C;Liu L;Chen X;Shan J;Shen J;Zhu W;Qian C
肝细胞癌是导致癌症死亡的第三大原因。这种高死亡率通常被归因于残留的癌症干细胞(CSCs)的存在。同时，MEK1信号被认为是肝细胞癌维持和发展的关键分子。然而，还没有人弄清楚MEK1信号如何调节肝脏CSCs自我更新的特定机制。在这项研究中，我们发现在体外和体内条件下，抑制或耗尽MEK1可以显著降低肝脏CSCs的自我更新和肿瘤生长。此外，我们还证明MEK1信号通过维持SIRT1水平来促进肝脏CSCs的自我更新和致瘤性。从机制上讲，MEK1信号通过激活SIRT1泛素化来保持SIRT1蛋白的稳定，从而抑制蛋白酶体的降解。临床分析表明，MEK1和SIRT1的共同表达与患者的生存不良有关。我们的发现表明，MEK1-SIRT1可以作为一种新的诊断生物标志物，抑制MEK1可能是靶向治疗肝脏CSCs的一个可行的治疗选择。
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death. This high mortality has been commonly attributed to the presence of residual cancer stem cells (CSCs). Meanwhile, MEK1 signaling is regarded as a key molecular in HCC maintenance and development. However, nobody has figured out the particular mechanisms that how MEK1 signaling regulates liver CSCs self-renewal. In this study, we show that inhibition or depletion of MEK1 can significantly decrease liver CSCs self-renewal and tumor growth both in vitro and vivo conditions. Furthermore, we demonstrate that MEK1 signaling promotes liver CSCs self-renewal and tumorigenicity by maintaining SIRT1 level. Mechanistically, MEK1 signaling keeps SIRT1 protein stabilization through activating SIRT1 ubiquitination, which inhibits proteasomal degradation. Clinical analysis shows that patients co-expression of MEK1 and SIRT1 are associated with poor survival. Our finding indicates that MEK1-SIRT1 can act as a novel diagnostic biomarker and inhibition of MEK1 may be a viable therapeutic option for targeting liver CSCs treatment.