CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT
CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT
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CD166 通过 AKT 抑制 FOXO 蛋白，在肝癌细胞中发挥促癌作用
DOI：
10.3892/or.2014.3226
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发表时间：
2014-08-05
期刊：
影响因子：
4.2
通讯作者：
Sun, Fenyong
中科院分区：
文献类型：
--
作者：
Yu, Wenjun;Wang, Jiayi;Sun, Fenyong
CD166 （Cluster of differentiation 166）是一种细胞表面膜蛋白，在多种上皮肿瘤中被认为是一种有价值的预后标志物。我们之前报道过CD166通过增强肝癌细胞中的YAP功能发挥其促癌作用。然而，YAP并不能完全挽救CD166基因沉默增加的抗癌作用，其下游效应还有待进一步研究。在这里，我们发现CD166的敲低抑制了抗癌FOXO蛋白的磷酸化。与对照组相比，CD166的过表达不仅导致蛋白质降解速度加快，而且使FOX的泛素化积累更多（）。此外，CD166的过表达促进了FOX（）蛋白从细胞核部分向细胞质部分的定位，表明CD166通过改变其亚细胞定位来调节FOX蛋白的稳定性。此外，在体外和体内，CD166同时过表达部分逆转了FOX（）过表达引起的抗癌作用。此外，CD166敲低诱导的抗癌作用和FOXO蛋白的去磷酸化通过AKT的过表达得以恢复。在肝癌组织中，我们还观察到CD166、phospho-AKT、total AKT和phospho-FOXO的高表达水平与total FOXO的低表达水平相关，这表明CD166的上调导致AKT的激活，进而促进FOXO的磷酸化和降解。综上所述，我们的数据表明，在肝癌细胞中，AKT是上游调节因子CD166和下游效应因子FOXO之间的中间介质。破坏CD166与AKT/FOXO轴之间的关系可能成为肝癌患者新的治疗靶点。
Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti-carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOX() compared to the control. Moreover, overexpression of CD166 facilitated FOX() protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOX protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOX() both in vitro and in vivo. Furthermore, CD166 knockdown-induced anti-carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho-FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients.