Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma
Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma
复制标题
Vps4A介导β-连环蛋白的定位和外泌体释放以抑制肝细胞癌中的上皮间质转化
DOI：
10.1016/j.canlet.2019.04.035
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Min, Jun
中科院分区：
文献类型：
--
作者：
Han, Qingfang;Lv, Lihong;Min, Jun
我们以前报道过Vps 4A通过影响外泌体及其亲本细胞在肝细胞癌（HCC）中的microRNA谱而作为肿瘤抑制因子。然而，潜在的机制以及Vps 4A是否有助于将蛋白质分选到外泌体中尚不清楚。在这里，我们对免疫沉淀的Vps 4A复合物进行了质谱分析，并证实Vps 4A与β-连环蛋白和CHMP 4 B相关。通过这种相互作用，Vps 4A促进了β-连环蛋白的质膜（PM）定位和外泌体释放。沉默Vps 4A或CHMP 4 B降低了β-连环蛋白的PM定位和外泌体分选。Vps 4A过表达可降低β-catenin信号通路，抑制HCC细胞的上皮-间质转化（EMT）和运动。并且，沉默Vps 4A或CHMP 4 B促进HCC中的EMT。此外，Vps 4A的表达与HCC组织中的几种EMT标志物的表达显著相关，并且转移性HCC患者中的外泌体β-连环蛋白水平显著低于对照患者。综上所述，Vps 4A通过与CHMP 4 B和beta-catenin相互作用，调节beta-catenin的PM定位和外泌体分选，从而降低beta-catenin信号传导，从而抑制HCC的EMT和转移。
We previously reported that Vps4A acted as a tumor suppressor by influencing the microRNA profiles of exosomes and their parental cells in hepatocellular carcinoma (HCC). However, the underlying mechanism and if Vps4A contributes to sorting proteins into exosomes are not well known. Here, we performed mass spectrometry analysis of the immunoprecipitated Vps4A complex and confirmed that Vps4A was associated with beta-catenin and CHMP4B. Through this interaction, Vps4A promoted the plasma membrane (PM) localization and exosome release of beta-catenin. Silencing Vps4A or CHMP4B decreased the PM localization and exosome sorting of beta-catenin. Vps4A overexpression decreased beta-catenin signaling pathway and inhibited epithelial-mesenchymal transition (EMT) and motility of HCC cells. And, silencing Vps4A or CHMP4B promoted EMT in HCC. Furthermore, the expression of Vps4A was significantly related to that of several EMT markers in HCC tissues and the level of exosomal beta-catenin in patients with metastatic HCC was significantly lower compared to that of control patients. In conclusion, through the interaction with CHMP4B and beta-catenin, Vps4A regulates the PM localization and exosome sorting of beta-catenin, consequently decreases beta-catenin signaling, and thereby inhibits EMT and metastasis in HCC.