Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, 510120, China.
Clinical Trial Institution of Pharmaceuticals, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
Cancer Lett. 2019 Aug 10;457:47-59. doi: 10.1016/j.canlet.2019.04.035. Epub 2019 May 3.
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 β-catenin and CHMP4B. Through this interaction, Vps4A promoted the plasma membrane (PM) localization and exosome release of β-catenin. Silencing Vps4A or CHMP4B decreased the PM localization and exosome sorting of β-catenin. Vps4A overexpression decreased β-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 β-catenin in patients with metastatic HCC was significantly lower compared to that of control patients. In conclusion, through the interaction with CHMP4B and β-catenin, Vps4A regulates the PM localization and exosome sorting of β-catenin, consequently decreases β-catenin signaling, and thereby inhibits EMT and metastasis in HCC.
我们之前报道过 Vps4A 通过影响肝癌（HCC）中外泌体及其亲本细胞的 microRNA 谱发挥肿瘤抑制因子的作用。然而，其潜在机制以及 Vps4A 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 Vps4A 复合物进行了质谱分析，并证实 Vps4A 与 β-catenin 和 CHMP4B 相关。通过这种相互作用，Vps4A 促进了 β-catenin 的质膜（PM）定位和外泌体释放。沉默 Vps4A 或 CHMP4B 会降低 β-catenin 的 PM 定位和外泌体分选。Vps4A 过表达会降低 β-catenin 信号通路，并抑制 HCC 细胞的上皮间质转化（EMT）和迁移。而且，沉默 Vps4A 或 CHMP4B 会促进 HCC 中的 EMT。此外，Vps4A 的表达与 HCC 组织中几种 EMT 标志物的表达显著相关，转移性 HCC 患者外泌体中 β-catenin 的水平明显低于对照组患者。总之，通过与 CHMP4B 和 β-catenin 的相互作用，Vps4A 调节了 β-catenin 的 PM 定位和外泌体分选，从而降低了 β-catenin 信号，进而抑制了 HCC 中的 EMT 和转移。
