Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, China.
College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, China.
Hepatology. 2018 Jul;68(1):317-332. doi: 10.1002/hep.29798. Epub 2018 Mar 23.
Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity leads to a weakness of cell adhesion and connection, the induction of epithelial-mesenchymal transition, and eventually the occurrence of hepatocellular carcinoma (HCC). Cluster of differentiation 147 (CD147), a tumor-related glycoprotein, promotes epithelial-mesenchymal transition and the invasion of HCC. However, the function of CD147 in hepatocyte depolarization is unknown. Here we identified that CD147 was basolaterally polarized in hepatocyte membrane of liver tissues and HepG2 cells. CD147 not only promoted transforming growth factor-β1-mediated hepatocyte polarity loss but also directly induced endocytosis and down-regulation of E-cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation and subsequently recruited ubiquitin ligase Hakai for E-cadherin ubiquitination and lysosomal degradation, leading to decreases of partitioning defective 3 expression and β-catenin nuclear translocation. This signal transduction was initiated by competitive binding of CD147 with integrin β1 that interrupted the interaction between the Arg-Gly-Asp motif of fibronectin and integrin β1. The specific antibodies targeting integrin α5 and β1 reversed the decrease of E-cadherin and partitioning defective 3 levels induced by CD147 overexpression. In human liver tissues, CD147 polarity rates significantly declined from liver cirrhosis (71.4%) to HCC (10.4%). CD147-polarized localization negatively correlated with Child-Pugh scores in human liver cirrhosis (r = -0.6092, P < 0.0001) and positively correlated with differentiation grades in HCC (r = 0.2060, P = 0.004). HCC patients with CD147-polarized localization had significantly better overall survival than patients with CD147 nonpolarity (P = 0.021).
The ectopic CD147-polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of the CD147-integrin α5β1-E-cadherin ubiquitination-partitioning defective 3 decrease and β-catenin translocation signaling cascade, replenishing a molecular pathway in hepatic carcinogenesis. (Hepatology 2018;68:317-332).
肝细胞是具有高度特化极性的上皮细胞。肝细胞极性的紊乱和丧失导致细胞黏附连接力减弱，诱导上皮-间充质转化，最终发生肝细胞癌（HCC）。CD147 是一种肿瘤相关糖蛋白，促进上皮-间充质转化和 HCC 的侵袭。然而，CD147 在肝细胞去极化中的作用尚不清楚。本研究鉴定出 CD147 在肝组织和 HepG2 细胞的肝细胞质膜基底外侧呈极化分布。CD147 不仅促进转化生长因子-β1 介导的肝细胞极性丧失，而且直接诱导 E-钙黏蛋白内吞和下调，导致肝细胞去极化。CD147 的过表达诱导Src 激活，随后募集泛素连接酶 Hakai 对 E-钙黏蛋白进行泛素化和溶酶体降解，导致分隔缺陷 3 表达和 β-连环蛋白核转位减少。该信号转导是由 CD147 与整合素β1 的竞争结合起始的，这种结合中断了纤连蛋白 Arg-Gly-Asp 基序与整合素β1 的相互作用。针对整合素α5 和β1 的特异性抗体逆转了 CD147 过表达诱导的 E-钙黏蛋白和分隔缺陷 3 水平的降低。在人类肝组织中，从肝硬化（71.4%）到 HCC（10.4%），CD147 的极性率显著下降。CD147 极化定位与人类肝硬化的 Child-Pugh 评分呈负相关（r = -0.6092，P < 0.0001），与 HCC 的分化等级呈正相关（r = 0.2060，P = 0.004）。CD147 极化定位的 HCC 患者总生存期明显长于 CD147 非极性患者（P = 0.021）。
细胞表面异常极化分布的 CD147 通过激活 CD147-整合素α5β1-E-钙黏蛋白泛素化-分隔缺陷 3 减少和 β-连环蛋白转位信号级联反应促进肝细胞去极化，为肝发生提供了一个分子途径。（Hepatology 2018;68:317-332）。
