Basolateral CD147 Induces Hepatocyte Polarity Loss by E-cadherin Ubiquitination and Degradation in Hepatocellular Carcinoma Progress

Abstract

Hepatocytes are epithelial cells with highly specialized polarity. The disorder and loss of hepatocyte polarity lead to the weakness of cell adhesion and connection, the induction of epithelial-mesenchymal transition and eventually the occurrence of hepatocellular carcinoma (HCC). 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 the transforming growth factor-β1-mediated hepatocyte polarity loss, but also directly induced endocytosis and downregulation of E-cadherin which contributed to hepatocyte depolarization. Overexpression of CD147 induced Src activation, subsequently recruited ubiquitin ligase Hakai for E-cadherin ubiquitination and lysosomal degradation, leading to decrease of Par3 expression and β-catenin nuclear translocation. This signal transduction was initiated by competitively binding of CD147 with integrin β1 that interrupted the interaction between Arg-Gly-Asp motif of fibronectin and integrin β1. The specific antibodies targeting integrin α5 and β1 reversed the decrease of E-cadherin and Par3 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 in human liver cirrhosis (r = -0.6092, P < 0.0001) and positively correlated with differentiation grade in HCC (r = 0.2060, P = 0.004). HCC patients with CD147-polarized localization had significantly better overall survival than patients with CD147 non-polarity (P = 0.021). Conclusion：The ectopic CD147-polarized distribution on basolateral membrane promotes hepatocyte depolarization by activation of "CD147–intergrin α5β1–E-cadherin ubiquitination–Par3 decrease & β-catenin translocation" signaling cascade that replenishes a novel molecular pathway in hepatic carcinogenesis. This article is protected by copyright. All rights reserved.

http://ift.tt/2Du8ooa