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 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). Conclusion: 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).

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

“…After excluding nonspecific antigenic interference, the integral optical density summary (IOD SUM) was obtained. All images were measured by using the same conditions . Based on the IOD SUM of Notch1, the patients were divided into two groups, Notch1‐High and Notch1‐Low according to the median value.…”

“…CD147, encoded by the BSG gene, is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily that is highly expressed in various cancer cells, such as breast cancer , non‐small cell lung cancer , and HCC. In HCC cells, overexpression of CD147 promotes dedifferentiation , invasion and migration of HCC cells and is significantly associated with the poor survival of patients with HCC . Moreover, studies have shown that CD147 is shed by ADAM10 , which is a precondition for hydrolysis by the γ‐secretase complex.…”

CBLL1 is highly expressed in non‐small cell lung cancer and promotes cell proliferation and invasion

“…Studies have shown that CBLL1 plays an important role in tumorigenesis . First, CBLL1 expression is upregulated in human colon and gastric cancer tissues, and CBLL1 has been reported to induce anchorage‐dependent cell growth.…”

“…Studies have shown that CBLL1 plays an important role in tumorigenesis. [15][16][17][18][19][20][21][22][23][24] First, CBLL1 expression is upregulated in human colon and gastric cancer tissues, and CBLL1 has been reported to induce anchorage-dependent cell growth. In colorectal epithelial cells, the autocrine Slit-Robo pathway promotes CBLL1-mediated downregulation of E-cadherin to promote carcinogenesis.…”

CD147 promotes progression of head and neck squamous cell carcinoma via NF‐kappa B signaling

“…CD147, a transmembrane glycoprotein, belongs to the immunoglobulin superfamily and is widely expressed on the surface of cancer cells . Reports showed that CD147 was over‐expressed in many types of cancer, such as human malignant melanoma, hepatocellular carcinoma, lung cancer, gastric cancer, breast cancer and so on . CD147 is also reported to involve in tumor progression, angiogenic function and immune response …”