Basolateral CD147 induces hepatocyte polarity loss by E-cadherin ubiquitination and degradation in hepatocellular carcinoma progress.
Basolateral CD147 induces hepatocyte polarity loss by E-cadherin ubiquitination and degradation in hepatocellular carcinoma progress.
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基底外侧 CD147 在肝细胞癌进展过程中通过 E-钙粘蛋白泛素化和降解诱导肝细胞极性丧失。
DOI：
10.1002/hep.29798
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Bian H
中科院分区：
文献类型：
--
作者：
Lu M;Wu J;Hao ZW;Shang YK;Xu J;Nan G;Li X;Chen ZN;Bian H
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粘附和连接的减弱，诱导上皮-间质转化，并最终导致肝细胞癌（HCC）的发生。分化簇147（CD 147）是一种肿瘤相关糖蛋白，可促进上皮-间质转化和HCC的侵袭。然而，CD 147在肝细胞去极化中的功能尚不清楚。在此，我们确定了CD 147在肝组织和HepG 2细胞的肝细胞膜上是基底向极化的。CD 147不仅促进转化生长因子-β1介导的肝细胞极性丧失，而且直接诱导内吞和下调E-钙粘蛋白，从而促进肝细胞去极化。CD 147的过表达诱导Src活化，随后招募泛素连接酶Hakai进行E-钙粘蛋白泛素化和溶酶体降解，导致分配缺陷3表达和β-连环蛋白核转位减少。该信号转导通过CD 147与整合素β1的竞争性结合而启动，其中断了纤连蛋白的Arg-Gly-Asp基序与整合素β1之间的相互作用。靶向整合素α5和β1的特异性抗体逆转了由CD 147过表达诱导的E‐钙粘蛋白和分配缺陷3水平的降低。在人肝组织中，从肝硬化（71.4%）到HCC（10.4%），CD 147极性率显著下降。CD 147极化定位与肝硬化Child-Pugh评分呈负相关（r =-0.6092，P < 0.0001），与HCC分化程度呈正相关（r = 0.2060，P = 0.004）。CD 147极化定位的HCC患者的总生存率显著高于CD 147非极性患者（P = 0.021）。结论：基底外侧膜上的异位CD 147极化分布通过激活CD 147-整合素α5β1-E-钙粘蛋白泛素化分配缺陷3减少和β-连环蛋白易位信号级联反应促进肝细胞去极化，补充了肝癌发生的分子途径。（Hepatology 2018;68：317 - 332）。
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).
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影响因子：
5.3
作者：
Palacios, F;Tushir, JS;D'Souza-Schorey, C
通讯作者：
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影响因子：
3.7
作者：
Kiwanuka, Elizabeth;Andersson, Lauren;Eriksson, Elof
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影响因子：
10.3
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影响因子：
9.2
作者：
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影响因子：
13.5
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