Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma
Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma
复制标题
DOI：
10.1002/path.5316
复制
发表时间：
2019-10
期刊：
影响因子：
--
通讯作者：
Yu‐Le Yong;Renyu Zhang;Ze-Kun Liu;D. Wei;Yu-Kui Shang;Jiao Wu;Zhi-Yun Zhang;Can Li;Zhi-Nan Chen
中科院分区：
文献类型：
--
作者：
Yu‐Le Yong;Renyu Zhang;Ze-Kun Liu;D. Wei;Yu-Kui Shang;Jiao Wu;Zhi-Yun Zhang;Can Li;Zhi-Nan Chen
γ-分泌酶复合物是一种参与多种I型跨膜蛋白的膜内切割的早老素依赖性γ-酰基蛋白酶。作为I型跨膜蛋白，CD 147在肝癌细胞中高度表达，并促进细胞增殖、迁移和侵袭。然而，CD 147如何促进癌细胞增殖的直接潜在机制尚不清楚。在这里，我们证明了CD 147通过γ-分泌酶在赖氨酸231处进行膜内切割以释放其细胞内结构域（ICD）。CD 147 ICD的核转位通过直接结合到NOTCH 1启动子来调节Notch 1的表达，并促进Notch信号通路的激活。同时，CD 147 ICD的过表达通过Notch 1信号传导促进癌细胞增殖。在102例人肝细胞癌（HCC）组织中，核CD 147 ICD表达阳性率高的患者的总生存率明显低于核CD 147 ICD表达阳性率低的患者。我们证实，核CD 147 ICD预测人类肝癌预后不良。在原位移植HCC小鼠模型中，γ分泌酶复合物抑制剂和CD 147定向抗体的联合治疗显示出比单药治疗更好的疗效。总之，CD 147被γ-分泌酶切割并将CD 147 ICD释放到细胞核，通过直接结合NOTCH 1启动子促进Notch 1表达。© 2019大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
The γ‐secretase complex is a presenilin‐dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ‐secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ‐secretase complex inhibitor and CD147‐directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ‐secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.