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

Abstract

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.

Detachment Activated CyPA/CD147 Induces Cancer Stem Cell Potential in Non-stem Breast Cancer Cells

“…Furthermore, the co-expression of CD147 and pSTAT3 Y705 was higher in detached cells than in adherent cells (Supplementary Figure S6D). These data are consistent with our recent reports that CD147 undergoes endocytosis, which removes membrane proteins in the cytoplasm, releases the intracellular domains in the nucleus, and contributes to liver cancer progression and poor prognosis (Wu et al, 2017;Yong et al, 2019). Moreover, cytoplasmic CD147 expression was significantly associated with pSTAT3 expression (Spearman r = 0.184, P = 0.03; Supplementary Figure S6E).…”

Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology

“…In contrast, we found a high level of Notch1 and its ligand DLL1 on LCH cells, with transcriptional evidence for Notch signaling within LCH cells (e.g., HES1). MMP inducer CD147, which has been implicated as a Notch regulator in one study performed in the context of liver cancer (49), was expressed at a higher level on DC3/mono-like cells in our study. Our data support the premise of Notch-mediated cross-talk between DC2 and DC3/mono lineages and suggest that a cooperative relationship between these lineages could lead to self-amplifying acquisition of the LCH differentiation program.…”

Identification and Validation of a Prognostic lncRNA Signature for Hepatocellular Carcinoma

“…The biological effects of those determined lncRNAs on HCC have not been investigated or reported. However, our pathway enrichment results suggested the potential influence of these lncRNAs on HCC occurrence and progression via the notch (21,22), p53 (23,24), VEGF (25,26), or Wnt signal transduction pathways (27)(28)(29)(30)(31). These findings offer new evidence to support that lncRNAs whose biological functions have not been reported in published articles could potentially serve as HCC prognostic predictors.…”