CD97 Promotes Tumor Aggressiveness Through the Traditional G Protein–Coupled Receptor–Mediated Signaling in Hepatocellular Carcinoma

Abstract

Cluster of differentiation 97 (CD97) is a member of the epidermal growth factor seven-transmembrane family belonging to the class B G protein-coupled receptors (GPCRs). The protein affects tumor aggressiveness through its cellular ligand CD55 stimulation and exhibits adhesive properties. Studies have demonstrated the involvement of CD97 in dedifferentiation, migration, invasiveness, and metastasis of tumors. However, little information is currently available on the specific role of CD97 in hepatocellular carcinoma (HCC). Here, we have shown that CD97 up-regulation in HCCs is positively correlated with tumor metastasis. Functionally, CD97 promoted cell migration and invasion in vitro. In an in vivo mouse model, overexpression of CD97 in HCC cells led to accelerated lung metastasis. Mechanistically, CD97 cooperated with the altered regulator, GPCR kinase 6 (GRK6), to mediate GPCR desensitization and internalization. Down-regulation of GRK6 suppressed CD97 internalization and promoted CD97 expression. Integrated regulatory interactions between CD97 and GRK6 stimulated downstream matrix metalloproteinase 2/9 secretion and, consequently, HCC metastasis. Conclusion: Our collective findings support the utility of CD97 as an effective potential prognosticator and therapeutic target for HCC.

G Protein-Coupling of Adhesion GPCRs ADGRE2/EMR2 and ADGRE5/CD97, and Activation of G Protein Signalling by an Anti-EMR2 Antibody

“…CD97 coupling via G α12/13 has been indicated, involving heterodimerization with the lysophosphatidic acid receptor LPAR1 31 ; and the PTX-sensitive lysophosphatidylethanolamine (LPE) response of LPAR1 in MDA-MB-231 cells requires CD97 42 . GRK6-mediated desensitisation of CD97 33 further indicates its participation in classical GPCR signalling mechanisms. In view of the complexity of interpreting signalling pathways from primary cell data, we were interested to identify defined recombinant systems to investigate aGPCR signalling mechanisms under well-controlled conditions.…”

Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis

“…CD97, which is dependent on interaction with CD55 in order to lead to downstream signalling, is usually internalised following activation by the binding of β‐arrestin‐1, preventing over‐stimulation. However, in HCC, it was found that aberrant internalisation, due to disruption of GRK6‐mediated arrestin binding, leads to overexpression of CD97 and increased secretion of MMP‐2 and MMP‐9 .…”

Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion

“…Although CD97 is not directly involved in trophoblast invasion, it reportedly regulates the invasiveness and adhesion of cancer cells [ 31 – 32 ] . Indeed, another study reported that CD97 stimulated tumor migration via G-protein-coupled receptor-mediated signaling in hepatocellular carcinoma [ 33 ] . Furthermore, CD97 synergistically initiated endothelial cell invasion by co-engaging α5β1 integrin and chondroitin sulfate proteoglycan (CSPG)4 [ 34 ] .…”