CD97 Promotes Tumor Aggressiveness Through The Traditional G Protein-Coupled Receptor-mediated Signaling In Hepatocellular Carcinoma

Human hepatocellular carcinoma(HCC)is emerging as the sixth most common carcinoma and the third leading cause of cancer-associated mortality worldwide.Aggressiveness,invasiveness(in particular,intrahepatic)and frequent postoperative recurrence are the most significant characteristics of HCC.In this regard,elucidation of the mechanisms underlying HCC initiation and early metastasis is essential to improve both early diagnosis and prognosis.At present,the mechanism study underlying the development of HCC mainly focuses on genetics,epigenetics and the regulation of related signaling pathways.The initiation and development of HCC is highly related to the abnormal expression of oncogene and inactivation of tumor suppressor.The occurrence and metastasis of HCC involves cell dysfunction,virus-mediated immune microenvironment alteration,matrix destruction,angiogenesis and many other processes,including multifactor-induced and multiple-gene involved complex pathological process.Therefore,it is an important step to ensure clinical therapeutic effect and improve survival rate by excavating efficient occurrence or metastasis related biomarkers.With the aid of gene knockout technique and mouse tail vein xenograft model,researchers have been explaining the mechanism of the development of HCC,however quantities of HCC metastasis related genes remain uncovered.Cluster of differentiation 97(CD97)is a member of the epidermal growth factor-seven transmembrane(EGF-TM7)family belonging to the class B G-protein-coupled receptors(GPCR).The protein affects tumor aggressiveness through its cellular ligand CD55 stimulation,and exhibits adhesive properties.Previous 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 upregulation 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,G protein-coupled receptor kinase 6(GRK6),to mediate GPCR desensitization and internalization.Downregulation of GRK6 suppressed CD97 internalization and promoted CD97 expression.Integrated regulatory interactions between CD97 and GRK6 stimulated downstream matrix metalloproteinase(MMP)2/9 secretion,and consequently,HCC metastasis.To sum up,our collective findings support the utility of CD97 as an effective potential prognosticator and therapeutic target for HCC.