Abstract
Hepatocellular carcinoma (HCC) is characterized by high prevalence, morbidity, and mortality. Liver cancer is the sixth most common cancer worldwide; and its subtype, HCC, accounts for nearly 80% of cases. HCC progresses rapidly, and to date, there is no efficacious treatment for advanced HCC. Tetraspanins belong to a protein family characterized by four transmembrane domains. Thirty-three known tetraspanins are widely expressed on the surface of most nucleated cells and play important roles in different biological processes. In our review, we summarize the functions of tetraspanins and their underlying mechanism in the life cycle of HCC, from its initiation, progression, and finally to treatment. CD9, TSPAN15, and TSPAN31 can promote HCC cell proliferation or suppress apoptosis. CD63, CD151, and TSPAN8 can also facilitate HCC metastasis, while CD82 serves as a suppressor of metastasis. TSPAN1, TSPAN8, and CD151 act as prognosis indicators and are inversely correlated to the overall survival rate of HCC patients. In addition, we discuss the potential of role of the tetraspanin family proteins as novel therapeutic targets and as an approach to overcome drug resistance, and also provide suggestions for further research.
Highlights
Liver cancer was the sixth most common cancer worldwide in 2018, with an annual death toll of over 782,000
Similar to CD151, human umbilical vein endothelial cells (HUVECs) were co-cultured with TSPAN8 knockdown Hepatocellular carcinoma (HCC) cells to reduce HUVEC tube formation, which is an indicator of low angiogenic activity, when compared with HUVEC cells cocultured with control HCC cells [46]
It is reported that in HCC the expression of TSPAN8 is regulated by astrocyte elevated gene-1 (AEG-1), an oncogene upregulated in various cancers; and TSPAN8 acts as one essential effector on its pro-metastasis effect [46]
Summary
Liver cancer was the sixth most common cancer worldwide in 2018, with an annual death toll of over 782,000. Tetraspanins can make an impact on their partners directly by influencing the Abbreviations: HCC, hepatocellular carcinoma; TM, transmembrane; ECL, extracellular loop; ADAM10, A Disintegrin And Metalloprotease Domain 10; HSECs, hepatic sinusoidal endothelial cells; VCAM-1, Vascular Cell Adhesion Molecule-1; CTGF, connective tissue growth factor; EpCAM, epithelial cell adhesion molecule; CK19, cytokeratin-19; YAP, Yes-associated Protein; CREB, cAMP-response element-binding protein; KLF4, Krüppel-like factor 4; NET-1, neuroepithelial transforming gene 1; GEF, guanine nucleotide exchange factor; CDK4, cyclin-dependent kinase 4; Rb, retinoblastoma; MMP9, metalloproteinase 9; GPCRs, G protein-coupled receptors; TEMs, membrane microdomains; HGFR, hepatocyte growth factor receptor; EGFR, epidermal growth factor receptor; TGFb, transforming growth factor-b; HUVECs, human umbilical vein endothelial cells; EMT, epithelial–mesenchymal transition; ceRNAs, competing endogenous RNAs; ADAM12m, A Disintegrin And Metalloproteinase Domain 12; AEG-1, astrocyte elevated gene-1; CRC, colorectal cancer; TSPAN-LEL, TSPAN8 large extracellular loop; TIMP-1, metalloproteinase-1; HSCs, hepatic stellate cells; VEGF, vascular endothelial growth factor; NS, not significant. We present the interaction between tetraspanins and HCC and their potential as targets for HCC treatment
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