Downregulation of A20 increases the cytotoxicity of IFN-gamma in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is a highly fatal disease mandating development of novel, effective therapeutic strategy. Interferon-gamma (IFN-gamma)is a pleiotropic cytokine with immunomodulatory, antiviral, and antitumor effects. Although IFN-gamma is a promising antitumor agent, its application is limited by resistance in tumor cells. A20 is a zinc-finger protein that was initially identified as a gene product induced by tumor necrosis factor a in human umbilical vein endothelial cells. In this study, we found that silencing of A20 combined with IFN-gamma significantly represses cell viability, and induces apoptosis and cell-cycle arrest in HCC cells. By investigating mechanisms implicated in A20 and IFN-gamma-mediated signaling pathways, we revealed that the phosphoinositide 3-kinase/ Akt signaling pathway and antiapoptotic B-cell lymphoma 2 proteins were repressed. Moreover, we also found that phosphorylation of STAT1 and STAT3 was significantly enhanced after the downregulation of A20 in combination with treatment of IFN-gamma. Inhibitor of STAT1 but not STAT3 could block the antitumor effect of IFN-gamma. Therefore, targeting A20 enhances the cytotoxicity of IFN-gamma against HCC cells and may present a promising therapeutic strategy for HCC.