Biochemical and Biophysical Research Communications, Vol.522, No.2, 525-531, 2020
IL-17 promotes hepatocellular carcinoma through inhibiting apoptosis induced by IFN-gamma
Interleukin-17 (IL-17) and interferon-gamma (IFN-gamma), two inflammatory cytokines, are present in cancerous liver tissues. IL-17 was recently identified as an oncogenic factor in hepatocellular carcinoma (HCC), but its underlying mechanisms are largely obscure. Here, we aimed to investigate the interaction between IL-17 and IFN-gamma and its influence on HCC cell apoptosis and growth in vitro and in vivo. We found that the expression of IL-17, but not IFN-gamma, was obviously increased in HCC tissues. Higher IL-17 expression in tumor tissues correlated with shorter survival times. IFN-gamma apparently increased apoptosis of HCC cells. IL-17 alone had no effect on apoptosis of HCC cells but reversed apoptosis induced by IFN-gamma. IFN-gamma mildly promoted the expression of protein inhibitor of activated signal transducer and activators of transcription 1 (PIAS1) and the activation of NF-KB, and these effects were greatly enhanced when combined with IL-17. PIAS1 silencing not only further amplified apoptosis induced by IFN-y alone but also abolished the inhibitory effects of IL-17 on IFN-gamma-induced apoptosis in HCC cells. An NF-kappa B inhibitor obviously decreased the upregulated expression of PIAS1 induced by IFN-gamma plus IL-17 and IFN-gamma alone. IFN-gamma treatment retarded the tumor growth of HCC cells in an in vivo xenograft tumor model, which could be largely inhibited by combined treatment with IL-17. In conclusion, IL-17 obviously inhibits the antitumor effects of IFN-gamma in hepatoma cells and, in turn, accelerates HCC development through upregulating the expression of the negative feedback regulator PIAS1 of the JAK/STAT1 pathway via enhancing activation of NF-kappa B. (C) 2019 Elsevier Inc. All rights reserved.