Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
Biochem Biophys Res Commun. 2020 Feb 5;522(2):525-531. doi: 10.1016/j.bbrc.2019.11.134. Epub 2019 Nov 26.
Interleukin-17 (IL-17) and interferon-γ (IFN-γ), 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-γ 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-γ, was obviously increased in HCC tissues. Higher IL-17 expression in tumor tissues correlated with shorter survival times. IFN-γ apparently increased apoptosis of HCC cells. IL-17 alone had no effect on apoptosis of HCC cells but reversed apoptosis induced by IFN-γ. IFN-γ mildly promoted the expression of protein inhibitor of activated signal transducer and activators of transcription 1 (PIAS1) and the activation of NF-κB, and these effects were greatly enhanced when combined with IL-17. PIAS1 silencing not only further amplified apoptosis induced by IFN-γ alone but also abolished the inhibitory effects of IL-17 on IFN-γ-induced apoptosis in HCC cells. An NF-κB inhibitor obviously decreased the upregulated expression of PIAS1 induced by IFN-γ plus IL-17 and IFN-γ alone. IFN-γ 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-γ 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-κB.
白细胞介素-17（IL-17）和干扰素-γ（IFN-γ）是两种炎症细胞因子，存在于癌变的肝组织中。IL-17 最近被鉴定为肝细胞癌（HCC）的致癌因子，但它的潜在机制在很大程度上仍不清楚。在这里，我们旨在研究 IL-17 和 IFN-γ 之间的相互作用及其对 HCC 细胞凋亡和生长的影响。我们发现，IL-17 的表达，而不是 IFN-γ，在 HCC 组织中明显增加。肿瘤组织中 IL-17 表达较高与较短的生存时间相关。IFN-γ 明显增加 HCC 细胞的凋亡。IL-17 单独对 HCC 细胞凋亡没有影响，但可逆转 IFN-γ 诱导的凋亡。IFN-γ 轻度促进蛋白抑制物激活信号转导和转录激活因子 1（PIAS1）的表达和 NF-κB 的激活，当与 IL-17 结合时，这些作用大大增强。PIAS1 沉默不仅进一步放大了 IFN-γ 单独诱导的凋亡，而且消除了 IL-17 对 HCC 细胞中 IFN-γ 诱导的凋亡的抑制作用。NF-κB 抑制剂明显降低了 IFN-γ 加 IL-17 和 IFN-γ 单独诱导的 PIAS1 表达的上调。IFN-γ 处理在体内异种移植肿瘤模型中延迟了 HCC 细胞的肿瘤生长，这可以通过与 IL-17 联合治疗来大大抑制。总之，IL-17 明显抑制了 IFN-γ 在肝癌细胞中的抗肿瘤作用，并且通过增强 NF-κB 的激活，上调 JAK/STAT1 通路的负反馈调节剂 PIAS1 的表达，从而加速 HCC 的发展。
