Downregulation of A20 increases the cytotoxicity of IFN-γ in hepatocellular carcinoma cells.
Downregulation of A20 increases the cytotoxicity of IFN-γ in hepatocellular carcinoma cells.
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A20 下调增加 IFN-γ 在肝细胞癌细胞中的细胞毒性
DOI：
10.2147/dddt.s135993
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Zhang YJ
中科院分区：
文献类型：
--
作者：
Yin L;Fang Z;Shen NJ;Qiu YH;Li AJ;Zhang YJ
肝细胞癌（HCC）是一种高度致命的疾病，需要开发新颖、有效的治疗策略。干扰素-γ (IFN-γ) 是一种多效细胞因子，具有免疫调节、抗病毒和抗肿瘤作用。尽管IFN-γ是一种有前途的抗肿瘤药物，但其应用受到肿瘤细胞耐药性的限制。 A20是一种锌指蛋白，最初被鉴定为人脐静脉内皮细胞中肿瘤坏死因子α诱导的基因产物。在这项研究中，我们发现 A20 沉默与 IFN-γ 联合显着抑制 HCC 细胞的细胞活力，并诱导细胞凋亡和细胞周期停滞。通过研究 A20 和 IFN-γ 介导的信号通路中涉及的机制，我们发现磷酸肌醇 3-激酶/Akt 信号通路和抗凋亡 B 细胞淋巴瘤 2 蛋白受到抑制。此外，我们还发现下调A20并结合IFN-γ治疗后，STAT1和STAT3的磷酸化显着增强。 STAT1 抑制剂而非 STAT3 抑制剂可以阻断 IFN-γ 的抗肿瘤作用。因此，靶向 A20 增强了 IFN-γ 对 HCC 细胞的细胞毒性，可能为 HCC 提供一种有前景的治疗策略。
Hepatocellular carcinoma (HCC) is a highly fatal disease mandating development of novel, effective therapeutic strategy. Interferon-gamma (IFN-γ) is a pleiotropic cytokine with immunomodulatory, antiviral, and antitumor effects. Although IFN-γ 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 α in human umbilical vein endothelial cells. In this study, we found that silencing of A20 combined with IFN-γ significantly represses cell viability, and induces apoptosis and cell-cycle arrest in HCC cells. By investigating mechanisms implicated in A20 and IFN-γ-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-γ. Inhibitor of STAT1 but not STAT3 could block the antitumor effect of IFN-γ. Therefore, targeting A20 enhances the cytotoxicity of IFN-γ against HCC cells and may present a promising therapeutic strategy for HCC.