Yin Lei, Fang Zheng, Shen Ning-Jia, Qiu Ying-He, Li Ai-Jun, Zhang Yong-Jie
The Second Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Drug Des Devel Ther. 2017 Sep 26;11:2841-2850. doi: 10.2147/DDDT.S135993. eCollection 2017.
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.
肝细胞癌（HCC）是一种高致死性疾病，需要开发新的有效治疗策略。干扰素-γ（IFN-γ）是一种具有免疫调节、抗病毒和抗肿瘤作用的多效性细胞因子。尽管IFN-γ是一种有前景的抗肿瘤药物，但其应用受到肿瘤细胞耐药性的限制。A20是一种锌指蛋白，最初被鉴定为肿瘤坏死因子α在人脐静脉内皮细胞中诱导产生的基因产物。在本研究中，我们发现沉默A20并联合IFN-γ可显著抑制肝癌细胞的活力，并诱导其凋亡和细胞周期停滞。通过研究A20和IFN-γ介导的信号通路相关机制，我们发现磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路和抗凋亡的B细胞淋巴瘤2（Bcl-2）蛋白受到抑制。此外，我们还发现，在下调A20并联合IFN-γ处理后，信号转导和转录激活因子1（STAT1）和信号转导和转录激活因子3（STAT3）的磷酸化显著增强。STAT1抑制剂而非STAT3抑制剂可阻断IFN-γ的抗肿瘤作用。因此，靶向A20可增强IFN-γ对肝癌细胞的细胞毒性，可能为肝癌提供一种有前景的治疗策略。
