HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma
HRG switches TNFR1-mediated cell survival to apoptosis in Hepatocellular Carcinoma
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HRG 将 TNFR1 介导的肝细胞癌细胞存活转变为细胞凋亡
DOI：
10.7150/thno.47286
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Liu, Li
中科院分区：
文献类型：
--
作者：
Zou, Xuejing;Zhang, Dongyan;Liu, Li
背景：肿瘤坏死因子受体 1 (TNFR1) 信号传导在肝细胞癌 (HCC) 的发展中发挥多效性作用。 TNFR1-复合物 I 的形成支持细胞存活，而 TNFR1-复合物 II 导致细胞凋亡，并且这些 TNFR1 复合物在 HCC 中转化的潜在机制仍不清楚。方法：通过GST Pulldown实验、免疫沉淀和质谱鉴定TNFR1的相互作用蛋白。进行体外和体内测定，以探索富含组氨酸糖蛋白（HRG）调节 TNFR1 信号的生物学特征和机制。利用公共数据库和 HCC 样本的数据来分析 HRG 的表达和临床相关性。结果：HRG 直接与 TNFR1 相互作用，并通过减少 Lys(K)-48 泛素化介导的降解来稳定 TNFR1 蛋白。 HRG 过表达通过上调 TNFR1 的 Lys(K)-63 泛素化促进了 TNFR1 复合物 II 的形成。此外，HRG 的过度表达通过削弱 TNFR1 存在下 NF-κB 信号传导的激活来抑制促生存基因的表达。此外，HRG 的下调是 HCC 中 NF-κB 激活反馈抑制的结果。与 HRG 诱导后 TNFR1 信号转导的促凋亡开关一致，HRG 的过度表达抑制了 HCC 中的细胞增殖并增加了细胞凋亡。结论：我们的研究结果表明，HRG 通过使 TNFR1 倾向于促凋亡细胞表型，在抑制 HCC 方面发挥着至关重要的作用。恢复 HCC 组织中的 HRG 表达可能是一种有前途的药理学方法，可以通过将细胞命运从细胞存活转变为细胞凋亡来阻止肿瘤进展。
Background: Tumor necrosis factor receptor 1 (TNFR1) signaling plays a pleiotropic role in the development of hepatocellular carcinoma (HCC). The formation of TNFR1-complex I supports cell survival while TNFR1-complex II leads to apoptosis, and the underlying mechanisms of the transformation of these TNFR1 complexes in HCC remain poorly defined. Methods: The interaction protein of TNFR1 was identified by GST pulldown assay, immunoprecipitation and mass spectrometry. In vitro and in vivo assay were performed to explore the biological features and mechanisms underlying the regulation of TNFR1 signals by histidine-rich glycoprotein (HRG). Data from the public databases and HCC samples were utilized to analyze the expression and clinical relevance of HRG. Results: HRG directly interacted with TNFR1 and stabilized TNFR1 protein by decreasing the Lys(K)-48 ubiquitination mediated-degradation. The formation of TNFR1-complex II was prompted by HRG overexpression via upregulating Lys(K)-63 ubiquitination of TNFR1. Besides, overexpression of HRG suppressed expression of pro-survival genes by impairing the activation of NF-κB signaling in the presence of TNFR1. Moreover, downregulation of HRG was a result of feedback inhibition of NF-κB activation in HCC. In line with the pro-apoptotic switch of TNFR1 signaling after HRG induction, overexpression of HRG inhibited cell proliferation and increased apoptosis in HCC. Conclusions: Our findings illustrate a crucial role for HRG in suppressing HCC via inclining TNFR1 to a pro-apoptotic cellular phenotype. Restoring HRG expression in HCC tissues might be a promising pharmacological approach to blocking tumor progression by shifting cellular fate from cell survival to apoptosis.