The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma
The Roles of GSK-3β in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma
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GSK-3β 在肝细胞癌中视黄醇信号传导和索拉非尼治疗反应调节中的作用
DOI：
10.7150/thno.38711
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Zeng, Jin-Zhang
中科院分区：
文献类型：
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作者：
Zhang, Shuaishuai;Gao, Weiwei;Zeng, Jin-Zhang
原理：糖原合成酶激酶-3 β（GSK-3 β）在代谢和许多细胞过程中起关键作用。最近证实GSK-3 β的过表达可促进肿瘤生长。然而，GSK-3 β在肝细胞癌（HCC）中的表达和功能在很大程度上仍未被探索。本研究旨在探讨GSK-3 β在肝癌中的作用及治疗靶点价值。鉴于偏离的类维生素A信号传导对HCC的发展至关重要，我们研究了GSK-3 β是否参与了调控。由于索拉非尼目前用于治疗HCC，因此确定GSK-3 β参与索拉非尼治疗反应。采用免疫共沉淀、GST pull down、体外激酶试验、荧光素酶报告基因和染色质免疫共沉淀等方法探讨其分子机制。结果：GSK-3 β在肝癌组织中高表达，并与较短的总生存期（OS）相关。GSK-3 β的过表达赋予HCC细胞集落形成和异种移植肿瘤生长。肿瘤相关GSK-3 β与视黄酸受体-β（RAR β）的表达降低相关，这是由GSK-3 β介导的磷酸化和类视黄醇X受体（RXR α）与RAR β启动子上的RAR α的异源二聚化消除引起的。功能性GSK-3 β的过表达损害类维生素A反应并抑制索拉非尼抗HCC作用。Tideglusib灭活GSK-3 β 3可增强9-cis-RA对索拉非尼敏感性的增强作用（肿瘤抑制率从48.3%提高至93.4%）。有效诱导RAR β的tideglusib/9-cis-RA是增强索拉非尼的治疗效果所必需的，其效果被大大抑制敲低RAR β。结论：我们的研究结果表明，GSK-3 β是一个破坏类维生素A信号传导和索拉非尼在肝癌中的一个新的耐药因素。以GSK-3 β为靶点可能成为临床治疗肝癌的一个有前景的策略。
Rationale: Glycogen synthase kinase-3 beta (GSK-3 beta) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3 beta can confer tumor growth. However, the expression and function of GSK-3 beta in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3 beta in HCC.Methods: We firstly clarified the expression of GSK-3 beta in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3 beta could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3 beta in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments.Results: We demonstrated that GSK-3 beta is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3 beta confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3 beta is correlated with reduced expression of retinoic acid receptor-beta (RAR beta), which is caused by GSK-3 beta-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXR alpha) with RAR alpha on RAR beta promoter. Overexpression of functional GSK-3 beta impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3 beta 3 by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RAR beta by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RAR beta.Conclusions: Our findings demonstrate that GSK-3 beta is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3 beta may be a promising strategy for HCC treatment in clinic.