Gao Shegan, Li Shuoguo, Duan Xiaoxian, Gu Zhen, Ma Zhikun, Yuan Xiang, Feng Xiaoshan, Wang Huizhi
Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical college of Henan University of Science and Technology, Luoyang, China.
Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky.
Mol Carcinog. 2017 Oct;56(10):2301-2316. doi: 10.1002/mc.22685. Epub 2017 Jul 4.
Although GSK3β has been reported to have contrasting effects on the progression of different tumors, it's possible functions in esophageal squamous cell carcinoma (ESCC) and the related molecular mechanisms remain unknown. Here, we investigated the expression, function, and molecular mechanism of GSK3β in the development of ESCC in vitro and in vivo. Though the expression of total GSK3β was significantly increased, the phosphorylated (inactivated) form of GSK3β (Ser9) was concurrently decreased in the cancerous tissues of patients with ESCC compared with controls, suggesting that GSK3β activity was enhanced in cancerous tissues. Further pathological data analysis revealed that higher GSK3β expression was associated with poorer differentiation, higher metastasis rates, and worse prognosis of ESCC. These results were confirmed in different ESCC cell lines using a pharmacological inhibitor and specific siRNA to block GSK3β. Using a cancer phospho-antibody array, we found that STAT3 is a target of GSK3β. GSK3 inhibition reduced STAT3 phosphorylation, and overexpression of constitutively active GSK3β had the opposite effect. Moreover, STAT3 inhibition mimicked the effects of GSK3β inhibition on ESCC cell migration and viability, while overexpression of a plasmid encoding mutant STAT3 (Y705F) abrogated these effects, and these results were further substantiated by clinicopathological data. In addition, a GSK3 inhibitor (LiCl) and/or STAT3 inhibitor (WP-1066) efficiently suppressed the growth of ESCC cells in a xenograft tumor model. Altogether, these results reveal that higher GSK3β expression promotes ESCC progression through STAT3 in vitro and in vivo, and GSK3β-STAT3 signaling could be a potential therapeutic target for ESCC treatment.
尽管已有报道称糖原合成酶激酶3β（GSK3β）对不同肿瘤的进展有相反作用，但其在食管鳞状细胞癌（ESCC）中的可能功能及相关分子机制仍不清楚。在此，我们在体外和体内研究了GSK3β在ESCC发生发展中的表达、功能及分子机制。与对照组相比，ESCC患者癌组织中总GSK3β的表达显著增加，而GSK3β的磷酸化（失活）形式（Ser9）同时减少，提示癌组织中GSK3β活性增强。进一步的病理数据分析显示，较高的GSK3β表达与ESCC的低分化、高转移率及较差预后相关。使用药理学抑制剂和特异性小干扰RNA（siRNA）阻断GSK3β，在不同的ESCC细胞系中证实了这些结果。通过癌症磷酸化抗体芯片，我们发现信号转导和转录激活因子3（STAT3）是GSK3β的一个靶点。抑制GSK3可降低STAT3磷酸化，而过表达组成型活性GSK3β则有相反作用。此外，抑制STAT3模拟了抑制GSK3β对ESCC细胞迁移和活力的影响，而过量表达编码突变型STAT3（Y705F）的质粒则消除了这些影响，临床病理数据进一步证实了这些结果。此外，在异种移植肿瘤模型中，GSK3抑制剂（氯化锂）和/或STAT3抑制剂（WP - 1066）可有效抑制ESCC细胞生长。总之，这些结果表明，较高的GSK3β表达在体外和体内通过STAT3促进ESCC进展，GSK3β - STAT3信号通路可能是ESCC治疗的一个潜在靶点。
