Inhibition of glycogen synthase kinase 3 beta (GSK3β) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity.
Inhibition of glycogen synthase kinase 3 beta (GSK3β) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity.
复制标题
DOI：
10.1002/mc.22685
复制
发表时间：
2017-10
影响因子：
4.6
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Gao S;Li S;Duan X;Gu Z;Ma Z;Yuan X;Feng X;Wang H
虽然已有报道称GSK3β在不同肿瘤的进展中具有不同的作用，但其在食管鳞状细胞癌（ESCC）中的可能功能及其相关分子机制尚不清楚。我们在体外和体内研究了GSK3β在ESCC发生过程中的表达、功能和分子机制。虽然GSK3β总表达量显著增加，但与对照组相比，ESCC患者癌组织中GSK3β磷酸化（失活）形式（Ser9）同时降低，表明GSK3β活性在癌组织中增强。进一步的病理数据分析显示，GSK3β高表达与ESCC分化差、转移率高、预后差相关。这些结果在不同的ESCC细胞系中得到证实，使用药理学抑制剂和特异性siRNA来阻断GSK3β。使用癌症磷酸化抗体阵列，我们发现STAT3是GSK3β的靶标。抑制GSK3β可降低STAT3的磷酸化，而过表达组成活性GSK3β则具有相反的作用。此外，STAT3抑制与GSK3β抑制对ESCC细胞迁移和活力的影响相似，而编码突变体STAT3 （Y705F）的质粒过表达则消除了这些影响，这些结果进一步得到了临床病理数据的证实。此外，GSK3抑制剂（LiCl）和/或STAT3抑制剂（WP-1066）在异种移植物肿瘤模型中有效抑制ESCC细胞的生长。综上所述，这些结果表明，GSK3β的高表达通过STAT3在体外和体内促进ESCC的进展，GSK3β-STAT3信号可能是ESCC治疗的潜在治疗靶点。
While GSK3β has been reported to have contrasting effects on the progression of different tumors, its 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. GSK3β 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.
登录
查看更多内容
DOI：
10.1158/1541-7786.mcr-09-0313
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Dabir S;Kluge A;Dowlati A
通讯作者：
Dowlati A
影响因子：
5.6
作者：
Gao H;Teng C;Huang W;Peng J;Wang C
通讯作者：
Wang C
影响因子：
4.8
作者：
Beurel, Eleonore;Jope, Richard S.
通讯作者：
Jope, Richard S.
影响因子：
9.3
作者：
Beurel E;Jope RS
通讯作者：
Jope RS
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE