Inhibition of glycogen synthase kinase 3 beta (GSK3β) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity
Authors: Shuoguo Li
Xiaoshan Feng
Huizhi Wang
Zhikun Ma
Zhen Gu
Shegan Gao
Xiang Yuan
Xiaoxian Duan
Journal: Molecular Carcinogenesis (2017)
Discipline: CLINICAL MEDICINE
Keywords: GSK3β; PI3-kinase; STAT3; esophageal cancer.
Affiliations: 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.

Abstract:  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. 

Retracted: No

PubPeer comments:
 Multiple images in figure 3 appear to overlap. **Funding**: This study was supported by the Natural Science Foundation of China (NSFC, GS 81472234; NSFC, YX U1404817) and partially by the National Institute of Dental and Craniofacial Research at the National Institutes of Health, USA, DE023633 (HW). *** ![file] , 
 Corrigendum published: 05 August 2021 In Gao et al.,1 the following error was published on page 2307 in Figure 3. Following publication, the authors discovered that there were two mismatched images in the figure (panel F and H) due to the loss of original data in the lab movement. The experiment was repeated by the authors and the results exactly recapitulated the phenomena observed in the previous study. The results and conclusions were not affected by the mismatched images. The corrected version of Figure 3, panels F to M, appears below. The authors apologize for the errors. ![file] ,