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GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma

PURPOSE: Chordoma is a rare malignant bone tumor transformed from the remnants of notochord. It is characterized as highly aggressive and locally invasive, difficult to be completely removed by surgery, and has a poor clinical prognosis. Glycogen synthase kinase 3 beta (GSK-3β) is involved in many c...

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Autores principales: Chen, Li, Zuo, Yi, Pan, Ru, Ye, Zhen, Wei, Kailun, Xia, Shaohuai, Li, Wencai, Tan, Jie, Xia, Xuewei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810826/
https://www.ncbi.nlm.nih.gov/pubmed/33469364
http://dx.doi.org/10.2147/CMAR.S289883
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author Chen, Li
Zuo, Yi
Pan, Ru
Ye, Zhen
Wei, Kailun
Xia, Shaohuai
Li, Wencai
Tan, Jie
Xia, Xuewei
author_facet Chen, Li
Zuo, Yi
Pan, Ru
Ye, Zhen
Wei, Kailun
Xia, Shaohuai
Li, Wencai
Tan, Jie
Xia, Xuewei
author_sort Chen, Li
collection PubMed
description PURPOSE: Chordoma is a rare malignant bone tumor transformed from the remnants of notochord. It is characterized as highly aggressive and locally invasive, difficult to be completely removed by surgery, and has a poor clinical prognosis. Glycogen synthase kinase 3 beta (GSK-3β) is involved in many cellular processes. GSK-3β overexpression has been shown to promote the development of many cancers, according to previous studies. However, the role of GSK-3β in chordoma remains unclear. METHODS: Immunohistochemistry (IHC) and Western blotting (WB) were performed on clinical specimens to measure GSK-3β expression in chordoma, and immunofluorescence and quantitative real-time polymerase chain reaction (QRT-PCR) were performed to examine the expression of GSK-3β and P21 in cell lines. Cell proliferation was detected by the CCK-8 assay and colony formation analysis, cell migration and invasion checked by Transwell experiments, and cell apoptosis was determined by Annexin V/propidium iodide staining. P21 was predicted as a downstream target gene of GSK-3β using STRING and UNIHI databases. Moreover, we used immunoprecipitation to confirm that GSK-3β and P21 interacted with each other. The double luciferase reporter gene assay showed that GSK-3β could regulate the promoter activity of P21. Finally, the role of the GSK-3β -P21 pathway in chordoma tumorigenesis was analyzed in vivo in nude mice. RESULTS: Our study showed that GSK-3β was significantly higher in chordoma tissues than in paracancer tissues, and siRNA knockdown of GSK-3β inhibited chordoma cell proliferation and promoted cell apoptosis. Additionally, our research found that GSK-3β bound and downregulated the expression of the P21 gene, and the expression of silencing P21 partially reversed the inhibitory effect of knockdown GSK-3β on chordoma. Furthermore, xenografts showed that knockdown GSK-3β inhibited the formation of chordomas in vivo. CONCLUSION: Our results indicated that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for the clinical treatment of this disorder.
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spelling pubmed-78108262021-01-18 GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma Chen, Li Zuo, Yi Pan, Ru Ye, Zhen Wei, Kailun Xia, Shaohuai Li, Wencai Tan, Jie Xia, Xuewei Cancer Manag Res Original Research PURPOSE: Chordoma is a rare malignant bone tumor transformed from the remnants of notochord. It is characterized as highly aggressive and locally invasive, difficult to be completely removed by surgery, and has a poor clinical prognosis. Glycogen synthase kinase 3 beta (GSK-3β) is involved in many cellular processes. GSK-3β overexpression has been shown to promote the development of many cancers, according to previous studies. However, the role of GSK-3β in chordoma remains unclear. METHODS: Immunohistochemistry (IHC) and Western blotting (WB) were performed on clinical specimens to measure GSK-3β expression in chordoma, and immunofluorescence and quantitative real-time polymerase chain reaction (QRT-PCR) were performed to examine the expression of GSK-3β and P21 in cell lines. Cell proliferation was detected by the CCK-8 assay and colony formation analysis, cell migration and invasion checked by Transwell experiments, and cell apoptosis was determined by Annexin V/propidium iodide staining. P21 was predicted as a downstream target gene of GSK-3β using STRING and UNIHI databases. Moreover, we used immunoprecipitation to confirm that GSK-3β and P21 interacted with each other. The double luciferase reporter gene assay showed that GSK-3β could regulate the promoter activity of P21. Finally, the role of the GSK-3β -P21 pathway in chordoma tumorigenesis was analyzed in vivo in nude mice. RESULTS: Our study showed that GSK-3β was significantly higher in chordoma tissues than in paracancer tissues, and siRNA knockdown of GSK-3β inhibited chordoma cell proliferation and promoted cell apoptosis. Additionally, our research found that GSK-3β bound and downregulated the expression of the P21 gene, and the expression of silencing P21 partially reversed the inhibitory effect of knockdown GSK-3β on chordoma. Furthermore, xenografts showed that knockdown GSK-3β inhibited the formation of chordomas in vivo. CONCLUSION: Our results indicated that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for the clinical treatment of this disorder. Dove 2021-01-11 /pmc/articles/PMC7810826/ /pubmed/33469364 http://dx.doi.org/10.2147/CMAR.S289883 Text en © 2021 Chen et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Chen, Li
Zuo, Yi
Pan, Ru
Ye, Zhen
Wei, Kailun
Xia, Shaohuai
Li, Wencai
Tan, Jie
Xia, Xuewei
GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title_full GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title_fullStr GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title_full_unstemmed GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title_short GSK-3β Regulates the Expression of P21 to Promote the Progression of Chordoma
title_sort gsk-3β regulates the expression of p21 to promote the progression of chordoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810826/
https://www.ncbi.nlm.nih.gov/pubmed/33469364
http://dx.doi.org/10.2147/CMAR.S289883
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