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FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer
Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced G...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437149/ https://www.ncbi.nlm.nih.gov/pubmed/30918291 http://dx.doi.org/10.1038/s41598-019-41717-w |
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author | Wang, Sen Ran, Longke Zhang, Wanfeng Leng, Xue Wang, Kexin Liu, Geli Song, Jing Wang, Yujing Zhang, Xianqin Wang, Yitao Zhang, Lian Ma, Yan Liu, Kun Li, Haiyu Zhang, Wei Qin, Guijun Song, Fangzhou |
author_facet | Wang, Sen Ran, Longke Zhang, Wanfeng Leng, Xue Wang, Kexin Liu, Geli Song, Jing Wang, Yujing Zhang, Xianqin Wang, Yitao Zhang, Lian Ma, Yan Liu, Kun Li, Haiyu Zhang, Wei Qin, Guijun Song, Fangzhou |
author_sort | Wang, Sen |
collection | PubMed |
description | Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced GC patients. Emerging evidence has revealed a close correlation between forkhead box (FOX) proteins and cancer development. However, the prognostic significance of forkhead box S1 (FOXS1) in patients with GC and the function of FOXS1 in GC progression remain undefined. In this study, we found that upregulation of FOXS1 was frequently detected in GC tissues and strongly correlated with an aggressive phenotype and poor prognosis. Functional assays confirmed that FOXS1 knockdown suppressed cell proliferation and colony numbers, with induction of cell arrest in the G0/G1 phase of the cell cycle, whereas forced expression of FOXS1 had the opposite effect. Additionally, forced expression of FOXS1 accelerated tumor growth in vivo and increased cell migration and invasion through promoting epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, the core promoter region of FOXS1 was identified at nucleotides −660~ +1, and NFKB1 indirectly bind the motif on FOXS1 promoters and inhibit FOXS1 expression. Gene set enrichment analysis revealed that the FOXS1 gene was most abundantly enriched in the hedgehog signaling pathway and that GLI1 expression was significantly correlated with FOXS1 expression in GC. GLI1 directly bound to the promoter motif of FOXS1 and significantly decreased FOXS1 expression. Finally, we found that miR-125a-5p repressed FOXS1 expression at the translational level by binding to the 3′ untranslated region (UTR) of FOXS1. Together, these results suggest that FOXS1 can promote GC development and could be exploited as a diagnostic and prognostic biomarker for GC. |
format | Online Article Text |
id | pubmed-6437149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-64371492019-04-03 FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer Wang, Sen Ran, Longke Zhang, Wanfeng Leng, Xue Wang, Kexin Liu, Geli Song, Jing Wang, Yujing Zhang, Xianqin Wang, Yitao Zhang, Lian Ma, Yan Liu, Kun Li, Haiyu Zhang, Wei Qin, Guijun Song, Fangzhou Sci Rep Article Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced GC patients. Emerging evidence has revealed a close correlation between forkhead box (FOX) proteins and cancer development. However, the prognostic significance of forkhead box S1 (FOXS1) in patients with GC and the function of FOXS1 in GC progression remain undefined. In this study, we found that upregulation of FOXS1 was frequently detected in GC tissues and strongly correlated with an aggressive phenotype and poor prognosis. Functional assays confirmed that FOXS1 knockdown suppressed cell proliferation and colony numbers, with induction of cell arrest in the G0/G1 phase of the cell cycle, whereas forced expression of FOXS1 had the opposite effect. Additionally, forced expression of FOXS1 accelerated tumor growth in vivo and increased cell migration and invasion through promoting epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, the core promoter region of FOXS1 was identified at nucleotides −660~ +1, and NFKB1 indirectly bind the motif on FOXS1 promoters and inhibit FOXS1 expression. Gene set enrichment analysis revealed that the FOXS1 gene was most abundantly enriched in the hedgehog signaling pathway and that GLI1 expression was significantly correlated with FOXS1 expression in GC. GLI1 directly bound to the promoter motif of FOXS1 and significantly decreased FOXS1 expression. Finally, we found that miR-125a-5p repressed FOXS1 expression at the translational level by binding to the 3′ untranslated region (UTR) of FOXS1. Together, these results suggest that FOXS1 can promote GC development and could be exploited as a diagnostic and prognostic biomarker for GC. Nature Publishing Group UK 2019-03-27 /pmc/articles/PMC6437149/ /pubmed/30918291 http://dx.doi.org/10.1038/s41598-019-41717-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wang, Sen Ran, Longke Zhang, Wanfeng Leng, Xue Wang, Kexin Liu, Geli Song, Jing Wang, Yujing Zhang, Xianqin Wang, Yitao Zhang, Lian Ma, Yan Liu, Kun Li, Haiyu Zhang, Wei Qin, Guijun Song, Fangzhou FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title | FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title_full | FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title_fullStr | FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title_full_unstemmed | FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title_short | FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer |
title_sort | foxs1 is regulated by gli1 and mir-125a-5p and promotes cell proliferation and emt in gastric cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437149/ https://www.ncbi.nlm.nih.gov/pubmed/30918291 http://dx.doi.org/10.1038/s41598-019-41717-w |
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