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NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4
We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Her...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910430/ https://www.ncbi.nlm.nih.gov/pubmed/29679017 http://dx.doi.org/10.1038/s41598-018-24444-6 |
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author | Ferrandez, Eva Gutierrez, Olga Segundo, David San Fernandez-Luna, Jose L. |
author_facet | Ferrandez, Eva Gutierrez, Olga Segundo, David San Fernandez-Luna, Jose L. |
author_sort | Ferrandez, Eva |
collection | PubMed |
description | We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity. |
format | Online Article Text |
id | pubmed-5910430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59104302018-04-30 NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 Ferrandez, Eva Gutierrez, Olga Segundo, David San Fernandez-Luna, Jose L. Sci Rep Article We have previously described that the NFκB pathway is upregulated during differentiation of glioblastoma stem-like cells (GSCs) which keeps differentiating GSCs in a proliferative astrocytic precursor state. However, extracellular signals and cellular mediators of this pathway are not clear yet. Here, we show that TLR4 is a key factor to promote NFκB activation in differentiating GSCs. TLR4 is upregulated during differentiation of GSCs and promotes transcriptional activation of NFκB as determined by luciferase-reporter assays and expression of NFκB target genes. Downregulation of TLR4 by shRNAs or blockade with anti-TLR4 specific antibodies drastically inhibited NFκB activity which promoted further differentiation and reduced proliferation of GSCs. We found that hyaluronic acid (HA), a main component of brain extracellular matrix, triggers the TLR4-NFκB pathway in differentiating GSCs. Moreover, HA is synthesized and released by GSCs undergoing differentiation and leads to transcriptional activation of NFκB, which is inhibited following downregulation of TLR4 or blockade of HA synthesis. Thus, we have demonstrated that during the process of differentiation, GSCs upregulate TLR4 and release the TLR4 ligand HA, which activates the TLR4-NFκB signaling pathway. This strategy may efficiently be used by differentiating GSCs to maintain their proliferative potential and consequently their tumorigenic capacity. Nature Publishing Group UK 2018-04-20 /pmc/articles/PMC5910430/ /pubmed/29679017 http://dx.doi.org/10.1038/s41598-018-24444-6 Text en © The Author(s) 2018 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 Ferrandez, Eva Gutierrez, Olga Segundo, David San Fernandez-Luna, Jose L. NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title | NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title_full | NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title_fullStr | NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title_full_unstemmed | NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title_short | NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4 |
title_sort | nfκb activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through tlr4 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910430/ https://www.ncbi.nlm.nih.gov/pubmed/29679017 http://dx.doi.org/10.1038/s41598-018-24444-6 |
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