NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4

Abstract 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...

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Autores principales:	Eva Ferrandez, Olga Gutierrez, David San Segundo, Jose L. Fernandez-Luna
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9c154a045e8d4b4dbe4f141ef5005fdb
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spelling	oai:doaj.org-article:9c154a045e8d4b4dbe4f141ef5005fdb2021-12-02T15:08:25ZNFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR410.1038/s41598-018-24444-62045-2322https://doaj.org/article/9c154a045e8d4b4dbe4f141ef5005fdb2018-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-24444-6https://doaj.org/toc/2045-2322Abstract 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.Eva FerrandezOlga GutierrezDavid San SegundoJose L. Fernandez-LunaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Eva Ferrandez Olga Gutierrez David San Segundo Jose L. Fernandez-Luna NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4
description	Abstract 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	article
author	Eva Ferrandez Olga Gutierrez David San Segundo Jose L. Fernandez-Luna
author_facet	Eva Ferrandez Olga Gutierrez David San Segundo Jose L. Fernandez-Luna
author_sort	Eva Ferrandez
title	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_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_sort	nfκb activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through tlr4
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/9c154a045e8d4b4dbe4f141ef5005fdb
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NFκB activation in differentiating glioblastoma stem-like cells is promoted by hyaluronic acid signaling through TLR4

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