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NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells

Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulatio...

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Autores principales: García‐Gómez, Pedro, Golán, Irene, S. Dadras, Mahsa, Mezheyeuski, Artur, Bellomo, Claudia, Tzavlaki, Kalliopi, Morén, Anita, Carreras‐Puigvert, Jordi, Caja, Laia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067149/
https://www.ncbi.nlm.nih.gov/pubmed/35203105
http://dx.doi.org/10.1002/1878-0261.13200
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author García‐Gómez, Pedro
Golán, Irene
S. Dadras, Mahsa
Mezheyeuski, Artur
Bellomo, Claudia
Tzavlaki, Kalliopi
Morén, Anita
Carreras‐Puigvert, Jordi
Caja, Laia
author_facet García‐Gómez, Pedro
Golán, Irene
S. Dadras, Mahsa
Mezheyeuski, Artur
Bellomo, Claudia
Tzavlaki, Kalliopi
Morén, Anita
Carreras‐Puigvert, Jordi
Caja, Laia
author_sort García‐Gómez, Pedro
collection PubMed
description Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
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spelling pubmed-90671492022-05-09 NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells García‐Gómez, Pedro Golán, Irene S. Dadras, Mahsa Mezheyeuski, Artur Bellomo, Claudia Tzavlaki, Kalliopi Morén, Anita Carreras‐Puigvert, Jordi Caja, Laia Mol Oncol Research Articles Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology. John Wiley and Sons Inc. 2022-03-14 2022-05 /pmc/articles/PMC9067149/ /pubmed/35203105 http://dx.doi.org/10.1002/1878-0261.13200 Text en © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
García‐Gómez, Pedro
Golán, Irene
S. Dadras, Mahsa
Mezheyeuski, Artur
Bellomo, Claudia
Tzavlaki, Kalliopi
Morén, Anita
Carreras‐Puigvert, Jordi
Caja, Laia
NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title_full NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title_fullStr NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title_full_unstemmed NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title_short NOX4 regulates TGFβ‐induced proliferation and self‐renewal in glioblastoma stem cells
title_sort nox4 regulates tgfβ‐induced proliferation and self‐renewal in glioblastoma stem cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9067149/
https://www.ncbi.nlm.nih.gov/pubmed/35203105
http://dx.doi.org/10.1002/1878-0261.13200
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