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NOX4 regulates TGF ...
NOX4 regulates TGF beta-induced proliferation and self-renewal in glioblastoma stem cells
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- Garcia-Gomez, Pedro (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Golan, Irene (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Dadras, Mahsa Shahidi (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Mezheyeuski, Artur (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi
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- Bellomo, Claudia (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Tzavlaki, Kalliopi (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi
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- Morén, Anita (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Carreras-Puigvert, Jordi (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Caja, Laia (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2022-03-14
- 2022
- English.
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In: Molecular Oncology. - : John Wiley & Sons. - 1574-7891 .- 1878-0261. ; 16:9, s. 1891-1912
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Abstract
Subject headings
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- Y 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 beta (TGF beta) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGF beta 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 TGF beta in several patient-derived GSCs showed that TGF beta does indeed induce NOX4 expression and increases ROS production in a NOX4-dependent manner. NOX4 downstream of TGF beta regulates GSC proliferation, and NOX4 expression is necessary for TGF beta-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 TGF beta in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- glioblastoma
- NOX4
- proliferation
- ROS
- stem cells
- TGF beta
Publication and Content Type
- ref (subject category)
- art (subject category)
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