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

Molecular Oncology

Artur Mezheyeuski¹  Mahsa S. Dadras²  Pedro García‐Gómez²  Kalliopi Tzavlaki²  Irene Golán²  Claudia Bellomo²  Laia Caja²  Anita Morén²  Jordi Carreras‐Puigvert³ 

[1] Department of Immunology, Genetics and Pathology Rudbeck Laboratory Science for Life Laboratory Uppsala University Sweden;Department of Medical Biochemistry and Microbiology Science for Life Laboratory Biomedical Center Uppsala University Sweden;Department of Pharmaceutical Biosciences Biomedical Center Uppsala University Sweden;

关键词: glioblastoma;    NOX4;    proliferation;    ROS;    stem cells;    TGFβ;   

DOI  :  10.1002/1878-0261.13200

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown