PMID- 35203105 OWN - NLM STAT- MEDLINE DCOM- 20220505 LR - 20220716 IS - 1878-0261 (Electronic) IS - 1574-7891 (Print) IS - 1574-7891 (Linking) VI - 16 IP - 9 DP - 2022 May TI - NOX4 regulates TGFbeta-induced proliferation and self-renewal in glioblastoma stem cells. PG - 1891-1912 LID - 10.1002/1878-0261.13200 [doi] AB - 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 (TGFbeta) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFbeta 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 TGFbeta in several patient-derived GSCs showed that TGFbeta does indeed induce NOX4 expression and increases ROS production in a NOX4-dependent manner. NOX4 downstream of TGFbeta regulates GSC proliferation, and NOX4 expression is necessary for TGFbeta-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 TGFbeta in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology. CI - (c) 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. FAU - Garcia-Gomez, Pedro AU - Garcia-Gomez P AUID- ORCID: 0000-0003-0694-3942 AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - Golan, Irene AU - Golan I AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - S Dadras, Mahsa AU - S Dadras M AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - Mezheyeuski, Artur AU - Mezheyeuski A AD - Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, Sweden. FAU - Bellomo, Claudia AU - Bellomo C AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - Tzavlaki, Kalliopi AU - Tzavlaki K AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - Moren, Anita AU - Moren A AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. FAU - Carreras-Puigvert, Jordi AU - Carreras-Puigvert J AD - Department of Pharmaceutical Biosciences, Biomedical Center, Uppsala University, Sweden. FAU - Caja, Laia AU - Caja L AUID- ORCID: 0000-0002-8786-8763 AD - Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. AD - Ludwig Cancer Research, Science for Life Laboratory, Biomedical Center, Uppsala University, Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220314 PL - United States TA - Mol Oncol JT - Molecular oncology JID - 101308230 RN - 0 (NF-E2-Related Factor 2) RN - 0 (Reactive Oxygen Species) RN - 0 (Transforming Growth Factor beta) RN - EC 1.6.3.- (NADPH Oxidase 4) RN - EC 1.6.3.- (NOX4 protein, human) SB - IM MH - Cell Proliferation MH - *Glioblastoma/genetics MH - Humans MH - NADPH Oxidase 4/genetics MH - NF-E2-Related Factor 2 MH - Neoplastic Stem Cells MH - Reactive Oxygen Species MH - Transforming Growth Factor beta/pharmacology PMC - PMC9067149 OTO - NOTNLM OT - NOX4 OT - ROS OT - TGFbeta OT - glioblastoma OT - proliferation OT - stem cells COIS- The authors declare no conflict of interest. EDAT- 2022/02/25 06:00 MHDA- 2022/05/06 06:00 PMCR- 2022/05/01 CRDT- 2022/02/24 20:17 PHST- 2022/01/19 00:00 [revised] PHST- 2020/05/20 00:00 [received] PHST- 2022/02/21 00:00 [accepted] PHST- 2022/02/25 06:00 [pubmed] PHST- 2022/05/06 06:00 [medline] PHST- 2022/02/24 20:17 [entrez] PHST- 2022/05/01 00:00 [pmc-release] AID - MOL213200 [pii] AID - 10.1002/1878-0261.13200 [doi] PST - ppublish SO - Mol Oncol. 2022 May;16(9):1891-1912. doi: 10.1002/1878-0261.13200. Epub 2022 Mar 14.