Abstract
Glioblastoma are known to be aggressive and therapy-resistant tumors, due to the presence of glioblastoma stem cells inside this heterogeneous tumor. We investigate here the involvement of FGFR1 in glioblastoma stem-like cells (GSLC) radioresistance mechanisms. We first demonstrated that the survival after irradiation was significantly diminished in FGFR1-silenced (FGFR1-) GSLC compared to control GSLC. The transcriptome analysis of GSLCs FGFR1(-) showed that FOX family members are differentially regulated by FGFR1 inhibition, particularly with an upregulation of FOXN3 and a downregulation of FOXM1. GSLC survival after irradiation was significantly increased after FOXN3 silencing and decreased after FOXM1 inhibition, showing opposite effects of FGFR1/FOX family members on cell response to ionizing radiation. Silencing FGFR1 or FOXM1 downregulated genes involved in mesenchymal transition such as GLI2, TWIST1, and ZEB1 in glioblastoma stem-like cells. It also dramatically reduced GSLC migration. Databases analysis confirmed that the combined expression of FGFR1/FOXM1/MELK/GLI2/ZEB1/TWIST1 is significantly associated with patients overall survival after chemo-radiotherapy treatment. All these results, associated with our previous conduced ones with differentiated cells, clearly established that FGFR1-FOXM1 dependent glioblastoma stem-like cells radioresistance pathway is a central actor of GBM treatment resistance and a key target to inhibit in the aim to increase the sensitivity of GBM to the radiotherapy.
Highlights
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults
Databases analysis confirmed that the combined expression of FGFR1/FOXM1/MELK/GLI2/ZEB1/TWIST1 is significantly associated with patients overall survival after chemo-radiotherapy treatment
SubG1 level was increased in GC1FGFR1(-) and GC2FGFR1(-) compared to control cells by 61% and 75%, respectively (Figure 2C and Figure 2D) strongly suggesting that FGFR1 silencing increased glioblastoma stem-like cell death induced by radiation
Summary
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Because FGF-2 binds to FGFR-1, 2 and 4 (for review [5]), we examined the role of these receptors in GBM radioresistance. We first showed that FGFR1 in tumor cells is independent of bad prognostic factors of overall survival and time to progression in glioblastoma [6]. We recently showed that silencing FGFR1 induces an in vitro and in vivo radiosensitization of GBM cell lines via PLCγ and HIF1α [7]. These data led us to hypothesize that FGF2/FGFR1 pathway might be a central pathway sustaining the GBM cell radioresistance
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