FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1

To explore the role of forkhead box protein O1(FOXO1)in the progression of glioblastoma multiforme(GBM)and related drug resistance,we deciphered the roles of FOXO1 and miR-506 in proliferation,apoptosis,migration,invasion,autophagy,and temozolomide(TMZ)sensitivity in the U251 cell line using in vitro and in vivo experiments.Cell viability was tested by a cell counting kit-8(CCK8)kit;migration and invasion were checked by the scratching assay;apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)staining and flow cytometry.The construction of plasmids and dual-luciferase reporter experiment were carried out to find the interaction site between FOXO1 and miR-506.Immunohistochemistry was done to check the protein level in tumors after the in vivo experiment.We found that the FOXO1-miR-506 axis suppresses GBM cell invasion and migration and promotes GBM chemosensitivity to TMZ,which was mediated by autophagy.FOXO1 upregulates miR-506 by binding to its promoter to enhance transcriptional activation.MiR-506 could downregulate E26 transformation-specific 1(ETS1)expression by targeting its 3'-untranslated region(UTR).Interestingly,ETS1 promoted FOXO1 translocation from the nucleus to the cytosol and further suppressed the FOXO1-miR-506 axis in GBM cells.Consistently,both miR-506 inhibition and ETS1 overexpression could rescue FOXO1 overactivation-mediated TMZ chemosensitivity in mouse models.Our study demonstrated a negative feedback loop of FOXO1/miR-506/ETS1/FOXO1 in GBM in regulating invasiveness and chemosensitivity.Thus,the above axis might be a promising therapeutic target for GBM.