为了探索转录因子FOXO1在胶质母细胞瘤（GBM）发展及相关药物耐药中的作用，我们通过体外和体内实验，解析了FOXO1和miR-506在U251细胞系的增殖、凋亡、迁移、侵袭、自噬以及卡马之多醇（TMZ）敏感性中的作用。细胞存活能力通过细胞计数试剂盒-8（CCK8）进行检测；迁移和侵袭通过拉伤法进行检测；凋亡通过末端脱氧核苷酸转移酶dUTP末端标记（TUNEL）染色和流式细胞术进行评估。采用质粒构建和双荧光素酶报告实验来确定FOXO1和miR-506的相互作用位点。在体内实验后，用免疫组织化学法检测肿瘤中的蛋白水平。我们发现，FOXO1-miR-506轴抑制GBM细胞的侵袭和迁移，并促进GBM对TMZ的化疗敏感性，这是通过自噬介导的。FOXO1通过结合miR-506的启动子而上调其表达，从而增强其转录活性。miR-506可以通过靶向E26转换特异性1（ETS1）的3'-UTR，下调ETS1的表达。有趣的是，ETS1促进了FOXO1从细胞核转位到胞质，并进一步抑制了GBM细胞中的FOXO1-miR-506轴。一致地，miR-506抑制和ETS1过表达能够拯救FOXO1过度激活导致的TMZ化疗敏感性在小鼠模型中。我们的研究揭示了一个FOXO1/miR-506/ETS1/FOXO1的负反馈调节GBM侵袭性和化疗敏感性的回路。因此，上述轴可能是GBM的一个有希望的治疗靶点。

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.