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

Chao Chen; Yu'e Liu; Hongxiang Wang; Xu Zhang; Yufeng Shi; Juxiang Chen

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

Author: Chao CHEN ¹ ; Yu'e LIU ² ; Hongxiang WANG ¹ ; Xu ZHANG ¹ ; Yufeng SHI ³ ; Juxiang CHEN ⁴
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1. Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
2. Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China.
3. Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China. yshi@tongji.edu.cn.
4. Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. juxiangchen@126.com.
Publication Type:Journal Article
Keywords: Chemosensitivity; E26 transformation specific-1 (ETS1); Forkhead box protein O1 (FOXO1); Glioblastoma; MiR-506
MeSH: Animals; Mice; Brain Neoplasms/genetics*; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Feedback; Gene Expression Regulation, Neoplastic; Glioblastoma/metabolism*; MicroRNAs/metabolism*; Temozolomide/therapeutic use*; Humans; Forkhead Box Protein O1/metabolism*
From: Journal of Zhejiang University. Science. B 2023;24(8):698-710
CountryChina
Language:English
Abstract: 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.