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

doi:10.1631/jzus.B2200503

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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

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Research Article | Updated：2023-08-08

FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1
FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1
FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1
Journal of Zhejiang University-SCIENCE B(Biomedicine & Biotechnology) Vol. 24, Issue 8, Pages: 698-710(2023)
Affiliations：

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
Funds：
DOI：10.1631/jzus.B2200503
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Chao CHEN, Yu’e LIU, Hongxiang WANG, et al. FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1. [J]. Journal of Zhejiang University-SCIENCE B(Biomedicine & Biotechnology) 24(8):698-710(2023)
DOI：

Chao CHEN, Yu’e LIU, Hongxiang WANG, et al. FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1. [J]. Journal of Zhejiang University-SCIENCE B(Biomedicine & Biotechnology) 24(8):698-710(2023) DOI： 10.1631/jzus.B2200503.

摘要

为了探索FOXO1在胶质母细胞瘤（GBM）进展和化疗耐药中的作用和机制，本研究采用体外细胞学实验和动物实验分析FOXO1和miR-506对GBM细胞系U251增殖、凋亡、迁移、侵袭、自噬和替莫唑胺（TMZ）化疗敏感性的影响，并通过双荧光素酶报告实验分析FOXO1与miR-506相互作用的靶点。结果显示：FOXO1-miR-506轴可抑制GBM细胞侵袭和迁移能力，并促进其对TMZ的化疗敏感性，且自噬参与其中；FOXO1作为转录因子可与miR-506启动子区域相结合并上调其表达；此外，miR-506可结合在E26转录因子-1（ETS-1） 3'-UTR区并下调ETS1表达，而ETS1可促进FOXO1从细胞核向细胞浆转移进而抑制FOXO1-miR-506轴。裸鼠动物实验结果显示，过表达FOXO1可促进GBM对TMZ的化疗敏感性，但miR-506抑制剂和过表达ETS1均可逆转该现象。综上所述，FOXO1/miR-506/ETS1/FOXO1环路参与GBM侵袭性和化疗敏感性的调节，可作为GBM治疗的潜在靶点。

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.

关键词

胶质母细胞瘤FOXO1MiR-506E26转录因子-1（ETS-1）化疗敏感性

Keywords

GlioblastomaForkhead box protein O1 (FOXO1)MiR-506E26 transformation specific-1 (ETS1)Chemosensitivity

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