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On-line Access: 2023-08-08

Received: 2022-10-25

Revision Accepted: 2023-03-22

Crosschecked: 2023-08-08

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Chao CHEN

https://orcid.org/0000-0001-8173-218X

Yufeng SHI

https://orcid.org/0000-0003-3833-1035

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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.8 P.698-710

http://doi.org/10.1631/jzus.B2200503


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


Author(s):  Chao CHEN, Yu'e LIU, Hongxiang WANG, Xu ZHANG, Yufeng SHI, Juxiang CHEN

Affiliation(s):  Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China; more

Corresponding email(s):   juxiangchen@126.com, yshi@tongji.edu.cn

Key Words:  Glioblastoma, Forkhead box protein O1 (FOXO1), MiR-506, E26 transformation specific-1 (ETS1), Chemosensitivity


Chao CHEN, Yu'e LIU, Hongxiang WANG, Xu ZHANG, Yufeng SHI, Juxiang CHEN. 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, 2023, 24(8): 698-710.

@article{title="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, Yu'e LIU, Hongxiang WANG, Xu ZHANG, Yufeng SHI, Juxiang CHEN",
journal="Journal of Zhejiang University Science B",
volume="24",
number="8",
pages="698-710",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200503"
}

%0 Journal Article
%T FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1
%A Chao CHEN
%A Yu'e LIU
%A Hongxiang WANG
%A Xu ZHANG
%A Yufeng SHI
%A Juxiang CHEN
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 8
%P 698-710
%@ 1673-1581
%D 2023
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200503

TY - JOUR
T1 - FOXO1-miR-506 axis promotes chemosensitivity to temozolomide and suppresses invasiveness in glioblastoma through a feedback loop of FOXO1/miR-506/ETS1/FOXO1
A1 - Chao CHEN
A1 - Yu'e LIU
A1 - Hongxiang WANG
A1 - Xu ZHANG
A1 - Yufeng SHI
A1 - Juxiang CHEN
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 8
SP - 698
EP - 710
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200503


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.

FOXO1/miR-506/ETS1/FOXO1环路抑制胶质母细胞瘤侵袭性并促进替莫唑胺化疗敏感性

陈超1,刘玉娥2,王洪祥1,张旭1,施裕丰2,陈菊祥1
1海军军医大学第一附属医院神经外科,中国上海市,200433
2同济大学医学院第十人民医院肿瘤中心,中国上海市,200092
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。

关键词:胶质母细胞瘤;FOXO1;MiR-506;E26转录因子-1(ETS-1);化疗敏感性

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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