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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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Yufeng SHI


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


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.

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author="Chao CHEN, Yu'e LIU, Hongxiang WANG, Xu ZHANG, Yufeng SHI, Juxiang CHEN",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

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%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 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

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 - 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

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.




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


[1]BhatKPL, BalasubramaniyanV, VaillantB, et al., 2013. Mesenchymal differentiation mediated by NF‍‍-‍κB promotes radiation resistance in glioblastoma. Cancer Cell, 24(3):331-346.

[2]ChenC, XuT, ZhouJX, et al., 2013. High cytoplasmic FOXO1 and pFOXO1 expression in astrocytomas are associated with worse surgical outcome. PLoS ONE, 8(7):e69260.

[3]ChenC, HanGS, LiYN, et al., 2019. FOXO1 associated with sensitivity to chemotherapy drugs and glial-mesenchymal transition in glioma. J Cell Biochem, 120(1):882-893.

[4]ChengYC, TsaoMJ, ChiuCY, et al., 2018. Magnolol inhibits human glioblastoma cell migration by regulating N-cadherin. J Neuropathol Exp Neurol, 77(6):426-436.

[5]ChunY, KimJ, 2018. Autophagy: an essential degradation program for cellular homeostasis and life. Cells, 7(12):278.

[6]de la RosaJ, UrdiciainA, ZazpeI, et al., 2020. The synergistic effect of DZ‑NEP, panobinostat and temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells. Int J Oncol, 56(1):283-300.

[7]FanLX, TaoL, LaiYC, et al., 2022. Cx32 promotes autophagy and produces resistance to SN‑induced apoptosis via activation of AMPK signalling in cervical cancer. Int J Oncol, 60:10.

[8]GaoXY, XiaX, LiFY, et al., 2021. Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigenicity through activation of EGFR-STAT3 signalling. Nat Cell Biol, 23(3):278-291.

[9]JiangS, LiT, YangZ, et al., 2018. Deciphering the roles of FOXO1 in human neoplasms. Int J Cancer, 143(7):1560-1568.

[10]LapointeS, PerryA, ButowskiNA, 2018. Primary brain tumours in adults. Lancet, 392(10145):432-446.

[11]LiZ, LiuZM, DongSW, et al., 2015. MiR-506 inhibits epithelial-to-mesenchymal transition and angiogenesis in gastric cancer. Am J Pathol, 185(9):2412-2420.

[12]LimEJ, KimS, OhY, et al., 2020. Crosstalk between GBM cells and mesenchymal stemlike cells promotes the invasiveness of GBM through the C5a/p38/ZEB1 axis. Neuro Oncol, 22(10):1452-1462.

[13]LouisDN, PerryA, WesselingP, et al., 2021. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol, 23(8):1231-1251.

[14]LwinZ, MacFaddenD, Al-ZahraniA, et al., 2013. Glioblastoma management in the temozolomide era: have we improved outcome? J Neurooncol, 115(2):303-310.

[15]MahabirR, TaninoM, ElmansuriA, et al., 2014. Sustained elevation of Snail promotes glial‍-mesenchymal transition after irradiation in malignant glioma. Neuro Oncol, 16(5):671-685.

[16]MatiasD, Balça-SilvaJ, DuboisLG, et al., 2017. Dual treatment with shikonin and temozolomide reduces glioblastoma tumor growth, migration and glial-to-mesenchymal transition. Cell Oncol (Dordr), 40(3):247-261.

[17]OsukaS, ZhuD, ZhangZB, et al., 2021. N-cadherin upregulation mediates adaptive radioresistance in glioblastoma. J Clin Invest, 131(6):e136098.

[18]PawI, CarpenterRC, WatabeK, et al., 2015. Mechanisms regulating glioma invasion. Cancer Lett, 362(1):1-7.

[19]PhillipsHS, KharbandaS, ChenRH, et al., 2006. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell, 9(3):157-173.

[20]SchneiderB, LampN, ZimpferA, et al., 2023. Comparing tumor microRNA profiles of patients with long‑ and short‑term‑surviving glioblastoma. Mol Med Rep, 27:8.

[21]SimpsonJE, GammohN, 2020. The impact of autophagy during the development and survival of glioblastoma. Open Biol, 10(9):200184.

[22]SinghalR, BardJE, NowakNJ, et al., 2013. FOXO1 regulates expression of a microRNA cluster on X chromosome. Aging (Albany NY), 5(5):347-356.

[23]The Cancer Genome Atlas Research Network, 2008. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216):1061-1068.

[24]TomarMS, KumarA, SrivastavaC, et al., 2021. Elucidating the mechanisms of Temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer, 1876(2):188616.

[25]VerhaakRGW, HoadleyKA, PurdomE, et al., 2010. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell, 17(1):98-110.

[26]VishnoiK, ViswakarmaN, RanaA, et al., 2020. Transcription factors in cancer development and therapy. Cancers (Basel), 12(8):2296.

[27]Vollmann-ZwerenzA, LeidgensV, FelicielloG, et al., 2020. Tumor cell invasion in glioblastoma. Int J Mol Sci, 21(6):1932.

[28]WangGJ, JiaoBP, LiuYJ, et al., 2019. Reactivation of microRNA-506 inhibits gastric carcinoma cell metastasis through ZEB2. Aging (Albany NY), 11(6):1821-1831.

[29]WeiC, YangCG, WangSY, et al., 2019. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer, 18:64.

[30]WhiteE, DiPaolaRS, 2009. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res, 15(17):5308-5316.

[31]XuB, MaR, RussellL, et al., 2019. An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma. Nat Biotechnol, 37(1):45-54.

[32]YachiK, TsudaM, KohsakaS, et al., 2018. miR-23a promotes invasion of glioblastoma via HOXD10-regulated glial-mesenchymal transition. Signal Transduct Target Ther, 3:33.

[33]ZhaoZ, ZhangKN, WangQW, et al., 2021. Chinese Glioma Genome Atlas (CGGA): a comprehensive resource with functional genomic data from Chinese glioma patients. Genomics Proteomics Bioinformatics, 19(1):1-12.

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