CircFOXO3 promotes glioblastoma progression by acting as a competing endogenous RNA for NFAT5

Author:

Zhang Shuai1,Liao Keman2,Miao Zengli1,Wang Qing1,Miao Yifeng2,Guo Zhongye1,Qiu Yun1,Chen Binghong2,Ren Li3,Wei Zilong3,Lin Yingying2,Lu Xiaojie1,Qiu Yongming2

Affiliation:

1. Department of Neurosurgery, the Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University, Wuxi, China

2. Department of Neurosurgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

3. Department of Neurosurgery, Shanghai Pudong Hospital, Fudan University, Shanghai, China

Abstract

AbstractBackgroundCircular RNAs (circRNAs), a newly discovered type of endogenous noncoding RNA, have been proposed to mediate the progression of diverse types of tumors. Systematic studies of circRNAs have just begun, and the physiological roles of circRNAs remain largely unknown. Here, we focused on elucidating the potential role and molecular mechanism of circular forkhead box O3 (circFOXO3) in glioblastoma (GBM) progression.MethodsFirst, we analyzed circFOXO3 alterations in GBM and noncancerous tissues through real-time quantitative reverse transcription PCR (qRT-PCR). Next, we used loss- and gain-of-function approaches to evaluate the effect of circFOXO3 on GBM cell proliferation and invasion. Mechanistically, fluorescent in situ hybridization, RNA pull-down, dual luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the interaction between circFOXO3 and miR-138-5p/miR-432-5p in GBM. An animal model was used to verify the in vitro experimental findings.ResultsCircFOXO3 expression was significantly higher in GBM tissues than in noncancerous tissues. GBM cell proliferation and invasion were reduced by circFOXO3 knockdown and enhanced by circFOXO3 overexpression. Further biochemical analysis showed that circFOXO3 exerted its pro-tumorigenic activity by acting as a competing endogenous RNA (ceRNA) to increase expression of nuclear factor of activated T cells 5 (NFAT5) via sponging both miR-138-5p and miR-432-5p. Notably, tumor inhibition by circFOXO3 downregulation could be reversed by miR-138-5p/miR-432-5p inhibitors in GBM cells. Moreover, GBM cells with lower circFOXO3 expression developed less aggressive tumors in vivo.ConclusionsOur data demonstrate that circFOXO3 can exert regulatory functions in GBM and that ceRNA-mediated microRNA sequestration might be a potential strategy for GBM therapy.

Funder

Nanjing Medical University

Pudong New Area health system

Shanghai Pudong New Area health system

Pudong New Area science and technology development

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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