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CircRNA Uxs1/miR-335-5p/PGF axis regulates choroidal neovascularization via the mTOR/p70 S6k pathway

  • Jiali Wu
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
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  • Jieqiong Chen
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China

    Shanghai Key Laboratory of Fundus Diseases, Shanghai, China

    Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
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  • Jing Hu
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
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  • Mudi Yao
    Affiliations
    Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
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  • Min Zhang
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
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  • Xiaoling Wan
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China

    Shanghai Key Laboratory of Fundus Diseases, Shanghai, China

    Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
    Search for articles by this author
  • Huixun Jia
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
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  • Fenghua Wang
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China
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  • Xiaodong Sun
    Correspondence
    Corresponding author: Xiaodong Sun, Wujing Road No.85, Hongkou district, Shanghai, China, 200080
    Affiliations
    Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    National Clinical Research Center for Ophthalmic Diseases, Shanghai, China

    Shanghai Key Laboratory of Fundus Diseases, Shanghai, China

    Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
    Search for articles by this author
Published:January 20, 2023DOI:https://doi.org/10.1016/j.trsl.2023.01.003

      Abstract

      Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly population. Neovascular AMD is the late stage, characterized by choroidal neovascularization (CNV). Non-coding RNAs have been implicated in CNV; however, the role of circular RNAs (circRNAs) has not yet been elucidated. Herein, we comprehensively investigated circRNA profiles in laser-induced CNV mouse models and patient specimens. A novel circRNA, circRNA Uxs1, was identified, and its function in CNV regulation was investigated in the present study. CircRNA Uxs1 was consistently upregulated in CNV patient specimens and CNV mouse models. Knockdown of circRNA Uxs1 interrupted the tube formation, migration, and proliferation of endothelial cells in vitro. Silencing circRNA Uxs1 in vivo alleviated neovascularization formation, as shown by the decreased size of laser spots. Mechanistically, circRNA Uxs1 functioned by binding to miR-335-5p, which further upregulated the expression of placental growth factor (PGF) gene and activated the mammalian target of rapamycin/p70 S6 Kinase (mTOR/p70 S6k) pathway. By subretinal injections of adeno-associated virus (AAV), we demonstrated the anti-angiogenic function of circRNA Uxs1 knockdown in vivo. In conclusion, circRNA Uxs1 promoted CNV by sponging miR-335-5p, which stimulated PGF expression and subsequently activated the mTOR/p70 S6k pathway. Therefore, circRNA Uxs1 may serve as a promising therapeutic target for CNV.

      Keywords

      Abbreviations:

      age-related macular degeneration ((AMD)), choroidal neovascularization ((CNV)), circular RNAs ((circRNAs)), mammalian target of rapamycin/p70 S6 kinase ((mTOR/p70 S6k)), adeno-associated virus ((AAV)), neovascular AMD ((nAMD)), retinal pigmented epithelium ((RPE)), vascular endothelial growth factor ((VEGF)), microRNAs ((miRNAs)), long non-coding RNAs ((lncRNAs)), optical coherent tomography ((OCT)), fluorescein fundus angiography ((FFA)), human umbilical vein endothelial cells ((HUVECs)), small interfering RNAs ((siRNAs)), ribonuclease ((RNase)), Cell Counting Kit-8 ((CCK-8)), 5-ethynyl-2-deoxyuridine ((EdU)), untranslated region ((UTR), wild-type, (WT)), standard deviation ((SD)), actinomycin D ((actD)), placental growth factor ((PGF)), Kyoto Encyclopedia of Genes and Genomes ((KEGG)), rapamycin ((RAPA)), hypoxia-inducible factor-1 alpha ((HIF-1α))
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