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CYTOR-NFAT1 feedback loop regulates epithelial-mesenchymal transition of retinal pigment epithelial cells

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Abstract

Epithelial mesenchymal transition (EMT) occurring in retinal pigment epithelial cells (RPE) is a crucial mechanism that contributes to the development of age-related macular degeneration (AMD), a pivotal factor leading to permanent vision impairment. Long non-coding RNAs (lncRNAs) have emerged as critical regulators orchestrating EMT in RPE cells. In this study, we explored the function of the lncRNA CYTOR (cytoskeleton regulator RNA) in EMT of RPE cells and its underlying mechanisms. Through weighted correlation network analysis, we identified CYTOR as an EMT-related lncRNA associated with AMD. Experimental validation revealed that CYTOR orchestrates TGF-β1-induced EMT, as well as proliferation and migration of ARPE-19 cells. Further investigation demonstrated the involvement of CYTOR in regulating the WNT5A/NFAT1 pathway and NFAT1 intranuclear translocation in the ARPE-19 cell EMT model. Mechanistically, CHIP, EMSA and dual luciferase reporter assays confirmed NFAT1’s direct binding to CYTOR's promoter, promoting transcription. Reciprocally, CYTOR overexpression promoted NFAT1 expression, while NFAT1 overexpression increased CYTOR transcription. These findings highlight a mutual promotion between CYTOR and NFAT1, forming a positive feedback loop that triggers the EMT phenotype in ARPE-19 cells. These discoveries provide valuable insights into the molecular mechanisms of EMT and its association with AMD, offering potential avenues for targeted therapies in EMT-related conditions, including AMD.

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Funding

Natural Science Foundation for Young Scientists of Shanxi Province (No.202203021212071), Research Foundation of Shanxi Eye Hospital (No. Q202201) and Scientific Research Project of Shanxi Administration of Traditional Chinese Medicine (No.2023ZYYC053) are gratefully acknowledged.

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Authors and Affiliations

  1. Department of Ophthalmology, Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, 030002, Shanxi, China

    Rong Zhang, Lin Wang, Kui Dong, Yajing Pei, Junmei Zhao, Gang Liu, Jing Li, Xiaodan Zhang, Tong Cui, Yan Gao, Wenjuan Wang, Yongrui Wang, Chenwei Gui & Guohong Zhou

  2. Department of Ophthalmology, Yuncheng Central Hospital, Yuncheng, 044000, Shanxi, China

    Yang Li

  3. Shanxi Province Cancer Hospital/ Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, 030013, Shanxi, China

    Yan Liu

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  1. Rong Zhang
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Correspondence to Guohong Zhou.

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Zhang, R., Wang, L., Li, Y. et al. CYTOR-NFAT1 feedback loop regulates epithelial-mesenchymal transition of retinal pigment epithelial cells. Human Cell (2024). https://doi.org/10.1007/s13577-024-01075-w

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