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

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-07-01 Epub Date: 2024-05-14 DOI:10.1007/s13577-024-01075-w
Rong Zhang, Lin Wang, Yang Li, Yan Liu, Kui Dong, Yajing Pei, Junmei Zhao, Gang Liu, Jing Li, Xiaodan Zhang, Tong Cui, Yan Gao, Wenjuan Wang, Yongrui Wang, Chenwei Gui, Guohong Zhou
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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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CYTOR-NFAT1反馈环调节视网膜色素上皮细胞的上皮-间质转化。
视网膜色素上皮细胞(RPE)中发生的上皮间充质转化(EMT)是导致老年性黄斑变性(AMD)的重要机制,而老年性黄斑变性是导致永久性视力损伤的关键因素。长非编码 RNA(lncRNA)已成为协调 RPE 细胞 EMT 的关键调控因子。在这项研究中,我们探讨了lncRNA CYTOR(细胞骨架调节RNA)在RPE细胞EMT中的功能及其内在机制。通过加权相关网络分析,我们发现CYTOR是与AMD相关的EMT相关lncRNA。实验验证表明,CYTOR 可协调 TGF-β1 诱导的 EMT 以及 ARPE-19 细胞的增殖和迁移。进一步研究表明,在 ARPE-19 细胞 EMT 模型中,CYTOR 参与了 WNT5A/NFAT1 通路和 NFAT1 核内转位的调控。从机理上讲,CHIP、EMSA 和双荧光素酶报告实验证实了 NFAT1 与 CYTOR 启动子的直接结合,促进了转录。反过来,CYTOR 的过表达促进了 NFAT1 的表达,而 NFAT1 的过表达增加了 CYTOR 的转录。这些发现突显了 CYTOR 和 NFAT1 之间的相互促进作用,形成了一个正反馈回路,触发了 ARPE-19 细胞的 EMT 表型。这些发现为EMT的分子机制及其与AMD的关联提供了宝贵的见解,为包括AMD在内的EMT相关疾病的靶向治疗提供了潜在的途径。
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CiteScore
7.20
自引率
4.30%
发文量
567
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