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Let-7c-3p suppresses lens epithelial-mesenchymal transition by inhibiting cadherin-11 expression in fibrotic cataract

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Abstract

Fibrotic cataract, including anterior subcapsular cataract (ASC) and posterior capsule opacification, always lead to visual impairment. Epithelial–mesenchymal transition (EMT) is a well-known event that causes phenotypic alterations in lens epithelial cells (LECs) during lens fibrosis. Accumulating studies have demonstrated that microRNAs are important regulators of EMT and fibrosis. However, the evidence explaining how microRNAs modulate the behavior and alter the cellular phenotypes of the lens epithelium in fibrotic cataract is insufficient. In this study, we found that hsa-let-7c-3p is downregulated in LECs in human ASC in vivo as well as in TGFβ2-induced EMT in vitro, indicating that hsa-let-7c-3p may participate in modulating the profibrotic processes in the lens. We then demonstrated that overexpression of hsa-let-7c-3p markedly suppressed human LEC proliferation and migration and attenuated TGFβ2-induced EMT and injury-induced ASC in a mouse model. In addition, hsa-let-7c-3p mediated lens fibrosis by directly targeting the CDH11 gene, which encodes cadherin-11 protein, an important mediator in the EMT signaling pathway. It decreased cadherin-11 protein expression at the posttranscriptional level but not at the transcriptional level by binding to a specific site in the 3-untranslated region (3′-UTR) of CDH11 mRNA. Moreover, blockade of cadherin-11 expression with a specific short hairpin RNA reversed TGFβ2-induced EMT in LECs in vitro. Collectively, these data demonstrated that hsa-let-7c-3p plays a clear role in attenuating ASC development and may be a novel candidate therapeutic for halting fibrosis and maintaining vision.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 81470615, 81770909 and No. 81970783).

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  1. Min Hou and Furong Luo have contributed equally and should be considered as co-first authors.

Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510623, China

    Min Hou, Yujie Ding, Xuan Bao, Xiaoyun Chen, Liangping Liu & Mingxing Wu

  2. Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Haikou, 570311, China

    Furong Luo

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Contributions

MH, FL and MW performed study concept and design. MH, FL, YD and XB conducted the experiment, provided acquisition and interpretation of data and statistical analysis. MH, FL, YD, XB and MW analyzed data. MH wrote of the paper, all authors critically reviewed, edited and approved the manuscript.

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Correspondence to Mingxing Wu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was also approved by the Institutional Review Board of Zhongshan Ophthalmic Center, Sun Yat-sen University (No. 2016MEKY047). The animal experiment was approved by Animal Use and Care Committee of Zhongshan Ophthalmic Center at Sun Yat-Sen University, Guangzhou.

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Hou, M., Luo, F., Ding, Y. et al. Let-7c-3p suppresses lens epithelial-mesenchymal transition by inhibiting cadherin-11 expression in fibrotic cataract. Mol Cell Biochem 479, 743–759 (2024). https://doi.org/10.1007/s11010-023-04758-4

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