期刊
CELL PROLIFERATION
卷 53, 期 11, 页码 -出版社
WILEY
DOI: 10.1111/cpr.12911
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资金
- National Natural Science Foundation of China [81300749, 81600707]
- Natural Science Foundation of Guangdong Province [2018A030313628]
- National Basic Research Program of China (973 Program) [2015CB964600]
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University
Objectives Fibrotic cataract, including posterior capsule opacification (PCO) and anterior subcapsular cataract (ASC), renders millions of people visually impaired worldwide. However, the underlying mechanism remains poorly understood. Here, we report a miRNA-based regulatory pathway that controls pathological fibrosis of lens epithelium. Materials and methods Expression of miR-22-3p and histone deacetylase 6 (HDAC6) in normal and PCO patient samples were measured by qPCR. Human lens epithelial explants were treated with TGF-beta 2 in the presence or absence of miR-22-3p mimics or inhibitor. Cell proliferation was determined by MTS assay, and migration was tested by transwell assay. Expression of HDAC6 and EMT-related molecules were analysed by Western blot, qPCR and immunocytochemical experiments. Results We identify miR-22-3p as a downregulated miRNA targeting HDAC6 in LECs during lens fibrosis and TGF-beta 2 treatment. Mechanistically, gain- and loss-of-function experiments in human LECs and lens epithelial explants reveal that miR-22-3p prevents proliferation, migration and TGF-beta 2 induced EMT of LECs via targeting HDAC6 and thereby promoting alpha-tubulin acetylation. Moreover, pharmacological targeting of HDAC6 deacetylase with Tubacin prevents fibrotic opaque formation through increasing alpha-tubulin acetylation under TGF-beta 2 stimulated conditions in both human lens epithelial explants and the whole rat lenses. Conclusions These findings suggest that miR-22-3p prevents lens fibrotic progression by targeting HDAC6 thereby promoting alpha-tubulin acetylation. The 'miR-22-HDAC6-alpha-tubulin (de)acetylation' signalling axis may be therapeutic targets for the treatment of fibrotic cataract.
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