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Dae Young Hur, Ga Bin Park, Daejin Kim, JaeWook Yang; Regulation of ADAM10 and ADAM17 by sorafenib inhibits epithelial-to-mesenchymal transition in EBV-infected retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4230.
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The a-disintegrin-and-metalloprotease (ADAM) family proteins are widely expressed in the different layers of the retina throughout development. The effect of ADAM proteins on the epithelial to mesenchymal transition (EMT) in proliferative vitreoretinopathy (PVR) or age-related macular degeneration (AMD) is yet to be elucidated. In this study we used Epstein-Barr virus (EBV)-transformed adult retinal pigment epithelial (ARPE) cells to investigate how sorafenib, a multikinase inhibitor, modulates ADAM proteins to control EMT.
EMT and related-mechanisms in EBV-infected ARPE cells were determined by RT-PCR, western blot, invasion assay, ELISA assay, and gene silencing with siRNA.
Mesenchymal-like ARPE/EBV cells exhibited considerably increased cellular migration and invasion compared to ARPE cells and produced EMT-related cytokines. Sorafenib significantly inhibited production of TGF-β1, VEGF, IL-6, IL-8, MCP-1, and TNF-α and blocked the activation of migration-related signaling molecules such as HIF-1α, p-STAT3, MMP2, and Ang-1. The expression of mature ADAM10 and ADAM17 proteins in ARPE/EBV cells was downregulated after treatment with sorafenib through the regulatory activity of nardilysin (NRD-1). Gene silencing of NRD-1 in ARPE/EBV cells attenuated secretion of EMT-related cytokines and expression of ADAM10 and 17 and upregulated epithelial markers.
Sorafenib controls the mesenchymal characteristics of EBV-infected ARPE cells. NRD-1 and ADAM family proteins might be new targets for the prevention or control of EMT in retinal diseases.
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