Invest Ophthalmol Vis Sci. 2015 Aug;56(9):5162-73. doi: 10.1167/iovs.14-16058.
Regulation of ADAM10 and ADAM17 by Sorafenib Inhibits Epithelial-to-Mesenchymal Transition in Epstein-Barr Virus-Infected Retinal Pigment Epithelial Cells.
Park GB1, Kim D1, Kim YS2, Kim JW3, Sun H3, Roh KH4, Yang JW5, Hur DY1.
1Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea 2Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea.
2Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea.
3Department of Plastic Surgery, Inje University Busan Paik Hospital, Busan, Republic of Korea.
4Department of Microbiology and Immunology, Inje University College of Medicine, Busan, Republic of Korea.
5Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea 5Department of Ophthalmology, Inje University Busan Paik Hospital, Busan, Republic of Korea.
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 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.
Epithelial to mesenchymal transition 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 with 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, ADAM17, and cleaved Notch 1 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. Nardilysin and ADAM family proteins might be new targets for the prevention or control of EMT in retinal diseases.