title: Regulation of ADAM10 and ADAM17 by Sorafenib Inhibits Epithelial-to-Mesenchymal Transition in Epstein-Barr Virus-Infected Retinal Pigment Epithelial Cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department 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.
authors.forename: Ga Bin
authors.initials: GB
authors.lastname: Park
authors.affiliation: Department 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.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Yeong Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Plastic Surgery, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Plastic Surgery, Inje University Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Hook
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Inje University College of Medicine, Busan, Republic of Korea.
authors.forename: Kug-Hwan
authors.initials: KH
authors.lastname: Roh
authors.affiliation: Ocular 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.
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Yang
authors.affiliation: Department 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.
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D002465:Cell Movement; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D004854:Herpesvirus 4, Human; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077157:Sorafenib; D014409:Tumor Necrosis Factor-alpha; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: D008565:Membrane Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D004247:DNA; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human