Blockade of Jagged/Notch pathway abrogates transforming growth factor β2-induced epithelial-mesenchymal transition in human retinal pigment epithelium cells

Curr Mol Med. 2014 May;14(4):523-34. doi: 10.2174/1566524014666140331230411.

Abstract

The epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays a key role in proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), which lead to the loss of vision. The Jagged/Notch pathway has been reported to be essential in EMT during embryonic development, fibrotic diseases and cancer metastasis. However, the function of Jagged/Notch signaling in EMT of RPE cells is unknown. Thus, we hypothesized that a crosstalk between Notch and transforming growth factor β2 (TGF-β2) signaling could induce EMT in RPE cells, which subsequently contributes to PVR and PDR. Here, we demonstrate that Jagged-1/Notch pathway is involved in the TGF-β2-mediated EMT of human RPE cells. Blockade of Notch pathway with DAPT (a specific inhibitor of Notch receptor cleavage) and knockdown of Jagged-1 expression inhibited TGF-β2-induced EMT through regulating the expression of Snail, Slug and ZEB1. Besides the canonical Smad signaling pathway, the noncanonical PI3K/Akt and MAPK pathway also contributed to TGF-β2-induced up-regulation of Jagged-1 in RPE cells. Overexpression of Jagged-1 could mimic TGF-β2 induce EMT. Our data suggest that the Jagged-1/Notch signaling pathway plays a critical role in TGF-β2-induced EMT in human RPE cells, and may contribute to the development of PVR and PDR. Inhibition of the Jagged/Notch signaling pathway, therefore, may have therapeutic value in the prevention and treatment of PVR and PDR.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition* / drug effects
  • Epithelial-Mesenchymal Transition* / genetics
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Notch / metabolism*
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / metabolism*
  • Retinal Pigment Epithelium / pathology*
  • Serrate-Jagged Proteins
  • Signal Transduction* / drug effects
  • Smad Proteins / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transforming Growth Factor beta2 / metabolism*
  • Transforming Growth Factor beta2 / pharmacology
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Calcium-Binding Proteins
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • RNA, Small Interfering
  • Receptors, Notch
  • SNAI1 protein, human
  • Serrate-Jagged Proteins
  • Smad Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta2
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Amyloid Precursor Protein Secretases