Blockade of Jagged/Notch Pathway Abrogates Transforming Growth Factor β2-Induced Epithelial-Mesenchymal Transition in Human Retinal Pigment Epithelium Cells

被引:74
作者
Chen, X. [1 ]
Xiao, W. [1 ]
Liu, X. [1 ]
Zeng, M. [1 ]
Luo, L. [1 ]
Wu, M. [1 ]
Ye, S. [1 ]
Liu, Y. [1 ]
机构
[1] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, State Key Lab Ophthalmol, Guangzhou 510060, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
Epithelial-mesenchymal transition (EMT); Jagged/Notch signaling; proliferative diabetic retinopathy (PDR); proliferative vitreoretinopathy (PVR); retinal pigment epithelium (RPE) cells; PROLIFERATIVE VITREORETINAL DISEASES; TGF-BETA; SIGNALING PATHWAY; NOTCH; EXPRESSION; CANCER; PATHOGENESIS; INVOLVEMENT; SLUG;
D O I
10.2174/1566524014666140331230411
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 beta 2 (TGF-beta 2) 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-beta 2-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-beta 2-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-beta 2-induced up-regulation of Jagged-1 in RPE cells. Overexpression of Jagged-1 could mimic TGF-beta 2 induce EMT. Our data suggest that the Jagged-1/Notch signaling pathway plays a critical role in TGF-beta 2-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.
引用
收藏
页码:523 / 534
页数:12
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