Blockade of Jagged/Notch Pathway Abrogates Transforming Growth Factor β2-Induced Epithelial-Mesenchymal Transition in Human Retinal Pigment Epithelium Cells
Blockade of Jagged/Notch Pathway Abrogates Transforming Growth Factor β2-Induced Epithelial-Mesenchymal Transition in Human Retinal Pigment Epithelium Cells
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DOI：
10.2174/1566524014666140331230411
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发表时间：
2014-05-01
影响因子：
2.5
通讯作者：
Liu, Y.
中科院分区：
文献类型：
--
作者：
Chen, X.;Xiao, W.;Liu, Y.
视网膜色素上皮（retinal pigment epithelium，RPE）细胞的上皮-间质转化（epithelial-mesenchymal transition，EMT）在增生性玻璃体视网膜病变（proliferative vitreoretinopathy，PVR）和增生性糖尿病视网膜病变（proliferative diabetic retinopathy，PDR）中起着关键作用，导致视力丧失。据报道，Jagged/Notch通路在胚胎发育、纤维化疾病和癌症转移期间的EMT中是必需的。然而，Jagged/Notch信号在RPE细胞EMT中的功能尚不清楚。因此，我们假设Notch和转化生长因子β 2（TGF-β 2）信号之间的串扰可以诱导RPE细胞中的EMT，其随后导致PVR和PDR。在这里，我们证明了Jagged-1/Notch通路参与了TGF-β 2介导的人RPE细胞EMT。用DAPT（一种特异性Notch受体切割抑制剂）阻断Notch通路并敲低Jagged-1表达可通过调节Snail、Slug和ZEB 1的表达来抑制TGF-β 2诱导的EMT。除经典的Smad信号通路外，非经典的PI 3 K/Akt和MAPK信号通路也参与了TGF-β 2诱导的RPE细胞Jagged-1表达上调。过表达Jagged-1可模拟TGF-β 2诱导EMT。我们的数据表明，Jagged-1/Notch信号通路在TGF-β 2诱导的人RPE细胞EMT中起着关键作用，并可能有助于PVR和PDR的发展。因此，抑制Jagged/Notch信号通路可能在预防和治疗PVR和PDR中具有治疗价值。
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.