Discipline of Anatomy and Histology, Bosch Institute, The University of Sydney, Australia; Save Sight Institute, The University of Sydney, Australia.
Discipline of Anatomy and Histology, Bosch Institute, The University of Sydney, Australia.
Exp Eye Res. 2019 Jan;178:108-121. doi: 10.1016/j.exer.2018.09.021. Epub 2018 Oct 2.
Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) plays a critical role in the pathogenesis of fibrotic cataract. Transforming growth factor-beta (TGFβ) is a potent inducer of this fibrotic process in lens. Recent studies in cancer progression have shown that in addition to activating the canonical Smad signaling pathway, TGFβ can also transactivate the epidermal growth factor receptor (EGFR) to enhance invasive cell migration. The present study aims to elucidate the involvement of EGFR-signaling in TGFβ-induced EMT in LECs. Treatment with TGFβ2 induced transdifferentiation of LECs into myofibroblastic cells, typical of an EMT. TGFβ2 induced the phosphorylation of the EGFR and upregulation of Egfr and Hb-egf gene expression. Pharmacologic inhibition of EGFR-signaling using PD153035 inhibited TGFβ-induced EMT, including the upregulation of mesenchymal markers and downregulation of epithelial markers. Crosstalk between TGFβ2-induced EGFR and ERK1/2 was evident, with both pathways impacting on Smad2/3-signaling. Our finding that TGFβ2 transactivates downstream EGFR-signaling reveals a previously unknown mechanism in the pathogenesis of cataract. Understanding the complex interplay between divergent canonical and non-canonical signaling pathways, as well as downstream target genes involved in TGFβ-induced EMT, will enable the development of more effective targeted therapies in the pharmacological treatment of cataract.
上皮-间充质转化（EMT）在纤维性白内障的发病机制中起着关键作用。转化生长因子-β（TGFβ）是晶状体中这种纤维化过程的有力诱导剂。最近在癌症进展方面的研究表明，TGFβ除了激活经典的 Smad 信号通路外，还可以转激活表皮生长因子受体（EGFR），以增强侵袭性细胞迁移。本研究旨在阐明 EGFR 信号在 TGFβ诱导的晶状体上皮细胞（LEC）EMT 中的作用。TGFβ2 处理诱导 LEC 向肌成纤维细胞的转化，这是 EMT 的典型特征。TGFβ2 诱导 EGFR 的磷酸化和 Egfr 和 Hb-egf 基因表达的上调。使用 PD153035 抑制 EGFR 信号通路可抑制 TGFβ 诱导的 EMT，包括间充质标志物的上调和上皮标志物的下调。TGFβ2 诱导的 EGFR 和 ERK1/2 之间的串扰是明显的，两条途径都影响 Smad2/3 信号。我们发现 TGFβ2 转激活下游 EGFR 信号，揭示了白内障发病机制中的一个以前未知的机制。了解不同的经典和非经典信号通路以及 TGFβ 诱导的 EMT 中涉及的下游靶基因之间的复杂相互作用，将能够为白内障的药理学治疗开发更有效的靶向治疗。
