Cigarette smoke-induced EGFR activation promotes epithelial mesenchymal migration of human retinal pigment epithelial cells through regulation of the FAK-mediated Syk/Src pathway

Park,Ga  Bin; Kim,Daejin

doi:10.3892/mmr.2017.8355

Cigarette smoke-induced EGFR activation promotes epithelial mesenchymal migration of human retinal pigment epithelial cells through regulation of the FAK-mediated Syk/Src pathway

Authors:
- Ga Bin Park
- Daejin Kim
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Affiliations: Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea, Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea
Published online on: December 27, 2017 https://doi.org/10.3892/mmr.2017.8355
Pages: 3563-3574
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is inevitable change of age‑related macular degeneration (AMD). Smoking is a major risk factor for the development of EMT in several diseases, including lung cancer. Cigarette smoke‑induced stress promotes the production of epidermal growth factor (EGF) in RPE cells. However, the underlying signaling pathways induced by aberrant EGF receptor (EGFR) expression in cigarette smoke-exposed RPE cells remain largely unknown. In the present study, the morphological transformation and production of EMT-associated cytokines were investigated to analyze the effect of smoking on the retina. Furthermore, EGF‑treated or cigarette smoke‑exposed RPE cells, as well as the downstream targets of EGFR, were investigated to identify the key molecules involved in EMT of cigarette smoke‑stimulated RPE cells via immunoblotting. Exposure of RPE cells to cigarette smoke extract (CSE) induced secretion of VEGF and TGF‑β1, and increased the expression of EMT markers. CSE‑mediated focal adhesion kinase (FAK) activation resulted in the phosphorylation and activation of spleen associated tyrosine kinase (Syk)/Src proto‑oncogene, non‑receptor tyrosine kinase (Src), leading to migration and invasion of RPE cells. Knockdown of FAK or pharmacological inhibition of Syk/Src abrogated CSE‑mediated VEGF and TGF‑β1 production and blocked the phosphorylation of Smad2/3 in CSE‑stimulated RPE cells. Erlotinib (an EGFR inhibitor) suppressed EGF and CSE‑mediated switch from an epithelial to mesenchymal phenotype. Baicalein, an inhibitor of 12/15‑lipooxygenase, also efficiently suppressed CSE‑induced EMT processes by inhibiting EGFR‑associated downstream signaling transduction. The results identified a novel signaling pathway mediated by EGFR in CSE‑activated RPE cells, and suggest baicalein as a potential new therapeutic drug for CSE‑associated retinopathy.

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