Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Clinical College of Ophthalmology Tianjin Medical University, Tianjin, China.
Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China.
Invest Ophthalmol Vis Sci. 2022 Jul 8;63(8):24. doi: 10.1167/iovs.63.8.24.
Both epidermal growth factor receptor (EGFR) and the Yes-associated protein (YAP) signaling pathway are implicated in cell proliferation and differentiation. In this study, we explored whether the formation of proliferative vitreoretinopathy (PVR) depends on the interaction of the EGFR receptor and YAP pathway.
We studied the effects of EGFR and YAP activation on retinal fibrosis in a PVR mouse model as well as in knockout mice (conditional deletion of EGFR or YAP specifically in RPE cells). Reversal and knockdown experiments were performed to induce a model of ARPE-19 cells treated with TGF-β2 in vitro. The effect of EGFR/YAP signaling blockade on the PVR-induced cell cycle and TGF-β2-induced ARPE-19 cell activation was determined.
The EGFR inhibitor erlotinib or conditional deletion of EGFR attenuated YAP activation and decreased the expression of YAP and its downstream target Cyr61 and of connective tissue growth factor in vivo and in vitro. EGFR-PI3K-PDK1 signaling induced by PVR promoted YAP activation and cell cycle progression. Furthermore, activated EGFR signaling bypassed RhoA to increase the protein levels of YAP, C-Myc, CyclinD1, and Bcl-xl.
Our work highlights that EGFR-PI3K-PDK1-dependent YAP activation plays a crucial role in the formation of PVR. Targeting EGFR and the YAP pathway provides promising therapeutic treatments for PVR.
表皮生长因子受体（EGFR）和 Yes 相关蛋白（YAP）信号通路都与细胞增殖和分化有关。在这项研究中，我们探讨了增殖性玻璃体视网膜病变（PVR）的形成是否依赖于 EGFR 受体和 YAP 通路的相互作用。
我们研究了 EGFR 和 YAP 激活对 PVR 小鼠模型以及 EGFR 或 YAP 特异性在 RPE 细胞中缺失的敲除小鼠（条件性缺失）中视网膜纤维化的影响。进行了逆转和敲低实验，以诱导体外 TGF-β2 处理的 ARPE-19 细胞模型。确定 EGFR/YAP 信号阻断对 PVR 诱导的细胞周期和 TGF-β2 诱导的 ARPE-19 细胞激活的影响。
EGFR 抑制剂厄洛替尼或 EGFR 的条件性缺失减弱了 YAP 的激活，并降低了体内和体外 YAP 及其下游靶标 Cyr61 和结缔组织生长因子的表达。由 PVR 诱导的 EGFR-PI3K-PDK1 信号促进了 YAP 的激活和细胞周期进程。此外，激活的 EGFR 信号绕过 RhoA 增加了 YAP、C-Myc、CyclinD1 和 Bcl-xl 的蛋白水平。
我们的工作强调了 EGFR-PI3K-PDK1 依赖性 YAP 激活在 PVR 形成中起着关键作用。靶向 EGFR 和 YAP 通路为 PVR 提供了有前途的治疗方法。
