Chen Zhen, Ni Ninghua, Mei Yan, Yang Zhengrong
Department of Ophthalmology, The First People's Hospital of Yunnan, Kunming, Yunnan 650032, P.R. China.
Research Center of Fundus Disease of Yunnan, The First People's Hospital of Yunnan, Kunming, Yunnan 650032, P.R. China.
Exp Ther Med. 2017 Nov;14(5):4951-4957. doi: 10.3892/etm.2017.5187. Epub 2017 Sep 22.
Retinal pigment epithelial (RPE) cells have crucial roles in the initiation and development of human ophthalmic diseases. Our previous study suggested that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a potential target in the progression and pathogenesis of human proliferative vitreoretinopathy disease. The present study further analyzed the role of TAK1 inhibitor, LYTAK1, in human RPE cells and explored the potential molecular mechanism of LYTAK1-mediated proliferation of human RPE cells. Proliferation of human RPE cells was investigated following treatment with LYTAK1 and knockdown of TGF-β. TGF-β-mediated epithelial-mesenchymal transition (EMT) through regulation of the extracellular signal-regulated kinase (ERK)protein kinase B (AKT) signaling pathway was also explored to analyze the LYTAK1-mediated mechanism of proliferation in human RPE cells. The present results demonstrated that LYTAK1 administration suppressed TAK1 gene and protein expression in human RPE cells. LYTAK1 administration also inhibited proliferation and migration of human RPE cells . Outcomes indicated that LYTAK1 treatment downregulated expression levels of TGF-β1 and EMT markers, including cadherin, fibronectin and α-smooth muscle actin in human RPE cells. Notably, results demonstrated that the ERKAKT signal pathway was blocked by LYTAK1 in human RPE cells. Knockdown of TGF-β markedly inhibited phosphorylation and activity of TAK1 and suppressed the LYTAK1-mediated ERKAKT signaling pathway in RPE cells, which further canceled inhibition of RPE cell proliferation by LYTAK1. In conclusion, these findings indicated that LYTAK1 may inhibit RPE cell proliferation through the TGF-β-mediated EMTERKAKT signaling pathway, suggesting that TAK1 may be a potential target for the treatment of RPE diseases.
视网膜色素上皮（RPE）细胞在人类眼科疾病的发生和发展中起着关键作用。我们之前的研究表明，转化生长因子-β（TGF-β）激活激酶1（TAK1）是人类增殖性玻璃体视网膜病变疾病进展和发病机制中的一个潜在靶点。本研究进一步分析了TAK1抑制剂LYTAK1在人RPE细胞中的作用，并探讨了LYTAK1介导人RPE细胞增殖的潜在分子机制。在用LYTAK1处理并敲低TGF-β后，研究了人RPE细胞的增殖情况。还探讨了TGF-β通过调节细胞外信号调节激酶（ERK）蛋白激酶B（AKT）信号通路介导的上皮-间质转化（EMT），以分析LYTAK1介导的人RPE细胞增殖机制。目前的结果表明，给予LYTAK1可抑制人RPE细胞中TAK1基因和蛋白的表达。给予LYTAK1还可抑制人RPE细胞的增殖和迁移。结果表明，LYTAK1处理可下调人RPE细胞中TGF-β1和EMT标志物的表达水平，包括钙黏蛋白、纤连蛋白和α-平滑肌肌动蛋白。值得注意的是，结果表明LYTAK1在人RPE细胞中阻断了ERK-AKT信号通路。敲低TGF-β可显著抑制TAK1的磷酸化和活性，并抑制RPE细胞中LYTAK1介导的ERK-AKT信号通路，这进一步消除了LYTAK1对RPE细胞增殖的抑制作用。总之，这些发现表明LYTAK1可能通过TGF-β介导的EMT-ERK-AKT信号通路抑制RPE细胞增殖，提示TAK1可能是治疗RPE疾病的一个潜在靶点。
