NFκB-Mediated Expression of Phosphoinositide 3-Kinase δ Is Critical for Mesenchymal Transition in Retinal Pigment Epithelial Cells
Haote Han,
Yanhui Yang,
Zhuo Han,
Luping Wang,
Lijun Dong,
Hui Qi,
Bing Liu,
Jingkui Tian,
Bart Vanhaesebroeck,
Andrius Kazlauskas,
Guoming Zhang,
Shaochong Zhang,
Hetian Lei
Affiliations
Haote Han
Institute of Basic Medicine and Cancer, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 100864, China
Yanhui Yang
Ningxia Key Laboratory of Prevention and Control of Common Infectious Diseases, The School of Basic Medical Sciences, Ningxia Medical University, Yinchuan 750101, China
Zhuo Han
Institute of Basic Medicine and Cancer, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 100864, China
Luping Wang
Institute of Basic Medicine and Cancer, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 100864, China
Lijun Dong
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518000, China
Hui Qi
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518000, China
Bing Liu
Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA 02114, USA
Jingkui Tian
Institute of Basic Medicine and Cancer, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 100864, China
Bart Vanhaesebroeck
Cancer Institute, University College London, London WC1E 6BT, UK
Andrius Kazlauskas
Department of Ophthalmology and Visual Sciences, Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60607, USA
Guoming Zhang
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518000, China
Shaochong Zhang
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518000, China
Hetian Lei
Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen 518000, China
Epithelial mesenchymal transition (EMT) plays a vital role in a variety of human diseases including proliferative vitreoretinopathy (PVR), in which retinal pigment epithelial (RPE) cells play a key part. Transcriptomic analysis showed that the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was up-regulated in human RPE cells upon treatment with transforming growth factor (TGF)-β2, a multifunctional cytokine associated with clinical PVR. Stimulation of human RPE cells with TGF-β2 induced expression of p110δ (the catalytic subunit of PI3Kδ) and activation of NFκB/p65. CRISPR-Cas9-mediated depletion of p110δ or NFκB/p65 suppressed TGF-β2-induced fibronectin expression and activation of Akt as well as migration of these cells. Intriguingly, abrogating expression of NFκB/p65 also blocked TGF-β2-induced expression of p110δ, and luciferase reporter assay indicated that TGF-β2 induced NFκB/p65 binding to the promoter of the PIK3CD that encodes p110δ. These data reveal that NFκB/p65-mediated expression of PI3Kδ is essential in human RPE cells for TGF-β2-induced EMT, uncovering hindrance of TGF-β2-induced expression of p110δ as a novel approach to inhibit PVR.
