MicroRNA-184 promotes differentiation of the retinal pigment epithelium by targeting the <i>AKT2</i>/mTOR signaling pathway

Abstract

// Chao Jiang 1 , Bing Qin 1, 2 , Guohua Liu 3 , Xiantao Sun 4 , Houxia Shi 1 , Sijia Ding 1 , Yuan Liu 5 , Meidong Zhu 6 , Xue Chen 1 , Chen Zhao 1, 7, 8 1 Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China 2 Department of Ophthalmology, The First People&rsquo;s Hospital of Suqian, Suqian, China 3 Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, China 4 Department of Ophthalmology, Children&rsquo;s Hospital of Zhengzhou, Zhengzhou, China 5 Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China 6 Save Sight Institute, Discipline of Clinical Ophthalmology and Eye Health (CO9), The University of Sydney, Sydney, Australia 7 Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, China 8 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat Sen University, Guangzhou, China Correspondence to: Chen Zhao, email: dr_zhaochen@163.com Xue Chen, email: drcx1990@163.com Keywords: miR-184, retinal pigment epithelium, differentiation, AKT2, mTOR Received: February 14, 2016&emsp;&emsp;&emsp;&emsp; Accepted: June 30, 2016&emsp;&emsp;&emsp;&emsp; Published: July 13, 2016 ABSTRACT Dedifferentiation of retinal pigment epithelium (RPE) cells is a crucial contributing factor to the pathology of retinal degenerative diseases, including age-related macular degeneration (AMD). Herein, we aim to reveal the roles of microRNAs (miRNAs) in RPE dedifferentiation and seek for potential therapeutic targets. Based on the microarray data, miR-184 was sorted out as the most up-regulated signature along with the differentiation from human induced pluripotent stem cells (hiPSC) to RPE cells, suggesting its potential promotive role in RPE differentiation. In vitro study indicated that miR-184 insufficiency suppressed RPE differentiation, typified by reduction of RPE markers, and promoted cell proliferation and migration. The role of miR-184 in maintaining regular RPE function was further proved in zebrafish studies. We also noticed that miR-184 expression was reduced in the macular RPE-choroid from a donor with RPE dysfunction compared to a healthy control. We next demonstrated that RAC-beta serine/threonine-protein kinase ( AKT2 ) was a direct target for miR-184. MiR-184 promoted RPE differentiation via suppression of AKT2/mammalian target of rapamycin (mTOR) signaling pathway. We also found that AKT2 was up-regulated in macular RPE-choroid of the donor with RPE dysfunction and dry AMD patients. Taken together, our findings suggest that miR-184 insufficiency is involved in the pathogenesis of dry AMD. MiR-184 promotes RPE differentiation via inhibiting the AKT2/mTOR signaling pathway. MiR-184 based supplementary therapeutics and mTOR blocker, like rapamycin, are prospective options for AMD treatment.