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Lncrna NR 003923 Promotes Cell Proliferation, Migration, Fibrosis, And

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Lncrna NR 003923 Promotes Cell Proliferation, Migration, Fibrosis, And Zhao et al. Cell Death and Disease (2019) 10:594 https://doi.org/10.1038/s41419-019-1829-1 Cell Death & Disease ARTICLE Open Access LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/ IL22RA1 axis in human Tenon’scapsule fibroblasts Yang Zhao1,FengZhang1, Zheng Pan1,HaominLuo1,KeLiu1 and Xuanchu Duan1,2 Abstract Noncoding RNAs (ncRNAs), including long ncRNAs (lncRNA) have manifested an important role in the pathophysiology of many diseases. Glaucoma is a primary cause of irreversible blindness worldwide. However, the involvement of lncRNAs in glaucoma remains largely unknown. Here, we performed the lncRNA expression assay based on clinical tissues and identified a specific functional lncRNA, NR_003923, and investigated its potential role in glaucoma. Knockdown of NR_003923 in human Tenon’s capsule fibroblast cells (HTFs) inhibited TGF-β-induced cell migration, proliferation, fibrosis, and autophagy. The dual luciferase reporter assay confirmed that miR-760 and miR- 215-3p interacted with NR_003923. miR-760 and miR-215-3p inhibitor reversed the effects of NR_003923 and TGF- β-induced cell apoptosis. Moreover, the expression of miR-760 and miR-215-3p was decreased in glaucoma comparing 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; with control. Furthermore, through microarray we found IL22RA1 was increased in glaucoma and both of miR-760 and miR-215-3p bound to the 3′ UTR of IL22RA1. Overexpression of IL22RA1 enhanced HTFs migration and proliferation, while miR-760 and miR-215-3p mimics reversed these promotive biological roles induced by IL22RA1. In conclusion, NR_003923 and IL22RA1 might contribute to glaucoma progression and be a novel and potential biomarkers and therapeutic targets for glaucoma. Introduction evidence has indicated that glaucoma are associated with cell Glaucoma is a severe eye disease and a major cause of proliferation, fibrosis, migration, and autophagy, which irreversible blindness throughout the world. Glaucoma is induced by wound healing after surgery3.Proliferationof characterized by the irreversible apoptosis of retinal ganglion Tenon’scapsulefibroblasts (HTFs) has been demonstrated as cells and visual field loss1. Filtering surgery is currently a key role in conjunctival repair and scarring4.HTFsbecome regarded as the most effective therapy for glaucoma, exces- activated to promote wound-healing processes such as cell sive scarring due to filtering surgery is the most common proliferation and migration, the synthesis of extracellular reason for an unsuccessful surgical treatment2. Accumulating matrix components (ECM)1,andautophagy5.Phenotype transition from fibroblasts to myofibroblasts has demon- strated as a key proof of subconjunctival fibrosis5. Correspondence: Xuanchu Duan ([email protected]) Transforming growth factor β (TGF-β) shown to play a 1Department of Ophthalmology, The Second Xiangya Hospital, Central South crucial role in excessive subconjunctival fibrosis caused University, Changsha, Hunan Province, China failure after glaucoma-filtering surgery and as a stimulator 2Changsha Aier Eye Hospital, Aier Glaucoma Research Institute, Aier School of Ophthalmology, Central South University, Changsha, Hunan Province, China in cell proliferation, migration, and autophagy processes Edited by I. Amelio © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Zhao et al. Cell Death and Disease (2019) 10:594 Page 2 of 13 – in an in vivo rabbit model and HTFs in vivo6 9. However, with normal tissues, we collected tissue specimens from the underlying mechanism of physiological and patholo- glaucoma patients and analyzed by using microarray gical contexts associated with glaucoma or the TGF-β1- methods. Our lncRNA expression profiles showed that induced cell model still need to be fully understood. 3093 lncRNAs were differentially expressed in glaucoma Genome-sequencing projects have discovered that <2% of comparing with normal tissues, 1638 of the DE-lncRNAs genes in the total human genome code for proteins, and the were upregulated in the glaucoma tissues, and 1455 were remainder (>90%) are transcribed as noncoding RNAs downregulated (Fig. 1a). Among the DE-lnRNAs, (ncRNAs)10. Among those ncRNAs, long noncoding RNAs 705 showed a >twofold change in expression in glaucoma (lncRNAs), (ncRNAs > 200 nucleotides in length), have long tissues and 768 showed a lesser but still significant degree been regarded as junk RNAs. Recently, however, lncRNAs of change in the glaucoma tissues (p < 0.05) (Fig. 1b). have been shown to play various roles in the development of Hierarchical-clustering results showed the distinguishing diseases, including glaucoma11.Previousstudysuggestedthat expression profiles of the 1475 DE-lncRNAs in glaucoma the interaction between lncRNA MEG3 and Nrf2 plays as a tissues and control tissues (Fig. 1c). Among the upregu- keyroleinmediatingtheproliferationofHTFs12.Specifically, lated DE-LncRNAs, we first validated the expression of lncRNA MEG3 appears to inhibit HTFs proliferation by lncRNA NR_003923 by using real-time PCR. Our results directly binding to Nrf212. Another LncRNA, LncRNA indicated that NR_003923 levels were elevated in glau- MALAT1 inhibits retinal ganglion cell apoptosis via the coma tissues, and this finding was consistent with the activation PI3K/AKT signaling pathway in the chronic high- results of our microarray assays (Fig. 1d). To strengthen intraocular pressure (IOP) rat model of glaucoma13. Little the validation, we also determined the change in expres- doubt now exists that lncRNAs play a crucial role in main- sion of other eight randomly selected lncRNAs in glau- taining the homeostasis of a microenvironment. However, coma tissues relative to their expression in the control the underlying mechanism by which lncRNAs affect the tissues (Fig. 1e). occurrence and development of glaucoma remains unclear. In this study, we performed microarray assays to obtain NR_003923 promoted the TGF-β-induced proliferation, an overview of the expression profiles of various lncRNAs migration, and fibrosis of HTFs via the sponging of miR- and mRNAs in glaucoma and normal tissues. We found 760 and miR-215-3p that two miRNAs (miR-760 and miR-215) were down- We used TGF-β-treated human tenon’s capsule fibro- regulated in glaucoma tissues had been reported to be blasts to mimics the glaucoma model in vitro. As shown associated with the status of both oral submucous fibrosis in Fig. S1, TGF-β significantly enhanced cell viability in a and cancer fibrosis14,15. Furthermore, a target predication dose-dependent manner after incubation for 24 h and study identified interleukin-22 receptor alpha-1 48 h (Fig. S1, A). In addition, TGF-β at 1, 2, or 4 ng/mL (IL22RA1) as a target of both miR-760 and miR-215. promoted cell migration (Fig. S1, B, C) and significantly IL22 induction induced both IL22RA1 and FN1 expres- elevated expression of α-SMA and fibronectin (FN), and sion in pancreatic stellate cells16, indicating its protective suppressed E-cadherin and β-catenin expression (Fig. S1, role in pancreatic fibrosis. Lastly, a novel lncRNA D–F). (lncRNA NR_003923) that is transcribed by the gene that To explored the role of NR_003923 in TGF-β-induced encodes the guanylyl cyclase subunit beta 2 (GUCY1B2), a HTFs, the interactions between lncRNA NR_003923 and member of the soluble guanylate cyclase family that plays miRNAs were predicted by KangChen Bio-tech (Shang- crucial roles in glaucoma17, was identified from a list of hai, China), DIANA database, Target Human Scan soft- differentially expressed lncRNAs (DE-lncRNAs) as possi- ware (Version 7.2; http://www.targetscan.org/vert_72/), bly being capable of interacting with miR-760 or miR-215. and lncRNA downstream target database of StarBase Accordingly, we speculated that such an interaction or the v2.0,25. Two miRNAs (miR-760 and miR-215-3p) with NR_003923-miR-760/miR-325-3p-IL22RA1 axis might predicted binding sites for NR_003923 (Fig. 2a) were play an important role in mediating HTFs proliferation, selected for investigation. A real-time PCR analysis migration, fibrosis, and autophagy. This study was per- showed that NR_003923 expression was increased in formed to investigate the role played by this axis in HTFs treated with TGF-β. However, the expression of glaucoma, and our results provide novel information that NR_003923 was suppressed by siRNA-targeting can be used in future investigations of glaucoma. NR_003923 (Fig. 2b). Interestingly, both miR-760 and miR-215-3p displayed an expression trend that was Results opposite of that displayed by NR_003923. Specifically, Analysis of differentially expressed lncRNAs in glaucoma miR-760 and miR-215-3p
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