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«International Journal of Molecular Sciences Review Novel Insights into the Role of Long Noncoding RNA in Ocular Diseases Fang Li †, Xuyang Wen † ...»

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International Journal of

Molecular Sciences


Novel Insights into the Role of Long Noncoding

RNA in Ocular Diseases

Fang Li †, Xuyang Wen †, He Zhang * and Xianqun Fan *

Department of Ophthalmology, Ninth People’s Hospital, School of Medicine, Shanghai JiaoTong University,

Shanghai 200025, China; lifangniuniu@126.com (F.L.); winston-a@hotmail.com (X.W.)

* Correspondence: zhanghe@sjtu.edu.cn (H.Z.); fanxq@sh163.net (X.F.);

Tel.: +86-21-6313-5606 (H.Z. & X.F.); Fax: +86-21-6313-7148 (H.Z. & X.F.) † These authors contributed equally to this work.

Academic Editor: Martin Pichler Received: 11 February 2016; Accepted: 18 March 2016; Published: 31 March 2016 Abstract: Recent advances have suggested that long noncoding RNAs (lncRNAs) are differentially expressed in ocular tissues and play a critical role in the pathogenesis of different types of eye diseases.

Here, we summarize the functions and mechanisms of known aberrantly-expressed lncRNAs and present a brief overview of relevant reports about lncRNAs in such ocular diseases as glaucoma, proliferative vitreoretinopathy (PVR), diabeticretinopathy (DR), and ocular tumors. We intend to highlight comprehensive studies that provide detailed data about the mechanisms of lncRNAs, their applications as diagnostic or prognostic biomarkers, and their potential therapeutic targets. Although our understanding of lncRNAs is still in its infancy, these examples may provide helpful insights into the methods by which lncRNAs interfere with ocular diseases.

Keywords: epigenetics; long noncoding RNA; ocular disease

1. Introduction The dramatically increasing prevalence of ocular disorders worldwide, including ocular diseases that lead to visual impairment and eventual blindness, such as glaucoma, retinal degeneration, and ocular tumors, will likely continue, particularly in underdeveloped countries but also in developed regions. Ocular diseases can seriously affect an individual’s health and quality of life, while also imposing a substantial emotional, medical, and economic burden on patients and society [1]. Thus, early detection and prompt treatment is of great importance to prevent visual impairment by disease.

To date, the occurrence and development of eye diseases have been primarily attributed to specific gene mutations, such as RB1 for retinoblastoma [2,3] and GNAQ, GNA11, EIF1AX, SF3B1, BAP1, and PLCB4 for uveal melanoma [4–7]. However, some cases include non-Mendelian distributions, and their variability remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm for understanding and potentially explaining the onset and progression of some ocular diseases. In addition, epigenetic alterations are generally reversible, which will undoubtedly make them attractive targets for potential new epigenetic therapies in the future. Epigenetic modifications mainly include DNA methylation, histone modifications, chromatin structure, and noncoding RNAs. In this review, we focus on the most recently discovered class, namely long noncoding RNAs (lncRNAs).

LncRNAs are recognized as transcripts that are longer than 200 nucleotides and that structurally resemble mRNA but have little or no protein-coding potential. Most lncRNAs are located in the nucleus, but a substantial minority of nearly 15% are located in the cytoplasm [8]. According to their genomic locations, lncRNAs can be divided into several types [9]. Certain lncRNAs that overlap with, or are antisense transcribed to, protein-coding genes are defined as sense or antisense. A lncRNA Int. J. Mol. Sci. 2016, 17, 478; doi:10.3390/ijms17040478 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2016, 17, 478 2 of 11 can also be bidirectional if its promoter and a coding transcript are in close proximity, oriented in a head-to-head fashion. Intronic lncRNAs are genes derived from the introns of protein-coding genes, and the term lincRNA refers to a lncRNA located within an intergenic region of the genome [10–12].

Compared with linear ncRNA, circular RNA (circRNA) represents a distinct group of RNA molecules that are longer than 200 nucleotides [13].

Studies have shown that lncRNAs play important regulatory roles in multiple biological processes, such as stem cell maintenance, cell lineage commitment, and cellular phenotype differentiation [14–16].

Most lncRNAs exert a broad influence on transcriptional regulation through several modes, including signal, decoy, guide, and scaffold [17]. Briefly, a lncRNA may act as a signal in response to various stimuli, recruiting corresponding complexes to activate or silence gene expression. Additionally, a lncRNA may guide or sequester transcription factors to bind to a specific site of action, or it may interact with multiple components, thereby repressing or activating gene expression [18–20].

Additionally, some lncRNAs may affect gene expression through post-transcriptional events [21].

LncRNAs can enhance or reduce protein translation via mRNA alternative splicing, turnover, export, and translocation, or they may reduce the effect of microRNAs (miRNAs) on mRNA stability by acting as competing endogenous RNAs or RNA sponges when they contain an miRNA-binding sequence [22,23].

In addition, lncRNAs also participate in the post-translational modification of proteins.

Defining the functions and potential mechanisms of lncRNAs has been the focus of recent and intense research. To date, several lncRNAs have been implicated in common ocular diseases, such as corneal vascularization, glaucoma, proliferative vitreoretinopathy, diabetic retinopathy, and ocular tumors, among others. However, the functions and detailed mechanisms by which lncRNAs affect these diseases remain largely unknown. Here, we review and summarize the currently identified lncRNAs as follows (Table 1).

Table 1. Long noncoding RNAs (lncRNAs) involved in different types of ocular diseases.

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2. Roles of lncRNAs in Ocular Disease

2.1. Role of lncRNA in Corneal Neovascularization (CN) Chronic hypoxia or various inflammatory stimuli, such as bacterial keratitis, alkaline burns, and graft rejections, can lead to corneal neovascularization, which results in visual impairment or even blindness [39]. Huang et al. [24] identified 154 differentially-expressed lncRNAs between vascularized and normal corneas, including 60 down-regulated lncRNAs and 94 up-regulated lncRNAs. The lncRNA NR_033585 was significantly up-regulated in vascularized corneas and presented a similar expression pattern as pro-angiogenic factors, such as VEGF, MMP-9, and Ang-2, whereas the lincRNA chr8:129102060–129109035 reverse strand was markedly down-regulated in vascularized corneas and showed a similar expression pattern to the anti-angiogenesis factor PDGF [40]. This study provides a novel insight into CN pathogenesis, namely that lncRNAs can perform pro-angiogenic or anti-angiogenicroles in vascularization, and dysregulated lncRNAs may, thus, become potential targets for prevention or treatment.

2.2. Role of lncRNAs in Glaucoma Primary open-angle glaucoma (POAG) is the most frequent subtype of glaucoma, and it is characterized pathologically by a progressive loss of retinal ganglion cells and a corresponding loss of the visual field. Evidence from several studies has shown that genetic variants at the chromosome 9p21 locus, including CDKN2B-AS1, CDKN2A, and CDKN2B genes, are associated with POAG [25,26,41–44].

CDKN2B-AS, also known as ANRIL, is a lncRNA transcribed in the antisense direction of CDKN2A and CDKN2B. ANRIL is a well-established tumor suppressor whose function is disabled in human cancers [45]. Additionally, ANRIL has been widely implicated in increased susceptibility to many diseases, including coronary artery disease, myocardial infarction, type 2 diabetes, and Alzheimer disease [46,47]. The extensive roles of ANRIL in disease were discovered in a series of linkage studies, in which single-nucleotide polymorphisms (SNPs) in a region spanning 120 kb around the INK4b-ARF-INK4a locus were associated with disease. The molecular mechanisms underlying the association between ANRIL and POAG are not well understood [48]. One possible explanation is that the occurrence of polymorphisms at these loci alters the expression of target genes that regulate the cell cycle or acts through epigenetic mechanisms, subsequently inducing a tendency toward retinal ganglion cell apoptosis and glaucoma [25–27]. Another study identified associations between 9p21 variants and glaucoma features, suggesting that the ANRIL region modifies the vulnerability of the optic nerve to glaucomatous change, further implying a role of ANRIL in modulating optic nerve degeneration [42]. Compared with patients who lack glaucoma risk alleles, patients carrying the risk alleles have a lower intraocular pressure (IOP) and a larger vertical cup-to-disc ratio (VCDR) [49] and are predisposed to the development of POAG at lower IOP levels; in other words, these patients exhibit stronger associations with normal tension glaucoma (NTG) and advanced glaucoma phenotypes [44].

All of this evidence supports a key regulatory role for ANRIL in the development of glaucoma.

POAG can be difficult to diagnose at early stages, and defining high- or low-risk alleles may be useful for the early determination of whether patients with suspected glaucoma should receive prioritized treatment to slow disease progression and avoid blindness.

2.3. Role of lncRNAs in Proliferative Vitreoretinopathy Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment and vitreoretinal surgery, and epiretinal membrane (ERM) formation leads to severe reductions in vision.

Zhou et al. [28] performed a microarray to identify PVR-related lncRNAs, and the lncRNA MALAT1 was found to be significantly up-regulated in the fibrovascular membrane. MALAT1, also known as nuclear-enriched transcript 2 (NEAT2), is a lncRNA that is highly expressed in individuals who are high risk for the metastasis of non-small cell lung tumors [50]. The increased expression of MALAT1 has been associated with retinal pigment epithelium proliferation and migration, promotion Int. J. Mol. Sci. 2016, 17, 478 4 of 11 of ERM formation, and PVR pathogenesis. Moreover, MALAT1 is also up-regulated in peripheral blood samples from PVR patients, implying that it may represent an easily detectable biomarker for noninvasive diagnosis to identify high-risk PVR patients [28].

2.4. Role of lncRNAs in Diabeticretinopathy Diabeticretinopathy (DR) is one of the most common vascular complications in patients with long-term diabetes. Visual deterioration is tightly related to retinal inflammation, retinal neovascularization, vascular hyperpermeability, and vascular cell apoptosis [51,52]. During the pathogenesis and progression of retinopathy, certain lncRNAs show a potential association.

Myocardial infarction-associated transcript (MIAT), also known as Gomafu or retinal noncoding RNA 2 (RNCR2), was first identified as a susceptibility locus for myocardial infarction patients [53] and is reportedly highly expressed in retinal precursor cells [54]. Yan et al. [29] showed that the MIAT level is clearly up-regulated following treatment with high-glucose or oxidative stress and this up-regulation contributes to endothelial cell proliferation and migration, thus leading to microvascular dysfunction.

To further explore the therapeutic effects of MIAT in diabetic retinas, they also investigated the role of MIAT in cultured endothelial cells. Down-regulating MIAT using siRNA significantly inhibited endothelial inflammatory responses. The underlying mechanisms may be related to the role of MIAT as a competing endogenous RNA (ceRNA) in the regulation of VEGF levels, thereby promoting retinal neovascularization. The ceRNA phenomenon is a recently-proposed hypothesis in which all RNA transcripts that share miRNA-binding sites can communicate with, and regulate, each other by competing specifically for shared miRNAs [55]. MIAT can bind to the same site as miR-150-5p, thus alleviating the miR-150-5p repression effect and up-regulating the level of the miR-150-5p target gene VEGF. Moreover, MIAT knockdown inhibits the up-regulation of TNF-α and ICAM-1, thereby alleviating vascular leakage and inflammation; as these are the key features of different stages of DR, MIAT knockdown shows an impressive therapeutic benefit [56].

MALAT1 is highly expressed in a wide range of tumors, including lung cancer, liver cancer, renal cell carcinoma, bladder cancer, and osteosarcoma, and it also participates in the pathogenesis of DR [57].

Yan et al. [30] performed lncRNA profiling in a murine model of DR using microarray analysis, and they identified 303 aberrantly expressed lncRNAs. MALAT1 expression was significantly up-regulated in a RF/6A cell model of hyperglycemia, in aqueous humor samples, and in the fibrovascular membranes of diabetic patients. Moreover, experimental evidence has shown that MALAT1 plays an important role in diabetes-induced retinal vessel dysfunction. Liu et al. [32] found that MALAT1 regulated retinal endothelial cell function and pathological microvascular growth under diabetic conditions.

Knockdown of MALAT1 significantly alleviates diabetes-induced microvascular dysfunction in vivo and inhibits endothelial cell proliferation, migration, and tube formation in vitro by changing the levels of phosphorylated p38 MAPKs. Michalik et al. [31] also confirmed that genetic ablation of MALAT1 in vivo inhibits the proliferation of endothelial cells and reduces neonatal retinal vascularization.

All the above lines of evidence show that MIAT and MALAT1 are involved in DR. Thus, both of these lncRNAs can help us understand the pathogenesis of DR, and they provide new, promising therapeutic targets for DR treatment in the future.

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