Long non-coding RNAs: Diverse roles in various disorders

Abstract

BACKGROUND:

Long non-coding RNAs (lncRNAs) are a group of transcripts larger than 200 nucleotides that are not translated to proteins. These transcripts regulate expression of numerous genes at different levels by acting as decoys, scaffolds, and enhancers. Thus they regulate cell development, differentiation and fate.

OBJECTIVE:

To find the role of lncRNAs in various diseases.

METHODS:

We searched PubMed and google scholar and summarized the data regarding the role of lncRNAs in cancer and neurologic disorders.

RESULTS:

Several recent studies have shown that their expressions are up-/down-regulated in malignant tissues. Consequently, they have suggested that lncRNAs can differentiate cancer samples from normal samples. Their application as biomarker is not limited to cancers. In several neurologic or psychiatric disorders researchers have found aberrant expression of lncRNAs.

CONCLUSIONS:

Taken together, lncRNAs constitute a novel vast area of research to find answer to fundamental biologic questions.

Keywords

Long non-coding RNA lncRNA cancer

1. Introduction

Novel sequencing methods have provided detailed genomic and transcriptomic data showing transcription of up to 85% of the human genome [1, 2]. Encyclopedia of DNA Elements (ENCODE) have demonstrated that most of RNA transcripts do not translate to proteins [3]. A group of these non-coding RNAs are called as long non-coding RNAs (lncRNAs) based on their length that is much than 200 nucleotides up to several kilobases. LncRNAs share some characteristics with mRNAs such as being transcribed by RNA polymerase II, having 5 ${}^{\prime}$ caps and 3 ${}^{\prime}$ polyadenylated tails [4]. LncRNAs participate in various functions such as DNA repair [5, 6], regulation of germ cell functions [7], modulation of signaling pathways [8], senescence [9], control of hormone receptor signaling [10, 11, 12] and cell differentiation [13]. The latter in shown by the presence of discrete lncRNA signatures throughout lineage-specific differentiation. Moreover, lncRNAs are structured in constellations and are co-regulated. An in vitro study has shown certain lncRNAs that control myocyte differentiation [13]. Several lncRNAs such as CCAT2, ASBEL, RBM5-AS1 and LincRoR affect function of WNT signaling pathway in diverse cancers [14]. In addition to these oncogenic lncRNAs, this pathway is modulated by a number of tumor suppressor lncRNAs including NBAT1 [14]. A certain lncRNA namely XLOC_023166 has been shown to postpone senescence, since down-regulation of this lncRNA has promoted the advent of senescence signs in cells [9]. LncRNAs construct interactive networks with transcription factors and other types of regulatory RNAs such as microRNAs to modulate signaling pathways [15]. LncRNAs bind to many DNA binding proteins such as transcription factors that alter expression of several genes. Vitamin D signaling pathway is among pathways that are substantially modulated by lncRNAs [16].

2. Role of lncRNAs in cancers

Expression analyses have shown dysregulation of lncRNAs in various malignancies including breast cancer [17], gliobastoma [18], ovarian cancer [19], colorectal cancer [20], bladder cancer [21], blood cancers [22], renal cell carcinoma [23], cervical cancer [24, 25], lung cancer [26] and hepatocellular carcinoma [27].

Some lncRNAs have specific expression in malignant tissues but not non-malignant tissue of the same source [28]. Certain lncRNAs reside in genomic locations that are frequently altered in cancers [29]. The 8q24 genomic region has several cancer-related single nucleotide polymorphisms (SNPs) some of them regulate expression of lncRNAs which are involved in malignancies such as CCAT2 (in malignancy of digestive system) and PCAT-1 (malignancy of prostate) [30]. An lncRNA named PVT1 resides in the breakpoint of the t(2:8) rearrangement in Burkitt’s lymphoma. Animal studies have shown that amplification of Myc alone cannot promote tumorigenesis while amplification of Myc along with Pvt1 stimulated carcinogenesis [31].

Totally, lncRNAs might exert oncogenic roles [32], tumor suppressor effects [33] or both depending on the cancer type [34]. The number of recognized lncRNAs with these properties is being increased. LncRNAs affect apoptosis by different mechanisms. For instance, BX357664 augments the functions of caspase-3 and caspase-9 [35]. LncRNAs can also alter expression of mRNA coding genes via different mechanisms. A new field of research is simultaneous assessment of an lncRNA and its putative target in cancer tissues to find their integrated contribution in cancer course [36, 37]. In some cases, a naturally occurring antisense (NAT) RNA is involved in the regulation of an mRNA transcribed from the sense strand [38]. Expression of NATs have been associated with malignant behavior of cancer cells [39]. Notably, evidences point to contribution of some NATs in both regulation of immune response and carcinogenesis [40]. Expression analysis of mRNA coding genes and the corresponding NATs revealed correlations between them in different contexts [41].

LncRNAs contain single nucleotide polymorphisms (SNPs) that might alter their expression, function or interaction with microRNAs (miRNAs) and mRNAs. Consequently, variations in these loci might alter risk of cancer. For instance, SNPs within HOTAIR and ANRIL have been shown to confer risk of prostate cancer [42, 43]. Studies in breast cancer patients have verified association between a certain SNP in ANRIL and breast cancer risk [44], but fail to show association between HOTAIR and breast cancer [45].

Expression of the lncRNA-ATB is controlled by TGF- $\beta$ . This lncRNA regulates malignant behavior of liver cancer cells including epithelial to mesenchymal transition (EMT) and invasion [46]. Notably, the lncRNA-ATB also participates in promotion of EMT in gastric cancer cells via the TGF- $\beta$ /miR-200 s/ZEB axis [47]. The lncRNA MEG3 binds with PRC2 and JARID2 control expression of TGF- $\beta$ signaling pathway [48]. In other cancer types, MEG3 also regulates activity of JARID2 and PRC2 leading to induction of EMT [49].

Some lncRNAs have been used as predictive markers for response of patients to therapy. For instance, CCAT1 modulates response of colorectal cancer patients to BET inhibitors [50], while HOTAIR modulates response of ovarian cancer patients to Platinum [51]. The lncRNA HORAS5 participates in determination of outcome of castration-resistant prostate cancer [52].

3. Role of lncRNAs in neurological disorders

Altered expressions of lncRNAs have been detected in various neurological disorders such as multiple sclerosis (MS) [53, 54], autism spectrum disorders (ASD) [55], schizophrenia [56] and bipolar disorder [57]. A recent study using lncRNA PCR arrays has reported a widespread dysregulation of lncRNAs in peripheral blood cells of MS patients compared with healthy subjects among them were NRON and TUG1 [58]. Expression of TUG1, RN7SK RNA and NEAT1 has been shown to be increased in the serum of relapsing remitting-MS patients [59]. IN peripheral blood mononuclear cells (PBMCs) of MS patients expressions of ENSG00000231898.3, XLOC_009626, and XLOC_010881 have been increased, while expression of ENSG00000233392.1, ENSG00000259906.1 and lncRNA XLOC_010931 were decreased [60]. Moreover, researchers have identified certain haplotypes within lncRNA coding genes that are involved in the risk of MS [61]. Disruption of normal regulatory network between lncRNAs and their targets have been noticed in MS patients [62].

Few studies have addressed the role of lncRNAs in epilepsy with variable results ranging from lack of association [63] to their role in epilepsy in animal models [64]. The levels of the lncRNA BC1 has been decreased in the hippocampus of the epilepsy-susceptible Wistar Audiogenic Rat compared to non-susceptible animals. Further studies have demonstrated possible disturbance in signaling pathways, upstream of BC1 in these epilepsy-susceptible rats [64]. A microarray study in mice has shown dysregulation of tens of lncRNAs in two temporal lobe epilepsy models compared with normal animals. Gene Ontology analysis has shown participation of these lncRNAs in morphogenesis and neuron differentiation [65]. In addition, studies in lithium chloride-pilocarpine-provoked epilepsy animal model has demonstrated up-regulation of the lncRNA UCA1 and NF-kB in both brain and blood tissues compared with normal rats. Authors have proposed a role for UCA1 in the development of epilepsy [66].

A post-mortem high throughput gene signature assessment in ASD patients showed aberrant expression of lncRNAs and diminution of normal alterations in gene profiles of the frontal and temporal lobes in these patients [67]. Another study in the peripheral blood of ASD patients and controls has shown differential expression of hundreds of lncRNAs especially those related with synaptic vesicle cycling and transport [68]. Microarray assessment of lncRNAs and mRNA transcripts in autopsied prefrontal cortex and cerebellum tissue has also shown tens of dysregulated lncRNAs between ASD cases and normal individuals [69].

Researchers have also compared lncRNAs profile in PBMCs of schizophrenic patients and normal subjects. Synchronized with the substantial reduction of the PANSS scores of patients following therapies, expression of NONHSAT089447 and NONHSAT041499 has been down-regulated [70].

Finally, studies in major depressive disorder have shown down-regulation of a number of lncRNAs including TCONS_00019174, ENST00000566208 and NONHSAG045500 in these patients compared to controls and suggested them as biomarker for this disorder [71].

4. Discussion

LncRNAs are possible biomarkers for various disorders ranging from cancer [72] to neurologic disorders [73]. Even in a certain cancer type, lncRNAs expression pattern might be different between patients [74] in association with patients demographic data [75] or other variables [76]. This note should be considered when designing targeted therapies against lncRNAs. Based on unavailability of brain tissue as a source of biomarker, measurement of lncRNAs in serum, plasma or whole blood has been suggested for assessment of patients affected by psychiatric disorders. Although the results of these studies are preliminary, lncRNAs role in this aspect are promising. However, assessment of their sensitivity and specificity should be performed in large scale studies including patients in different stages of diseases to validate their biomarker role. Moreover, dysregulation of some lncRNAs have been detected in a number of discrete psychiatric disorders. Although this fact shows extensive roles of lncRNA in brain physiology, limits their potential as disease-specific biomarkers. Whenever up-regulation of a certain lncRNA is involved in the pathogenesis of a disease, siRNA and antisense oligonucleotides are putative therapeutic options. These options have been used in the preclinical situations in cancers [77].

Finally, some studies have shown that a number of acknowledged lncRNAs code for small, translated open reading frames. These data might blur the differentiation between mRNA and lncRNA [78].

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