Next Article in Journal
Dosimetric Characteristics of a Two-Dimensional Diode Array Detector Irradiated with Passively Scattered Proton Beams
Next Article in Special Issue
MicroRNAs and Chinese Medicinal Herbs: New Possibilities in Cancer Therapy
Previous Article in Journal / Special Issue
MicroRNAs in Cancer: A Historical Perspective on the Path from Discovery to Therapy
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis

Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China
*
Author to whom correspondence should be addressed.
Cancers 2015, 7(3), 1406-1424; https://doi.org/10.3390/cancers7030843
Submission received: 12 June 2015 / Revised: 22 July 2015 / Accepted: 23 July 2015 / Published: 29 July 2015
(This article belongs to the Special Issue Non-Coding RNAs in Cancers)

Abstract

:
Long non-coding RNAs (LncRNAs) represent a novel class of RNAs with no functional protein-coding ability, yet it has become increasingly clear that interactions between lncRNAs with other molecules are responsible for important gene regulatory functions in various contexts. Given their relatively high expressions in the brain, lncRNAs are now thought to play important roles in normal brain development as well as diverse disease processes including gliomagenesis. Intriguingly, certain lncRNAs are closely associated with the initiation, differentiation, progression, recurrence and stem-like characteristics in glioma, and may therefore be exploited for the purposes of sub-classification, diagnosis and prognosis. LncRNAs may also serve as potential therapeutic targets as well as a novel biomarkers in the treatment of glioma. In this article, the functional aspects of lncRNAs, particularly within the central nervous system (CNS), will be briefly discussed, followed by highlights of the important roles of lncRNAs in mediating critical steps during glioma development. In addition, the key lncRNA players and their possible mechanistic pathways associated with gliomagenesis will be addressed.

1. Introduction

The large repertoire of non-protein-coding RNAs found in transcriptional output has intrigued and inspired scientists about the fundamental functions of these genomic sequences, and has become a significant milestone in non-coding RNAs (ncRNAs) research [1,2]. As early as 1980s, RNA transcripts without significant protein-coding potentials were examined in Drosophila [3]. It was shown that these transcripts had genetic effects and were all spatial-temporally regulated. Moreover, interruptions of the encoding DNAs were found to cause phenotypic changes in Drosophila. This diverse subgroup of RNA species were later identified also in human as ncRNAs that have no protein-coding ability, and were shown to function intrinsically at the RNA level [4,5]. Over the evolutionary course of time, it was found that some ultraconserved elements in Drosophila were located within the non-coding regions of its genome [6]. Alterations of these ncRNA-associated ultraconserved sequences could lead to fatal diseases including cancers [7]. Although these ncRNAs do not code for proteins [8,9], they appear to have structural and regulatory roles that are important for normal cellular function as well as disease pathogenesis [10]. NcRNAs generally lack open reading frames. In terms of structure, long non-coding RNAs (lncRNAs) differ from other RNA species such as miRNAs, snoRNAs, siRNAs, piRNAs, snRNAs and tRNAs, in that the former are longer than 200nt while the latter group encompasses transcripts shorter than 200nt [2,11,12,13,14,15].
Gliomas are the most common form of primary malignant brain tumor, and glioblastoma multiforme (GBM) is the most aggressive form of glioma with a median survival of 15 months following standard treatment [16,17]. GBM cells are known to carry multiple molecular and genetic aberrations [18]. For example, methylation of the promoter of the DNA repair enzyme, O-6-methylguanine-DNA methyltransferase (MGMT), is found in about 50% of all GBM cases [19]. MGMT promoter methylation silences its expression, and eventually limits the tumor’s ability to repair DNA breakages following temozolomide. This enhances the cytotoxic effects of temozolomide and thus treatment efficacy [20,21]. Although the current multimodal treatment regime with surgical resection, concurrent chemoirradiation and adjuvant temozolomide has provided significant improvement in patient survival, tumor recurrence occurs in most if not all cases [22,23,24]. As a rescue therapy, bevacizumab, an antiangiogenic drug, is often used in clinical practice upon tumor recurrence [25]. However, bevacizumab can only slow down recurrent tumor growth without exerting any beneficial effects on overall survival [26].
NcRNAs have recently emerged as potentially promising therapeutic targets in cancer therapy. Various experimental approaches, including direct RNA sequencing, cloning, microarray and genomic SELEX (genomic systemic evolution of ligands by exponential enrichment), have been developed for the studying of RNomics [27]. Based on microarray-based data, we have previously shown that specific lncRNA expression patterns were associated with different histological subtypes and malignant behaviors in glioma [28]. Furthermore, certain lncRNAs were found to be of prognostic significance, suggesting that lncRNAs may have important roles in gliomagenesis and may serve as novel therapeutic targets and biomarkers [29]. In this review, we discuss the functional aspects of lncRNAs within the central nervous system (CNS) and their roles in glioma pathogenesis. In addition, the key lncRNA players and their possible mechanistic pathways associated with gliomagenesis will be addressed.

2. Overview on lncRNAs

It has now become clear that lncRNAs are involved in various genetic phenomena, including imprinting, DNA methylation, X-chromosome dosage compensation as well as transcriptional, post-transcriptional and epi-genetic regulations [9,30,31,32,33,34]. Mounting evidence has also demonstrated that lncRNAs may regulate gene expressions through interactions with DNAs, RNAs, proteins or chromatin remodeling [35,36]. In recent years, new bioinformatical and experimental strategies have been established which allow the identification of a large number of novel lncRNA transcripts. With the aids of current biocomputational research tools such as lncRNAdb, ChIPBase, LNCipeida and lncRNAtor, the number of lncRNAs being identified is rapidly increasing [37,38,39,40]. These tools have also provided very useful platforms for biophysical analyses that can predict lncRNA interactions with other genomic elements.
The diverse transcription patterns of lncRNAs have significant implications for their gene regulatory functions. LncRNAs can be expressed in intergenic or intronic regions, or in overlapping or antisense loci adjacent to protein-coding genes, on which lncRNAs may exert regulatory functions [41,42,43]. Gene expression may also be regulated through lncRNAs’ interactions with chromatin modifying complexes. Many studies have demonstrated lncRNA-EZH2 interaction. EHZ2 is an enhancer of zeste homolog 2 (a predominant component of chromatin modifying protein PRC2, polycomb repressive complex 2)-dependent tumor suppressive/oncogenic activities. This association may also serve to guide these chromatin modifying complexes to the target loci [44,45,46]. There is accumulating evidence suggesting that the association of lncRNAs with EZH2 is implicated in cancer biology through up/downregulation of gene expressions [47,48]. Compared to protein-coding genes, lncRNAs are highly tissue-specific, and are often co-expressed with neighboring coding genes [49]. Novel functions of lncRNAs are steadily emerging. More recent findings suggested that lncRNAs may in fact affect protein-coding directly. It was shown that, instead of being localized within the nucleus, the majority of lncRNAs were found within the cytoplasm in association with ribosomes where they may serve as repositories for the evolution of new protein species [50,51].
As suggested by the hypothesis of competitive endogenous RNA (ceRNA), it attributes novel function of lncRNAs in the “communication” network across the RNA transcriptome, through microRNA binding sites (or microRNA response elements—MREs) covered within RNAs [52]. Current experimental evidences are in support with this hypothesis [53,54,55,56], whereas pseudogenes and/or lncRNAs forms a ceRNA network of RNA crosstalk by acting as molecular sponges for microRNAs thereby modulates its gene repressive activity. This ceRNA activity implicates a novel ceRNA function of lncRNAs, and perturbation of ceRNA might have consequences in pathological conditions including cancer [53,57].

3. Functional Roles of lncRNAs within the CNS

Of the tens of thousands of lncRNAs so far identified, relatively few have been functionally tested and their precise roles in the diversity of cellular processes remain unknown [14,58]. Since lncRNAs are predominantly expressed within the CNS [14,58,59] and are spatial-temporally regulated during development [34,60], they are now thought to serve important functions in CNS development while perturbations of their expressions may lead to various CNS pathologies [60,61,62]. Many lncRNAs exhibit specific expression profiles in distinct neuroanatomical regions, and are associated with specific cell types and subcellular compartments [61]. This presence of a huge proportion of lncRNAs within the brain may underlie their complexity and sophistication as compared to the case in other tissue types [14,63].
In a functional analysis of evolutionarily conserved intergenic lncRNAs in mouse, “brain clusters” of lncRNAs were identified [64]. These were found to be differentially expressed during developmental transitions, indicating that lncRNAs may mediate crucial functions in neural differentiation [65]. One functional study performed by Sauvageau et al. has provided strong evidence that lncRNAs, in particular BRN1B, are critical for life, organ and brain development in vivo using several lncRNA knockout models [66]. Many other studies on lncRNA ablation also suggested that certain lncRNAs are required for normal brain development although loss of function would result in only subtle phenotypic abnormalities, if any [67,68,69,70]. LncRNAs also play roles in determining neural cell fate. This is partly mediated through the lncRNA Sox2OT, a counterpart of the important stem cell regulator gene Sox2 [71]. Another lncRNA, Nkx2.2AS, was shown to be critical for the lineage differentiation of oligodendrocytes during neural stem cell (NSC) differentiation [72]. As mentioned, dysregulation of lncRNAs may cause brain malformations, and are closely linked to the pathophysiology of various CNS diseases such as Down’s syndrome, Alzheimer’s disease, multiple sclerosis, brain tumor and schizophrenia [60]. Some of the known lncRNAs associated CNS diseases are summarized in Table 1.
Table 1. LncRNA-associated diseases in the CNS.
Table 1. LncRNA-associated diseases in the CNS.
LncRNALncRNA-Associated CNS DiseasesReferences
Ube3a-asNeurodevelopmental disorder—Angelman syndrome [73]
DGCR5Neurodevelopmental disorder—Velocardiofacial syndrome[74]
NRONNeurodevelopmental disorder—Down’s syndrome[75]
BACE1-ASNeurodegenerative disorder—Alzheimer’s disease[76]
BC200Neurodegenerative disorder—Alzheimer’s disease[77]
Tmevpg1Neuroimmunological disorder—Multiple sclerosis[78]
H19Neurooncological disorder—CNS tumors[79]
DISC2Psychiatric disorders
Schizophrenia, bipolar disorder, depression, autistic spectrum disorder[80,81,82]

4. LncRNAs in Glioma

Given that numerous lncRNAs are involved in a wide range of CNS pathophysiology, it has generally been accepted that they may also be key regulators in brain cancers. Genome-wide profiling studies have revealed differential expression patterns of lncRNAs in normal and cancerous tissues as well as across different cancer types [83,84,85,86]. Information on the central role of lncRNAs in gliomagenesis has only become clearer during the past few years. LncRNAs appear to be exceptionally important in all different aspects of glioma pathophysiology, from malignant transformation to tumor recurrence, and also in disease prognosis.

4.1. Glioma Initiation, Progression and Recurrence

In the context of cancer initiation and transformation, lncRNA expression profiles between normal brain tissue and gliomas are significantly different. Certain lncRNAs are involved in cancer progression, and gliomas of different malignancy grades have also been shown to have differential lncRNA expressions [28,87,88]. One example is H19. Its expression is highly upregulated in gliomas. It can bind with transcription factor c-Myc to drive tumor transformation and contribute to tumorigenic phenotypes [89]. The expressions of H19, MALAT1 and POU3F3, for instance, were positively correlated with more malignant glioma phenotypes, and H19 also modulates glioma cell invasion [88,90,91]. Han et al. has also described the role of lncRNAs in glioma recurrence. Through comprehensive pathway analysis, the PPAR signaling pathway was found to be the most significant pathway through which glioma-associated lncRNAs may act [85]. Analyses on lncRNA-gene network in this pathway indicated that both ASLNC22381 and ASLNC20819 would target IGF-1, which is strongly implicated in glioma recurrence [85,92]. Currently, there is no evidence showing any correlation of lncRNAs in brain tumor metastasis, which is, afterall, relatively uncommon due to the impermeable nature of the blood brain barrier [93]. In spite of this, HOTAIR has been demonstrated in promoting metastasis in other cancer types via the modulation of epigenome [94].

4.2. Glioma Classification and Prognostication

Profiling studies on lncRNAs have important clinical implications for glioma subclassification as well as disease prognostication. LncRNA-based molecular subclassification by Li et al., has revealed three distinct subtypes of glioma. More specifically, they can be classified into lncRNA signature subgroups: (i) astrocytic tumor with high EGFR amplification; (ii) neuronal-type tumor; and (iii) oligodendrocytic tumor enriched with IDH1 mutation and 1p19q co-deletion. This lncRNA-based classification was found to be strongly correlated with patient survival [95]. Furthermore, an analysis on previously published microarray data has explored a six-lncRNA signature as a set of prognostic genes in glioma. PART1, MGC21881, MIAT, GAS5 and PAR5 were correlated with prolonged survival, while KIAA0495 was associated with poorer survival [29]. In another study, MALAT1 expression was shown to be elevated in glioma tissues when compared with adjacent normal brain tissue; increased expression was correlated with poorer overall patient survival [91]. HOTAIR expression level was also identified as another strong prognostic factor [96].

4.3. LncRNAs in Glioma Stem Cells (GSCs)

It has been proposed that GSCs possess much greater tumorigenic potential than their “non-stem” counterparts [97,98], and that GSCs are relatively resistant to radiation as well as chemotherapies [99]. The functional role of lncRNAs in GSCs has been demonstrated in a recent comparative analysis of microarray data. In this, glioma lncRNA expressions from several different stemness-related datasets were examined. Within the same tumor bulk, subpopulations of tumor cells were derived from their parental GBM cells based on differentiation status and surface marker CD133+ expression. These subpopulations were found to possess different patterns of lncRNA expression, such as the upregulations of H19, XIST and MIAT in undifferentiated tumor cells. In another dataset, lncRNAs H19 and HOTAIR expressions were also dysregulated in CD133+ subtype as compared to CD133- cells. The author also compared between GSCs and NSCs, and found relatively upregulated HOTAIRM1 and H19 expressions in the former. These results strongly implicate the role of lncRNAs in the maintenance of stemness and tumor propagation. A more detailed review on lncRNA in GCSs has been described by Zhang et al. [100].

5. LncRNA Dysregulation in Glioma

LncRNAs are involved in many biological processes in glioma cells, including cell proliferation, apoptosis and invasion [68,90,101]. Aberrant expressions of lncRNAs in gliomas have been reported extensively in genome-wide studies [36,85], and are potentially implicated in determining glioma development through interaction with different molecules and through diverse signaling pathways. For example, MEG3 controls proliferation via interacting with p53 and MDM2 protein [102]; CRNDE regulates glioma cell growth via mTOR signaling [103]; and ASLNC22381 and ASLNC20819 promote proliferation through the IGF-1R signaling pathway [104].
Figure 1. Gene regulatory network of lncRNAs in glioma oncogenesis. Different molecules and various cellular conditions are able to regulate lncRNAs expressions. From which dysregulations of lncRNA would cause pro-tumorigenic alterations in epigenetics and/or global gene expressions that promotes glioma development and the associated malignant phenotypes.
Figure 1. Gene regulatory network of lncRNAs in glioma oncogenesis. Different molecules and various cellular conditions are able to regulate lncRNAs expressions. From which dysregulations of lncRNA would cause pro-tumorigenic alterations in epigenetics and/or global gene expressions that promotes glioma development and the associated malignant phenotypes.
Cancers 07 00843 g001
However, the mechanisms through which lncRNAs regulate signaling pathways remain largely unknown. Figure 1 illustrates the regulatory networks of lncRNAs that have been reported so far. It has been proposed that dysregulation of lncRNAs are particularly associated in glioma pathogenesis [105]. One mechanism is, for instance, the transcriptional regulation by transcription factors (TF). Biocomputational analyses have demonstrated abundant TF binding sites in lncRNA promoter regions [38,100,106]. Moreover, TF could bind directly to lncRNAs and regulate their expressions. Ma et al. showed that HOTAIR is a direct target of TF c-Myc, by which HOTAIR is activated and can drive tumor progression [106]. c-Myc can induce H19 expression and may play an important role in tumor transformation [89]. LncRNA expressions are also regulated by epigenetic changes through DNA hypo/hypermethylation [107].
Under stress conditions induced by genotoxic agents, changes in lncRNA expression may occur in response to DNA damage in glioma cells. In particular, MEG3 and ST7OT1 were upregulated during genotoxic stress-induced cell death; TUG1, BC200 and MIR155HG were downregulated [108]. These suggest that distinct pathways of lncRNAs are regulated in response to different conditions. LncRNA gain- and loss-of-function studies showed that these responses may have specific oncogenic or tumor suppressive functions [88,105,106,109,110]. A numbers of lncRNAs have been consistently found to be dysregulated in glioma, and which are extraordinarily associated with malignant transformation. Here, we will discuss the key lncRNAs as mediators in glioma pathogenesis.

6. Examples of Well-Characterized lncRNAs in Glioma

6.1. H19

H19 was the first lncRNA reported as a tumor suppressor in mammalian cells in 1993 [111,112]. Hao et al. suggested an anti-tumorigenic effect of H19 following the observation that ectopic expression of H19 would retard embryonic tumor growth. In addition, both clonogenicity and tumorigenicity were compromised in vivo with the addition of H19 constructs [111]. Interestingly, recent analyses showed inconsistent patterns of expressions in several human cancers [113,114]. Abundant binding sites for TF c-Myc has been revealed in H19 promoter region [100]. Upon direct binding of c-Myc to H19, H19 gene transcription was significantly induced through histone acetylation in tumor cells [89]. On the other hand, several studies reported that H19 expression was positively correlated with glioma grading and that its expression is critical in tumor progression as well as invasion [90]. H19 is one of the most highly expressed lncRNAs in the placenta and was found at high levels particularly during embryonic development within endodermal and mesodermal embryonic tissues. Its expression level would become relatively downregulated after birth [115,116]. As such, H19 expression has been functionally implicated in the maintenance of stemness in hematopoietic/embryonic stem cells [117,118]. Consistent findings are also seen in the context of GSCs, as H19 is one of the most highly upregulated lncRNAs in GSCs as compared to its differentiated counterparts of glioma cells [100]. To date, the underlying role and mechanisms by which H19 may affect glioma development and in GSCs remain unclear.

6.2. HOTAIR (HOX Transcript Antisense Intergenic RNA)

As a well-recognized lncRNA, HOTAIR primarily serves as a negative prognostic gene in different cancers including GBM [119]. The expression patterns of HOTAIR are closely associated with glioma staging, and its increased expression with tumor progression [96]. In addition to lncRNA profiling, Pastori et al. performed a single molecule sequencing (SMS) expression analysis that robustly identified differential patterns of lncRNA alterations in GBMs. HOTAIR was found to be highly upregulated in GBM cells compared with control, and glioma cell growth was significantly reduced following depletion of HOTAIR transcript [86].
Functional studies have demonstrated that loss of HOTAIR would render glioma cells more susceptible to cell-cycle arrest, with retarded tumor growth and reduced tumor cell invasiveness [96,119]. In glioma, HOTAIR expression can be activated in c-Myc targeted transcription, which has been shown to drive tumor progression while suppressing miRNA-130a expression [106]. The pro-oncogenic activity of HOTAIR may also be mediated through direct binding to its target chromatin modifying complexes PRC2. As a result of this interaction, histone H3K27 is trimethylated, leading to epigenetic silencing of gene expression [120].
Given the role of HOTAIR in epigenetic regulation through PRC2, inhibition of the bromodomain and extraterminal (BET) proteins may exert antiproliferative effect on GBM cells while reducing HOTAIR expression. Together with the observation that BET proteins could bind directly to HOTAIR promoter, these findings strongly suggest that BET protein may regulate cell proliferation at least partly through HOTAIR [86]. Despite mounting evidence suggesting the oncogenic role of HOTAIR in glioma, the mechanisms by which it regulates gene expression is incompletely understood.

6.3. CRNDE (Colorectal Neoplasia Differentially Expressed)

CRNDE was firstly identified as a novel lncRNA biomarker for colorectal cancer, in which its expression is highly upregulated [121,122,123]. Over 90% of colorectal adenoma and adenocarcinoma displayed elevated expressions of CRNDE compared to normal colorectal tissue in a microarray study. Strikingly, it was found that individual CRNDE transcript isoforms, CRNDE-h, could be detected in patient plasma with promising value as a biomarker [123]. Indeed, CRNDE expression is also overexpressed in many other cancers including glioma [28,123,124,125]. It is found to be the most upregulated lncRNAs in GBM, with a 32-fold increase over that in normal brain tissues. Results from the same study also indicated that CRNDE expression level was closely associated with glioma grading [28]. Forced overexpression of CRNDE have resulted in increased glioma cell growth and migration, while knockdown of CRNDE would suppress oncogenic activities [103].
Similar to the case of HOTAIR, binding of chromatin modifying complexes CoREST and PRC2 to CRNDE suggested that CRNDE may regulate gene expression via epigenetic changes of histone methylation/demethylation [126]. The progressive loss of CRNDE expression from birth is suggestive of a tentative link between CRNDE expression and cell differentiation. This notion is supported by the observation that CRNDE is required for maintaining pluripotency of mouse embryonic stem cell (moESC). The binding of pluripotency-related transcription factor to CRNDE transcript has provided evidence of CRNDE as a target of the stemness pathway [127]. On the other hand, EGFR expression has been linked to GSC phenotype, and may contribute to the aggressive behavior of tumor-initiating cells [128,129]. In consistent with these findings, CRNDE-expressing gliomas were found to have EGFR over-amplification, suggesting that, to a certain extent, CRNDE may be involved in the regulation of GSCs through the EGFR signaling pathway [130].

6.4. MEG3 (Maternally Expressed Gene 3)

Unlike most of the lncRNAs mentioned earlier in this article that possess pro-oncogenic properties, MEG3 represents a tumor suppressor lncRNA that is associated with prolonged survival in GBM patients [28,101,131,132]. It has been found to be highly expressed in normal brain tissue and downregulated in gliomas [28,101]. Glioma cell proliferation was inhibited with increased apoptosis when MEG3 was overexpressed [101]. This anti-proliferative function is exerted, in part, through suppressing MDM2 and the subsequent activation of p53 signaling pathway [102,132]. The MEG3 knockout mice model generated by Gordon et al. has revealed the functional role of MEG3 in regulating vascularization in the brain. An increase in microvessel formation was seen in the brains of MEG3-null embryos, together with elevated expression of genes involved in VEGF angiogenic pathway. Besides, lost expression of MEG3 was observed in the majority of clinically non-functioning pituitary adenomas [68,131]. Taken together, the potential implication of MEG3 as a therapeutic target in the treatment of glioma is considerable.

7. Clinical Implications of lncRNAs in Glioma

The discovery of this novel class of RNA transcripts has provided valuable insights into their exploitations as therapeutic targets. Differential expressions of lncRNAs between normal and different grades of gliomas offer significant promises of using lncRNA signatures in glioma diagnosis and prognostication. Some lncRNAs are detectable in body fluids of cancer patients, for example, DDA in urine samples of prostate cancer patients, and CRNDE in the plasma of colorectal cancer patients [123,133,134]. This provides a non-invasive method for the assessment of disease progression. Given that cancer stem cells contribute significantly to treatment resistance, it can be postulated that GSCs-associated lncRNAs would appeal as attractive targets for more effective cancer medicine in combating recurrent diseases [99]. For instance, epigenetic modulator proteins targeting GBM-specific lncRNAs may potentially restore the normal epigenetic landscape and provide clinical benefit [86].

8. Conclusions

LncRNAs are abundantly expressed in the brain compared to other regions. However, the vast majority of lncRNAs in the brain have not yet been functionally characterized. With extensive efforts, some of them are now emerging as important players in glioma and GSCs. It has been a rapid development in uncovering the functional roles of lncRNAs over the past few years although many of the studies are based on bioinformatics analyses without in vivo evidence. Several regulatory mechanisms have been proposed that might contribute to the dysregulation of lncRNAs, while its aberrant expressions are thought to increase the propensities of tumor development. Besides, the interactions of lncRNAs with different molecules have posited the formers’ roles as mediators in key signaling pathways, thus regulating global gene expression and affecting a wide range of cellular processes. In spite of all these progresses, the regulatory network of lncRNA in glioma remains largely elusive. We believe that future investigations will eventually give rise to fruitful clinical translations of glioma-associated lncRNAs profiling into novel therapeutic paradigms.

Acknowledgments

Special thanks to Grace Pingde Zhang and Ning Li for constructive discussion and valuable comments.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012, 489, 57–74. [Google Scholar]
  2. Derrien, T.; Johnson, R.; Bussotti, G.; Tanzer, A.; Djebali, S.; Tilgner, H.; Guernec, G.; Martin, D.; Merkel, A.; Knowles, D.G. The gencode v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22, 1775–1789. [Google Scholar] [CrossRef] [PubMed]
  3. Lipshitz, H.; Peattie, D.; Hogness, D. Novel transcripts from the ultrabithorax domain of the bithorax complex. Genes Dev. 1987, 1, 307–322. [Google Scholar] [CrossRef] [PubMed]
  4. Sanchez-Elsner, T.; Gou, D.; Kremmer, E.; Sauer, F. Noncoding RNAs of trithorax response elements recruit Drosophila Ash1 to ultrabithorax. Science 2006, 311, 1118–1123. [Google Scholar] [CrossRef] [PubMed]
  5. Sanchez-Herrero, E.; Akam, M. Spatially ordered transcription of regulatory DNA in the bithorax complex of Drosophila. Development 1989, 107, 321–329. [Google Scholar] [PubMed]
  6. Kern, A.D.; Barbash, D.A.; Mell, J.C.; Hupalo, D.; Jensen, A. Highly constrained intergenic Drosophila ultraconserved elements are candidate ncrnas. Genome Biol. Evolut. 2015, 7, 689–698. [Google Scholar] [CrossRef] [PubMed]
  7. Calin, G.A.; Liu, C.-G.; Ferracin, M.; Hyslop, T.; Spizzo, R.; Sevignani, C.; Fabbri, M.; Cimmino, A.; Lee, E.J.; Wojcik, S.E. Ultraconserved regions encoding ncrnas are altered in human leukemias and carcinomas. Cancer Cell 2007, 12, 215–229. [Google Scholar] [CrossRef] [PubMed]
  8. Lipovich, L.; Johnson, R.; Lin, C.-Y. MacroRNA underdogs in a microRNA world: Evolutionary, regulatory, and biomedical significance of mammalian long non-protein-coding RNA. Biochim. Biophys. Acta 2010, 1799, 597–615. [Google Scholar] [CrossRef] [PubMed]
  9. Mercer, T.R.; Dinger, M.E.; Mattick, J.S. Long non-coding RNAs: Insights into functions. Nat. Rev. Genet. 2009, 10, 155–159. [Google Scholar] [CrossRef] [PubMed]
  10. Amaral, P.P.; Dinger, M.E.; Mercer, T.R.; Mattick, J.S. The eukaryotic genome as an RNA machine. Science 2008, 319, 1787–1789. [Google Scholar] [CrossRef] [PubMed]
  11. Dinger, M.E.; Amaral, P.P.; Mercer, T.R.; Mattick, J.S. Pervasive transcription of the eukaryotic genome: Functional indices and conceptual implications. Brief. Funct. Genomics Proteomec. 2009, 8, 407–423. [Google Scholar] [CrossRef] [PubMed]
  12. Sana, J.; Faltejskova, P.; Svoboda, M.; Slaby, O. Novel classes of non-coding RNAs and cancer. J. Transl. Med. 2012, 10, 103. [Google Scholar] [CrossRef] [PubMed]
  13. Birney, E.; Stamatoyannopoulos, J.A.; Dutta, A.; Guigó, R.; Gingeras, T.R.; Margulies, E.H.; Weng, Z.; Snyder, M.; Dermitzakis, E.T.; Thurman, R.E. Identification and analysis of functional elements in 1% of the human genome by the encode pilot project. Nature 2007, 447, 799–816. [Google Scholar] [CrossRef] [PubMed]
  14. Carninci, P.; Kasukawa, T.; Katayama, S.; Gough, J.; Frith, M.; Maeda, N.; Oyama, R.; Ravasi, T.; Lenhard, B.; Wells, C. The transcriptional landscape of the mammalian genome. Science 2005, 309, 1559–1563. [Google Scholar] [PubMed]
  15. Furuno, M.; Pang, K.C.; Ninomiya, N.; Fukuda, S.; Frith, M.C.; Bult, C.; Kai, C.; Kawai, J.; Carninci, P.; Hayashizaki, Y. Clusters of internally primed transcripts reveal novel long noncoding RNAs. PLoS Genet. 2006, 2, e37. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Tate, M.C.; Aghi, M.K. Biology of angiogenesis and invasion in glioma. Neurotherapeutics 2009, 6, 447–457. [Google Scholar] [CrossRef] [PubMed]
  17. Johnson, D.R.; O’Neill, B.P. Glioblastoma survival in the united states before and during the temozolomide era. J. Neuro-Oncol. 2012, 107, 359–364. [Google Scholar] [CrossRef] [PubMed]
  18. Crespo, I.; Vital, A.L.; Gonzalez-Tablas, M.; del Carmen Patino, M.; Otero, A.; Lopes, M.C.; de Oliveira, C.; Domingues, P.; Orfao, A.; Tabernero, M.D. Molecular and genomic alterations in glioblastoma multiforme. Am. J. Pathol. 2015, 185, 1820–1833. [Google Scholar] [CrossRef] [PubMed]
  19. Chan, D.; Kam, M.; Ma, B.; Ng, S.; Pang, J.; Lau, C.; Siu, D.; Ng, B.; Zhu, X.; Chen, G. Association of molecular marker o (6) methylguanine DNA methyltransferase and concomitant chemoradiotherapy with survival in southern chinese glioblastoma patients. Hong Kong Med. J. 2011, 17, 184–188. [Google Scholar] [PubMed]
  20. Kaina, B.; Christmann, M. DNA repair in resistance to alkylating anticancer drugs. Int. J. Clin. Pharmacol. Ther. 2002, 40, 354–367. [Google Scholar] [CrossRef] [PubMed]
  21. D'Incalci, M.; Citti, L.; Taverna, P.; Catapano, C.V. Importance of the DNA repair enzyme o 6-alkyl guanine alkyltransferase (at) in cancer chemotherapy. Cancer Treat. Rev. 1988, 15, 279–292. [Google Scholar] [CrossRef] [PubMed]
  22. Stupp, R.; Mason, W.P.; van Den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [Google Scholar] [CrossRef] [PubMed]
  23. Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the eortc-ncic trial. Lancet Oncol. 2009, 10, 459–466. [Google Scholar] [CrossRef]
  24. Nagasubramanian, R.; Dolan, M.E. Temozolomide: Realizing the promise and potential. Curr. Opin. Oncol. 2003, 15, 412–418. [Google Scholar] [CrossRef] [PubMed]
  25. Stark-Vance, V. Bevacizumab and cpt-11 in the Treatment of Relapsed Malignant Glioma. In Neuro-Oncology; Duke Univ Press: Durham, NC, USA, 2005; p. 369. [Google Scholar]
  26. Khasraw, M.; Ameratunga, M.; Grommes, C. Bevacizumab for the treatment of high-grade glioma: An update after phase III trials. Expert Opin. Biol. Ther. 2014, 14, 729–740. [Google Scholar] [CrossRef] [PubMed]
  27. Hüttenhofer, A.; Vogel, J. Experimental approaches to identify non-coding RNAs. Nucl. Acids Res. 2006, 34, 635–646. [Google Scholar] [CrossRef] [PubMed]
  28. Zhang, X.; Sun, S.; Pu, J.K.S.; Tsang, A.C.O.; Lee, D.; Man, V.O.Y.; Lui, W.M.; Wong, S.T.S.; Leung, G.K.K. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol. Dis. 2012, 48, 1–8. [Google Scholar] [CrossRef] [PubMed]
  29. Zhang, X.-Q.; Sun, S.; Lam, K.-F.; Kiang, K.M.-Y.; Pu, J.K.-S.; Ho, A.S.-W.; Lui, W.-M.; Fung, C.-F.; Wong, T.-S.; Leung, G.K.-K. A long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiol. Dis. 2013, 58, 123–131. [Google Scholar] [CrossRef] [PubMed]
  30. Geisler, S.; Coller, J. RNA in unexpected places: Long non-coding RNA functions in diverse cellular contexts. Nat. Rev. Mol. Cell Biol. 2013, 14, 699–712. [Google Scholar] [CrossRef] [PubMed]
  31. Wilusz, J.E.; Sunwoo, H.; Spector, D.L. Long noncoding RNAs: Functional surprises from the RNA world. Genes Dev. 2009, 23, 1494–1504. [Google Scholar] [CrossRef] [PubMed]
  32. Nagano, T.; Fraser, P. No-nonsense functions for long noncoding RNAs. Cell 2011, 145, 178–181. [Google Scholar] [CrossRef] [PubMed]
  33. Zhang, X.-Q.; Leung, G.K.-K. Long non-coding RNAs in glioma: Functional roles and clinical perspectives. Neurochem. Int. 2014, 77, 78–85. [Google Scholar] [CrossRef] [PubMed]
  34. Mercer, T.R.; Mattick, J.S. Structure and function of long noncoding RNAs in epigenetic regulation. Nat. Struct. Mol. Biol. 2013, 20, 300–307. [Google Scholar] [CrossRef] [PubMed]
  35. Mattick, J.S.; Gagen, M.J. The evolution of controlled multitasked gene networks: The role of introns and other noncoding RNAs in the development of complex organisms. Mol. Biol. Evol. 2001, 18, 1611–1630. [Google Scholar] [CrossRef] [PubMed]
  36. Khalil, A.M.; Guttman, M.; Huarte, M.; Garber, M.; Raj, A.; Morales, D.R.; Thomas, K.; Presser, A.; Bernstein, B.E.; van Oudenaarden, A. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc. Natl. Acad. Sci. USA 2009, 106, 11667–11672. [Google Scholar] [CrossRef] [PubMed]
  37. Amaral, P.P.; Clark, M.B.; Gascoigne, D.K.; Dinger, M.E.; Mattick, J.S. Lncrnadb: A reference database for long noncoding RNAs. Nucl. Acids Res. 2011, 39, D146–D151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Yang, J.-H.; Li, J.-H.; Jiang, S.; Zhou, H.; Qu, L.-H. Chipbase: A database for decoding the transcriptional regulation of long non-coding RNA and microRNA genes from chip-seq data. Nucl. Acids Res. 2013, 41, D177–D187. [Google Scholar] [CrossRef] [PubMed]
  39. Volders, P.-J.; Helsens, K.; Wang, X.; Menten, B.; Martens, L.; Gevaert, K.; Vandesompele, J.; Mestdagh, P. Lncipedia: A database for annotated human lncRNA transcript sequences and structures. Nucl. Acids Res. 2013, 41, D246–D251. [Google Scholar] [CrossRef] [PubMed]
  40. Park, C.; Yu, N.; Choi, I.; Kim, W.; Lee, S. Lncrnator: A comprehensive resource for functional investigation of long noncoding RNAs. Bioinformatics 2014. [Google Scholar] [CrossRef] [PubMed]
  41. Kaikkonen, M.U.; Lam, M.T.; Glass, C.K. Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc. Res. 2011, 90, 430–440. [Google Scholar] [CrossRef] [PubMed]
  42. Prasanth, K.V.; Spector, D.L. Eukaryotic regulatory RNAs: An answer to the “genome complexity” conundrum. Genes Dev. 2007, 21, 11–42. [Google Scholar] [CrossRef] [PubMed]
  43. Shamovsky, I.; Nudler, E. Gene control by large noncoding RNAS. STKE 2006, 355. [Google Scholar] [CrossRef] [PubMed]
  44. Rinn, J.L.; Kertesz, M.; Wang, J.K.; Squazzo, S.L.; Xu, X.; Brugmann, S.A.; Goodnough, L.H.; Helms, J.A.; Farnham, P.J.; Segal, E. Functional demarcation of active and silent chromatin domains in human hox loci by noncoding RNAs. Cell 2007, 129, 1311–1323. [Google Scholar] [CrossRef] [PubMed]
  45. Zhao, J.; Sun, B.K.; Erwin, J.A.; Song, J.-J.; Lee, J.T. Polycomb proteins targeted by a short repeat RNA to the mouse x chromosome. Science 2008, 322, 750–756. [Google Scholar] [CrossRef] [PubMed]
  46. Jeon, Y.; Lee, J.T. Yy1 tethers xist RNA to the inactive x nucleation center. Cell 2011, 146, 119–133. [Google Scholar] [CrossRef] [PubMed]
  47. Zhang, K.; Sun, X.; Zhou, X.; Han, L.; Chen, L.; Shi, Z.; Zhang, A.; Ye, M.; Wang, Q.; Liu, C. Long non-coding RNA hotair promotes glioblastoma cell cycle progression in an ezh2 dependent manner. Oncotarget 2015, 6, 537. [Google Scholar] [PubMed]
  48. Bian, E.B.; Li, J.; Xie, Y.S.; Zong, G.; Li, J.; Zhao, B. LncRNAs: New players in gliomas, with special emphasis on the interaction of lncRNAs with ezh2. J. Cell. Physiol. 2015, 230, 496–503. [Google Scholar] [CrossRef] [PubMed]
  49. Cabili, M.N.; Trapnell, C.; Goff, L.; Koziol, M.; Tazon-Vega, B.; Regev, A.; Rinn, J.L. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011, 25, 1915–1927. [Google Scholar] [CrossRef] [PubMed]
  50. Ruiz-Orera, J.; Messeguer, X.; Subirana, J.A.; Alba, M.M. Long non-coding RNAS as a source of new peptides. eLife 2014, 3, e03523. [Google Scholar] [CrossRef] [PubMed]
  51. Van Heesch, S.; van Iterson, M.; Jacobi, J.; Boymans, S.; Essers, P.B.; de Bruijn, E.; Hao, W.; MacInnes, A.W.; Cuppen, E.; Simonis, M. Extensive localization of long noncoding RNAs to the cytosol and mono-and polyribosomal complexes. Genome Biol. 2014, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Salmena, L.; Poliseno, L.; Tay, Y.; Kats, L.; Pandolfi, P.P. A ceRNA hypothesis: The rosetta stone of a hidden RNA language? Cell 2011, 146, 353–358. [Google Scholar] [CrossRef] [PubMed]
  53. Poliseno, L.; Salmena, L.; Zhang, J.; Carver, B.; Haveman, W.J.; Pandolfi, P.P. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 2010, 465, 1033–1038. [Google Scholar] [CrossRef] [PubMed]
  54. Franco-Zorrilla, J.M.; Valli, A.; Todesco, M.; Mateos, I.; Puga, M.I.; Rubio-Somoza, I.; Leyva, A.; Weigel, D.; García, J.A.; Paz-Ares, J. Target mimicry provides a new mechanism for regulation of microRNA activity. Nat. Genet. 2007, 39, 1033–1037. [Google Scholar] [CrossRef] [PubMed]
  55. Cazalla, D.; Yario, T.; Steitz, J.A. Down-regulation of a host microRNA by a herpesvirus saimiri noncoding RNA. Science 2010, 328, 1563–1566. [Google Scholar] [CrossRef] [PubMed]
  56. Wang, J.; Liu, X.; Wu, H.; Ni, P.; Gu, Z.; Qiao, Y.; Chen, N.; Sun, F.; Fan, Q. Creb up-regulates long non-coding RNA, hulc expression through interaction with microRNA-372 in liver cancer. Nucl. Acids Res. 2010, 38, 5366–5383. [Google Scholar] [CrossRef] [PubMed]
  57. Cesana, M.; Cacchiarelli, D.; Legnini, I.; Santini, T.; Sthandier, O.; Chinappi, M.; Tramontano, A.; Bozzoni, I. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 2011, 147, 358–369. [Google Scholar] [CrossRef] [PubMed]
  58. Mercer, T.R.; Dinger, M.E.; Sunkin, S.M.; Mehler, M.F.; Mattick, J.S. Specific expression of long noncoding RNAs in the mouse brain. Proc. Natl. Acad. Sci. USA 2008, 105, 716–721. [Google Scholar] [CrossRef] [PubMed]
  59. Ravasi, T.; Suzuki, H.; Pang, K.C.; Katayama, S.; Furuno, M.; Okunishi, R.; Fukuda, S.; Ru, K.; Frith, M.C.; Gongora, M.M. Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res. 2006, 16, 11–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Qureshi, I.A.; Mattick, J.S.; Mehler, M.F. Long non-coding RNAs in nervous system function and disease. Brain Res. 2010, 1338, 20–35. [Google Scholar] [CrossRef] [PubMed]
  61. Mehler, M.F.; Mattick, J.S. Noncoding RNAs and RNA editing in brain development, functional diversification, and neurological disease. Physiol. Rev. 2007, 87, 799–823. [Google Scholar] [CrossRef] [PubMed]
  62. Taft, R.J.; Pang, K.C.; Mercer, T.R.; Dinger, M.; Mattick, J.S. Non-coding RNAs: Regulators of disease. J. Pathol. 2010, 220, 126–139. [Google Scholar] [CrossRef] [PubMed]
  63. Mehler, M.F.; Mattick, J.S. Non-coding RNAs in the nervous system. J. Physiol. 2006, 575, 333–341. [Google Scholar] [CrossRef] [PubMed]
  64. Guttman, M.; Amit, I.; Garber, M.; French, C.; Lin, M.F.; Feldser, D.; Huarte, M.; Zuk, O.; Carey, B.W.; Cassady, J.P. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 2009, 458, 223–227. [Google Scholar] [CrossRef] [PubMed]
  65. Mercer, T.R.; Qureshi, I.A.; Gokhan, S.; Dinger, M.E.; Li, G.; Mattick, J.S.; Mehler, M.F. Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Neurosci. 2010, 11, 14. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Sauvageau, M.; Goff, L.A.; Lodato, S.; Bonev, B.; Groff, A.F.; Sanchez-Gomez, D.B.; Gerhardinger, C.; Hacisuleyman, E.; Li, E.; Spence, M. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife 2013, 2, e01749. [Google Scholar] [CrossRef] [PubMed]
  67. Ripoche, M.-A.; Kress, C.; Poirier, F.; Dandolo, L. Deletion of the H19 transcription unit reveals the existence of a putative imprinting control element. Genes Dev. 1997, 11, 1596–1604. [Google Scholar] [CrossRef] [PubMed]
  68. Gordon, F.E.; Nutt, C.L.; Cheunsuchon, P.; Nakayama, Y.; Provencher, K.A.; Rice, K.A.; Zhou, Y.; Zhang, X.; Klibanski, A. Increased expression of angiogenic genes in the brains of mouse meg3-null embryos. Endocrinology 2010, 151, 2443–2452. [Google Scholar] [CrossRef] [PubMed]
  69. Zhang, B.; Arun, G.; Mao, Y.S.; Lazar, Z.; Hung, G.; Bhattacharjee, G.; Xiao, X.; Booth, C.J.; Wu, J.; Zhang, C. The lncRNA Malat1 is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep. 2012, 2, 111–123. [Google Scholar] [CrossRef] [PubMed]
  70. Nakagawa, S.; Naganuma, T.; Shioi, G.; Hirose, T. Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice. J. Cell Biol. 2011, 193, 31–39. [Google Scholar] [CrossRef] [PubMed]
  71. Amaral, P.P.; Neyt, C.; Wilkins, S.J.; Askarian-Amiri, M.E.; Sunkin, S.M.; Perkins, A.C.; Mattick, J.S. Complex architecture and regulated expression of the sox2ot locus during vertebrate development. RNA 2009, 15, 2013–2027. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Tochitani, S.; Hayashizaki, Y. Nkx2. 2 antisense RNA overexpression enhanced oligodendrocytic differentiation. Biochem. Biophys. Res. Commun. 2008, 372, 691–696. [Google Scholar] [CrossRef] [PubMed]
  73. Johnstone, K.A.; DuBose, A.J.; Futtner, C.R.; Elmore, M.D.; Brannan, C.I.; Resnick, J.L. A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for angelman syndrome imprinting defects. Hum. Mol. Genet. 2006, 15, 393–404. [Google Scholar] [CrossRef] [PubMed]
  74. Sutherland, H.F.; Wadey, R.; McKie, J.M.; Taylor, C.; Atif, U.; Johnstone, K.A.; Halford, S.; Kim, U.-J.; Goodship, J.; Baldini, A. Identification of a novel transcript disrupted by a balanced translocation associated with digeorge syndrome. Am. J. Hum. Genet. 1996, 59, 23. [Google Scholar] [PubMed]
  75. Willingham, A.; Orth, A.; Batalov, S.; Peters, E.; Wen, B.; Aza-Blanc, P.; Hogenesch, J.; Schultz, P. A strategy for probing the function of noncoding RNAs finds a repressor of nfat. Science 2005, 309, 1570–1573. [Google Scholar] [CrossRef] [PubMed]
  76. Faghihi, M.A.; Modarresi, F.; Khalil, A.M.; Wood, D.E.; Sahagan, B.G.; Morgan, T.E.; Finch, C.E.; Laurent, G.S., III; Kenny, P.J.; Wahlestedt, C. Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of β-secretase. Nat. Med. 2008, 14, 723–730. [Google Scholar] [CrossRef] [PubMed]
  77. Mus, E.; Hof, P.R.; Tiedge, H. Dendritic bc200 RNA in aging and in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2007, 104, 10679–10684. [Google Scholar] [CrossRef] [PubMed]
  78. Tsunoda, I.; Fujinami, R.S. Neuropathogenesis of theiler’s murine encephalomyelitis virus infection, an animal model for multiple sclerosis. J. Neuroimmune Pharmacol. 2010, 5, 355–369. [Google Scholar] [CrossRef] [PubMed]
  79. Müller, S.; Zirkel, D.; Westphal, M.; Zumkeller, W. Genomic imprinting of IGF2 and H19 in human meningiomas. Eur. J. Cancer 2000, 36, 651–655. [Google Scholar] [CrossRef]
  80. Chubb, J.; Bradshaw, N.; Soares, D.; Porteous, D.; Millar, J. The disc locus in psychiatric illness. Mol. Psychiatry 2008, 13, 36–64. [Google Scholar] [CrossRef] [PubMed]
  81. Millar, J.K.; Wilson-Annan, J.C.; Anderson, S.; Christie, S.; Taylor, M.S.; Semple, C.A.; Devon, R.S.; St Clair, D.M.; Muir, W.J.; Blackwood, D.H. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 2000, 9, 1415–1423. [Google Scholar] [CrossRef] [PubMed]
  82. Williams, J.M.; Beck, T.F.; Pearson, D.M.; Proud, M.B.; Cheung, S.W.; Scott, D.A. A 1q42 deletion involving DISC1, DISC2, and TSNAX in an autism spectrum disorder. Am. J. Med. Genet. Part A 2009, 149, 1758–1762. [Google Scholar] [CrossRef] [PubMed]
  83. Brunner, A.L.; Beck, A.H.; Edris, B.; Sweeney, R.T.; Zhu, S.X.; Li, R.; Montgomery, K.; Varma, S.; Gilks, T.; Guo, X. Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers. Genome Biol. 2012, 13, R75. [Google Scholar] [CrossRef] [PubMed]
  84. Gibb, E.A.; Vucic, E.A.; Enfield, K.S.; Stewart, G.L.; Lonergan, K.M.; Becker-Santos, D.D.; Kennett, J.Y.; MacAulay, C.E.; Lam, S.; Brown, C.J. Human cancer long non-coding RNA transcriptomes. PLoS ONE 2011, 6, e25915. [Google Scholar] [CrossRef] [PubMed]
  85. Han, L.; Zhang, K.; Shi, Z.; Zhang, J.; Zhu, J.; Zhu, S.; Zhang, A.; Jia, Z.; Wang, G.; Yu, S. LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis. Int. J. Oncol. 2012, 40, 2004–2012. [Google Scholar] [PubMed]
  86. Pastori, C.; Kapranov, P.; Penas, C.; Peschansky, V.; Volmar, C.-H.; Sarkaria, J.N.; Bregy, A.; Komotar, R.; Laurent, G.S.; Ayad, N.G. The bromodomain protein brd4 controls hotair, a long noncoding RNA essential for glioblastoma proliferation. Proc. Natl. Acad. Sci. USA 2015, 112, 8326–8331. [Google Scholar] [CrossRef] [PubMed]
  87. Vital, A.L.; Tabernero, M.D.; Castrillo, A.; Rebelo, O.; Tão, H.; Gomes, F.; Nieto, A.B.; Oliveira, C.R.; Lopes, M.C.; Orfao, A. Gene expression profiles of human glioblastomas are associated with both tumor cytogenetics and histopathology. Neuro Oncol. 2010, 12, 991–1003. [Google Scholar] [CrossRef] [PubMed]
  88. Guo, H.; Wu, L.; Yang, Q.; Ye, M.; Zhu, X. Functional linc-POU3F3 is overexpressed and contributes to tumorigenesis in glioma. Gene 2015, 554, 114–119. [Google Scholar] [CrossRef] [PubMed]
  89. Barsyte-Lovejoy, D.; Lau, S.K.; Boutros, P.C.; Khosravi, F.; Jurisica, I.; Andrulis, I.L.; Tsao, M.S.; Penn, L.Z. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006, 66, 5330–5337. [Google Scholar] [CrossRef] [PubMed]
  90. Shi, Y.; Wang, Y.; Luan, W.; Wang, P.; Tao, T.; Zhang, J.; Qian, J.; Liu, N.; You, Y. Long non-coding RNA H19 promotes glioma cell invasion by deriving mir-675. PLoS ONE 2014, 9, e86295. [Google Scholar] [CrossRef] [PubMed]
  91. Ma, K.-X.; Wang, H.-J.; Li, X.-R.; Li, T.; Su, G.; Yang, P.; Wu, J.-W. Long noncoding RNA Malat1 associates with the malignant status and poor prognosis in glioma. Tumor. Biol. 2015, 36, 3355–3359. [Google Scholar] [CrossRef] [PubMed]
  92. Baritaki, S.; Chatzinikola, A.M.; Vakis, A.F.; Soulitzis, N.; Karabetsos, D.A.; Neonakis, I.; Bonavida, B.; Spandidos, D.A. YY1 over-expression in human brain gliomas and meningiomas correlates with TGF-β1, IGF-1 and FGF-2 mRNA levels. Cancer Investig. 2009, 27, 184–192. [Google Scholar] [CrossRef] [PubMed]
  93. Palmieri, D.; Chambers, A.F.; Felding-Habermann, B.; Huang, S.; Steeg, P.S. The biology of metastasis to a sanctuary site. Clin. Cancer Res. 2007, 13, 1656–1662. [Google Scholar] [CrossRef] [PubMed]
  94. Gupta, R.A.; Shah, N.; Wang, K.C.; Kim, J.; Horlings, H.M.; Wong, D.J.; Tsai, M.-C.; Hung, T.; Argani, P.; Rinn, J.L. Long non-coding RNA hotair reprograms chromatin state to promote cancer metastasis. Nature 2010, 464, 1071–1076. [Google Scholar] [CrossRef] [PubMed]
  95. Li, R.; Qian, J.; Wang, Y.Y.; Zhang, J.X.; You, Y.P. Long noncoding RNA profiles reveal three molecular subtypes in glioma. CNS Neurosci. Ther. 2014, 20, 339–343. [Google Scholar] [CrossRef] [PubMed]
  96. Zhang, J.-X.; Han, L.; Bao, Z.-S.; Wang, Y.-Y.; Chen, L.-Y.; Yan, W.; Yu, S.-Z.; Pu, P.-Y.; Liu, N.; You, Y.-P. Hotair, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol. 2013, 15, 1595–1603. [Google Scholar] [CrossRef] [PubMed]
  97. Bao, S.; Wu, Q.; McLendon, R.E.; Hao, Y.; Shi, Q.; Hjelmeland, A.B.; Dewhirst, M.W.; Bigner, D.D.; Rich, J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006, 444, 756–760. [Google Scholar] [CrossRef] [PubMed]
  98. Galli, R.; Binda, E.; Orfanelli, U.; Cipelletti, B.; Gritti, A.; de Vitis, S.; Fiocco, R.; Foroni, C.; Dimeco, F.; Vescovi, A. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004, 64, 7011–7021. [Google Scholar] [CrossRef] [PubMed]
  99. Cheng, L.; Bao, S.; Rich, J.N. Potential therapeutic implications of cancer stem cells in glioblastoma. Biochem. Pharmacol. 2010, 80, 654–665. [Google Scholar] [CrossRef] [PubMed]
  100. Zhang, X.; Kiang, K.M.-Y.; Zhang, G.P.-D.; Leung, G.K.K. Long non-coding RNAs dysregulation and function in glioblastoma stem cells. Non-Coding RNA 2015, 1, 69–86. [Google Scholar] [CrossRef] [Green Version]
  101. Wang, P.; Ren, Z.; Sun, P. Overexpression of the long non-coding RNA meg3 impairs in vitro glioma cell proliferation. J. Cell. Biochem. 2012, 113, 1868–1874. [Google Scholar] [CrossRef] [PubMed]
  102. Benetatos, L.; Vartholomatos, G.; Hatzimichael, E. Meg3 imprinted gene contribution in tumorigenesis. Int. J. Cancer 2011, 129, 773–779. [Google Scholar] [CrossRef] [PubMed]
  103. Wang, Y.; Wang, Y.; Li, J.; Zhang, Y.; Yin, H.; Han, B. Crnde, a long-noncoding RNA, promotes glioma cell growth and invasion through mtor signaling. Cancer Lett. 2015. [Google Scholar] [CrossRef]
  104. Trojan, L.; Kopinski, P.; Mazurek, A.; Chyczewski, L.; Ly, A.; Jarocki, P.; Nikliński, J.; Shevelev, A.; Trzos, R.; Pan, Y. Igf-I triple helix gene therapy of rat and human gliomas. Rocz. Akad. Med. w Bialymstoku (1995) 2002, 48, 18–27. [Google Scholar]
  105. Yao, Y.; Ma, J.; Xue, Y.; Wang, P.; Li, Z.; Liu, J.; Chen, L.; Xi, Z.; Teng, H.; Wang, Z. Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. Cancer Lett. 2015, 359, 75–86. [Google Scholar] [CrossRef] [PubMed]
  106. Ma, M.; Li, C.; Zhang, Y.; Weng, M.; Zhang, M.; Qin, Y.; Gong, W.; Quan, Z. Long non-coding RNA hotair, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol. Cancer 2014, 13, 156. [Google Scholar] [CrossRef] [PubMed]
  107. Katherine, K. Expression data from paediatric ependymoma short-term cell cultures. Unpublished study, 2013. The raw microarray data is accesible at public NCBI GEO database. Accession no. GSE45437.
  108. Liu, Q.; Sun, S.; Yu, W.; Jiang, J.; Zhuo, F.; Qiu, G.; Xu, S.; Jiang, X. Altered expression of long non-coding RNAs during genotoxic stress-induced cell death in human glioma cells. J. Neuro Oncol. 2015, 122, 283–292. [Google Scholar] [CrossRef] [PubMed]
  109. Qin, X.; Yao, J.; Geng, P.; Fu, X.; Xue, J.; Zhang, Z. LncRNA TSLC1-AS1 is a novel tumor suppressor in glioma. Int. J. Clin. Exp. Pathol. 2014, 7, 3065. [Google Scholar] [PubMed]
  110. Wang, P.; Liu, Y.-H.; Yao, Y.-L.; Li, Z.; Li, Z.-Q.; Ma, J.; Xue, Y.-X. Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21. Cell. Signal. 2015, 27, 275–282. [Google Scholar] [CrossRef] [PubMed]
  111. Hao, Y.; Crenshaw, T.; Moulton, T.; Newcomb, E.; Tycko, B. Tumour-suppressor activity of H19 RNA. Nature 1993, 365, 764–767. [Google Scholar] [CrossRef] [PubMed]
  112. Brannan, C.I.; Dees, E.C.; Ingram, R.S.; Tilghman, S.M. The product of the H19 gene may function as an RNA. Mol. Cell. Biol. 1990, 10, 28–36. [Google Scholar] [PubMed]
  113. Tanos, V.; Ariel, I.; Prus, D.; De-Groot, N.; Hochberg, A. H19 and IGF2 gene expression in human normal, hyperplastic, and malignant endometrium. Int. J. Gynecol. Cancer 2004, 14, 521–525. [Google Scholar] [CrossRef] [PubMed]
  114. Kondo, M.; Suzuki, H.; Ueda, R.; Osada, H.; Takagi, K.; Takahashi, T. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 1995, 10, 1193–1198. [Google Scholar] [PubMed]
  115. Keniry, A.; Oxley, D.; Monnier, P.; Kyba, M.; Dandolo, L.; Smits, G.; Reik, W. The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat. Cell Biol. 2012, 14, 659–665. [Google Scholar] [CrossRef] [PubMed]
  116. Poirier, F.; Chan, C.; Timmons, P.; Robertson, E.; Evans, M.; Rigby, P. The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo. Development 1991, 113, 1105–1114. [Google Scholar] [PubMed]
  117. Venkatraman, A.; He, X.C.; Thorvaldsen, J.L.; Sugimura, R.; Perry, J.M.; Tao, F.; Zhao, M.; Christenson, M.K.; Sanchez, R.; Jaclyn, Y.Y. Maternal imprinting at the H19-IGF2 locus maintains adult haematopoietic stem cell quiescence. Nature 2013, 500, 345–349. [Google Scholar] [CrossRef] [PubMed]
  118. Yin, Y.; Wang, H.; Liu, K.; Wang, F.; Ye, X.; Liu, M.; Xiang, R.; Liu, N.; Liu, L. Knockdown of H19 enhances differentiation capacity to epidermis of parthenogenetic embryonic stem cells. Curr. Mol. Med. 2014, 14, 737–748. [Google Scholar] [CrossRef] [PubMed]
  119. Zhou, X.; Ren, Y.; Zhang, J.; Zhang, C.; Zhang, K.; Han, L.; Kong, L.; Wei, J.; Chen, L.; Yang, J. Hotair is a therapeutic target in glioblastoma. Oncotarget 2015, 6, 8353–8365. [Google Scholar] [PubMed]
  120. Kogo, R.; Shimamura, T.; Mimori, K.; Kawahara, K.; Imoto, S.; Sudo, T.; Tanaka, F.; Shibata, K.; Suzuki, A.; Komune, S. Long noncoding RNA hotair regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res. 2011, 71, 6320–6326. [Google Scholar] [CrossRef] [PubMed]
  121. Hong, Y.; Ho, K.S.; Eu, K.W.; Cheah, P.Y. A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: Implication for tumorigenesis. Clin. Cancer Res. 2007, 13, 1107–1114. [Google Scholar] [CrossRef] [PubMed]
  122. Sabates-Bellver, J.; van der Flier, L.G.; de Palo, M.; Cattaneo, E.; Maake, C.; Rehrauer, H.; Laczko, E.; Kurowski, M.A.; Bujnicki, J.M.; Menigatti, M. Transcriptome profile of human colorectal adenomas. Mol. Cancer Res. 2007, 5, 1263–1275. [Google Scholar] [CrossRef] [PubMed]
  123. Graham, L.D.; Pedersen, S.K.; Brown, G.S.; Ho, T.; Kassir, Z.; Moynihan, A.T.; Vizgoft, E.K.; Dunne, R.; Pimlott, L.; Young, G.P. Colorectal neoplasia differentially expressed (crnde), a novel gene with elevated expression in colorectal adenomas and adenocarcinomas. Genes Cancer 2011, 2, 829–840. [Google Scholar] [CrossRef] [PubMed]
  124. Payton, J.E.; Grieselhuber, N.R.; Chang, L.-W.; Murakami, M.; Geiss, G.K.; Link, D.C.; Nagarajan, R.; Watson, M.A.; Ley, T.J. High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples. J. Clin. Investig. 2009, 119, 1714. [Google Scholar] [CrossRef] [PubMed]
  125. Eckerle, S.; Brune, V.; Döring, C.; Tiacci, E.; Bohle, V.; Sundström, C.; Kodet, R.; Paulli, M.; Falini, B.; Klapper, W. Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: Insights into its cellular origin, pathogenesis and relation to hodgkin lymphoma. Leukemia 2009, 23, 2129–2138. [Google Scholar] [CrossRef] [PubMed]
  126. Ellis, B.C.; Molloy, P.L.; Graham, L.D. CRNDE: A long non-coding RNA involved in cancer, neurobiology, and development. Front. Genet. 2012, 3. [Google Scholar] [CrossRef] [PubMed]
  127. Guttman, M.; Donaghey, J.; Carey, B.W.; Garber, M.; Grenier, J.K.; Munson, G.; Young, G.; Lucas, A.B.; Ach, R.; Bruhn, L. LincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011, 477, 295–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Mazzoleni, S.; Politi, L.S.; Pala, M.; Cominelli, M.; Franzin, A.; Sergi, L.S.; Falini, A.; de Palma, M.; Bulfone, A.; Poliani, P.L. Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. Cancer Res. 2010, 70, 7500–7513. [Google Scholar] [CrossRef] [PubMed]
  129. Jin, X.; Yin, J.; Kim, S.-H.; Sohn, Y.-W.; Beck, S.; Lim, Y.C.; Nam, D.-H.; Choi, Y.-J.; Kim, H. EGFR-AKT-Smad signaling promotes formation of glioma stem-like cells and tumor angiogenesis by ID3-driven cytokine induction. Cancer Res. 2011, 71, 7125–7134. [Google Scholar] [CrossRef] [PubMed]
  130. Ducray, F.; Idbaih, A.; de Reyniès, A.; Bièche, I.; Thillet, J.; Mokhtari, K.; Lair, S.; Marie, Y.; Paris, S.; Vidaud, M. Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Mol. Cancer 2008, 7, 41. [Google Scholar] [CrossRef] [PubMed]
  131. Zhang, X.; Zhou, Y.; Mehta, K.R.; Danila, D.C.; Scolavino, S.; Johnson, S.R.; Klibanski, A. A pituitary-derived meg3 isoform functions as a growth suppressor in tumor cells. J. Clin. Endocrinol. Metab. 2003, 88, 5119–5126. [Google Scholar] [CrossRef] [PubMed]
  132. Zhou, Y.; Zhong, Y.; Wang, Y.; Zhang, X.; Batista, D.L.; Gejman, R.; Ansell, P.J.; Zhao, J.; Weng, C.; Klibanski, A. Activation of p53 by MEG3 non-coding RNA. J. Biol. Chem. 2007, 282, 24731–24742. [Google Scholar] [CrossRef] [PubMed]
  133. Tinzl, M.; Marberger, M.; Horvath, S.; Chypre, C. DD3 PCA3 RNA analysis in urine—A new perspective for detecting prostate cancer. Eur. Urol. 2004, 46, 182–187. [Google Scholar] [CrossRef] [PubMed]
  134. Hessels, D.; Gunnewiek, J.M.K.; van Oort, I.; Karthaus, H.F.; van Leenders, G.J.; van Balken, B.; Kiemeney, L.A.; Witjes, J.A.; Schalken, J.A. DD3 PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur. Urol. 2003, 44, 8–16. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

Kiang, K.M.-Y.; Zhang, X.-Q.; Leung, G.K.-K. Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis. Cancers 2015, 7, 1406-1424. https://doi.org/10.3390/cancers7030843

AMA Style

Kiang KM-Y, Zhang X-Q, Leung GK-K. Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis. Cancers. 2015; 7(3):1406-1424. https://doi.org/10.3390/cancers7030843

Chicago/Turabian Style

Kiang, Karrie Mei-Yee, Xiao-Qin Zhang, and Gilberto Ka-Kit Leung. 2015. "Long Non-Coding RNAs: The Key Players in Glioma Pathogenesis" Cancers 7, no. 3: 1406-1424. https://doi.org/10.3390/cancers7030843

Article Metrics

Back to TopTop