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The functional role of long non-coding RNA in human carcinomas Gibb, Ewan A; Brown, Carolyn J; Lam, Wan L Apr 13, 2011

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REVIEW Open AccessThe functional role of long non-coding RNA inhuman carcinomasEwan A Gibb1*, Carolyn J Brown1,2 and Wan L Lam1,3AbstractLong non-coding RNAs (lncRNAs) are emerging as new players in the cancer paradigm demonstrating potentialroles in both oncogenic and tumor suppressive pathways. These novel genes are frequently aberrantly expressedin a variety of human cancers, however the biological functions of the vast majority remain unknown. Recently,evidence has begun to accumulate describing the molecular mechanisms by which these RNA species function,providing insight into the functional roles they may play in tumorigenesis. In this review, we highlight theemerging functional role of lncRNAs in human cancer.IntroductionOne of modern biology’s great surprises was the discoverythat the human genome encodes only ~20,000 protein-coding genes, representing <2% of the total genomesequence [1,2]. However, with the advent of tiling resolu-tion genomic microarrays and whole genome and tran-scriptome sequencing technologies it was determined thatat least 90% of the genome is actively transcribed [3,4].The human transcriptome was found to be more complexthan a collection of protein-coding genes and their splicevariants; showing extensive antisense, overlapping andnon-coding RNA (ncRNA) expression [5-10]. Althoughinitially argued to be spurious transcriptional noise, recentevidence suggests that the proverbial “dark matter” of thegenome may play a major biological role in cellular devel-opment and metabolism [11-17]. One such player, thenewly discovered long non-coding RNA (lncRNA) genes,demonstrate developmental and tissue specific expressionpatterns, and aberrant regulation in a variety of diseases,including cancer [18-27].NcRNAs are loosely grouped into two major classesbased on transcript size; small ncRNAs and lncRNAs(Table 1) [28-30]. Small ncRNAs are represented by abroad range of known and newly discovered RNA species,with many being associated with 5’ or 3’ regions of genes[4,31,32]. This class includes the well-documented miR-NAs, RNAs ~22 nucleotides (nt) long involved in the spe-cific regulation of both protein-coding, and putativelynon-coding genes, by post-transcriptional silencing orinfrequently by activation [33-35]. miRNAs serve as majorregulators of gene expression and as intricate componentsof the cellular gene expression network [33-38]. Anothernewly described subclass are the transcription initiationRNAs (tiRNAs), which are the smallest functional RNAsat only 18 nt in length [39,40]. While a number of smallncRNAs classes, including miRNAs, have established rolesin tumorigenesis, an intriguing association between theaberrant expression of ncRNA satellite repeats and cancerhas been recently demonstrated [41-46].In contrast to miRNAs, lncRNAs, the focus of this arti-cle, are mRNA-like transcripts ranging in length from200 nt to ~100 kilobases (kb) lacking significant openreading frames. Many identified lncRNAs are transcribedby RNA polymerase II (RNA pol II) and are polyadeny-lated, but this is not a fast rule [47,48]. There are exam-ples of lncRNAs, such as the antisense asOct4-pg5 or thebrain-associated BC200, which are functional, but notpolyadenylated [49-51]. Generally, lncRNA expressionlevels appear to be lower than protein-coding genes[52-55], and some lncRNAs are preferentially expressedin specific tissues [21]. However, recent findings havesuggested novel lncRNAs may contribute a significantportion of the aforementioned ‘dark matter’ of thehuman transcriptome [56,57]. In an exciting report byKapranov et.al., it was revealed the bulk of the relativemass of RNA in a human cell, exclusive of the ribosomaland mitochondrial RNA, is represented by non-codingtranscripts with no known function [57].* Correspondence: egibb@bccrc.ca1British Columbia Cancer Agency Research Centre, Vancouver, CanadaFull list of author information is available at the end of the articleGibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38© 2011 Gibb et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.Like miRNAs and protein-coding genes, some tran-scriptionally active lncRNA genes display histone H3K4trimethylation at their 5’-end and histone H3K36 tri-methylation in the body of the gene [8,58,59]. The smallnumber of characterized human lncRNAs have beenassociated with a spectrum of biological processes, forexample, epigenetics, alternative splicing, nuclearimport, as structural components, as precursors to smallRNAs and even as regulators of mRNA decay [4,60-70].Furthermore, accumulating reports of misregulatedlncRNA expression across numerous cancer types sug-gest that aberrant lncRNA expression may be a majorcontributor to tumorigenesis [71]. This surge in publica-tions reflects the increasing attention to this subject(Figure 1) and a number of useful lncRNA databaseshave been created (Table 2). In this review we highlightthe emerging functional role of aberrant lncRNA expres-sion, including transcribed ultraconserved regions(T-UCRs), within human carcinomas.Table 1 Types of human non-coding RNAsType Subclasses Symbol ReferencesTransfer RNAs tRNAs [222]MicroRNAs miRNAs [33,34]Ribosomal 5S and 5.8S RNAs rRNAs [223,224]Piwi interacting RNAs piRNAs [38,225]Tiny transcription initiation RNAs tiRNAs [39,40]Small interfering RNAs siRNA [32]Promoter-associated short RNAs PASRs [144,149]Termini-associated short RNAs TASRs [144,149]Antisense termini associated short RNAs aTASRs [226]Small ncRNA (18 to 200 nt in size) Small nucleolar RNAs snoRNAs [227,228]Transcription start site antisense RNAs TSSa-RNAs [229]Small nuclear RNAs snRNAs [230]Retrotransposon-derived RNAs RE-RNAs [231,232]3’UTR-derived RNAs uaRNAs [145]x-ncRNA x-ncRNA [233]Human Y RNA hY RNA [234]Unusually small RNAs usRNAs [235]Small NF90-associated RNAs snaRs [236,237]Vault RNAs vtRNAs [238]Ribosomal 18S and 28S RNAs rRNAs [223,224]Long or large intergenic ncRNAs lincRNAs [8,58]Transcribed ultraconserved regions T-UCRs [85]Pseudogenes none [239,240]GAA-repeat containing RNAs GRC-RNAs [241]Long ncRNA (lncRNAs, 200 nt to >100 kb in size) Long intronic ncRNAs none [242,243]Antisense RNAs aRNAs [244]Promoter-associated long RNAs PALRs [144,149]Promoter upstream transcripts PROMPTs [245]Stable excised intron RNAs none [56]Long stress-induced non-coding transcripts LSINCTs [25]Figure 1 Publications describing cancer-associated ncRNAs.Entries are based on a National Library of Medicine Pubmed searchusing the terms “ncRNA” or “non-coding RNA” or “noncoding RNA”or non-protein-coding RNA” with cancer and annual (Jan.1-Dec.31)date limitations.Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 2 of 17Background on Long Non-Coding RNANomenclature and Classification of LncRNAThe definition ‘non-coding RNA’ is typically used todescribe transcripts where sequence analysis has failedto identify an open reading frame. However, one shouldexercise caution when exploring putative non-codingtranscripts, as there are cases where ‘non-coding’ tran-scripts were found to encode short, functional peptides[72]. Currently, a universal classification scheme todefine lncRNAs does not exist and therefore there arenumerous synonyms describing the same type of tran-scripts. Terms such as large non-coding RNA, mRNA-like long RNA, and intergenic RNA all define cellularRNAs, exclusive of rRNAs, greater than 200 nt in lengthand having no obvious protein-coding capacity [62].Consequently, this has led to confusion in the literatureas to exactly which transcripts should constitute alncRNA. For example, one subclass of lncRNAs is calledlarge or long intergenic ncRNAs (lincRNAs). TheselncRNAs are exclusively intergenic and are marked by achromatin signature indicative of transcription [8,58].To further compound classification confusion, RNA spe-cies that are bifunctional preclude categorization intoeither group of protein-coding or ncRNAs as their tran-scripts function both at the RNA and protein levels [73].In these rare cases, they are classified on a case-by-casebasis, reserving the term ‘lncRNA’ to describe tran-scripts with no protein-coding capacity. In the mean-time, and for the purposes of this review, we willconsider lncRNAs as a blanket term to encompassmRNA-like ncRNAs, lincRNAs, as well as antisense andintron-encoded transcripts, T-UCRs and transcribedpseudogenes.Discovery of LncRNAsThe earliest reports describing lncRNA predated the dis-covery of miRNAs, although the term ‘lncRNA’ had notbeen coined at the time (Figure 2). One of the firstlncRNA genes reported was the imprinted H19 gene,which was quickly followed by the discovery of thesilencing X-inactive-specific transcript (XIST) lncRNAgene, which plays a critical function in X-chromosomeinactivation [74,75]. However, the discovery of the firstmiRNA lin-14 dramatically redirected the focus ofncRNA research from long ncRNAs to miRNAs [76].Moreover, during this time the discovery of miRNAsrevealed RNA could regulate gene expression and laterthat entire gene networks could be affected by ncRNAexpression and within the last decade miRNAs were dis-covered to be associated with cancer (Figure 2) [76-79].At the time of this writing there are approximately 1049human miRNAs described in miRBase V16 [80,81] withthe potential of affecting the expression of approxi-mately 60% of protein -coding genes [82,83]. Conversely,Table 2 Publically available long non-coding RNA online databasesDatabase Name Website ReferencencRNAimprint http://rnaqueen.sysu.edu.cn/ncRNAimprint/ [246]ncRNAdb http://research.imb.uq.edu.au/rnadb/ [247]Functional RNAdb http://www.ncrna.org/frnadb/ [248]NONCODE http://www.noncode.org/ [249]lncRNA db http://longnoncodingrna.com/ [250]Rfam http://rfam.sanger.ac.uk/ [251]NRED http://jsm-research.imb.uq.edu.au/nred/cgi-bin/ncrnadb.pl [252]Ncode (Invitrogen) http://escience.invitrogen.com/ncRNA/ N/ANcRNA Database http://biobases.ibch.poznan.pl/ncRNA/ [253]T-UCRs http://users.soe.ucsc.edu/~jill/ultra.html [202]NPInter http://www.bioinfo.org.cn/NPInter/ [254]Figure 2 Timeline of cancer-associated ncRNA discoveriesrelative to transcriptome analysis technologies (not drawn toscale).Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 3 of 17the variety and dynamics of lncRNA expression was notto be fully appreciated until the introduction of wholetranscriptome sequencing. With the advent of the FAN-TOM and ENCODE transcript mapping projects, it wasrevealed that the mammalian genome is extensivelytranscribed, although a large portion of this representednon-coding sequences [3,84]. Coupled with the novelfunctional annotation of a few lncRNAs, this discoverypromoted research focusing on lncRNA discovery andcharacterization. Recent reports have described newlncRNA classes such as lincRNAs and T-UCRs [8,58,85].Current estimates of the lncRNA gene content in thehuman genome ranges from ~7000 - 23,000 uniquelncRNAs, implying this class of ncRNA will represent anenormous, yet undiscovered, component of normal cel-lular networks that may be disrupted in cancer biology[62].Emerging Role of Long Non-Coding RNA inTumorigenesisA role for differential lncRNA expression in cancer hadbeen suspected for many years, however, lacked strongsupporting evidence [86]. With advancements in cancertranscriptome profiling and accumulating evidence sup-porting lncRNA function, a number of differentiallyexpressed lncRNAs have been associated with cancer(Table 3). LncRNAs have been implicated to regulate arange of biological functions and the disruption of some ofthese functions, such as genomic imprinting and transcrip-tional regulation, plays a critical role in cancer develop-ment. Here we describe some of the better characterizedlncRNAs that have been associated with cancer biology.Imprinted lncRNA genesImprinting is a process whereby the copy of a gene inher-ited from one parent is epigenetically silenced [87,88].Intriguingly, imprinted regions often include multiplematernal and paternally expressed genes with a high fre-quency of ncRNA genes. The imprinted ncRNA genesare implicated in the imprinting of the region by a varietyof mechanisms including enhancer competition andchromatin remodeling [89]. A key feature of cancer is theloss of this imprinting resulting in altered gene expres-sion [90,91]. Two of the best known imprinted genes arein fact lncRNAs.H19 The H19 gene encodes a 2.3 kb lncRNA that isexpressed exclusively from the maternal allele. H19 andTable 3 Human cancer-associated lncRNAsLncRNA Size Cytoband Cancer types ReferencesHOTAIR 2158 nt 12q13.13 Breast [18,68]MALAT1/a/NEAT2 7.5 kb 11q13.1 Breast, lung, uterus, pancreas, colon, prostate, liver, cervix1,neuroblastoma1, osteosarcoma[135,137-139,152,255,256]HULC 500 nt 6p24.3 Liver, hepatic colorectal metastasis [170,171]BC200 200 nt 2p21 Breast, cervix, esophagus, lung, ovary, parotid, tongue [50,51]H19 2.3 kb 11p15.5 Bladder, lung, liver, breast, endometrial, cervix, esophagus, ovary,prostate, choricarcinoma, colorectal[74,92,95,97,102,103,257-264]BIC/MIRHG155/MIRHG21.6 kb 21q11.2 B-cell lymphoma [153]PRNCR1 13 kb 8q24.2 Prostate [187]LOC285194 2105 nt 3q13.31 Osteosarcoma [265]PCGEM1 1643 nt 2q32.2 Prostate [188,266,267]UCA1/CUDR 1.4 kb, 2.2 kb, 2.7kb19p13.12 Bladder, colon, cervix, lung, thyroid, liver, breast, esophagus, stomach [268-270]DD3/PCA3 0.6 kb, 2 kb, 4 kb 9q21.22 Prostate [189,190]anti-NOS2A ~1.9 kb 17q23.2 Brain1 [271]uc.73A 201 nt 2q22.3 Colon [200]TUC338 (encodesuc.338)590 nt 12q13.13 Liver [203]ANRIL/p15AS/CDK2BAS34.8 kb & splicevariants9p21.3 Prostate, leukemia [175,176,183,272]MEG3 1.6 kb & splicingisoforms14q32.2 Brain (downregulated) [156-158,162]GAS5/SNHG2 Multiple isoforms 1q25.1 Breast (downregulated) [273]SRA-1/SRA(bifunctional)1965 nt 5q31.3 Breast, uterus, ovary (hormone responsive tissue) [274,275]PTENP1 ~3.9 kb 9p13.3 Prostate [173,174]ncRAN 2186 nt, 2087 nt 17q25.1 Bladder, neuroblastoma [276,277]1 Cell lines.Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 4 of 17its reciprocally imprinted protein-coding neighbor theInsulin-Like Growth Factor 2 or IGF2 gene at 11p15.5were among the first genes, non-coding or otherwise,found to demonstrate genomic imprinting [74,92]. Theexpression of H19 is high during vertebrate embryo devel-opment, but is downregulated in most tissues shortly afterbirth with the exception of skeletal tissue and cartilage[20,93,94]. Loss of imprinting and subsequent strong geneexpression has been well-documented in human cancers.Likewise, loss of imprinting at the H19 locus resulted inhigh H19 expression in cancers of the esophagus, colon,liver, bladder and with hepatic metastases [95-97].H19 has been implicated as having both oncogenic andtumor suppression properties in cancer. H19 is upregu-lated in a number of human cancers, including hepato-cellular, bladder and breast carcinomas, suggesting anoncogenic function for this lncRNA [97-99]. In coloncancer H19 was shown to be directly activated by theoncogenic transcription factor c-Myc, suggesting H19may be an intermediate functionary between c-Myc anddownstream gene expression [98]. Conversely, the tumorsuppressor gene and transcriptional activator p53 hasbeen shown to down-regulate H19 expression [100,101].H19 transcripts also serve as a precursor for miR-675, amiRNA involved in the regulation of developmentalgenes [102]. miR-675 is processed from the first exon ofH19 and functionally downregulates the tumor suppres-sor gene retinoblastoma (RB1) in human colorectal can-cer, further implying an oncogenic role for H19 [103].There is evidence suggesting H19 may also play a rolein tumor suppression [104,105]. Using a mouse modelfor colorectal cancer, it was shown that mice lacking H19manifested an increased polyp count compared to wild-type [106]. Secondly, a mouse teratocarcinoma modeldemonstrated larger tumor growth when the embryolacked H19, and finally in a hepatocarcinoma model,mice developed cancer much earlier when H19 wasabsent [107]. The discrepancy as to whether H19 hasoncogenic or tumor suppressive potential may be due inpart to the bifunctional nature of the lncRNA or may becontext dependent. In either case, the precise functionaland biological role of H19 remains to be determined.XIST - X-inactive-specific transcript The 17 kb lncRNAXIST is arguably an archetype for the study of functionallncRNAs in mammalian cells, having been studied fornearly two decades. In female cells, the XIST transcriptplays a critical role in X-chromosome inactivation by phy-sically coating one of the two X-chromosomes, and isnecessary for the cis-inactivation of the over one thou-sand X-linked genes [75,108-110]. Like the lncRNAsHOTAIR and ANRIL, XIST associates with polycomb-repressor proteins, suggesting a common pathway ofinducing silencing utilized by diverse lncRNAs. In mice,X inactivation in the extraembryonic tissues is non-random, and the initial expression of Xist is always pater-nal in origin, followed later by random X inactivation inthe epiblast associated with random mono-allelic expres-sion [111]. Intriguingly, regulation of Xist in mouse hasbeen shown to be controlled by interactions amongstadditional ncRNAs, including an antisense transcript,Tsix, enhancer-associated ncRNAs (Xite) and theupstream Jpx and Ftx lncRNAs [109,112-115]. Intrigu-ingly, murine Xist and Tsix duplexes are processed intosmall RNAs by an apparently Dicer-dependent manner,suggesting a significant overlap between the regulatorynetworks of both lncRNAs and sRNAs [116]. It is unclear,however, how much of this regulation is conserved inhumans, who do not show imprinted X inactivation[117]. While XIST expression levels are correlated withoutcome in some cancers, such as the therapeuticresponse in ovarian cancer [118], the actual role thatXIST may play in human carcinomas, if any, is notentirely clear.There is generally believed to be only a limited develop-mental window in which X inactivation can occur, andloss of XIST from an inactive X chromosome does notresult in reactivation of the X chromosome [119,120].Thus, tumors with additional X chromosomes generallykeep the inactivation status of the duplicated X. Fortumors in which two active X chromosomes are observed,as has been frequently observed in breast cancer, the mostcommon mechanism involves loss of the inactive X andduplication of the active X, often resulting in heteroge-neous XIST expression in these tumors [121-123]. Loss ofthe inactive X and abnormalities of XIST expression maybe indicative of more general heterochromatin defects[124]. Analogously, failure to properly reset XIST and Xinactivation may serve as a marker of proper resetting ofepigenetic marks in stem cells or induced pluripotentstem cells [125,126]. Correlations between XIST expres-sion and cancer state can also occur spuriously. Notably,in cytogenetically normal cells, XIST is found only infemales as males do not have an inactive X. Therefore incancers correlations can be observed with XIST expressiondue to differential presence of male or female samples,and many cancers do show different onsets and progres-sions in males and females. Furthermore, XIST expressionwill increase with the number of inactive X chromosomes.While it might be anticipated that there would be littleadvantage to a tumor acquiring inactive chromosomes, ithas been shown that approximately 15% of human X-linked genes continue to be expressed from the inactive Xchromosome [127].Involvement in metastasisHOTAIR - HOX antisense intergenic RNA SeverallncRNAs have been implicated in metastasis. One of thefirst lncRNAs described to have a fundamental role incancer was the metastasis-associated HOX AntisenseGibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 5 of 17Intergenic RNA (HOTAIR), a 2.2 kb gene located in themammalian HOXC locus on chromosome 12q13.13[18]. This lncRNA was found to be highly upregulatedin both primary and metastatic breast tumors, demon-strating up to 2000-fold increased transcription overnormal breast tissue [68]. High levels of HOTAIRexpression were found to be correlated with both metas-tasis and poor survival rate, linking a ncRNA with can-cer invasiveness and patient prognosis [68].Furthermore, it was demonstrated that if cells expres-sing HOTAIR were grafted into mouse mammary fatpads, a modest increase in the rate of primary tumorgrowth was observed [68]. Interestingly, there arereports indicating that numerous lncRNAs are tran-scribed from the HOX locus, suggesting that HOTAIRmay be only one example of a global regulatory phe-nomena [58].The spliced and polyadenylated HOTAIR RNA does notencode any proteins but has been demonstrated to be inti-mately associated with the mammalian polycomb repres-sive complex 2 (PRC2) which is comprised of the H3K27methylase EZH2, SUZ12 and EED [68,128,129] (Figure 3).Polycomb group proteins mediate repression of transcrip-tion of thousands of genes controlling differentiation path-ways during development, and have roles in stem cellpluripotency and human cancer [68,130-133].HOTAIR binding results in a genome-wide re-targetingof the PRC2 complex. The HOXD locus on chromosome2 is a PRC2 target (Figure 3). The consequence of PRC2/HOTAIR localization is the transcriptional silencing of a40 kb region of the HOXD locus which remodels thegene expression pattern of breast epithelial cells to moreclosely resemble that of embryonic fibroblasts [68]. TheHOTAIR RNA appears to act as a molecular scaffold,binding at least two distinct histone modification com-plexes. The 5’ region of the RNA binds the PRC2 com-plex responsible for H3K27 methylation, while the 3’region of HOTAIR binds LSD1, a histone lysine demethy-lase that mediates enzymatic demethylation of H3K4Me2[128,134]. Although, the precise mechanism of HOTAIRactivities remains to be elucidated, it is clear thatHOTAIR reprograms chromatin state to promote cancermetastasis.MALAT1 - Metastasis-associated lung adenocarcinomatranscript 1 The MALAT1 gene, or metastasis-associatedlung adenocarcinoma transcript 1, was first associatedwith high metastatic potential and poor patient prognosisduring a comparative screen of non-small cell lung cancerpatients with and without metastatic tumors [135]. ThislncRNA is widely expressed in normal human tissues[135,136] and is found to be upregulated in a variety ofhuman cancers of the breast, prostate, colon, liver anduterus [27,137-139]. Notably, the MALAT1 locus at11q13.1 has been identified to harbor chromosomal trans-location breakpoints associated with cancer [140-142].Intriguingly, cellular MALAT1 transcripts are subject topost-transcriptional processing to yield a short, tRNA-like molecule mascRNA and a long MALAT1 transcriptwith a poly(A) tail-like moiety [143] (Figure 4). Using themouse homologue to the human MALAT1 gene, it wasFigure 3 Proposed mechanism of HOTAIR mediated genesilencing of 40 kb of the HOXD locus, which is involved indevelopmental patterning. The HOTAIR lncRNA is transcribed fromthe HOXC locus and functions in the binding and recruitment andbinding of the PRC2 and LSD1 complex to the HOXD locus. Forclarity, only the PRC2 complex is indicated in the above figure.Through an undetermined mechanism, the HOTAIR-PRC2-LSD1complex is redirected to the HOXD locus on chromosome 2 wheregenes involved in metastasis suppression are silenced throughH3K27 methylation and H3K4 demethylation. This drives breastcancer cells to develop gene expression patterns that more closelyresemble embryonic fibroblasts than epithelial cells.Figure 4 Expression and processing of MALAT1 transcripts. Fulllength 7.5 kb MALAT1 RNA is processed by RNaseP and RNaseZ togenerate the small ncRNA mascRNA, which is then exported to thecytoplasm. The larger MALAT1 RNA is retained in the nuclearspeckles where it is thought to have a role in regulating alternativesplicing machinery.Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 6 of 17revealed that ribonuclease (RNase) P processing gener-ates the 3’ end of the long MALAT1 transcript and the 5’end of the mascRNA. The shorter mascRNA adopts atRNA clover-leaf structure and is subject to RNaseZ pro-cessing and the addition of a CCA to its 3’ end beforebeing exported to the cytoplasm. The generation of puta-tively functional sRNAs by post-transcriptional proces-sing of lncRNAs, such mascRNA from MALAT1, maybe reflective of a central, unexplored theme in ncRNAbiology [144]. Recent evidence suggests regulated post-transcriptional processing events, such as splicing andpost-cleavage capping, may increase the functionaldiversity of the metazoan transcriptome [145-149]. Incontrast, the long MALAT1 transcript is not polyade-nylated, but has a poly(A) tail-like sequence that isgenome encoded and is putatively present to protectthe MALAT1 transcript from degradation. Moreover,MALAT1 localizes to nuclear speckles in a transcrip-tion dependent manner [136,150].Following the correlation between high levels ofMALAT1 expression and metastasis, a number of studieshave implicated MALAT1 in the regulation of cell mobi-lity. For example, RNA interference (RNAi)-mediatedsilencing of MALAT1 impaired the in vitro migration oflung adenocarcinoma cells through concomitant regula-tion of motility regulated genes via transcriptional and/orpost-transcriptional means [151]. Similarly, short hairpinRNA inhibition of MALAT1 reduced cell proliferationand invasive potential of a cervical cancer cell line [152].Collectively, these studies suggest that MALAT1 regu-lates the invasive potential of metastatic tumor cells.Other examples of cancer-associated lncRNAs subject topost-transcriptional processing include the miR-155 hostgene BIC and the miR-17-92 cluster in B-cell lymphomaand neuroblastoma, respectively [153,154].Recent efforts have focused on elucidating the molecu-lar role of nuclear speckle localized MALAT1 transcripts,while the function for the mascRNA has yet to be deter-mined. Nuclear speckles are thought to be involved inthe assembly, modification and/or storage of pre-mRNAprocessing machinery [136,155]. A recent publicationrevealed MALAT1 RNA strongly associates with serine-arginine rich splicing factor (SR) proteins which areinvolved in both constitutive and alternative splicing andthe levels of MALAT1 regulated the cellular levels ofphosphorylated SR proteins [66]. These findings implythat the lncRNA MALAT1 may serve a function in theregulation of alternate splicing by modulating the activityof SR proteins, although precisely how this may contri-bute to tumorigenesis remains unknown.LncRNA-mediated tumor suppression by P53 stimulationMEG3 - Maternally expressed gene 3 The maternallyexpressed gene 3 (MEG3) was the first lncRNA proposedto function as a tumor suppressor. The MEG3 gene isexpressed in many normal human tissues, with the high-est expression in the brain and pituitary gland [156,157].MEG3 expression was not detectable in various braincancers, nor in a range of human cancer cell lines impli-cating a potential role of this lncRNA in suppression ofcell growth. Moreover, ectopic expression of MEG3RNA was found to suppress the growth of severalhuman cancer cell lines, further supporting the role ofMEG3 as a tumor suppressor [157]. In clinically non-functioning pituitary tumors, it was demonstrated thathypermethylation of the MEG3 regulatory region wasassociated with the loss of MEG3 expression, providingevidence for a mechanism of MEG3 inactivation [157].MEG3 is a paternally imprinted, single copy gene com-prised of 10 exons [156]. To date, 12 MEG3 isoforms havebeen detected (MEG3; a-3k) due to alternative splicing[158]. Each isoform contains the common exons 1-3 and 8-10, but varies in the combination of exons 4-7 in the middleof the transcript [158]. Notably, the last intron of MEG3encodes the evolutionarily conserved miR-770, a miRNAwith a number of putative mRNA targets [159]. Thisarrangement mirrors the presence of miR-675 in H19,except in that instance the miRNA was exon encoded[102]. The originally identified isoform of MEG3 isexpressed as a 1.6 kb polyadenylated transcript that is loca-lized to the nucleus where it is associated with chromatinalthough some cytoplasmic MEG3 transcripts have beendetected [156,160,161]. All 12MEG3 isoforms demonstratethree distinct secondary folding motifs designated M1, M2and M3 [158].Functionally, MEG3 has been implicated as a top-level regulatory RNA due to its ability to stimulateboth p53-dependent and p53-independent pathways[158,162]. Critically, the MEG3-mediated functionalactivation of p53 is dependent on the secondary struc-ture of the MEG3 RNA rather than on primarysequence conservation. In an elegant series of experi-ments, Zhang et al. demonstrated that replacing parti-cular regions of the MEG3 with unrelated sequencehad no effect on the activation of p53 provided the ori-ginal secondary structure was preserved [158]. Thisobservation strengthens the argument that the rapidevolution and relative lack of sequence conservationdoes not limit the potential functionality of theseunique RNA species [163]. Conversely, the novellincRNA-p21 has been described as a downstreamrepressor in the p53 transcriptional response, suggest-ing the complex p53 transcriptional network includesnumerous regulatory lncRNAs [164].Depletion of miRNAs by a lncRNA ‘molecular decoy’ or‘miRNA sponge’Expression of miRNAs in cancer can be deregulated bya range of mechanisms, including copy number altera-tions and epigenetic silencing [165-168]. Two recentGibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 7 of 17examples have demonstrated that lncRNAs can act asnatural ‘miRNA sponges’ to reduce miRNA levels [169].HULC - Highly Upregulated in Liver Cancer Themost highly upregulated transcript found in a microar-ray-based study of gene expression in hepatocellular car-cinoma was determined to be the ncRNA HULC, orHighly Upregulated in Liver Cancer [170]. Transcribedfrom chromosome 6p24.3, this lncRNA demonstratesthe hallmarks of a typical mRNA molecule, including asingle spliced GT-AG intron, canonical polyadenylationsignals upstream of the poly(A) tail and nuclear exportdemonstrating strong localization to the cytoplasm.Although HULC was found to co-purify with ribosomes,no translation product for this lncRNA has beendetected, supporting its classification as a non-codingtranscript [170]. In addition to liver cancer, HULC wasfound to be highly upregulated in hepatic colorectalcancer metastasis and in hepatocellular carcinoma celllines (HCC) producing hepatitis B virus (HBV) [171].A recent paper began to elucidate the mechanism ofupregulation of HULC in liver cancer cells, and to pro-vide a potential mechanism of HULC function [172].HULC exists as part of an intricate auto-regulatory net-work, which when perturbed, resulted in increasedHULC expression (Figure 5). The HULC RNA appearedto function as a ‘molecular decoy’ or ‘miRNA sponge’sequestering miR-372, of which one function is thetranslational repression of PRKACB, a kinase targetingcAMP response element binding protein (CREB). Onceactivated, the CREB protein was able to promote HULCtranscription by maintaining an open chromatin struc-ture at the HULC promoter resulting in increasedHULC transcription [172].Pseudogene pairs: PTEN and PTENP1 The discoverythat HULC can act as a molecular decoy or ‘miRNAsponge’ mirrors a recent report describing an intricaterelationship between the tumor suppressor phosphataseand tensin homolog (PTEN) and the matching lncRNAphosphatase and tensin homolog pseudogene 1 (PTENP1)[173]. The RNA transcripts of the PTEN/PTENP1 pairshare similar 3’ untranslated regions (3’UTRs) which bothbind the same miRNAs. By binding miRNAs, PTENP1transcripts reduce the effects of translational repressionon PTEN therefore allowing expression of this tumorsuppressor. In cancer, specific mutations inactivate thesemiRNA binding sites in PTENP1, therefore reducing thetranslation of PTEN and promoting tumor growth [173].This is especially pertinent as subtle changes in PTENlevels can influence cancer susceptibility [174].LncRNA-mediated deregulation of the tumor suppressorsANRIL - Antisense Non-coding RNA in the INK4 LocusLocated as part of the 42kb INK4b-ARF-INK4a locus onchromosome 9p21.3, the Antisense Non-coding RNA inthe INK4 Locus (ANRIL) is transcribed by RNA pol IIand processed into alternatively spliced isoforms, includ-ing an unspliced transcript of 34.8 kb termed p15AS[175,176]. The INK4b-ARF-INKa locus has an importantrole in cell cycle control, cell senescence, stem cellrenewal and apoptosis through P14ARF-MDM2-P53 andP16Ink4a/p15Ink4b-Cdk4/6-pRb pathways [177-179]. Amouse model suggests that the well-characterized tumorsuppressor genes encoded within this locus are regulatedby Polycomb proteins [180].Aberrant expression and single nucleotide polymorph-isms (SNPs) within ANRIL have been associated with sus-ceptibility to a range of human diseases, including cancer[181,182]. Moreover, the INK4b-ARF-INK4a locus is sub-ject to frequent deletion or hypermethylation in cancers,including leukemia, melanoma, lung and bladder cancers[181]. ANRIL has been associated with epigenetic silencingof the tumor suppressor gene p15, although the molecularevents leading to this silencing were unclear [175].Evidence has suggested an intriguing mechanisms forANRIL-mediated silencing of the INK4b-ARF-INK4alocus. Recently an interaction between chromatin modi-fying PRC complexes and ANRIL has been described,further elucidating the regulatory mechanism of thislncRNA. Like the lncRNA HOTAIR which binds boththe polycomb repressor complex PRC2 and the LSD1complex, ANRIL binds and recruits two polycombrepressor complexes modifying complexes, PRC1 andPRC2 [183,184]. This resulted in ANRIL/PRC mediatedsilencing of the genes in the INK4b-ARF-INK4a locus.While the distinct regions of the HOTAIR lncRNArequired for interactions with each protein complexwere determined [128], future studies will be necessaryto elucidate the structural requirements of lncRNAsFigure 5 Proposed mechanism of HULC upregulation inhepatocellular carcinoma. (1) The kinase PRKACB functions as anactivator of CREB. (2) Phosphorylated (activated) CREB forms part ofthe RNA pol II transcriptional machinery to activate HULCexpression. (3) Abundant HULC RNA acts as a molecular sponge tosequester and inactivate the repressive function miR-372. (4)PRKACB levels increase, as transcripts are normally translationallyrepressed by high miR-372 levels.Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 8 of 17such as ANRIL with chromatin regulators such as PRC1/PRC2.The molecular details of ANRIL-mediated tumor sup-pression are becoming more clear. However, othermechanisms of lncRNA-mediated suppression of tumorsuppressor genes have been reported. For example, achange in the expression ratio of bidirectional genes hasbeen shown to mediate the expression of the tumorsuppressor p21 [185]. Collectively, these observationssuggest that lncRNA-mediated silencing of tumor sup-pressor genes may be a major mechanism drivingtumorigenesis.Cancer type specific lncRNA expressionMany of the described lncRNAs are expressed in a vari-ety of cancers, however a select few thus far have beenassociated with a single cancer type. HOTAIR, for exam-ple, has only been described in breast cancer, whilethree lncRNAs PCGEM1, DD3 and PCNCR1 have beenassociated solely with prostate cancer [68,186,187]. Themost recently described of these, Prostate Cancer Non-Coding RNA 1 (PCNCR1) lncRNA, was identified in a‘gene desert’ on chromosome 8q24.2 and is associatedwith susceptibility to prostate cancer. PCNCR1 isexpressed as an intronless, ~13 kb transcript with apotential role in trans-activation of androgen receptor(AR), a key player in prostate cancer progression [187].Likewise, PCGEM1 (Prostate Specific Gene 1) was foundto have properties supporting tumorigenesis, as ectopicoverexpression of PCGEM1 RNA resulted in increasedcell growth and colony formation in cell lines [188]. ThelncRNA Differential Display Code 3 (DD3) is also highlyover expressed in prostate cancer, yet little is knownabout the role DD3 may play in prostate cancer progres-sion [189,190]. Finally, the liver associated lncRNAHULC is highly expressed in primary liver tumors, andin colorectal carcinomas that metastasized to the liver,but not in the primary colon tumors or in non-livermetastases [171].RNA polymerase III transcription of lncRNAThe lncRNAs described thus far are products of RNApol II transcription, yet many ncRNAs are transcribedby RNA polymerase III (RNA pol III) [191]. Importantly,RNA pol III is frequently deregulated in cancer cellsresulting in increased activity [192,193]. The molecularmechanisms driving increased RNA pol III activity intumor cells include overexpression of RNA pol III tran-scription factors, escape from RNA pol III repressorsand direct oncogene-mediated activation [193-195].Aberrant RNA pol III function may have consequencesto the expression of lncRNAs transcribed by thispolymerase.For example, the lncRNA BC200 is a small cytoplas-mic lncRNA in the neurons of primate nervous systemsand human cancers, but not in non-neuronal organs[20,50,51,196,197]. Unlike the majority of lncRNAsdescribed thus far, BC200 is transcribed by RNA pol IIIand shares unique homology with human Alu elements[196,198]. Similarly, the lncRNA HULC also shareshomology with mobile DNA, in this case with a longterminal repeat (LTR) retroelement [170]. The BC200RNA has been characterized as a negative regulator ofeIF4A-dependent translation initiation [199].Due to the fact that many whole transcriptome sequen-cing methods were developed to enrich for poly(A) puri-fied transcripts, RNA pol III transcripts may have beenexcluded from analysis. This suggests that other, yet uni-dentified RNA pol III lncRNAs over-expressed in cancermay be participating in tumorigenesis.Aberrant T-UCR expression in human carcinomaTranscribed ultraconserved Regions (T-UCRs) are evolu-tionary conserved sequences found in both intergenicand intragenic regions of the human genome [200,201].These unique sequences are defined as 481 segments ofDNA that are absolutely conserved between orthologousregions of the human, rat and mouse genomes [201,202].The transcription products of T-UCRs are 200-779 nt inlength and were originally classed into three categories,non-exonic, exonic and possibly exonic, according totheir overlap with known protein-coding genes [202].More recently, T-UCRs have been re-annotated into amore descriptive set of five categories: intergenic (38.7%),intronic (42.6%), exonic (4.2%), partly exonic (5%) or exo-nic containing (5.6%) (Figure 6) [59].The high degree of conservation of T-UCRs, combinedwith their tissue-specific expression, suggests thesencRNAs may play a critical role in cellular metabolismand development [200]. The expression of many T-UCRsis significantly altered in cancer, notably in adult chroniclymphocytic leukemias, colorectal and hepatocellular car-cinomas and neuroblastomas [85,200]. Their aberranttranscription profiles can be used to differentiate types ofhuman cancers and have been linked to patient outcome[85]. Some of the T-UCRs reside in genomic regions asso-ciated with specific types of cancer [200]. For example, incolon cancer, the T-UCR uc.73A is one of the most highlyFigure 6 Genomic locations of the five classes of T-UCRs. Theexons of coding genes are indicated by boxes, while the locationsof the T-UCR elements are marked by a double-T bar. The fivepossible positions are as indicated exonic, partly exonic, exoncontaining, intronic and intergenic.Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 9 of 17upregulated T-UCRs, and this lncRNA has been found toshow oncogenic properties by proliferation assays [200].Similarly, T-UCR uc.338 is significantly upregulated inhuman hepatocarcinoma tumor and cell lines, and uc.338was found to be part of a larger transcriptional unit coinedTUC338 which is involved in cell growth [203].The mechanism by which T-UCRs are differentiallyexpressed is unclear. A study profiling T-UCRs in neu-roblastomas did not find a consistent associationbetween genomic alterations and T-UCR expression,suggesting aberrant T-UCR expression may be a conse-quence of epigenetic mechanisms. Like miRNAs andcoding genes, T-UCR expression has been shown to berepressed by CpG island hypermethylation [85,204].Similarly, miRNAs have been shown to bind to, anddownregulate T-UCRs, suggesting a complex regulatorymechanism may exist between ncRNAs in human can-cers [85,200]. Collectively, these reports have suggestedthat aberrant T-UCR expression may have a yet unde-termined biological role in tumorigenesis.Utility of LncRNAs in Cancer Diagnostics and TherapiesLike their smaller non-coding miRNA counterparts,lncRNAs represent a significant untapped resource interms of developing diagnostics and therapies. Differentialor high level expression of certain cancer type-specificlncRNAs can be exploited for the development of novelbiomarkers as lncRNA expression or may potentiallycorrelate with patient response to chemotherapy. Under-standing the mechanism(s) by which lncRNAs act willcontinue to provide novel approaches to regulating genesincluding the development of mimetics to compete withbinding sites for miRNAs, chromatin remodelers, or DNA.It has been suggested that mediating transcriptional genesilencing (TGS) pathways, especially those of tumorsuppressors or oncogenes, could be of high therapeuticbenefit [205].It has been widely reported that cancer-specific miR-NAs are detectable in the blood, sputum and urine ofcancer patients [206-210]. Likewise, lncRNAs havedemonstrated utility as fluid-based markers of specificcancers. For example, the prostate specific lncRNA DD3has been developed into highly specific, nucleic acidamplification-based marker of prostate cancer, whichdemonstrated higher specificity than serum prostate-specific antigen (PSA) [211,212]. Similarly, the highlyexpressed hepatocarcinoma-associated lncRNA HULC isdetectable in the blood of hepatocarcinoma patients byconventional PCR methods [170].The use of lncRNAs as therapeutic agents is onlybeginning to be explored [213]. Although our under-standing of the molecular mechanisms of lncRNA func-tion is limited, some features of lncRNAs make themideal candidates for therapeutic intervention. ManylncRNAs appear to have protein-binding or functionalpotential that is dependent on secondary structure, thismay provide a means of intervention [214]. Preventingthe interactions of HOTAIR with the PRC2 or LSD1complexes, for example, may limit the metastatic poten-tial of breast cancer cells [215].The tumor expression of certain lncRNAs provides asource of regulatory regions that can be used to reducethe risk of affecting normal tissues during transgene-mediated treatment. For example, H19 is stronglyexpressed in embryonic cells and in a wide-range ofhuman cancers [20,93,94]. As such, a plasmid-based sys-tem has been developed to exploit the tumor-specificexpression of H19, primarily tested in treating bladdercancer. A plasmid construct, harboring a diptheria toxingene driven by H19 specific regulatory sequences, is eitheradministered via intratumoral injection as naked DNA, orcomplexed to the cationic polymer polyethylenimine (PEI)to form a polyplex vector [216]. PEI-complexed plasmid isthought to increase the efficiency of DNA uptakevia clathrin-dependent and -independent (cholesterol-dependent) pathways [217]. Upon uptake, high levels ofdiptheria toxin are expressed in the tumor, resulting in areduction in tumor size in human trials [218-221]. Collec-tively, these advances indicate the potential in developinglncRNA mediated diagnostics and therapies.ConclusionsDifferential expression of lncRNAs is becoming recog-nized as a hallmark feature in cancer, however the func-tional role for the vast majority of these unique genes isstill in question. In this review, we highlight character-ized lncRNAs described to play a functional role in can-cer-associated processes, such as metastasis and loss ofimprinting. Aberrant lncRNA expression participates incarcinogenesis by disrupting major biological processes,such as redirecting chromatin remodeling complexes orinactivating major tumor suppressor genes. We alsodescribe the potential role of dysregulated T-UCRs incancer, and place these unique RNAs in the lncRNAcategory. Finally, we note the potential utility oflncRNAs in cancer as diagnostic and prognostic mar-kers, as well as the potential of developing lncRNAmediated therapy.AbbreviationsANRIL: Antisense Non-coding RNA in the INK4 Locus; AR: androgen receptor;CREB: cAMP response element binding protein; DD3: Differential DisplayCode 3; HBV: hepatitis B virus; HCC: hepatocellular carcinoma cell lines;HOTAIR: HOX Antisense Intergenic RNA; HULC: Highly Upregulated in LiverCancer; IGF2: Insulin-Like Growth Factor 2; kb: kilobase; lincRNA: long orlarge intergenic non-coding RNA; lncRNA: long non-coding RNA; LTR: longterminal repeat; MALAT1: Metastatis-Associated Lung AdenocarcinomaTranscript 1; MEG3: Maternally Expressed Gene 3; miRNA: microRNA; ncRNA:non-coding RNA; nt: nucleotide; PCNCR1: Prostate Cancer Non-Coding RNA1; PEI: polyethylenimine; PRC: polycomb repressive complex; PTEN:Gibb et al. Molecular Cancer 2011, 10:38http://www.molecular-cancer.com/content/10/1/38Page 10 of 17phosphatase and tensin homolog; PTENP1: phosphatase and tensin homologpseudogene 1; RNase: ribonuclease; RNA pol II: RNA polymerase II; RNA polIII: RNA polymerase III; RNAi: RNA interference; SR: serine-arginine richsplicing proteins; TGS: transcriptional gene silencing; tiRNA: transcriptioninitiation RNAs; T-UCR: transcribed ultraconserved region; UTR: untranslatedregion; XIST: X-Inactive-Specific Transcript.AcknowledgementsWe would like to thank Chad Malloff and Gavin Wilson for their insightfulcomments. This work was supported by funds from the Canadian Institutes forHealth Research (MOP 86731, MOP 77903 to WLL and MOP 13690 to CJB),Canadian Cancer Society (CCS20485), NCI Early Detection Research Network(5U01 CA84971-10) and Department of Defense (CDMRP W81XWH-10-1-0634).Author details1British Columbia Cancer Agency Research Centre, Vancouver, Canada.2Department of Medical Genetics, University of British Columbia, Vancouver,Canada. 3Department of Pathology and Laboratory Medicine, University ofBritish Columbia, Vancouver, Canada.Authors’ contributionsEAG wrote the first draft of the article, CJB and WLL finalized the manuscript.All authors read and approved the final manuscript.Authors’ informationEAG is a research fellow at the BC Cancer Agency Research Centre,specializing in non-coding RNA gene structure and function. CJB is aprofessor of Medical Genetics at the University of British Columbia. Herresearch focuses on human X chromosome inactivation, in particular therole of XIST, a gene she first described during postdoctoral studies in theWillard lab. WLL is a professor of Pathology and Laboratory Medicine at theUniversity of British Columbia. His team invented tiling path arraytechnologies for whole genome and methylome analyses.Competing interestsThe authors declare that they have no competing interests.Received: 13 January 2011 Accepted: 13 April 2011Published: 13 April 2011References1. Stein LD: Human genome: end of the beginning. Nature 2004,431(7011):915-916.2. Ponting CP, Belgard TG: Transcribed dark matter: meaning or myth? HumMol Genet 2010, 19(R2):R162-168.3. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR,Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, et al:Identification and analysis of functional elements in 1% of the humangenome by the ENCODE pilot project. Nature 2007, 447(7146):799-816.4. 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