Skip to main content

Long non-coding RNA: a new player in cancer

Abstract

Emerging evidence showed that long non-coding RNAs (lncRNAs) play important roles in a wide range of biological processes and dysregulated lncRNAs are involved in many complex human diseases, including cancer. Although a few lncRNAs’ functions in cancer have been characterized, the detailed regulatory mechanisms of majority of lncRNAs in cancer initiation and progression remain largely unknown. In this review, we summarized recent progress on the mechanisms and functions of lncRNAs in cancer, especially focusing on the oncogenic and tumor suppressive roles of the newly identified lncRNAs, and the pathways these novel molecules might be involved in. Their potentials as biomarkers for diagnosis and prognosis in cancer are also discussed in this paper.

Introduction

Genome-wide transcriptome studies have revealed that there exist a large number of non-coding RNAs (ncRNAs), including short and long non-coding RNAs [1, 2]. Short ncRNAs have a length of under 200 nucleotides (nt) and include small interfering RNAs (siRNAs, 21-25 nt), piwi-associated RNAs (piRNAs, 24-33 nt) and well-documented microRNAs (miRNAs, 21-25 nt), while long ncRNAs (lncRNAs) are greater than 200 nt in length, frequently ranging up to 100 kb [3]. It has been known that lncRNAs, mRNA-like transcripts, are mainly transcribed by RNA polymerase II (RNA PII) and are polyadenylated, spliced, and mostly localized in the nucleus [35].

Recent studies estimated that the number of lncRNAs in humans is approximately 15,000 and found that most lncRNAs displayed tissue-specific expression patterns [6]. Based on their locations and characteristics, lncRNAs can be categorized into five subgroups: (1) sense, (2) antisense, (3) bidirectional, (4) intronic, and (5) intergenic [5]. Increasing studies have indicated that lncRNAs play important roles in a wide range of biological processes including stress response [7], development [8], embryonic stem cell pluripotency [9], localization [10], alternative splicing [11], chromatin remodeling [12] and mRNA decay [13]. Furthermore, lncRNAs can affect many cellular processes, such as cell cycle [14], survival [15], migration [16] and metabolism [17].

Because lncRNAs, like miRNAs, function as key regulators in gene regulation, it is not surprising that dysregulated lncRNAs are involved in many complicated human diseases including cancer. Mounting evidence showed that many lncRNAs, similar to miRNAs, have altered expression in various types of human cancer and dysregulated lncRNAs function as tumor suppressors or oncogenes [18, 19]. Undoubtedly, lncRNAs have become new players in cancer after miRNAs although the detailed mechanisms of most lncRNAs remain largely unknown. In this review, we overviewed the roles of lncRNAs in tumorigenesis, focusing on the currently known mechanisms and functions of lncRNAs, and their potentials as biomarkers and targets for novel therapeutic approaches in the future.

Regulatory mechanisms of lncRNAs

It has been known that ncRNAs function as a new class of regulators involved in a complicated molecular network, controlling gene expression and cellular activity. Among them, well-documented miRNAs were known to regulate gene expression at either the transcriptional or the post-transcriptional level usually by base-pairing to the 3′-untranslated region (3′ UTR) of target mRNAs with the miRNA 5′-proximal “seed” region (positions 2-8) in animals [20]. However, compared with miRNA, the regulatory mechanisms of lncRNA are more challenging to characterize, since these molecules are neither as conserved nor as abundantly expressed as miRNAs [21]. Recent studies have shown that lncRNAs regulate gene expression by diverse mechanisms.

Guiding role of lncRNAs in cis and in trans

Evidence showed that lncRNAs can bind and ‘guide’ chromatin modifying complexes to specific genomic sites to induce epigenetic changes and regulate gene expression in cis (on neighboring genes of the same chromosome) or in trans (on distantly located genes of the same or different chromosome) [22]. Several early discovered cis-regulatory lncRNAs were well-studied. For example, XIST represses genes on X chromosome by the recruitment of PRC2 (polycomb repressive complex 2) [23]; AIR and KCNQ1OT1 silence transcription of their target genes by recruiting G9a [24, 25]; HOTTIP recruits the MLL histone H3 lysine 4 (H3K4) methyltransferase complex to maintain active chromatin [26]. LncRNAs can also regulate gene expression by guiding site-specific recruitment of chromatin modifying complexes in trans. It has been shown the lncRNA HOTAIR mediates the epigenetic repression by increasing PRC2 and LSD1 recruitment to the genomic positions of target genes [16]. In addition, PCAT-1, JPX and lincRNA-p21 function by trans-regulation of genes [2729]. Interestingly, the lncRNA asOct4-ps5, an antisense to a pseudogene of Oct4, could regulate Oct4 by guiding the histone methyltransferase Ezh2 to the Oct4 promoter in trans[30].

Serving as scaffolds

Another regulation mechanism of lncRNAs is to serve as scaffolds. Studies demonstrated that lncRNA KCNQ1OT1 could bind both G9a and PRC2, and lncRNA HOTAIR could interact with PRC2 and LSD1, revealing these lncRNAs can serve as scaffolds for chromatin-modifying complexes besides their guide role [25, 26]. Similarly, lncRNA ANRIL and NEAT1 were also found acting as scaffolds [3133]. In addition, it was found that approximately 38% of large intergenic non-coding RNAs (lncRNAs) expressed in the cell types studied are reproducibly associated with chromatin-modifying complexes (PRC2, CoREST and SMCX) by RNA coimmunoprecipitation (RIP) with antibodies directed against several proteins involved in these complexes [34]. Thus, these studies implied that lincRNAs bind to chromatin modifying complexes first to serve as scaffolds, and then guide the complexes to specific genomic regions.

Transcriptional regulation

LncRNAs regulate gene expression at transcriptional level via multiple mechanisms. It was reported that by competing for binding sites, the lncRNA GAS5 (growth arrest specific 5) interacts directly with the DNA binding domain of glucocorticoid receptors (GR), preventing them from binding to their DNA response elements, thus functions in transcription inhibition as a molecular decoy [17]. In addition, recent studies revealed that novel classes of promoter-associated lncRNAs, the promoter upstream transcripts (PROMPTs) and enhancer-associated lncRNAs (eRNAs), are positively correlated with the level of messenger RNA synthesis and regulate the transcription activity of host protein-coding genes (PCGs) [35, 36].

Alternative splicing and translational regulation

The well-known example of mRNA splicing mediated by lncRNAs is that lncRNA MALAT1 interacts with the serine/arginine-rich splicing regulatory (SR) proteins involved in alternative splicing, suggesting that the lncRNA MALAT1 may serve a function in the regulation of alternate splicing [11]. Another example of translational regulation for lncRNAs is that lncRNA BACE1-AS can interact with the β-site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) transcript and increase BACE1 mRNA stability, thus generate more gene product [37]. Notably, some pseudogenes have been found to regulate translation. For example, lncRNA pseudo-NOS, a pseudogene of nitric oxide synthase (NOS), can bind and repress translation of nNOS (neuronal nitric oxide synthase) gene through influencing the association of the ribosome with the nNOS–pseudo-NOS duplex [38]. Another representative mechanism is that some lncRNAs including pseudogenes, such as lncRNA PTENP1, a pseudogene of PTEN, serve as ‘sponges’ to prevent specific miRNAs from binding to their target mRNAs by competitively binding to miRNAs [39, 40].

Dysregulated lncRNAs in cancer

Transcriptional profiling has revealed highly aberrant lncRNA expression in human cancers [41]. Though the function of most lncRNAs remains unknown, accumulating evidence showed that differentially expressed lncRNAs are associated with cancer pathogenesis and function as new regulators in cancer development. These dysregulated lncRNAs in cancer are listed in Table 1. In this section, we mainly discussed their potentials as biomarkers, and their functions as oncogenes and tumor suppressors, as well as the molecular pathways they might be involved in.

Table 1 Examples of dysregulated lncRNAs in cancer

Serving as biomarkers for diagnosis and prognosis

Seeking novel molecular biomarkers of malignancy is always important and helpful for clinical diagnosis and management. Like proteins, mRNAs and miRNAs, lncRNAs show their potentials as novel independent biomarkers for early diagnosis and prognosis prediction in cancer.

It has been found that lncRNA HOTAIR is highly upregulated in breast cancer, hepatocellular carcinoma (HCC), colorectal cancer and gastrointestinal stromal tumors (GIST). Furthermore high HOTAIR gene expression is correlated with metastasis in these four types of cancers, poor survival rate in breast cancer, increasing risk of recurrence after hepatectomy in HCC and high-risk grade in GIST, indicating HOTAIR may be a useful biomarker of poor prognosis and tumor metastasis in these cancers [16, 4447]. In HCC, another lncRNA MVIH was found overexpressed and significantly associated with frequent microvascular invasion, higher tumor node metastasis stage, decreased recurrence-free survival (RFS) and overall survival, revealing that the upregulation of MVIH can serve as an independent risk factor to predict poor RFS [42]. More recently, it was reported that lncRNA H19 is underexpressed in intratumoral HCC tissues (T), as compared with peritumoral tissues (L), and low T/L ratio of H19 is associated with shorter disease-free survival and can be used to predict poor prognosis [53]. Studies also showed that lncRNA MALAT1 is upregulated and serves as an independent prognostic parameter for patient survival in early stage non-small-cell lung cancer [49, 50]. LncRNA MALAT1 can also be used for predicting HCC recurrence after liver transplantation in HCC [51]. In prostate cancer, highly expressed lncRNA DD3 (PCA3) demonstrated better diagnostic efficiency than another promising biomarker telomerase reverse transcriptase (hTERT gene) for prostate cancer, and could be easily detected in prostate needle biopsies or bodily fluids such as blood, ejaculate, urine, or prostate massage fluid, thus lncRNA DD3 is a very sensitive and specific biomarker for the detection of prostate tumor cell [43].

Genome-wide association studies (GWAS) have revealed a large number of genetic variants related to diseases, including cancer. Recently, genetic variations in lncRNAs and their associations with cancer susceptibility have been reported, suggesting single nucleotide polymorphisms (SNPs) may also serve as biomarkers for diagnosis and prognosis. Studies showed that SNP rs2151280 in lncRNA ANRIL was significantly associated with higher number of plexiform neurofibromas (PNFs) in neurofibromatosis type 1 (NF1) patients, which suggests SNP rs2151280 in lncRNA ANRIL is a potential biomarker for PNF susceptibility [69]. Interestingly, it was found that the variant genotype of rs7763881 in lncRNA HULC is significantly associated with decreased risk to HCC in hepatitis B virus (HBV) persistent carriers, while variant rs10680577 within lncRNA RERT is a promising biomarker for early diagnosis of HCC [70, 71]. Another recent study found that two genetic variations (rs6434568 and rs16834898) in lncRNA PCGEM1 might increase prostate cancer (PCa) risk [72].

Oncogenic and tumor suppressive lncRNAs

Like protein-coding genes and miRNAs, lncRNAs can function as oncogenes or tumor suppressors during cancer progression. A further investigation of the roles and mechanisms of lncRNAs in cancer will provide novel lncRNA-based strategies for the treatment of human cancers. Some well-studied lncRNAs, such as HOTAIR [16, 48], MALAT1 [52], PCAT-1 [27], PCGEM1 [55], TUC338 [56], were reported as oncogenes, while GAS5 [63], linc-p21 [29], MEG3 [64] and PTENP1 [40] were reported as tumor suppressors. Here, we mainly focus on recently studied lncRNAs.

The newly identified lncRNA BANCR was found overexpressed in melanoma and required for full migratory capacity of melanoma cells by upregulating CXCL11, an important gene involved in cell migration, revealing the potential functional role of lncRNA BANCR [57]. Another novel lncRNA YIYA is upregulated in different cancers and promotes cell cycle progression at the G1/S transition, demonstrating it is a carcinogenesis-associated lncRNA [58]. A recent study found that lncRNA CRNDE is highly elevated in many solid tumors and in acute myeloid leukemias (AML), especially in M2 AML and M3 AML, and lncRNA CRNDE can promote cell growth and suppress apoptosis, which supports a role for CRNDE as a mediator of oncogenesis [59]. More recently, it was reported that lncRNA CCAT1, activated by c-Myc, is markedly increased in gastric carcinoma and promote cell proliferation and migration, implicating CCAT1 as a potential therapeutic target [60]. Studies also showed that induction of lncRNA HULC by Hepatitis B virus X protein (HBx) promotes proliferation of hepatoma cells through downregulating tumor suppressor gene p18 in vitro and in vivo[61]. In addition, it was found that lncRNA CUDR, a variant transcript of lncRNA UCA1, is upregulated in various human tumors and can significantly enhance proliferation, migration and invasion of the bladder cancer cell in vitro and in vivo, indicating lncRNA CUDR functions as an oncogene and may serve as a novel therapeutic target for bladder cancer [62]. Compared with these oncogenic lncRNAs, some lncRNAs showed a tumor suppressive role. The lncRNA MEG3 (maternally expressed gene 3), which is associated with meningioma pathogenesis and progression [64], was recently found markedly decreased in glioma tissues and ectopic expression of lncRNA MEG3 inhibited cell proliferation and promoted cell apoptosis via p53 activation in human glioma [65]. Very interestingly, a study reported that lncRNA PTCSC3 (Papillary Thyroid Carcinoma Susceptibility Candidate 3), located 3.2 kb downstream of SNP rs944289 at 14q.13.3, is strongly downregulated in papillary thyroid carcinoma (PTC). The overexpression of lncRNA PTCSC3 could inhibit PTC cell growth and affected the expression of genes involved in DNA replication, recombination and repair, cellular movement, tumor morphology, and cell death, implying that lncRNA PTCSC3 has the characteristics of a tumor suppressor [68]. Further study revealed that SNP rs944289 abolishes the binding site of both C/EBPα and C/EBPβ, which bind and activate the PTCSC3 promoter, thus, SNP rs944289 predisposes to PTC through downregulating tumor suppressive lncRNA PTCSC3 [68].

Pathways involving lncRNAs in cancer

Differentially expressed lncRNAs between cancer and normal tissues indicate these lncRNAs may exert a key role in cancer development. Understanding the pathways lncRNAs involved in helps to provide further insights into the pathogenesis of cancer. In HCC, PKA-mediated phosphorylation of CREB leads to formation of the CREB-p300-Brg I complex, loading of the CREB-p300-Brg I complex onto the lncRNA HULC promoter, and consequent activation of HULC expression [73]. In addition, lncRNA HULC can be activated by HBx via CREB protein and promotes proliferation of hepatoma cells through suppressing p18, an activator of p53 through its interaction with ataxia telangiectasia-mutated (ATM) in response to DNA damage [61, 74]. These results suggest that lncRNA HULC also is involved in the ATM/P53 pathway in HCC. In bladder cancer, lncRNA UCA1 upregulates CREB activity through enhancing AKT activity, while blocking PI3-K pathway by PI3 Kinase inhibitor can downregulate lncRNA UCA1 expression and reduce cell cycle progression. These findings indicate lncRNA UCA1 promotes cell proliferation and regulates cell cycle progression through CREB via PI3-K/AKT dependent signaling pathway [75]. Another lncRNA CUDR may promote tumorigenesis through upregulating PDGFB in tumorigenesis pathway and downregulating FAS and ATM in cell apoptosis pathway in bladder cancer [62]. In addition, lncRNA profile and mRNA profile revealed significant changes in PPAR pathway in glioblastoma group compared with the normal group by target gene-related pathway analysis, such as ASLNC22381 and ASLNC2081 were found to play roles in glioma signaling pathways [76]. Moreover, the relative abundance of a collection of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) was investigated, then intronic lncRNAs differentially expressed in PDAC metastases were enriched in genes associated to the MAPK pathway [77].

Conclusions and perspectives

Recent studies revealed lncRNAs, like miRNAs, function as important regulators in gene regulatory networks and exert crucial roles in cancer progression. LncRNAs have become new and important players and demonstrated potential applications in clinical diagnosis and treatment. Although a few lncRNAs’ functions have been reported, there are still many challenges that remain to be solved. In the future, it would be necessary to further investigate the functional motifs and secondary or tertiary structure of lncRNAs, to fully elucidate the diverse gene regulatory mechanisms of lncRNAs, and to develop new and effective methods to predict target genes of lncRNAs using bioinformatics, etc. These endeavors will provide new insights into the complicated gene regulatory network involving lncRNAs, and ultimately provide novel strategies for cancer diagnosis and therapy.

References

  1. 1.

    Davidson EH, Britten RJ: Regulation of gene expression: possible role of repetitive sequences. Science. 1979, 204 (4397): 1052-1059. 10.1126/science.451548.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007, 447 (7146): 799-816. 10.1038/nature05874.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Mercer TR, Dinger ME, Mattick JS: Long non-coding RNAs: insights into functions. Nat Rev Genet. 2009, 10 (3): 155-159. 10.1038/nrg2521.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Wu Q, Kim YC, Lu J, Xuan Z, Chen J, Zheng Y, Zhou T, Zhang MQ, Wu CI, Wang SM: Poly A-transcripts expressed in HeLa cells. PLoS One. 2008, 3 (7): e2803-10.1371/journal.pone.0002803.

    PubMed Central  Article  PubMed  Google Scholar 

  5. 5.

    Ponting CP, Oliver PL, Reik W: Evolution and functions of long noncoding RNAs. Cell. 2009, 136 (4): 629-641. 10.1016/j.cell.2009.02.006.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG: The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012, 22 (9): 1775-1789. 10.1101/gr.132159.111.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Mizutani R, Wakamatsu A, Tanaka N, Yoshida H, Tochigi N, Suzuki Y, Oonishi T, Tani H, Tano K, Ijiri K: Identification and characterization of novel genotoxic stress-inducible nuclear long noncoding RNAs in mammalian cells. PLoS One. 2012, 7 (4): e34949-10.1371/journal.pone.0034949.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S: Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell. 2013, 152 (3): 570-583. 10.1016/j.cell.2013.01.003.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Dinger ME, Amaral PP, Mercer TR, Pang KC, Bruce SJ, Gardiner BB, Askarian-Amiri ME, Ru K, Soldà G, Simons C: Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation. Genome Res. 2008, 18 (9): 1433-1445. 10.1101/gr.078378.108.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  10. 10.

    Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, Schultz PG: A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science. 2005, 309 (5740): 1570-1573. 10.1126/science.1115901.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA: The nuclearretained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell. 2010, 39 (6): 925-938. 10.1016/j.molcel.2010.08.011.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  12. 12.

    Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, Gabellini D: A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 2012, 149 (4): 819-831. 10.1016/j.cell.2012.03.035.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  13. 13.

    Gong C, Maquat LE: lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature. 2011, 470 (7333): 284-288. 10.1038/nature09701.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  14. 14.

    Meola N, Pizzo M, Alfano G, Surace EM, Banfi S: The long noncoding RNA Vax2os1 controls the cell cycle progression of photoreceptor progenitors in the mouse retina. RNA. 2012, 18 (1): 111-123. 10.1261/rna.029454.111.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  15. 15.

    Hung T, Wang Y, Lin MF, Koegel AK, Kotake Y, Grant GD, Horlings HM, Shah N, Umbricht C, Wang P: Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nat Genet. 2011, 43 (7): 621-629. 10.1038/ng.848.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  16. 16.

    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010, 464 (7291): 1071-1076. 10.1038/nature08975.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP: Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal. 2010, 3 (107): ra8-10.1126/scisignal.2000568.

    PubMed Central  PubMed  Google Scholar 

  18. 18.

    Prensner JR, Chinnaiyan AM: The emergence of lncRNAs in cancer biology. Cancer Discov. 2011, 1 (5): 391-407. 10.1158/2159-8290.CD-11-0209.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  19. 19.

    Qi P, Du X: The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Mod Pathol. 2013, 26 (2): 155-165. 10.1038/modpathol.2012.160.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004, 116 (2): 281-297. 10.1016/S0092-8674(04)00045-5.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Pang KC, Frith MC, Mattick JS: Rapid evolution of noncoding RNAs: lack of conservation does not mean lack of function. Trends Genet. 2006, 22 (1): 1-5. 10.1016/j.tig.2005.10.003.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Koziol MJ, Rinn JL: RNA traffic control of chromatin complexes. Curr Opin Genet Dev. 2010, 20 (2): 142-148. 10.1016/j.gde.2010.03.003.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  23. 23.

    Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT: Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008, 322 (5902): 750-756. 10.1126/science.1163045.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  24. 24.

    Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R, Fraser P: The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008, 322 (5908): 1717-1720. 10.1126/science.1163802.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C: Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level control. Mol Cell. 2008, 32 (2): 232-246. 10.1016/j.molcel.2008.08.022.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, Lajoie BR, Protacio A, Flynn RA, Gupta RA: A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011, 472 (7341): 120-124. 10.1038/nature09819.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  27. 27.

    Prensner JR, Iyer MK, Balbin OA, Dhanasekaran SM, Cao Q, Brenner JC, Laxman B, Asangani IA, Grasso CS, Kominsky HD: Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression. Nat Biotechnol. 2011, 29 (8): 742-749. 10.1038/nbt.1914.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  28. 28.

    Tian D, Sun S, Lee JT: The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell. 2010, 143 (3): 390-403. 10.1016/j.cell.2010.09.049.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  29. 29.

    Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M: A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 2010, 142 (3): 409-419. 10.1016/j.cell.2010.06.040.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  30. 30.

    Hawkins PG, Morris KV: Transcriptional regulation of Oct4 by a long non-coding RNA antisense to Oct4-pseudogene 5. Transcription. 2010, 1 (3): 165-175. 10.4161/trns.1.3.13332.

    PubMed Central  Article  PubMed  Google Scholar 

  31. 31.

    Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM: Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010, 38 (5): 662-674. 10.1016/j.molcel.2010.03.021.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  32. 32.

    Kotake Y, Nakagawa T, Kitagawa K, Suzuki S, Liu N, Kitagawa M, Xiong Y: Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15 (INK4B) tumor suppressor gene. Oncogene. 2011, 30 (16): 1956-1962. 10.1038/onc.2010.568.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  33. 33.

    Clemson CM, Hutchinson JN, Sara SA, Ensminger AW, Fox AH, Chess A, Lawrence JB: An architectural role for a nuclear noncoding RNA: NEAT1 RNA is essential for the structure of paraspeckles. Mol Cell. 2009, 33 (6): 717-726. 10.1016/j.molcel.2009.01.026.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  34. 34.

    Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, 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 (28): 11667-11672. 10.1073/pnas.0904715106.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  35. 35.

    Preker P, Nielsen J, Kammler S, Lykke-Andersen S, Christensen MS, Mapendano CK, Schierup MH, Jensen TH: RNA exosome depletion reveals transcription upstream of active human promoters. Science. 2008, 322 (5909): 1851-1854. 10.1126/science.1164096.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Kim TK, Hemberg M, Gray JM, Costa AM, Bear DM, Wu J, Harmin DA, Laptewicz M, Barbara-Haley K, Kuersten S: Widespread transcription at neuronal activity-regulated enhancers. Nature. 2010, 465 (7295): 182-187. 10.1038/nature09033.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  37. 37.

    Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G, Kenny PJ, Wahlestedt C: Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008, 14 (7): 723-730. 10.1038/nm1784.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  38. 38.

    Korneev SA, Park JH, O’Shea M: Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene. J Neurosci. 1999, 19 (18): 7711-7720.

    CAS  PubMed  Google Scholar 

  39. 39.

    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 (2): 358-369. 10.1016/j.cell.2011.09.028.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010, 465 (7301): 1033-1038. 10.1038/nature09144.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  41. 41.

    Gibb EA, Vucic EA, Enfield KS, Stewart GL, Lonergan KM, Kennett JY, Becker-Santos DD, MacAulay CE, Lam S, Brown CJ: Human cancer long non-coding RNA transcriptomes. PLoS One. 2011, 6 (10): e25915-10.1371/journal.pone.0025915.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  42. 42.

    Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, Yang Y, Wang RY, Yang S, Huo XS: Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology. 2012, 56 (6): 2231-2241. 10.1002/hep.25895.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, Swinkels DW, Schalken JA: DD3 (PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002, 62 (9): 2695-2698.

    CAS  PubMed  Google Scholar 

  44. 44.

    Geng YJ, Xie SL, Li Q, Ma J, Wang GY: Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 2011, 39 (6): 2119-2128. 10.1177/147323001103900608.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Ishibashi M, Kogo R, Shibata K, Sawada G, Takahashi Y, Kurashige J, Akiyoshi S, Sasaki S, Iwaya T, Sudo T: Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma. Oncol Rep. 2013, 29 (3): 946-950.

    CAS  PubMed  Google Scholar 

  46. 46.

    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 (20): 6320-6326. 10.1158/0008-5472.CAN-11-1021.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, Yamamoto E, Maruyama R, Nobuoka T, Miyazaki Y: Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res. 2012, 72 (5): 1126-1136. 10.1158/0008-5472.CAN-11-1803.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Tsai MC, Manor O, Wan Y, Mosammaparast N, Wang JK, Lan F, Shi Y, Segal E, Chang HY: Long noncoding RNA as modular scaffold of histone modification complexes. Science. 2010, 329 (5992): 689-693. 10.1126/science.1192002.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  49. 49.

    Müller-Tidow C, Diederichs S, Thomas M, Serve H: Genome-wide screening for prognosis-predicting genes in early-stage non-small-cell lung cancer. Lung Cancer. 2004, 45 (Suppl 2): 145-150.

    Article  Google Scholar 

  50. 50.

    Schmidt LH, Spieker T, Koschmieder S, Schäffers S, Humberg J, Jungen D, Bulk E, Hascher A, Wittmer D, Marra A: The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011, 6 (12): 1984-1992. 10.1097/JTO.0b013e3182307eac.

    Article  PubMed  Google Scholar 

  51. 51.

    Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, Wu LM, Chen LM, Zheng SS: Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 2012, 29 (3): 1810-1816. 10.1007/s12032-011-0004-z.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Gutschner T, Hämmerle M, Diederichs S: MALAT1 - a paradigm for long noncoding RNA function in cancer. J Mol Med (Berl). 2013, 10.1007/s00109-013-1028-y.

    Google Scholar 

  53. 53.

    Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS, Xu D, Bi HS, Wang F, Sun SH: Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis. 2013, 34 (3): 577-586. 10.1093/carcin/bgs381.

    Article  PubMed  Google Scholar 

  54. 54.

    Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E: The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007, 2 (9): e845-10.1371/journal.pone.0000845.

    PubMed Central  Article  PubMed  Google Scholar 

  55. 55.

    Gibb EA, Brown CJ, Lam WL: The functional role of long non-coding RNA in human carcinomas. Mol Cancer. 2011, 10: 38-10.1186/1476-4598-10-38.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  56. 56.

    Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ, Terracciano L, Croce CM, Patel T: Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2011, 108 (2): 786-791. 10.1073/pnas.1011098108.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  57. 57.

    Flockhart RJ, Webster DE, Qu K, Mascarenhas N, Kovalski J, Kretz M, Khavari PA: BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration. Genome Res. 2012, 22 (6): 1006-1014. 10.1101/gr.140061.112.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  58. 58.

    Yang F, Yi F, Zheng Z, Ling Z, Ding J, Guo J, Mao W, Wang X, Wang X, Ding X: Characterization of a carcinogenesis-associated long non-coding RNA. RNA Biol. 2012, 9 (1): 110-116.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Ellis BC, Molloy PL, Graham LD: CRNDE: A Long Non-Coding RNA Involved in CanceR, Neurobiology, and DEvelopment. Front Genet. 2012, 3: 270-

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  60. 60.

    Yang F, Xue X, Bi J, Zheng L, Zhi K, Gu Y, Fang G: Long noncoding RNA CCAT1, which could be, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol. 2013, 139 (3): 437-445. 10.1007/s00432-012-1324-x.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, Zhang X: Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. Biol Chem. 2012, 287 (31): 26302-26311. 10.1074/jbc.M112.342113.

    CAS  Article  Google Scholar 

  62. 62.

    Wang Y, Chen W, Yang C, Wu W, Wu S, Qin X, Li X: Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer. Int J Oncol. 2012, 41 (1): 276-284.

    CAS  PubMed  Google Scholar 

  63. 63.

    Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT: GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009, 28 (2): 195-208. 10.1038/onc.2008.373.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, Cheunsuchon P, Louis DN, Klibanski A: Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 2010, 70 (6): 2350-2358. 10.1158/0008-5472.CAN-09-3885.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  65. 65.

    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 (6): 1868-1874. 10.1002/jcb.24055.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, Negrini M, Miotto E, Croce CM, Patel T: microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 2011, 30 (47): 4750-4756. 10.1038/onc.2011.193.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  67. 67.

    Benetatos L, Hatzimichael E, Dasoula A, Dranitsaris G, Tsiara S, Syrrou M, Georgiou I, Bourantas KL: CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leuk Res. 2010, 34 (2): 148-153. 10.1016/j.leukres.2009.06.019.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Jendrzejewski J, He H, Radomska HS, Li W, Tomsic J, Liyanarachchi S, Davuluri RV, Nagy R, de la Chapelle A: The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type. Proc Natl Acad Sci USA. 2012, 109 (22): 8646-8651. 10.1073/pnas.1205654109.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  69. 69.

    Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, Ferkal S, Hernandez L, Leroy K, Valeyrie-Allanore L: Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst. 2011, 103 (22): 1713-1722. 10.1093/jnci/djr416.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Liu Y, Pan S, Liu L, Zhai X, Liu J, Wen J, Zhang Y, Chen J, Shen H, Hu Z: A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population. PLoS One. 2012, 7 (4): e35145-10.1371/journal.pone.0035145.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  71. 71.

    Zhu Z, Gao X, He Y, Zhao H, Yu Q, Jiang D, Zhang P, Ma X, Huang H, Dong D: An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk. Cancer Res. 2012, 72 (23): 6163-6172. 10.1158/0008-5472.CAN-12-0010.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Xue Y, Wang M, Kang M, Wang Q, Wu B, Chu H, Zhong D, Qin C, Yin C, Zhang Z: Association between lncrna PCGEM1 polymorphisms and prostate cancer risk. Prostate Cancer Prostatic Dis. 2013, 10.1038/pcan.2013.6.

    Google Scholar 

  73. 73.

    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. Nucleic Acids Res. 2010, 38 (16): 5366-5383. 10.1093/nar/gkq285.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  74. 74.

    Park BJ, Kang JW, Lee SW, Choi SJ, Shin YK, Ahn YH, Choi YH, Choi D, Lee KS, Kim S: The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell. 2005, 120 (2): 209-221. 10.1016/j.cell.2004.11.054.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Yang C, Li X, Wang Y, Zhao L, Chen W: Long non-coding RNA UCA1 regulated cell cycle distribution via CREB through PI3-K dependent pathway in bladder carcinoma cells. Gene. 2012, 496 (1): 8-16. 10.1016/j.gene.2012.01.012.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    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 (6): 2004-2012.

    CAS  PubMed  Google Scholar 

  77. 77.

    Tahira AC, Kubrusly MS, Faria MF, Dazzani B, Fonseca RS, Maracaja-Coutinho V, Verjovski-Almeida S, Machado MC, Reis EM: Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer. Mol Cancer. 2011, 10: 141-10.1186/1476-4598-10-141.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Science and Technology Department (973, 2011CB8113015) and the funds from National Natural Science Foundation of China (81071638), as well as supported by Scientific Research Foundation for Returned Scholars of Guangdong Medical College, China (XB1377) and STIF 201108, JB1207, XB0006.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Zhiwei He or Yueqin Chen.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

All authors have contributed to write and revise the manuscripts. All authors have read and approved the final manuscript.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zhang, H., Chen, Z., Wang, X. et al. Long non-coding RNA: a new player in cancer. J Hematol Oncol 6, 37 (2013). https://doi.org/10.1186/1756-8722-6-37

Download citation

Keywords

  • Acute Myeloid Leukemia
  • Papillary Thyroid Carcinoma
  • Plexiform Neurofibroma
  • Papillary Thyroid Carcinoma Cell
  • lncRNA MALAT1