Long Noncoding RNAs and Tumorigenesis

Abstract

In contrast to the long time, well‐established knowledge about the majority of human genome to be only ‘junk DNA’, it turned out that a great part of it is being pervasively transcribed. Among noncoding transcripts, long noncoding RNAs (lncRNAs) represent the most prevalent and functionally heterogeneous group of noncoding RNAs (ncRNAs). Despite only a few lncRNAs being well characterised, their biological meaning, mechanisms of function and their importance for normal development is being more and more recognised. Many studies in recent years have shown that the changes in lncRNAs expression and function are associated with some fundamental biological processes and various disease states, most notably cancer. In cancer, the function of lncRNAs shows through altered expression patterns in different tumour types and as such they represent potential diagnostic/prognostic biomarkers and new potential targets for cancer treatment.

Key Concepts

  • lncRNAs are important components of numerous biological pathways of cellular growth, cell division and differentiation.
  • lncRNAs directly or indirectly regulate the expression of protein‐coding genes on epigenetic, transcriptional and post‐transcriptional level.
  • Aberrant lncRNA expression leads to cell dysfunction and disease progression.
  • lncRNAs are potential drivers of various diseases, most notably of cancer.
  • They represent useful diagnostic biomarkers and indicators of patient's prognosis.
  • lncRNAs represent ideal candidates for targeted gene therapy.

Keywords: long noncoding RNA; regulatory RNAs; tumorigenesis; oncogenic lncRNAs; tumour suppressor lncRNAs; cancer; biomarkers; therapeutical targets

Figure 1. (a–e) Possible origins of lncRNAs.
Figure 2. lncRNA classification according to their proximity to protein‐coding genes.
Figure 3. LncRNAs and the hallmarks of cancer (adapted upon (Gutschner and Diederichs, )).
Figure 4. LncRNAs act as oncogenes and/or tumour‐suppressors.
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References

Derrien T, Johnson R, Bussotti G, et al. (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Research 22 (9): 1775–1789. DOI: 10.1101/gr.132159.111.

Dimitrova N, Zamudio JR, Jong RM, et al. (2014) LincRNA‐p21 activates p21 in cis to promote Polycomb target gene expression and to enforce the G1/S checkpoint. Molecular Cell 54 (5): 777–790. DOI: 10.1016/j.molcel.2014.04.025.

Esteller M (2011) Non‐coding RNAs in human disease. Nature Reviews Genetics 12 (12): 861–874. DOI: 10.1038/nrg3074.

Fenoglio C, Ridolfi E, Galimberti D and Scarpini E (2013) An emerging role for long non‐coding RNA dysregulation in neurological disorders. International Journal of Molecular Sciences 14 (10): 20427–20442. DOI: 10.3390/ijms141020427.

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

Gupta RA, Shah N, Wang KC, et al. (2010) Long non‐coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464 (7291): 1071–1076. DOI: 10.1038/nature08975.

Gutschner T and Diederichs S (2012) The hallmarks of cancer: a long non‐coding RNA point of view. RNA Biology 9 (6): 703–719. DOI: 10.4161/rna.20481.

Gutschner T, Hammerle M, Eissmann M, et al. (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Research 73 (3): 1180–1189. DOI: 10.1158/0008-5472.can-12-2850.

Guttman M, Amit I, Garber M, et al. (2009) Chromatin signature reveals over a thousand highly conserved large non‐coding RNAs in mammals. Nature 458 (7235): 223–227. DOI: 10.1038/nature07672.

Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100 (1): 57–70.

Hassler MR and Egger G (2012) Epigenomics of cancer – emerging new concepts. Biochimie 94 (11): 2219–2230. DOI: 10.1016/j.biochi.2012.05.007.

Hauptman N and Glavac D (2013) Long non‐coding RNA in cancer. International Journal of Molecular Sciences 14 (3): 4655–4669. DOI: 10.3390/ijms14034655.

Huarte M, Guttman M, Feldser D, et al. (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142 (3): 409–419. DOI: 10.1016/j.cell.2010.06.040.

Huarte M and Rinn JL (2010) Large non‐coding RNAs: missing links in cancer? Human Molecular Genetics 19 (R2): R152–R161. DOI: 10.1093/hmg/ddq353.

Hube F, Guo J, Chooniedass‐Kothari S, et al. (2006) Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines. DNA and Cell Biology 25 (7): 418–428. DOI: 10.1089/dna.2006.25.418.

Kaikkonen MU, Lam MT and Glass CK (2011) Non‐coding RNAs as regulators of gene expression and epigenetics. Cardiovascular Research 90 (3): 430–440. DOI: 10.1093/cvr/cvr097.

Karapetyan AR, Buiting C, Kuiper RA and Coolen MW (2013) Regulatory Roles for Long ncRNA and mRNA. Cancers (Basel) 5 (2): 462–490. DOI: 10.3390/cancers5020462.

Katayama S, Tomaru Y, Kasukawa T, et al. (2005) Antisense transcription in the mammalian transcriptome. Science 309 (5740): 1564–1566. DOI: 10.1126/science.1112009.

Kent OA and Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25 (46): 6188–6196. DOI: 10.1038/sj.onc.1209913.

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

Kogo R, Shimamura T, Mimori K, et al. (2011) Long noncoding RNA HOTAIR regulates polycomb‐dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Research 71 (20): 6320–6326. DOI: 10.1158/0008-5472.can-11-1021.

Leygue E, Dotzlaw H, Watson PH and Murphy LC (1999) Expression of the steroid receptor RNA activator in human breast tumors. Cancer Research 59 (17): 4190–4193.

Li H, Yu B, Li J, et al. (2014) Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 5 (8): 2318–2329.

Li X, Wu Z, Fu X and Han W (2013) Long noncoding RNAs: insights from biological features and functions to diseases. Medicinal Research Reviews 33 (3): 517–553. DOI: 10.1002/med.21254.

Lv XB, Lian GY, Wang HR, et al. (2013) Long noncoding RNA HOTAIR is a prognostic marker for esophageal squamous cell carcinoma progression and survival. PLoS One 8 (5): e63516. DOI: 10.1371/journal.pone.0063516.

Ma L, Bajic VB and Zhang Z (2013) On the classification of long non‐coding RNAs. RNA Biology 10 (6): 925–933. DOI: 10.4161/rna.24604.

Matouk IJ, DeGroot N, Mezan S, et al. (2007) The H19 non‐coding RNA is essential for human tumor growth. PLoS One 2 (9): e845. DOI: 10.1371/journal.pone.0000845.

Mercer TR, Dinger ME and Mattick JS (2009) Long non‐coding RNAs: insights into functions. Nature Reviews Genetics 10 (3): 155–159. DOI: 10.1038/nrg2521.

Mercer TR and Mattick JS (2013) Structure and function of long noncoding RNAs in epigenetic regulation. Nature Structural and Molecular Biology 20 (3): 300–307. DOI: 10.1038/nsmb.2480.

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

Nagano T, Mitchell JA, Sanz LA, et al. (2008) The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322 (5908): 1717–1720. DOI: 10.1126/science.1163802.

Niinuma T, Suzuki H, Nojima M, et al. (2012) Upregulation of miR‐196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Research 72 (5): 1126–1136. DOI: 10.1158/0008-5472.can-11-1803.

Park JY, Lee JE, Park JB, et al. (2014) Roles of Long Non‐Coding RNAs on Tumorigenesis and Glioma Development. Brain Tumor Resewarch and Treatment 2 (1): 1–6. DOI: 10.14791/btrt.2014.2.1.1.

Poliseno L, Salmena L, Zhang J, et al. (2010) A coding‐independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465 (7301): 1033–1038. DOI: 10.1038/nature09144.

Ponting CP and Belgard TG (2010) Transcribed dark matter: meaning or myth? Human Molecular Genetics 19 (R2): R162–R168. DOI: 10.1093/hmg/ddq362.

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

Qureshi IA, Mattick JS and Mehler MF (2010) Long non‐coding RNAs in nervous system function and disease. Brain Research 1338: 20–35. DOI: 10.1016/j.brainres.2010.03.110.

Qureshi IA and Mehler MF (2012) Emerging roles of non‐coding RNAs in brain evolution, development, plasticity and disease. Nature Reviews Neuroscience 13 (8): 528–541. DOI: 10.1038/nrn3234.

Reis EM and Verjovski‐Almeida S (2012) Perspectives of long non‐coding RNAs in cancer diagnostics. Frontiers in Genetics 3: 32. DOI: 10.3389/fgene.2012.00032.

Rinn JL and Chang HY (2012) Genome regulation by long noncoding RNAs. Annual Review of Biochemistry 81: 145–166. DOI: 10.1146/annurev-biochem-051410-092902.

Rinn JL, Kertesz M, Wang JK, et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129 (7): 1311–1323. DOI: 10.1016/j.cell.2007.05.022.

Serviss JT, Johnsson P and Grander D (2014) An emerging role for long non‐coding RNAs in cancer metastasis. Frontiers in Genetics 5: 234. DOI: 10.3389/fgene.2014.00234.

Shi X, Sun M, Liu H, Yao Y and Song Y (2013) Long non‐coding RNAs: a new frontier in the study of human diseases. Cancer Letters 339 (2): 159–166. DOI: 10.1016/j.canlet.2013.06.013.

Song X, Wang X, Arai S and Kurokawa R (2012) Promoter‐associated noncoding RNA from the CCND1 promoter. Methods in Molecular Biology 809: 609–622. DOI: 10.1007/978-1-61779-376-9_39.

Sun M, Jin FY, Xia R, et al. (2014) Decreased expression of long noncoding RNA GAS5 indicates a poor prognosis and promotes cell proliferation in gastric cancer. BMC Cancer 14: 319. DOI: 10.1186/1471-2407-14-319.

Weakley SM, Wang H, Yao Q and Chen C (2011) Expression and function of a large non‐coding RNA gene XIST in human cancer. World Journal of Surgery 35 (8): 1751–1756. DOI: 10.1007/s00268-010-0951-0.

Wu P, Zuo X, Deng H, et al. (2013) Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Research Bulletin 97: 69–80. DOI: 10.1016/j.brainresbull.2013.06.001.

Yang G, Lu X and Yuan L (2014) LncRNA: A link between RNA and cancer. Biochimica et Biophysica Acta. DOI: 10.1016/j.bbagrm.2014.08.012.

Zhang X, Rice K, Wang Y, et al. (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151 (3): 939–947. DOI: 10.1210/en.2009-0657.

Zhou Y, Zhang X and Klibanski A (2012) MEG3 noncoding RNA: a tumor suppressor. Journal of Molecular Endocrinology 48 (3): R45–R53. DOI: 10.1530/jme-12-0008.

Further Reading

Boštjančič E and Glavač D (2013) MicroRNAs and lncRNAs as tumour suppressors. In: Cheng Y, (ed). Future aspects of tumour suppressor gene, InTech, pp. 45–74.

Cheetham SW, Gruhl F, Mattick JS and Dinger ME (2013) Long noncoding RNAs and the genetics of cancer. British Journal of Cancer 108: 2419–2425.

Kung JTY, Colognori D and Lee JT (2013) Long noncoding RNAs: past, present, and future. Genetics 193 (3): 651–669.

Li CH and Chen Y (2013) Targeting long non‐coding RNAs in cancers: progress and prospects. International Journal of Biochemistry & Cell Biology 45: 1895–1910.

Mattick JS, Amaral PP, Dinger ME, Mercer TR and Mehler MF (2009) RNA regulation of epigenetic processes. Bioessays 31: 51–59.

Nie L, Wu H‐J, Hsu J‐M, et al. (2012) Long non‐coding RNAs: versatile master regulators of gene expression and crucial players in cancer. American Journal of Translational Research 4 (2): 127–150.

Prensner JR and Chinnaiyan AM (2011) The emergence of lncRNAs in cancer biology. Cancer Discovery 1: 391–407.

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Matjašič, Alenka, and Glavač, Damjan(Feb 2015) Long Noncoding RNAs and Tumorigenesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025688]