Long Noncoding RNAs and Cancer

Abstract

Long noncoding RNAs (lncRNAs), products of pervasive transcription of the human genome, have emerged as important epigenetic regulators of cancer development and progression. LncRNAs, with transcript size ranging from 200 bp to 100 Kb, perform a diverse array of biological roles including chromatin modification, pre‐ and post‐transcriptional regulation, control of cell division, cell‐cycle growth and proliferation and imprinting. They exhibit cell‐specific expression patterns as well as restricted subcellular distribution, and have shown to play a role in multiple cancers such as cancers of the breast, pancreas, liver, lung and colon. Owing to the role they play in cancer initiation and progression, they have emerged as a new class of prognostic indicators, markers of chemotherapy response and finally show promise as targeted therapy against cancer. This article explores the characteristics of lncRNAs, function and association with multiple cancers and highlights the recent progress made on these new molecules especially with respect to cancer.

Key Concepts:

  • Long noncoding RNAs are a new class of epigenetic regulatory molecules that are actively transcribed from the human genome.

  • Involved in multiple biological functions including imprinting, transcriptional and post‐transcriptional regulation of gene expression, cell growth, proliferation and differentiation.

  • Dysregulation of lncRNA observed in multiple cancer types, involved in cancer progression and metastasis.

  • LncRNAs can serve as biomarkers, prognostic indicators and predictors of chemotherapy response.

  • Attractive targets for a new group of targeted therapy.

Keywords: long noncoding RNAs; epigenetic regulation; chromatin remodelling; cancer initiation and progression; biomarkers; targeted therapy

Figure 1.

Generalised mechanisms and associated examples of lncRNAs involved in cancer progression. LncRNAs act through a variety of mechanisms such as remodelling of chromatin (a), transcriptional coactivation or transcriptional repression (b), protein inhibition (c), post‐transcriptional modifiers (d) or decoy elements (e). Consequently, misexpression of lncRNAs can lead to changed expression profiles of various target genes involved in different aspects of cell homoeostasis. Reprinted from Cheetham et al. (), with permission of Macmillan Publishers Ltd on behalf of Cancer Research UK. © Nature Publishing Group.

Figure 2.

Mechanisms of lncRNA‐targeting agents. (a) siRNAs are short‐stretched (19–30 nt) double‐stranded RNAs that target unpaired lncRNA molecules via sequence complementarity. (b) antisense oligonucleotides (ASOs) are single‐stranded DNAs or RNAs (between 8 and 50 nt) that target specific RNAs via sequence complementarity. The hybrids are recognised by endogenous RNAse H1 that cleaves the target lncRNA molecules. (c) Hammerhead ribozyme (HamRz) is a single‐stranded RNA in neutral condition and undergo folding in cells to expose the binding arms. The binding of HamRz to target sequence depends on complementary match with the homologous target site. Both arms of HamRz have to bind with target sites correctly in order to form functional catalytic motif. After binding, HamRz catalyses the cleavage of the flanked RNA region downstream via destabilising the phosphodiester backbone of target RNA. (d) Aptamers are short DNA or RNA oligonucleotides, or peptides that have a stable three‐dimensional structure in vivo. They specifically bind to their target lncRNAs that relies on fitting three‐dimensional shape of the lncRNA structures. Aptamers antagonise their lncRNA targets by blocking the interactions between lncRNAs and critical factors. (e) Small molecules are synthesised to specifically bind to the RNA‐binding pockets of lncRNAs. They compete with protein factors or intracellular small ligands for the binding of lncRNAs. The binding of small molecules may also induce conformational change within the lncRNA molecules and disrupt the formation of important lncRNA structures. Reprinted from Li and Chen (), with permission of Elsevier. © Elsevier.

close

References

Baldassarre A and Masotti A (2012) Long non‐coding RNAs and p53 regulation. International Journal of Molecular Science 13: 16708–16717.

Bourdoumis A, Papatsoris AG, Chrisofos M et al. (2010) The novel prostate cancer antigen 3 (PCA3) biomarker. International Brazilian Journal of Urology 36: 665–668 (discussion 669).

Brown CJ, Hendrich BD, Rupert JL et al. (1992) The human XIST gene: analysis of a 17 kb inactive X‐specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71: 527–542.

Carninci P, Kasukawa T, Katayama S et al. (2005) The transcriptional landscape of the mammalian genome. Science 309: 1559–1563.

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.

Deng Z, Norseen J, Wiedmer A, Riethman H and Lieberman PM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Molecular Cell 35: 403–413.

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: 1775–1789.

Djebali S, Davis CA, Merkel A et al. (2012) Landscape of transcription in human cells. Nature 489: 101–108.

Du Y, Kong G, You X et al. (2012) Elevation of highly up‐regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down‐regulating p18. Journal of Biological Chemistry 287: 26302–26311.

Flockhart RJ, Webster DE, Qu K et al. (2012) BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration. Genome Research 22: 1006–1014.

Gomes AQ, Nolasco S and Soares H (2013) Non‐coding RNAs: Multi‐tasking molecules in the cell. International Journal of Molecular Sciences 14: 16010–16039.

Guo F, Li Y, Liu Y, Wang J and Li G (2010) Inhibition of metastasis‐associated lung adenocarcinoma transcript 1 in CaSki human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochimica et Biophysica Sinica (Shanghai) 42: 224–229.

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

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: 409–419.

Ji P, Diederichs S, Wang W et al. (2003) MALAT‐1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early‐stage non‐small cell lung cancer. Oncogene 22: 8031–8041.

Kawakami T, Okamoto K, Ogawa O and Okada Y (2004) XIST unmethylated DNA fragments in male‐derived plasma as a tumour marker for testicular cancer. Lancet 363: 40–42.

Kim K, Jutooru I, Chadalapaka G et al. (2013) HOTAIR is a negative prognostic factor and exhibits pro‐oncogenic activity in pancreatic cancer. Oncogene 32: 1616–1625.

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: 6320–6326.

Kotake Y, Nakagawa T, Kitagawa K et al. (2011) Long non‐coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene 30: 1956–1962.

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.

Li D, Feng J, Wu T et al. (2013) Long intergenic noncoding RNA HOTAIR is overexpressed and regulates PTEN methylation in laryngeal squamous cell carcinoma. American Journal of Pathology 182: 64–70.

Matouk IJ, Abbasi I, Hochberg A et al. (2009) Highly upregulated in liver cancer noncoding RNA is overexpressed in hepatic colorectal metastasis. European Journal of Gastroenterology and Hepatology 21: 688–692.

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

Matouk IJ, Mezan S, Mizrahi A et al. (2010) The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochimica et Biophysica Acta 1803: 443–451.

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

Modarresi F, Faghihi MA, Lopez‐Toledano MA et al. (2012) Inhibition of natural antisense transcripts in vivo results in gene‐specific transcriptional upregulation. Nature Biotechnology 30: 453–459.

Pandey RR, Mondal T, Mohammad F et al. (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage‐specific transcriptional silencing through chromatin‐level regulation. Molecular Cell 32: 232–246.

Panzitt K, Tschernatsch MM, Guelly C et al. (2007) Characterization of HULC, a novel gene with striking up‐regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 132: 330–342.

Pasmant E, Laurendeau I, Heron D et al. (2007) Characterization of a germ‐line deletion, including the entire INK4/ARF locus, in a melanoma‐neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Research 67: 3963–3969.

Pasmant E, Sabbagh A, Vidaud M and Bieche I (2011) ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB Journal 25: 444–448.

Petrovics G, Zhang W, Makarem M et al. (2004) Elevated expression of PCGEM1, a prostate‐specific gene with cell growth‐promoting function, is associated with high‐risk prostate cancer patients. Oncogene 23: 605–611.

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

Redon S, Reichenbach P and Lingner J (2010) The non‐coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Research 38: 5797–5806.

Rinn JL and Chang HY (2012) Genome regulation by long noncoding RNAs. Annual Review of Biochemistry 81: 145–166.

Sasidharan R and Gerstein M (2008) Genomics: protein fossils live on as RNA. Nature 453: 729–731.

Schmidt LH, Spieker T, Koschmieder S et al. (2011) The long noncoding MALAT‐1 RNA indicates a poor prognosis in non‐small cell lung cancer and induces migration and tumor growth. Journal of Thoracic Oncology 6: 1984–1992.

Smaldone MC and Davies BJ (2010) BC‐819, a plasmid comprising the H19 gene regulatory sequences and diphtheria toxin A, for the potential targeted therapy of cancers. Current Opinion in Molecular Therapeutics 12: 607–616.

Srikantan V, Zou Z, Petrovics G et al. (2000) PCGEM1, a prostate‐specific gene, is overexpressed in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America 97: 12216–12221.

Suo G, Han J, Wang X et al. (2005) Oct4 pseudogenes are transcribed in cancers. Biochemical and Biophysical Research Communications 337: 1047–1051.

Tano K and Akimitsu N (2012) Long non‐coding RNAs in cancer progression. Frontiers in Genetics 3: 219.

Tano K, Mizuno R, Okada T et al. (2010) MALAT‐1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility‐related genes. FEBS Letters 584: 4575–4580.

Tripathi V, Ellis JD, Shen Z et al. (2010) The nuclear‐retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Molecular Cell 39: 925–938.

Tripathi V, Shen Z, Chakraborty A et al. (2013) Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B‐MYB. PLOS Genetics 9: e1003368.

Yang L, Lin C, Jin C et al. (2013) lncRNA‐dependent mechanisms of androgen‐receptor‐regulated gene activation programs. Nature 500: 598–602.

Yang L, Lin C, Liu W et al. (2011) ncRNA‐ and Pc2 methylation‐dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147: 773–788.

Yap KL, Li S, Munoz‐Cabello AM et al. (2010) Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Molecular Cell 38: 662–674.

Yildirim E, Kirby JE, Brown DE et al. (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152: 727–742.

Yuan SX, Yang F, Yang Y et al. (2012) 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 56: 2231–2241.

Zhang H, Chen Z, Wang X et al. (2013a) Long non‐coding RNA: a new player in cancer. Journal of Hematology & Oncology 6: 37.

Zhang L, Yang F, Yuan JH et al. (2013b) Epigenetic activation of the MiR‐200 family contributes to H19‐mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 34: 577–586.

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

Further Reading

Gutschner T, Hammerle M and Diederichs S (2013) MALAT1 – a paradigm for long noncoding RNA function in cancer. Journal of Molecular Medicine (Berlin) 91: 791–801.

Hajjari M, Khoshnevisan A and Shin YK (2013) Long non‐coding RNAs in hematologic malignancies: road to translational research. Frontiers in Genetics 4: 250.

Hauptman N and Glavac D (2013) MicroRNAs and long non‐coding RNAs: prospects in diagnostics and therapy of cancer. Radiology and Oncology 47: 311–318.

Ling H, Muller F and Calin GA (2013) MicroRNAs and other non‐coding RNAs as targets for anticancer drug development. Nature Reviews Drug Discovery 12(11): 847–865.

Matouk I, Raveh E, Ohana P et al. (2013) The increasing complexity of the oncofetal h19 gene locus: functional dissection and therapeutic intervention. International Journal of Molecular Sciences 14: 4298–4316.

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

Wahlestedt C (2013) Targeting long non‐coding RNA to therapeutically upregulate gene expression. Nature Reviews Drug Discovery 12: 433–446.

Wang KC and Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Molecular Cell 43: 904–914.

Wapinski O and Chang HY(2011) Long noncoding RNAs and human disease. Trends in Cell Biology 21(6): 354–361.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Garzon, Ramiro, and Ranganathan, Parvathi(Jun 2014) Long Noncoding RNAs and Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025252]