Skip to main content

Long Noncoding RNA as Novel Cancer Diagnostic and Effective Therapeutic Targets

  • Chapter
  • First Online:
Applied RNA Bioscience
  • 896 Accesses

Abstract

Recently large-scale genomic analyses have reported that the vast majority of somatic copy number alterations found in human cancers map to transcribed regions lacking protein-coding potential. This is not surprising considering that, although most of the human genome is transcribed into various classes of RNAs, less than 2% of them encodes for proteins. Among them, long noncoding RNAs (lncRNAs) constitute one of the most abundant classes of RNA, defined as RNA longer than 200 nucleotides not coding for proteins. Interestingly, lncRNAs are often expressed in a tissue- and cancer-specific manner, and their expression can be easily manipulated in vivo using antisense oligonucleotides (ASOs) making them attractive cancer-selective markers and therapeutic targets.

Emerging biochemical evidence has revealed an incredible functional diversity for lncRNAs as they can recruit chromatin-modifying proteins, organize nuclear architecture, regulate mRNA stability and translation by competing with microRNA and RNA-binding proteins, and even alter protein localization and function. Accordingly, lncRNAs are emerging as important regulators of cancer initiation and progression. Here we discuss the role of lncRNAs in cancer and their potential as a new promising avenue for the advancement of cancer cell-specific therapeutic design.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adriaens C, Standaert L, Barra J, Latil M, Verfaillie A, Kalev P, Boeckx B, Wijnhoven PW, Radaelli E, Vermi W, Leucci E, Lapouge G, Beck B, van den Oord J, Nakagawa S, Hirose T, Sablina AA, Lambrechts D, Aerts S, Blanpain C, Marine JC (2016) p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity. Nat Med 22:861–868

    CAS  PubMed  Google Scholar 

  • Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, Partridge TA, Lu QL (2006) Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 12:175–177

    Article  CAS  PubMed  Google Scholar 

  • Arun G, Diermeier S, Akerman M, Chang KC, Wilkinson JE, Hearn S, Kim Y, MacLeod AR, Krainer AR, Norton L, Brogi E, Egeblad M, Spector DL (2016) Differentiation of mammary tumors and reduction in metastasis upon Malat1 lncRNA loss. Genes Dev 30:34–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Babaian A, Mager DL (2016) Endogenous retroviral promoter exaptation in human cancer. Mob DNA 7:24

    Article  PubMed  PubMed Central  Google Scholar 

  • Bánfai B, Jia H, Khatun J, Wood E, Risk B, Gundling WE Jr, Kundaje A, Gunawardena HP, Yu Y, Xie L, Krajewski K, Strahl BD, Chen X, Bickel P, Giddings MC, Brown JB, Lipovich L (2012) Long noncoding RNAs are rarely translated in two human cell lines. Genome Res 22:1646–1657

    Article  PubMed  PubMed Central  Google Scholar 

  • Beltran M, Puig I, Peña C, García JM, Alvarez AB, Peña R, Bonilla F, de Herreros AG (2008) A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition. Genes Dev 22:756–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergeron-Sandoval LP, Safaee N, Michnick SW (2016) Mechanisms and consequences of macromolecular phase separation. Cell 165:1067–1079

    Article  CAS  PubMed  Google Scholar 

  • Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, DeMichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berry J, Weber SC, Vaidya N, Haataja M, Brangwynne CP (2015) RNA transcription modulates phase transition-driven nuclear body assembly. Proc Natl Acad Sci U S A 112:E5237–E5245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunner AL, Beck AH, Edris B, Sweeney RT, Zhu SX, Li R, Montgomery K, Varma S, Gilks T, Guo X, Foley JW, Witten DM, Giacomini CP, Flynn RA, Pollack JR, Tibshirani R, Chang HY, van de Rijn M, West RB (2012) Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers. Genome Biol 13:R75

    Article  PubMed  PubMed Central  Google Scholar 

  • Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N, Isaacs WB (1999) DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 59:5975–5979

    CAS  PubMed  Google Scholar 

  • Cabili MN, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, Rinn JL (2011) Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev 25:1915–1927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  • Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles DG, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown JB, Lipovich L, Gonzalez JM, Thomas M, Davis CA, Shiekhattar R, Gingeras TR, Hubbard TJ, Notredame C, Harrow J, Guigó R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dias N, Stein CA (2002) Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 1:347–355

    Article  CAS  PubMed  Google Scholar 

  • Dowdy SF (2017) Overcoming cellular barriers for RNA therapeutics. Nat Biotechnol 35:222–229

    Article  CAS  PubMed  Google Scholar 

  • Fatica A, Bozzoni I (2014) Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet 15:7–21

    Article  CAS  PubMed  Google Scholar 

  • Frazier KS (2015) Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist’s perspective. Toxicol Pathol 43:78–89

    Article  PubMed  Google Scholar 

  • Göke J, Ng HH (2016) CTRL+INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome. EMBO Rep 17:1131–1144

    Article  PubMed  PubMed Central  Google Scholar 

  • Guttman M, Russell P, Ingolia NT, Weissman JS, Lander ES (2013) Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. Cell 154:240–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hezroni H, Koppstein D, Schwartz MG, Avrutin A, Bartel DP, Ulitsky I (2015) Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep 11:1110–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirose T, Virnicchi G, Tanigawa A, Naganuma T, Li R, Kimura H, Yokoi T, Nakagawa S, Bénard M, Fox AH, Pierron G (2014) NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell 25(1):169–183

    Article  PubMed  Google Scholar 

  • Hoy SM (2017) Nusinersen: first global approval. Drugs 77:473–479

    Article  CAS  PubMed  Google Scholar 

  • Huarte M (2015) The emerging role of lncRNAs in cancer. Nat Med 21:1253–1261

    Article  CAS  PubMed  Google Scholar 

  • Ingolia NT, Brar GA, Stern-Ginossar N, Harris MS, Talhouarne GJS, Jackson SE, Wills MR, Weissman JS (2014) Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Rep 8:1365–1379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, Barrette TR, Prensner JR, Evans JR, Zhao S, Poliakov A, Cao X, Dhanasekaran SM, Wu YM, Robinson DR, Beer DG, Feng FY, Iyer HK, Chinnaiyan AM (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Publ Group 47(3):199–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain A, Vale RD (2017) RNA phase transitions in repeat expansion disorders. Nature 546(7657):243–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Juliano RL (2016) The delivery of therapeutic oligonucleotides. Nucleic Acids Res 44(14):6518–6548

    Article  PubMed  PubMed Central  Google Scholar 

  • Kelley D, Rinn J (2012) Transposable elements reveal a stem cell-specific class of long noncoding RNAs. Genome Biol 13:R107

    Article  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  • Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Kopp F, Chang TC, Sataluri A, Chen B, Sivakumar S, Yu H, Xie Y, Mendell JT (2016) Noncoding RNA NORAD regulates genomic stability by sequestering PUMILIO proteins. Cell 164:69–80

    Article  CAS  PubMed  Google Scholar 

  • Leucci E, Vendramin R, Spinazzi M, Laurette P, Fiers M, Wouters J, Radaelli E, Eyckerman S, Leonelli C, Vanderheyden K, Rogiers A, Hermans E, Baatsen P, Aerts S, Amant F, Van Aelst S, van den Oord J, de Strooper B, Davidson I, Lafontaine DL, Gevaert K, Vandesompele J, Mestdagh P, Marine JC (2016) Melanoma addiction to the long non-coding RNA SAMMSON. Nature 531:518–522

    Article  CAS  PubMed  Google Scholar 

  • Lin Y, Protter DS, Rosen MK, Parker R (2015) Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol Cell 60:208–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorenzen JM, Thum T (2016) Long noncoding RNAs in kidney and cardiovascular diseases. Nat Rev Nephrol 12:360–373

    Article  CAS  PubMed  Google Scholar 

  • Mayer G, Raddatz M-SL, Grunwald JD, Famulok M (2007) RNA ligands that distinguish metabolite-induced conformations in the TPP riboswitch. Angew Chem Int Ed Eng 46:557–560

    Article  CAS  Google Scholar 

  • Mello SS, Sinow C, Raj N, Mazur PK, Bieging-Rolett K, Broz DK, Imam JFC, Vogel H, Wood LD, Sage J, Hirose T, Nakagawa S, Rinn J, Attardi LD (2017) Neat1 is a p53-inducible lincRNA essential for transformation suppression. Genes Dev 31:1095–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melton C, Reuter JA, Spacek DV, Snyder M (2015) Recurrent somatic mutations in regulatory regions of human cancer genomes. Nat Genet 47:710–716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimoto Y, Nakagawa S, Hirose T, Okano HJ, Takao M, Shibata S, Suyama S, Kuwako K, Imai T, Murayama S, Suzuki N, Okano H (2013) The long non-coding RNA nuclear-enriched abundant transcript 1_2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. Mol Brain 6:31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nissan A, Stojadinovic A, Mitrani-Rosenbaum S, Halle D, Grinbaum R, Roistacher M, Bochem A, Dayanc BE, Ritter G, Gomceli I, Bostanci EB, Akoglu M, Chen YT, Old LJ, Gure AO (2012) Colon cancer associated transcript-1: a novel RNA expressed in malignant and pre-malignant human tissues. Int J Cancer 130:1598–1606

    Article  CAS  PubMed  Google Scholar 

  • Ortega-Molina A, Serrano M (2013) PTEN in cancer, metabolism, and aging. Trends Endocrinol Metab 24:184–189

    Article  CAS  PubMed  Google Scholar 

  • Pedram Fatemi R, Salah-Uddin S, Modarresi F, Khoury N, Wahlestedt C, Faghihi MA (2015) Screening for small-molecule modulators of long noncoding RNA-protein interactions using AlphaScreen. J Biomol Screen 20:1132–1141

    Article  PubMed  PubMed Central  Google Scholar 

  • Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, Booten SL, Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze EE, Seth PP (2014) Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 42:8796–8807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prensner JR, Zhao S, Erho N, Schipper M, Iyer MK, Dhanasekaran SM, Magi-Galluzzi C, Mehra R, Sahu A, Siddiqui J, Davicioni E, Den RB, Dicker AP, Karnes RJ, Wei JT, Klein EA, Jenkins RB, Chinnaiyan AM, Feng FY (2014) RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol 15:1469–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62

    Article  CAS  PubMed  Google Scholar 

  • Rivas E, Clements J, Eddy SR (2017) A statistical test for conserved RNA structure shows lack of evidence for structure in lncRNAs. Nat Methods 14:45–48

    Article  CAS  PubMed  Google Scholar 

  • Shain AH, Bastian BC (2016) From melanocytes to melanomas. Nat Rev Cancer 16:345–358

    Article  CAS  PubMed  Google Scholar 

  • Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707–714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephenson ML, Zamecnik PC (1978) Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A 75(1):285–288

    Article  CAS  Google Scholar 

  • Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y (2014) Oligonucleotide aptamers: new tools for targeted cancer therapy. Mol Ther Nucleic Acids 3:e182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szpakowski S, Sun X, Lage JM, Dyer A, Rubinstein J, Kowalski D, Sasaki C, Costa J, Lizardi PM (2009) Loss of epigenetic silencing in tumors preferentially affects primate-specific retroelements. Gene 448:151–167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teschendorff AE, Lee SH, Jones A, Fiegl H, Kalwa M, Wagner W, Chindera K, Evans I, Dubeau L, Orjalo A, Horlings HM, Niederreiter L, Kaser A, Yang W, Goode EL, Fridley BL, Jenner RG, Berns EM, Wik E, Salvesen HB, Wisman GB, van der Zee AG, Davidson B, Trope CG, Lambrechts S, Vergote I, Calvert H, Jacobs IJ, Widschwendter M (2015) HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome Med 7:108

    Article  PubMed  PubMed Central  Google Scholar 

  • The FANTOM Consortium (2005) The transcriptional landscape of the mammalian genome. Science 309(5740):1559–1563

    Google Scholar 

  • Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, Ronning P, Reuland B, Guenther K, Beadnell TC, Essig J, Otto GM, O’Sullivan MG, Largaespada DA, Schwertfeger KL, Marahrens Y, Kawakami Y, Bagchi A (2014) PVT1 dependence in cancer with MYC copy-number increase. Nature 512:82–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ulitsky I, Shkumatava A, Jan CH, Sive H, Bartel DP (2011) Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution. Cell 147:1537–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Heesch S, van Iterson M, Jacobi J, Boymans S, Essers PB, de Bruijn E, Hao W, MacInnes AW, Cuppen E, Simonis M (2014) Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes. Genome Biol 15:R6

    Article  PubMed  PubMed Central  Google Scholar 

  • Wan Y, Qu K, Zhang QC, Flynn RA, Manor O, Ouyang Z, Zhang J, Spitale RC, Snyder MP, Segal E, Chang HY (2014) Landscape and variation of RNA secondary structure across the human transcriptome. Nature 505:706–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watts JK, Deleavey GF, Damha MJ (2008) Chemically modified siRNA: tools and applications. Drug Discov Today 13:842–855

    Article  CAS  PubMed  Google Scholar 

  • Yan X, Hu Z, Feng Y, Hu X, Yuan J, Zhao SD, Zhang Y, Yang L, Shan W, He Q, Fan L, Kandalaft LE, Tanyi JL, Li C, Yuan CX, Zhang D, Yuan H, Hua K, Lu Y, Katsaros D, Huang Q, Montone K, Fan Y, Coukos G, Boyd J, Sood AK, Rebbeck T, Mills GB, Dang CV, Zhang L (2015) Comprehensive genomic characterization of long non-coding RNAs across human cancers. Cancer Cell 28:529–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT (2013) Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152:727–742

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Elbaum-Garfinkle S, Langdon EM, Taylor N, Occhipinti P, Bridges AA, Brangwynne CP, Gladfelter AS (2015) RNA controls PolyQ protein phase transitions. Mol Cell 60(2):220–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Zuo X, Yang B, Li Z, Xue Y, Zhou Y, Huang J, Zhao X, Zhou J, Yan Y, Zhang H, Guo P, Sun H, Guo L, Zhang Y, Fu XD (2014) MicroRNA directly enhances mitochondrial translation during muscle differentiation. Cell 158:607–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Figures were prepared using somersault libraries available from www.somersault1824.com.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eleonora Leucci .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Leucci, E. (2018). Long Noncoding RNA as Novel Cancer Diagnostic and Effective Therapeutic Targets. In: Masuda, S., Izawa, S. (eds) Applied RNA Bioscience. Springer, Singapore. https://doi.org/10.1007/978-981-10-8372-3_12

Download citation

Publish with us

Policies and ethics