Skip to main content
SpringerLink
Log in

Small-Molecule Regulation of MicroRNA Function

  • Chapter
  • First Online:
Book cover MicroRNA in Cancer

  • 1282 Accesses

Abstract

MicroRNAs (miRNAs) are single-stranded noncoding RNAs of 21–23 nucleotides, which regulate the expression of genes by binding to the 3′ untranslated regions of target messenger RNAs (mRNAs). MicroRNAs down-regulate gene expression by either inhibiting translation or accelerating the degradation of the mRNA. It is estimated that miRNAs are involved in the regulation of about 30 % of all genes and almost every genetic pathway, making miRNAs an important class of gene regulators. Variations in miRNA expression are involved in many human diseases including cancer, immune disorders, diabetes, and cardiovascular diseases. Thus, small molecule modifiers of miRNA function have potential as new therapeutic agents, as probes for the elucidation of detailed mechanisms of miRNA function and regulation, and as tools for the discovery of new targets for the treatment of human diseases. A variety of different assay systems have been developed and used in the discovery of small molecule modifiers of miRNA function. Identified small molecules regulate the miRNA pathway in either a general or a miRNA-specific fashion. The discovery and development of these molecules demonstrates that the miRNA pathway represents a feasible small molecule target. Several of these small molecules have also shown therapeutic potential in cell based experiments, supporting the idea that modifiers of miRNA function could lead to the identification of new drugs.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

  1. Lee R, Feinbaum R, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  PubMed  CAS  Google Scholar 

  2. Reinhart B, Slack F, Basson M, Pasquinelli A, Bettinger J et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906

    Article  PubMed  CAS  Google Scholar 

  3. Pasquinelli A, Reinhart B, Slack F, Martindale M, Kuroda M et al (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89

    Article  PubMed  CAS  Google Scholar 

  4. Winter J, Jung S, Keller S, Gregory R, Diederichs S (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11:228–234

    Article  PubMed  CAS  Google Scholar 

  5. Ghildiyal M, Zamore P (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108

    Article  PubMed  CAS  Google Scholar 

  6. Carthew R, Sontheimer E (2009) Origins and Mechanisms of miRNAs and siRNAs. Cell 136:642–655

    Article  PubMed  CAS  Google Scholar 

  7. Garzon R, Marcucci G, Croce C (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9:775–789

    Article  PubMed  CAS  Google Scholar 

  8. Shenouda S, Alahari S (2009) MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev 28:369–378

    Article  PubMed  CAS  Google Scholar 

  9. Esquela-Kerscher A, Slack F (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

    Article  PubMed  CAS  Google Scholar 

  10. Carthew R (2006) Gene regulation by microRNAs. Curr Opin Genet Dev 16:203–208

    Article  PubMed  CAS  Google Scholar 

  11. Vasudevan S, Tong Y, Steitz J (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318:1931–1934

    Article  PubMed  CAS  Google Scholar 

  12. Vasudevan S, Tong Y, Steitz JA (2008) Cell-cycle control of microRNA-mediated translation regulation. Cell Cycle 7:1545–1549

    Article  PubMed  CAS  Google Scholar 

  13. Appasani K (2008) MicroRNAs: from basic science to disease biology. Cambridge University Press, Cambridge

    Google Scholar 

  14. Sevignani C, Calin G, Siracusa L, Croce C (2006) Mammalian microRNAs: a small world for fine-tuning gene expression. Mamm Genome 17:189–202

    Article  PubMed  CAS  Google Scholar 

  15. Zhang S, Chen L, Jung E, Calin G (2010) Targeting MicroRNAs With Small Molecules: From Dream to Reality. Clin Pharmacol Ther 87:754–758

    Google Scholar 

  16. Medina PP, Nolde M, Slack FJ (2010) OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467:86–90

    Article  PubMed  CAS  Google Scholar 

  17. Du T, Zamore P (2005) microPrimer: the biogenesis and function of microRNA. Development 132:4645–4652

    Article  PubMed  CAS  Google Scholar 

  18. Lee Y, Ahn C, Han J, Choi H, Kim J et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419

    Article  PubMed  CAS  Google Scholar 

  19. Bernstein E, Caudy A, Hammond S, Hannon G (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366

    Article  PubMed  CAS  Google Scholar 

  20. Grishok A, Pasquinelli A, Conte D, Li N, Parrish S et al (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106:23–34

    Article  PubMed  CAS  Google Scholar 

  21. Hutvágner G, McLachlan J, Pasquinelli A, Bálint E, Tuschl T et al (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838

    Article  PubMed  Google Scholar 

  22. Ketting R, Fischer S, Bernstein E, Sijen T, Hannon G et al (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 15:2654–2659

    Article  PubMed  CAS  Google Scholar 

  23. Yi R, Qin Y, Macara I, Cullen B (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–3016

    Article  PubMed  CAS  Google Scholar 

  24. Pillai RS (2005) MicroRNA function: multiple mechanisms for a tiny RNA? RNA 11:1753–1761

    Article  PubMed  CAS  Google Scholar 

  25. He L, Hannon G (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522–531

    Article  PubMed  CAS  Google Scholar 

  26. Bartel D (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  PubMed  CAS  Google Scholar 

  27. Chan S, Slack F (2006) microRNA-mediated silencing inside P-bodies. RNA Biol 3:97–100

    Article  PubMed  CAS  Google Scholar 

  28. Lelandais-Brière C, Sorin C, Declerck M, Benslimane A, Crespi M et al (2010) Small RNA diversity in plants and its impact in development. Curr Genomics 11:14–23

    Article  PubMed  Google Scholar 

  29. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    PubMed  CAS  Google Scholar 

  30. Zhang X, Zeng Y (2010) Regulation of mammalian microRNA expression. J Cardiovasc Transl Res 3:197–203

    Article  PubMed  Google Scholar 

  31. He L, Thomson J, Hemann M, Hernando-Monge E, Mu D et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833

    Article  PubMed  CAS  Google Scholar 

  32. Calin G, Sevignani C, Dumitru C, Hyslop T, Noch E et al (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 101:2999–3004

    Article  PubMed  CAS  Google Scholar 

  33. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S et al (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 99:15524–15529

    Article  PubMed  CAS  Google Scholar 

  34. Saito Y, Liang G, Egger G, Friedman J, Chuang J et al (2006) Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9:435–443

    Article  PubMed  CAS  Google Scholar 

  35. Zhang L, Huang J, Yang N, Greshock J, Megraw M et al (2006) microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci U S A 103:9136–9141

    Article  PubMed  CAS  Google Scholar 

  36. Shi X, Tepper C, deVere White R (2008) Cancerous miRNAs and their regulation. Cell Cycle 7:1529–1538

    Article  PubMed  CAS  Google Scholar 

  37. O’Donnell K, Wentzel E, Zeller K, Dang C, Mendell J (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843

    Article  PubMed  Google Scholar 

  38. Kim J, Inoue K, Ishii J, Vanti W, Voronov S et al (2007) A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317:1220–1224

    Article  PubMed  CAS  Google Scholar 

  39. Thomson J, Newman M, Parker J, Morin-Kensicki E, Wright T et al (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20:2202–2207

    Article  PubMed  CAS  Google Scholar 

  40. Davis B, Hilyard A, Lagna G, Hata A (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454:56–61

    Article  PubMed  CAS  Google Scholar 

  41. Trabucchi M, Briata P, Garcia-Mayoral M, Haase A, Filipowicz W et al (2009) The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459:1010–1014

    Article  PubMed  CAS  Google Scholar 

  42. Viswanathan S, Daley G (2010) Lin28: A microRNA regulator with a macro role. Cell 140:445–449

    Article  PubMed  CAS  Google Scholar 

  43. Hagan J, Piskounova E, Gregory R (2009) Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 16:1021–1025

    Article  PubMed  CAS  Google Scholar 

  44. Heo I, Joo C, Cho J, Ha M, Han J et al (2008) Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell 32:276–284

    Article  PubMed  CAS  Google Scholar 

  45. Esau C (2008) Inhibition of microRNA with antisense oligonucleotides. Methods 44:55–60

    Article  PubMed  CAS  Google Scholar 

  46. Veedu R, Wengel J (2010) Locked nucleic acids: promising nucleic acid analogs for therapeutic applications. Chem Biodivers 7:536–542

    Article  PubMed  CAS  Google Scholar 

  47. Brown B, Naldini L (2009) Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nat Rev Genet 10:578–585

    Article  PubMed  CAS  Google Scholar 

  48. Liu Z, Sall A, Yang D (2008) MicroRNA: An emerging therapeutic target and intervention tool. Int J Mol Sci 9:978–999

    Article  PubMed  CAS  Google Scholar 

  49. Grünweller A, Hartmann R (2007) Locked nucleic acid oligonucleotides: the next generation of antisense agents? BioDrugs 21:235–243

    Article  PubMed  Google Scholar 

  50. Ebert M, Neilson J, Sharp P (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4:721–726

    Article  PubMed  CAS  Google Scholar 

  51. Carè A, Catalucci D, Felicetti F, Bonci D, Addario A et al (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13:613–618

    Article  PubMed  Google Scholar 

  52. Zhang S, Chen L, Jung E, Calin G (2010) Targeting microRNAs with small molecules: from dream to reality. Clin Pharmacol Ther 87:754–758

    Article  PubMed  CAS  Google Scholar 

  53. Davies B, Arenz C (2006) A homogenous assay for micro RNA maturation. Angew Chem Int Ed Engl 45:5550–5552

    Article  PubMed  CAS  Google Scholar 

  54. Shan G, Li Y, Zhang J, Li W, Szulwach K et al (2008) A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol 26:933–940

    Article  PubMed  CAS  Google Scholar 

  55. Bhanot SK, Singh M, Chatterjee NR (2001) The chemical and biological aspects of fluoroquinolones: reality and dreams. Curr Pharm Des 7:311–335

    Article  PubMed  CAS  Google Scholar 

  56. Watashi K, Yeung M, Starost M, Hosmane R, Jeang K (2010) Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J Biol Chem 285:24707–24716

    Article  PubMed  CAS  Google Scholar 

  57. Chiu Y, Dinesh C, Chu C, Ali A, Brown K et al (2005) Dissecting RNA-interference pathway with small molecules. Chem Biol 12:643–648

    Article  PubMed  CAS  Google Scholar 

  58. Calin G, Dumitru C, Shimizu M, Bichi R, Zupo S et al (2002) Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 99:15524–15529

    Article  PubMed  CAS  Google Scholar 

  59. Dong JT, Boyd JC, Frierson HF (2001) Loss of heterozygosity at 13q14 and 13q21 in high grade, high stage prostate cancer. Prostate 49:166–171

    Article  PubMed  CAS  Google Scholar 

  60. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949

    Article  PubMed  CAS  Google Scholar 

  61. Baudry A, Mouillet-Richard S, Schneider B, Launay J, Kellermann O (2010) miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science 329:1537–1541

    Article  PubMed  CAS  Google Scholar 

  62. Tong A, Nemunaitis J (2008) Modulation of miRNA activity in human cancer: a new paradigm for cancer gene therapy? Cancer Gene Ther 15:341–355

    Article  PubMed  CAS  Google Scholar 

  63. Ciafrè S, Galardi S, Mangiola A, Ferracin M, Liu C et al (2005) Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun 334:1351–1358

    Article  PubMed  Google Scholar 

  64. Iorio M, Ferracin M, Liu C, Veronese A, Spizzo R et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070

    Article  PubMed  CAS  Google Scholar 

  65. Si M, Zhu S, Wu H, Lu Z, Wu F et al (2007) miR-21-mediated tumor growth. Oncogene 26:2799–2803

    Article  PubMed  CAS  Google Scholar 

  66. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob S et al (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658

    Article  PubMed  CAS  Google Scholar 

  67. Corsten M, Miranda R, Kasmieh R, Krichevsky A, Weissleder R et al (2007) MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res 67:8994–9000

    Article  PubMed  CAS  Google Scholar 

  68. Mattie M, Benz C, Bowers J, Sensinger K, Wong L et al (2006) Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5:24

    Article  PubMed  Google Scholar 

  69. Wickramasinghe N, Manavalan T, Dougherty S, Riggs K, Li Y et al (2009) Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res 37:2584–2595

    Article  PubMed  CAS  Google Scholar 

  70. Bhat-Nakshatri P, Wang G, Collins N, Thomson M, Geistlinger T et al (2009) Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res 37:4850–4861

    Article  PubMed  CAS  Google Scholar 

  71. Shin VY, Jin H, Ng EK, Cheng AS, Chong WW et al (2010) NF-kappaB targets miR-16 and miR-21 in gastric cancer: involvement of prostaglandin E receptors. Carcinogenesis

    Google Scholar 

  72. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    Article  PubMed  CAS  Google Scholar 

  73. Rossi L, Bonmassar E, Faraoni I (2007) Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro. Pharmacol Res 56:248–253

    Article  PubMed  CAS  Google Scholar 

  74. Valeri N, Gasparini P, Braconi C, Paone A, Lovat F et al (2010) MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc Natl Acad Sci U S A 107:21098–21103

    Google Scholar 

  75. Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A et al (2010) MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer 103:1617–1626

    Article  PubMed  CAS  Google Scholar 

  76. Zhou J, Zhou Y, Yin B, Hao W, Zhao L et al (2010) 5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro. Oncol Rep 23:121–128

    PubMed  CAS  Google Scholar 

  77. Shah MY, Pan X, Fix LN, Farwell MA, Zhang B (2011) 5-Fluorouracil drug alters the microRNA expression profiles in MCF-7 breast cancer cells. J Cell Physiol 226:1868–1878

    Google Scholar 

  78. Gumireddy K, Young D, Xiong X, Hogenesch J, Huang Q et al (2008) Small-molecule inhibitors of microrna miR-21 function. Angew Chem Int Ed Engl 47:7482–7484

    Article  PubMed  CAS  Google Scholar 

  79. Schmittgen TD, Jiang J, Liu Q, Yang L (2004) A high-throughput method to monitor the expression of microRNA precursors. Nucleic Acids Res 32:e43

    Google Scholar 

  80. Chang J, Nicolas E, Marks D, Sander C, Lerro A et al (2004) miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 1:106–113

    Article  PubMed  CAS  Google Scholar 

  81. Esau C, Davis S, Murray S, Yu X, Pandey S et al (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3:87–98

    Article  PubMed  CAS  Google Scholar 

  82. Parkin D, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  83. Lin C, Gong H, Tseng H, Wang W, Wu J (2008) miR-122 targets an anti-apoptotic gene, Bcl-w, in human hepatocellular carcinoma cell lines. Biochem Biophys Res Commun 375:315–320

    Article  PubMed  CAS  Google Scholar 

  84. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S et al (2007) Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67:6092–6099

    Article  PubMed  CAS  Google Scholar 

  85. Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S et al (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27:5651–5661

    Article  PubMed  CAS  Google Scholar 

  86. Yang JD, Roberts LR (2010) Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol 7:448–458

    Article  PubMed  Google Scholar 

  87. Jopling C, Yi M, Lancaster A, Lemon S, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581

    Article  PubMed  CAS  Google Scholar 

  88. Jopling C, Norman K, Sarnow P (2006) Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122. Cold Spring Harb Symp Quant Biol 71:369–376

    Article  PubMed  CAS  Google Scholar 

  89. Lanford R, Hildebrandt-Eriksen E, Petri A, Persson R, Lindow M et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201

    Article  PubMed  CAS  Google Scholar 

  90. Young D, Connelly C, Grohmann C, Deiters A (2010) Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc 132:7976–7981

    Article  PubMed  CAS  Google Scholar 

  91. Yi M, Lemon S (2004) Adaptive mutations producing efficient replication of genotype 1a hepatitis C virus RNA in normal Huh7 cells. J Virol 78:7904–7915

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, North Carolina State University, 27695-8204, Raleigh, NC, USA

    Colleen M. Connelly & Alexander Deiters

Authors
  1. Colleen M. Connelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Deiters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander Deiters .

Editor information

Editors and Affiliations

  1. and Molecular Biology, Stanley S. Scott Cancer Center, Department of Biochemistry, Perdido Street 1901, New Orleans, 70112, Louisiana, USA

    Suresh Alahari

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Connelly, C., Deiters, A. (2013). Small-Molecule Regulation of MicroRNA Function. In: Alahari, S. (eds) MicroRNA in Cancer. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4655-8_8

Download citation

Publish with us

Policies and ethics

Search

Navigation