Advertisement

MicroRNAs in the Pathogenesis of Viral Infections and Cancer

  • Derek M. DykxhoornEmail author
Chapter
  • 1k Downloads

Abstract

MicroRNAs (miRNAs) have emerged as a class of broadly conserved small RNAs that facilitate the sequence-specific, post-transcriptionally regulation of gene expression. These small regulatory RNAs have been shown to play essential roles in many important biological processes from metabolism to apoptosis. Alterations in miRNA expression profiles can have pathogenic consequences. This article will examine the role that miRNAs play in the pathophysiology of viral infections and cancer.

Keywords

High Mobility Group AT-hook 2 (HMGA2) P53 Up-regulated Modulator Of Apoptosis (PUMA) Kaposi’s Sarcoma-associated Herpes Virus (KSHV) BCL2-associated Transcription Factor 1 (BCLAF1) DiGeorge Syndrome Critical Region Gene 8 (DGCR8) 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  2. 2.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCrossRefGoogle Scholar
  3. 3.
    Carthew RW, Sontheimer EJ (2009) Origins and Mechanisms of miRNAs and siRNAs. Cell 136:642–655PubMedCrossRefGoogle Scholar
  4. 4.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854PubMedCrossRefGoogle Scholar
  5. 5.
    Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862PubMedCrossRefGoogle Scholar
  6. 6.
    Reinhart BJ et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906PubMedCrossRefGoogle Scholar
  7. 7.
    Pasquinelli AE et al (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89PubMedCrossRefGoogle Scholar
  8. 8.
    Molnar A, Schwach F, Studholme DJ, Thuenemann EC, Baulcombe DC (2007) miRNAs control gene expression in the single-cell alga Chlamydomonas reinhardtii. Nature 447:1126–1129PubMedCrossRefGoogle Scholar
  9. 9.
    Grimson A et al (2008) Early origins and evolution of microRNAs and Piwi-interacting RNAs in animals. Nature 455:1193–1197PubMedCrossRefGoogle Scholar
  10. 10.
    Kim VN, Nam, JW (2006) Genomics of microRNA. Trends Genet 22:165–173PubMedCrossRefGoogle Scholar
  11. 11.
    Schanen BC, Li X Transcriptional regulation of mammalian miRNA genes. Genomics 97:1–6Google Scholar
  12. 12.
    Lee Y et al (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23:4051–4060PubMedCrossRefGoogle Scholar
  13. 13.
    Cai X, Hagedorn CH, Cullen BR (2004) Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 10:1957–1966PubMedCrossRefGoogle Scholar
  14. 14.
    Chen JF et al (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38:228–33PubMedCrossRefGoogle Scholar
  15. 15.
    Kim VN (2005) MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 6:376–385PubMedCrossRefGoogle Scholar
  16. 16.
    Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–39PubMedCrossRefGoogle Scholar
  17. 17.
    Han J et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–27PubMedCrossRefGoogle Scholar
  18. 18.
    Han J et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125:887–901PubMedCrossRefGoogle Scholar
  19. 19.
    Gregory RI, Chendrimada TP, Shiekhattar R (2006) MicroRNA biogenesis: isolation and characterization of the microprocessor complex. Methods Mol Biol 342:33–47PubMedGoogle Scholar
  20. 20.
    Seitz H, Zamore PD (2006) Rethinking the microprocessor. Cell 125:827–829PubMedCrossRefGoogle Scholar
  21. 21.
    Yi R et al (2009) DGCR8-dependent microRNA biogenesis is essential for skin development. Proc Natl Acad Sci USA 106:498–502PubMedCrossRefGoogle Scholar
  22. 22.
    Yeom KH, Lee Y, Han J, Suh MR, Kim VN (2006) Characterization of DGCR8/Pasha, the essential cofactor for Drosha in primary miRNA processing. Nucleic Acids Res 34:4622–4629PubMedCrossRefGoogle Scholar
  23. 23.
    Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 14:2162–2167PubMedCrossRefGoogle Scholar
  24. 24.
    Zeng Y, Cullen BR (2005) Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences. J Biol Chem 280:27595–27603PubMedCrossRefGoogle Scholar
  25. 25.
    Bohnsack MT, Czaplinski K, Gorlich D (2004) Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10:185–191PubMedCrossRefGoogle Scholar
  26. 26.
    Lund E, Guttinger S, Calado A, Dahlberg JE, Kutay U (2004) Nuclear export of microRNA precursors. Science 303:95–98PubMedCrossRefGoogle Scholar
  27. 27.
    Yi R, Qin Y, Macara IG, Cullen BR (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–6PubMedCrossRefGoogle Scholar
  28. 28.
    Grishok A et al (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106:23–34PubMedCrossRefGoogle Scholar
  29. 29.
    Hutvagner G et al (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838PubMedCrossRefGoogle Scholar
  30. 30.
    Ketting RF et al (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 15:2654–2659PubMedCrossRefGoogle Scholar
  31. 31.
    Khvorova A, Reynolds A, Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115:209–216PubMedCrossRefGoogle Scholar
  32. 32.
    Schwarz DS et al (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115:199–208PubMedCrossRefGoogle Scholar
  33. 33.
    Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 5:396–400PubMedCrossRefGoogle Scholar
  34. 34.
    Farh KK et al (2005) The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 310:1817–1821PubMedCrossRefGoogle Scholar
  35. 35.
    Baek D et al (2008) The impact of microRNAs on protein output. Nature 455, 64–71PubMedCrossRefGoogle Scholar
  36. 36.
    Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedCrossRefGoogle Scholar
  37. 37.
    Guo H, Ingolia NT, Weissman JS, Bartel DP Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840Google Scholar
  38. 38.
    Shin C et al Expanding the microRNA targeting code: functional sites with centered pairing. Mol Cell 38:789–802Google Scholar
  39. 39.
    Selbach M et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63PubMedCrossRefGoogle Scholar
  40. 40.
    Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20PubMedCrossRefGoogle Scholar
  41. 41.
    Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB (2003) Prediction of mammalian microRNA targets. Cell 115:787–798PubMedCrossRefGoogle Scholar
  42. 42.
    Lim LP, Glasner ME, Yekta S, Burge CB, Bartel DP (2003) Vertebrate microRNA genes. Science 299:1540PubMedCrossRefGoogle Scholar
  43. 43.
    Lim LP et al (2003) The microRNAs of Caenorhabditis elegans. Genes Dev 17:991–1008PubMedCrossRefGoogle Scholar
  44. 44.
    Lal A et al (2009) miR-24 Inhibits cell proliferation by targeting E2F2, MYC, and other cell-cycle genes via binding to “seedless” 3′UTR microRNA recognition elements. Mol Cell 35:610–625PubMedCrossRefGoogle Scholar
  45. 45.
    Lim LP et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773PubMedCrossRefGoogle Scholar
  46. 46.
    Lu R, Martin-Hernandez AM, Peart JR, Malcuit I, Baulcombe DC (2003) Virus-induced gene silencing in plants. Methods 30:296–303PubMedCrossRefGoogle Scholar
  47. 47.
    Mueller S et al RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila. Proc Natl Acad Sci USA 107:19390–19395Google Scholar
  48. 48.
    van Rij RP, Berezikov E (2009) Small RNAs and the control of transposons and viruses in Drosophila. Trends Microbiol 17:163–171PubMedCrossRefGoogle Scholar
  49. 49.
    Saleh, M.C. et al (2009) Antiviral immunity in Drosophila requires systemic RNA interference spread. Nature 458:346–350PubMedCrossRefGoogle Scholar
  50. 50.
    Aliyari R et al (2008) Mechanism of induction and suppression of antiviral immunity directed by virus-derived small RNAs in Drosophila. Cell Host Microbe 4:387–397PubMedCrossRefGoogle Scholar
  51. 51.
    Flynt A, Liu N, Martin R, Lai EC (2009) Dicing of viral replication intermediates during silencing of latent Drosophila viruses. Proc Natl Acad Sci USA 106:5270–5275PubMedCrossRefGoogle Scholar
  52. 52.
    Kim J et al (2004) Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci USA 101:360–365PubMedCrossRefGoogle Scholar
  53. 53.
    Grad Y et al (2003) Computational and experimental identification of C. elegans microRNAs. Mol Cell 11:1253–1263PubMedCrossRefGoogle Scholar
  54. 54.
    Adai A et al (2005) Computational prediction of miRNAs in Arabidopsis thaliana. Genome Res 15:78–91PubMedCrossRefGoogle Scholar
  55. 55.
    Li SC et al Identification of homologous microRNAs in 56 animal genomes. Genomics 96:1–9Google Scholar
  56. 56.
    Farazi TA, Juranek SA, Tuschl T (2008) The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members. Development 135:1201–1214PubMedCrossRefGoogle Scholar
  57. 57.
    Hafner M et al (2008) Identification of microRNAs and other small regulatory RNAs using cDNA library sequencing. Methods 44:3–12PubMedCrossRefGoogle Scholar
  58. 58.
    Landgraf P et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414PubMedCrossRefGoogle Scholar
  59. 59.
    Pfeffer S et al (2005) Identification of microRNAs of the herpesvirus family. Nat Methods 2:269–276PubMedCrossRefGoogle Scholar
  60. 60.
    Pfeffer S et al (2004) Identification of virus-encoded microRNAs. Science 304:734–736PubMedCrossRefGoogle Scholar
  61. 61.
    Cai X, Cullen BR (2006) Transcriptional origin of Kaposi’s sarcoma-associated herpesvirus microRNAs. J Virol 80:2234–2242PubMedCrossRefGoogle Scholar
  62. 62.
    Cai X et al (2005) Kaposi’s sarcoma-associated herpesvirus expresses an array of viral microRNAs in latently infected cells. Proc Natl Acad Sci USA 102:5570–5575PubMedCrossRefGoogle Scholar
  63. 63.
    Cai X et al (2006) Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog 2:e23PubMedCrossRefGoogle Scholar
  64. 64.
    Xing L, Kieff E (2007) Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication. J Virol 81:9967–9975PubMedCrossRefGoogle Scholar
  65. 65.
    Samols MA, Hu J, Skalsky RL, Renne R (2005) Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi’s sarcoma-associated herpesvirus. J Virol 79:9301–9305PubMedCrossRefGoogle Scholar
  66. 66.
    Zhu JY et al (2009) Identification of novel Epstein-Barr virus microRNA genes from nasopharyngeal carcinomas. J Virol 83:3333–3341PubMedCrossRefGoogle Scholar
  67. 67.
    Grundhoff A, Sullivan CS, Ganem D (2006) A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses. RNA 12:733–750PubMedCrossRefGoogle Scholar
  68. 68.
    Umbach JL et al (2008) MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454:780–783PubMedGoogle Scholar
  69. 69.
    Umbach JL, Nagel MA, Cohrs RJ, Gilden DH, Cullen BR (2009) Analysis of human alphaherpesvirus microRNA expression in latently infected human trigeminal ganglia. J Virol 83:10677–10683PubMedCrossRefGoogle Scholar
  70. 70.
    Cui C et al (2006) Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 80:5499–5508PubMedCrossRefGoogle Scholar
  71. 71.
    Tang S, Patel A, Krause PR (2009) Novel less-abundant viral microRNAs encoded by herpes simplex virus 2 latency-associated transcript and their roles in regulating ICP34.5 and ICP0 mRNAs. J Virol 83:1433–1442PubMedCrossRefGoogle Scholar
  72. 72.
    Tang S et al (2008) An acutely and latently expressed herpes simplex virus 2 viral microRNA inhibits expression of ICP34.5, a viral neurovirulence factor. Proc Natl Acad Sci U S A 105:10931–10936PubMedCrossRefGoogle Scholar
  73. 73.
    Umbach JL et al Identification of viral microRNAs expressed in human sacral ganglia latently infected with herpes simplex virus 2. J Virol 84:1189–1192Google Scholar
  74. 74.
    Dunn W et al (2005) Human cytomegalovirus expresses novel microRNAs during productive viral infection. Cell Microbiol 7:1684–1695PubMedCrossRefGoogle Scholar
  75. 75.
    Grey F et al (2005) Identification and characterization of human cytomegalovirus-encoded microRNAs. J Virol 79:12095–12099PubMedCrossRefGoogle Scholar
  76. 76.
    Walz N, Christalla T, Tessmer U, Grundhoff A A global analysis of evolutionary conservation among known and predicted gammaherpesvirus microRNAs. J Virol 84:716–728Google Scholar
  77. 77.
    Gottwein E, Cai X, Cullen BR (2006) Expression and function of microRNAs encoded by Kaposi’s sarcoma-associated herpesvirus. Cold Spring Harb Symp Quant Biol 71:357–364PubMedCrossRefGoogle Scholar
  78. 78.
    Ahmed M, Lock M, Miller CG, Fraser NW (2002) Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. J Virol 76:717–729PubMedCrossRefGoogle Scholar
  79. 79.
    Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW (2006) Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442:82–85PubMedGoogle Scholar
  80. 80.
    Jones C (2003) Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin Microbiol Rev 16:79–95PubMedCrossRefGoogle Scholar
  81. 81.
    Inman M et al (2001) Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture. J Virol 75:3636–3646PubMedCrossRefGoogle Scholar
  82. 82.
    Bogerd HP et al A mammalian herpesvirus uses noncanonical expression and processing mechanisms to generate viral MicroRNAs. Mol Cell 37:135–142Google Scholar
  83. 83.
    Diebel KW, Smith AL, van Dyk LF Mature and functional viral miRNAs transcribed from novel RNA polymerase III promoters. RNA 16:170–185Google Scholar
  84. 84.
    Rodriguez A et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611PubMedCrossRefGoogle Scholar
  85. 85.
    Thai TH et al (2007) Regulation of the germinal center response by microRNA-155. Science 316:604–608PubMedCrossRefGoogle Scholar
  86. 86.
    Burnside J et al (2006) Marek’s disease virus encodes MicroRNAs that map to meq and the latency-associated transcript. J Virol 80:8778–8786PubMedCrossRefGoogle Scholar
  87. 87.
    Skalsky RL et al (2007) Kaposi’s sarcoma-associated herpesvirus encodes an ortholog of miR-155. J Virol 81:12836–12845PubMedCrossRefGoogle Scholar
  88. 88.
    Bolisetty MT, Dy G, Tam W, Beemon KL (2009) Reticuloendotheliosis virus strain T induces miR-155, which targets JARID2 and promotes cell survival. J Virol 83:12009–12017PubMedCrossRefGoogle Scholar
  89. 89.
    Yin Q et al (2008) MicroRNA-155 is an Epstein-Barr virus-induced gene that modulates Epstein-Barr virus-regulated gene expression pathways. J Virol 82:5295–5306PubMedCrossRefGoogle Scholar
  90. 90.
    Xiao C, Rajewsky K (2009) MicroRNA control in the immune system: basic principles. Cell 136:26–36PubMedCrossRefGoogle Scholar
  91. 91.
    Waidner LA et al (2009) MicroRNAs of Gallid and Meleagrid herpesviruses show generally conserved genomic locations and are virus-specific. Virology 388:128–136PubMedCrossRefGoogle Scholar
  92. 92.
    Mathews MB, Shenk T (1991) Adenovirus virus-associated RNA and translation control. J Virol 65:5657–5662PubMedGoogle Scholar
  93. 93.
    Andersson MG et al (2005) Suppression of RNA interference by adenovirus virus-associated RNA. J Virol 79:9556–9565PubMedCrossRefGoogle Scholar
  94. 94.
    Lu S, Cullen BR (2004) Adenovirus VA1 noncoding RNA can inhibit small interfering RNA and MicroRNA biogenesis. J Virol 78:12868–12876PubMedCrossRefGoogle Scholar
  95. 95.
    Seo GJ, Chen CJ, Sullivan CS (2009) Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression. Virology 383:183–187PubMedCrossRefGoogle Scholar
  96. 96.
    Sullivan CS et al (2009) Murine Polyomavirus encodes a microRNA that cleaves early RNA transcripts but is not essential for experimental infection. Virology 387:157–167PubMedCrossRefGoogle Scholar
  97. 97.
    Sullivan CS, Grundhoff AT, Tevethia S, Pipas JM, Ganem D (2005) SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells. Nature 435:682–686PubMedCrossRefGoogle Scholar
  98. 98.
    Cantalupo P et al (2005) Complete nucleotide sequence of polyomavirus SA12. J Virol 79:13094–13104PubMedCrossRefGoogle Scholar
  99. 99.
    Grimson A et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105PubMedCrossRefGoogle Scholar
  100. 100.
    Seo GJ, Fink LH, O’Hara B, Atwood WJ, Sullivan CS (2008) Evolutionarily conserved function of a viral microRNA. J Virol 82:9823–9828PubMedCrossRefGoogle Scholar
  101. 101.
    Barth S et al (2008) Epstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viral DNA polymerase BALF5. Nucleic Acids Res 36:666–675PubMedCrossRefGoogle Scholar
  102. 102.
    Cullen BR (2009) Viral and cellular messenger RNA targets of viral microRNAs. Nature 457:421–425PubMedCrossRefGoogle Scholar
  103. 103.
    Murphy E, Vanicek J, Robins H, Shenk T, Levine AJ (2008) Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: implications for latency. Proc Natl Acad Sci USA 105:5453–5458PubMedCrossRefGoogle Scholar
  104. 104.
    Grey F, Nelson J (2008) Identification and function of human cytomegalovirus microRNAs. J Clin Virol 41:186–191PubMedCrossRefGoogle Scholar
  105. 105.
    Grey F, Meyers H, White EA, Spector DH, Nelson J (2007) A human cytomegalovirus-encoded microRNA regulates expression of multiple viral genes involved in replication. PLoS Pathog 3:e163PubMedCrossRefGoogle Scholar
  106. 106.
    Bellare P, Ganem D (2009) Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation. Cell Host Microbe 6:570–575PubMedCrossRefGoogle Scholar
  107. 107.
    Samols MA et al (2007) Identification of cellular genes targeted by KSHV-encoded microRNAs. PLoS Pathog 3:e65PubMedCrossRefGoogle Scholar
  108. 108.
    Ziegelbauer JM, Sullivan CS, Ganem D (2009) Tandem array-based expression screens identify host mRNA targets of virus-encoded microRNAs. Nat Genet 41:130–134PubMedCrossRefGoogle Scholar
  109. 109.
    Gottwein E et al (2007) A viral microRNA functions as an orthologue of cellular miR-155. Nature 450:1096–1099PubMedCrossRefGoogle Scholar
  110. 110.
    Choy EY et al (2008) An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J Exp Med 205:2551–2560PubMedCrossRefGoogle Scholar
  111. 111.
    Xia T et al (2008) EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. Cancer Res 68:1436–1442PubMedCrossRefGoogle Scholar
  112. 112.
    Nachmani D, Stern-Ginossar N, Sarid R, Mandelboim O (2009) Diverse herpesvirus microRNAs target the stress-induced immune ligand MICB to escape recognition by natural killer cells. Cell Host Microbe 5:376–385PubMedCrossRefGoogle Scholar
  113. 113.
    Stern-Ginossar N et al (2007) Host immune system gene targeting by a viral miRNA. Science 317:376–381PubMedCrossRefGoogle Scholar
  114. 114.
    Dykxhoorn DM (2009) RNA interference as an anticancer therapy: a patent perspective. Expert Opin Ther Pat 19:475–491PubMedCrossRefGoogle Scholar
  115. 115.
    Dykxhoorn DM, Chowdhury D, Lieberman J (2008) RNA interference and cancer: endogenous pathways and therapeutic approaches. Adv Exp Med Biol 615:299–329PubMedCrossRefGoogle Scholar
  116. 116.
    Dykxhoorn DM MicroRNAs and metastasis: little RNAs go a long way. Cancer Res 70:6401–6406Google Scholar
  117. 117.
    Calin GA 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 99:15524–15529PubMedCrossRefGoogle Scholar
  118. 118.
    Diosdado B et al (2009) MiR-17–92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression. Br J Cancer 101:707–714PubMedCrossRefGoogle Scholar
  119. 119.
    Kumar MS et al (2009) Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev 23:2700–2704PubMedCrossRefGoogle Scholar
  120. 120.
    Merritt WM et al (2008) Dicer, Drosha, and outcomes in patients with ovarian cancer. N Engl J Med 359:2641–2650PubMedCrossRefGoogle Scholar
  121. 121.
    Martello G et al (2010) A MicroRNA targeting dicer for metastasis control. Cell 141:1195–1207PubMedCrossRefGoogle Scholar
  122. 122.
    Chang TC et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752PubMedCrossRefGoogle Scholar
  123. 123.
    He X, He L, Hannon GJ (2007) The guardian’s little helper: microRNAs in the p53 tumor suppressor network. Cancer Res 67:11099–11101PubMedCrossRefGoogle Scholar
  124. 124.
    He L, He X, Lowe SW, Hannon GJ (2007) microRNAs join the p53 network–another piece in the tumour-suppression puzzle. Nat Rev Cancer 7:819–822PubMedCrossRefGoogle Scholar
  125. 125.
    He L et al (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134PubMedCrossRefGoogle Scholar
  126. 126.
    Chang TC et al (2008) Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet 40:43–50PubMedCrossRefGoogle Scholar
  127. 127.
    Johnson SM et al (2005) RAS is regulated by the let-7 microRNA family. Cell 120:635–647PubMedCrossRefGoogle Scholar
  128. 128.
    Garzon R et al (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411–6418PubMedCrossRefGoogle Scholar
  129. 129.
    Fabbri M et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810PubMedCrossRefGoogle Scholar
  130. 130.
    Mott JL, Kobayashi S, Bronk SF, Gores GJ (2007) mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26:6133–6140PubMedCrossRefGoogle Scholar
  131. 131.
    Garzon R et al (2009) MicroRNA 29b functions in acute myeloid leukemia. Blood 114:5331–5341PubMedCrossRefGoogle Scholar
  132. 132.
    Saito Y 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 9:435–443PubMedCrossRefGoogle Scholar
  133. 133.
    Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222PubMedCrossRefGoogle Scholar
  134. 134.
    Lujambio A et al (2007) Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 67:1424–1429PubMedCrossRefGoogle Scholar
  135. 135.
    Hackanson B et al (2008) Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia. Cancer Res 68:3142–3151PubMedCrossRefGoogle Scholar
  136. 136.
    Pallasch CP et al (2010) Blood. 114:3255Google Scholar
  137. 137.
    Chin LJ et al (2008) A SNP in a let-7 microRNA complementary site in the KRAS 3’ untranslated region increases non-small cell lung cancer risk. Cancer Res 68:8535–8540PubMedCrossRefGoogle Scholar
  138. 138.
    Keane FK, Ratner ES The KRAS-Variant Genetic Test As a Marker of Increased Risk of Ovarian Cancer. Rev Obstet Gynecol 3:118–121Google Scholar
  139. 139.
    Ratner E et al A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk. Cancer Res 70:6509–6515Google Scholar
  140. 140.
    Nicoloso MS et al Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res 70:2789–2798Google Scholar
  141. 141.
    Liang D et al (2010) Genetic variants in MicroRNA biosynthesis pathways and binding sites modify ovarian cancer risk, survival, and treatment response. Cancer Res 70:9765–9776PubMedCrossRefGoogle Scholar
  142. 142.
    Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579PubMedCrossRefGoogle Scholar
  143. 143.
    Mayr C, Bartel DP (2009) Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138:673–684PubMedCrossRefGoogle Scholar
  144. 144.
    Du T, Zamore PD (2005) microPrimer: the biogenesis and function of microRNA. Development 132:4645–4652PubMedCrossRefGoogle Scholar
  145. 145.
    Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 21:4663–4670PubMedCrossRefGoogle Scholar
  146. 146.
    Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (2004) Processing of primary microRNAs by the Microprocessor complex. Nature 432:231–235PubMedCrossRefGoogle Scholar
  147. 147.
    Lee Y et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419PubMedCrossRefGoogle Scholar
  148. 148.
    Lee Y, Han J, Yeom KH, Jin H, Kim VN (2006) Drosha in primary microRNA processing. Cold Spring Harb Symp Quant Biol 71:51–57PubMedCrossRefGoogle Scholar
  149. 149.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366PubMedCrossRefGoogle Scholar
  150. 150.
    Chendrimada TP et al (2005) TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436:740–744PubMedCrossRefGoogle Scholar
  151. 151.
    Matranga C, Tomari Y, Shin C, Bartel DP, Zamore PD (2005) Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. Cell 123:607–620PubMedCrossRefGoogle Scholar
  152. 152.
    Hutvagner G, Simard MJ, Mello CC, Zamore PD (2004) Sequence-specific inhibition of small RNA function. PLoS Biol 2:E98PubMedCrossRefGoogle Scholar
  153. 153.
    Hutvagner G, Zamore PD (2002) A microRNA in a multiple-turnover RNAi enzyme complex. Science 297:2056–2060PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Dr. John T. Macdonald Foundation of Human Genetics and the Department of Microbiology and Immunology, John P. Hussman Institute for Human GenomicsUniversity of Miami Miller School of MedicineMiamiUSA

Personalised recommendations