MicroRNAs in Human Cancer

  • Thalia A. Farazi
  • Jessica I. Hoell
  • Pavel Morozov
  • Thomas Tuschl
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 774)

Abstract

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20–23-nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the translation and stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and invasion. miRNA targeting is initiated through specific base-pairing interactions between the 5′ end (“seed” region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3′ UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis, and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease specific expression, they hold potential as therapeutic targets and novel biomarkers.

Keywords

microRNA Cancer mRNA destabilization 3′ UTR Genomics Deep sequencing Post-transcriptional gene regulation 

Notes

Acknowledgements

We thank Iddo Ben-Dov for sharing his unpublished data and Miguel Brown and Aleksandra Mihailovic for assistance with figure generation. We thank Markus Hafner, Kemal Akat, and Neil Renwick for their help with editing the manuscript. T.F. is supported by Grant #UL1 TR000043 from the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS), NIH. J.I.H. is supported by the Deutsche Forschungsgemeinschaft. T.T. is an HHMI investigator, and work in his laboratory was supported by NIH grant MH08442, RC1CA145442 and the Starr Cancer Foundation. We apologize to those investigators whose work we could not cite due to space constraints.

References

  1. 1.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854PubMedGoogle Scholar
  2. 2.
    Reinhart BJ, Slack FJ, Basson M et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906PubMedGoogle Scholar
  3. 3.
    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 75:855–862PubMedGoogle Scholar
  4. 4.
    Wightman B, Burglin TR, Gatto J et al (1991) Negative regulatory sequences in the lin-14 3′-untranslated region are necessary to generate a temporal switch during Caenorhabditis elegans development. Genes Dev 5:1813–1824PubMedGoogle Scholar
  5. 5.
    Lagos-Quintana M, Rauhut R, Lendeckel W et al (2001) Identification of novel genes coding for small expressed RNAs. Science 294:853–858PubMedGoogle Scholar
  6. 6.
    Lagos-Quintana M, Rauhut R, Yalcin A et al (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739PubMedGoogle Scholar
  7. 7.
    Lau NC, Lim LP, Weinstein EG et al (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294:858–862PubMedGoogle Scholar
  8. 8.
    Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864PubMedGoogle Scholar
  9. 9.
    Garofalo M, Croce CM (2010) microRNAs: master regulators as potential therapeutics in cancer. Annu Rev Pharmacol Toxicol 51:25–43Google Scholar
  10. 10.
    Medina PP, Slack FJ (2008) microRNAs and cancer: an overview. Cell Cycle 7:2485–2492PubMedGoogle Scholar
  11. 11.
    Ventura A, Jacks T (2009) MicroRNAs and cancer: short RNAs go a long way. Cell 136:586–591PubMedGoogle Scholar
  12. 12.
    Calin GA, Sevignani C, Dumitru CD 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 101:2999–3004PubMedCentralPubMedGoogle Scholar
  13. 13.
    Calin GA, Liu CG, Sevignani C et al (2004) MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci U S A 101:11755–11760PubMedCentralPubMedGoogle Scholar
  14. 14.
    Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838PubMedGoogle Scholar
  15. 15.
    Aravin A, Tuschl T (2005) Identification and characterization of small RNAs involved in RNA silencing. FEBS Lett 579:5830–5840PubMedGoogle Scholar
  16. 16.
    Creighton CJ, Reid JG, Gunaratne PH (2009) Expression profiling of microRNAs by deep sequencing. Brief Bioinform 10:490–497PubMedGoogle Scholar
  17. 17.
    Meyer SU, Pfaffl MW, Ulbrich SE (2010) Normalization strategies for microRNA profiling experiments: a ‘normal’ way to a hidden layer of complexity? Biotechnol Lett 32(12):1777–1788PubMedGoogle Scholar
  18. 18.
    Lawrie CH, Soneji S, Marafioti T et al (2007) MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer 121:1156–1161PubMedGoogle Scholar
  19. 19.
    Weng L, Wu X, Gao H et al (2010) MicroRNA profiling of clear cell renal cell carcinoma by whole-genome small RNA deep sequencing of paired frozen and formalin-fixed, paraffin-embedded tissue specimens. J Pathol 222:41–51PubMedGoogle Scholar
  20. 20.
    Xi Y, Nakajima G, Gavin E et al (2007) Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. RNA 13:1668–1674PubMedGoogle Scholar
  21. 21.
    Barad O, Meiri E, Avniel A et al (2004) MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res 14:2486–2494PubMedGoogle Scholar
  22. 22.
    Baskerville S, Bartel DP (2005) Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA 11:241–247PubMedGoogle Scholar
  23. 23.
    Thomson JM, Parker JS, Hammond SM (2007) Microarray analysis of miRNA gene expression. Methods Enzymol 427:107–122PubMedGoogle Scholar
  24. 24.
    Nelson PT, Baldwin DA, Scearce LM et al (2004) Microarray-based, high-throughput gene expression profiling of microRNAs. Nat Methods 1:155–161PubMedGoogle Scholar
  25. 25.
    Bissels U, Wild S, Tomiuk S et al (2009) Absolute quantification of microRNAs by using a universal reference. RNA 15:2375–2384PubMedGoogle Scholar
  26. 26.
    Peltier HJ, Latham GJ (2008) Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA 14:844–852PubMedGoogle Scholar
  27. 27.
    Fiedler SD, Carletti MZ, Christenson LK (2010) Quantitative RT-PCR methods for mature microRNA expression analysis. Methods Mol Biol 630:49–64PubMedGoogle Scholar
  28. 28.
    Mestdagh P, Van Vlierberghe P, De Weer A et al (2009) A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol 10:R64PubMedCentralPubMedGoogle Scholar
  29. 29.
    Smith RD, Brown B, Ikonomi P et al (2003) Exogenous reference RNA for normalization of real-time quantitative PCR. Biotechniques 34:88–91PubMedGoogle Scholar
  30. 30.
    Taulli R, Bersani F, Foglizzo V et al (2009) The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest 119:2366–2378PubMedCentralPubMedGoogle Scholar
  31. 31.
    Berezikov E, Thuemmler F, van Laake LW et al (2006) Diversity of microRNAs in human and chimpanzee brain. Nat Genet 38:1375–1377PubMedGoogle Scholar
  32. 32.
    Houbaviy HB, Murray MF, Sharp PA (2003) Embryonic stem cell-specific microRNAs. Dev Cell 5:351–358PubMedGoogle Scholar
  33. 33.
    Landgraf P, Rusu M, Sheridan R et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414PubMedCentralPubMedGoogle Scholar
  34. 34.
    Witten D, Tibshirani R, Gu SG et al (2010) Ultra-high throughput sequencing-based small RNA discovery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls. BMC Biol 8:58PubMedCentralPubMedGoogle Scholar
  35. 35.
    Vigneault F, Sismour AM, Church GM (2008) Efficient microRNA capture and bar-coding via enzymatic oligonucleotide adenylation. Nat Methods 5:777–779PubMedGoogle Scholar
  36. 36.
    Hafner M, Renwick N, Brown M et al (2011) RNA-ligase-dependent biases in miRNA representation in deep-sequenced small RNA cDNA libraries. RNA 17:1697–1712PubMedGoogle Scholar
  37. 37.
    Git A, Dvinge H, Salmon-Divon M et al (2010) Systematic comparison of microarray profiling, real-time PCR, and next-generation sequencing technologies for measuring differential microRNA expression. RNA 16:991–1006PubMedGoogle Scholar
  38. 38.
    Ugras S, Brill E, Jacobsen A et al (2011) Small RNA sequencing and functional characterization reveals microRNA-143 tumor suppressor activity in liposarcoma. Cancer Res 71:5659–5669PubMedCentralPubMedGoogle Scholar
  39. 39.
    Farazi TA, Horlings HM, Ten Hoeve JJ et al (2011) MicroRNA sequence and expression analysis in breast tumors by deep sequencing. Cancer Res 71:4443–4453PubMedCentralPubMedGoogle Scholar
  40. 40.
    Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A 98:5116–5121PubMedCentralPubMedGoogle Scholar
  41. 41.
    Berninger P, Gaidatzis D, van Nimwegen E et al (2008) Computational analysis of small RNA cloning data. Methods 44:13–21PubMedGoogle Scholar
  42. 42.
    Robinson MD, McCarthy DJ, Smyth GK (2010) EdgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140PubMedGoogle Scholar
  43. 43.
    Nelson PT, Baldwin DA, Kloosterman WP et al (2006) RAKE and LNA-ISH reveal microRNA expression and localization in archival human brain. RNA 12:187–191PubMedGoogle Scholar
  44. 44.
    Pena JT, Sohn-Lee C, Rouhanifard SH et al (2009) miRNA in situ hybridization in formaldehyde and EDC-fixed tissues. Nat Methods 6:139–141PubMedCentralPubMedGoogle Scholar
  45. 45.
    Sempere LF, Christensen M, Silahtaroglu A et al (2007) Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer. Cancer Res 67:11612–11620PubMedGoogle Scholar
  46. 46.
    Johnston RJ, Hobert O (2003) A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans. Nature 426:845–849PubMedGoogle Scholar
  47. 47.
    Griffiths-Jones S, Saini HK, van Dongen S et al (2008) miRBase: tools for microRNA genomics. Nucleic Acids Res 36:D154–D158PubMedCentralPubMedGoogle Scholar
  48. 48.
    Kozomara A, Griffiths-Jones S (2010) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39:D152–D157PubMedCentralPubMedGoogle Scholar
  49. 49.
    Chiang HR, Schoenfeld LW, Ruby JG et al (2010) Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev 24:992–1009PubMedGoogle Scholar
  50. 50.
    Calin GA, Dumitru CD, Shimizu M 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 99:15524–15529PubMedCentralPubMedGoogle Scholar
  51. 51.
    Tagawa H, Seto M (2005) A microRNA cluster as a target of genomic amplification in malignant lymphoma. Leukemia 19:2013–2016PubMedGoogle Scholar
  52. 52.
    Mavrakis KJ, Wolfe AL, Oricchio E et al (2010) Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol 12:372–379PubMedCentralPubMedGoogle Scholar
  53. 53.
    Huse JT, Brennan C, Hambardzumyan D et al (2009) The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo. Genes Dev 23:1327–1337PubMedGoogle Scholar
  54. 54.
    Gauwerky CE, Huebner K, Isobe M et al (1989) Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia. Proc Natl Acad Sci U S A 86:8867–8871PubMedCentralPubMedGoogle Scholar
  55. 55.
    Etiemble J, Moroy T, Jacquemin E et al (1989) Fused transcripts of c-myc and a new cellular locus, hcr in a primary liver tumor. Oncogene 4:51–57PubMedGoogle Scholar
  56. 56.
    Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610PubMedGoogle Scholar
  57. 57.
    Chang TC, Wentzel EA, Kent OA et al (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752PubMedCentralPubMedGoogle Scholar
  58. 58.
    He L, He X, Lowe SW et al (2007) microRNAs join the p53 network – another piece in the tumour-suppression puzzle. Nat Rev Cancer 7:819–822PubMedGoogle Scholar
  59. 59.
    Hatley ME, Patrick DM, Garcia MR et al (2010) Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell 18:282–293PubMedCentralPubMedGoogle Scholar
  60. 60.
    Huang TH, Wu F, Loeb GB et al (2009) Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion. J Biol Chem 284:18515–18524PubMedGoogle Scholar
  61. 61.
    O’Donnell KA, Wentzel EA, Zeller KI et al (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843PubMedGoogle Scholar
  62. 62.
    He L, Thomson JM, Hemann MT et al (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833PubMedGoogle Scholar
  63. 63.
    Han L, Witmer PD, Casey E et al (2007) DNA methylation regulates MicroRNA expression. Cancer Biol Ther 6:1284–1288PubMedGoogle Scholar
  64. 64.
    Saito Y, Jones PA (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222PubMedGoogle Scholar
  65. 65.
    Saito Y, Liang G, Egger G 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 9:435–443PubMedGoogle Scholar
  66. 66.
    Lehmann U, Hasemeier B, Christgen M et al (2008) Epigenetic inactivation of microRNA gene hsa-mir-9-1 in human breast cancer. J Pathol 214:17–24PubMedGoogle Scholar
  67. 67.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedGoogle Scholar
  68. 68.
    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCentralPubMedGoogle Scholar
  69. 69.
    Brodersen P, Voinnet O (2009) Revisiting the principles of microRNA target recognition and mode of action. Nat Rev Mol Cell Biol 10:141–148PubMedGoogle Scholar
  70. 70.
    Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655PubMedCentralPubMedGoogle Scholar
  71. 71.
    Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108PubMedCentralPubMedGoogle Scholar
  72. 72.
    Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139PubMedGoogle Scholar
  73. 73.
    Winter J, Jung S, Keller S et al (2009) Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 11:228–234PubMedGoogle Scholar
  74. 74.
    Kwak PB, Iwasaki S, Tomari Y (2010) The microRNA pathway and cancer. Cancer Sci 101(11):2309–2315PubMedGoogle Scholar
  75. 75.
    Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402PubMedCentralPubMedGoogle Scholar
  76. 76.
    Nishikura K (2010) Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79:321–349PubMedCentralPubMedGoogle Scholar
  77. 77.
    Yi R, Pasolli HA, Landthaler M et al (2009) DGCR8-dependent microRNA biogenesis is essential for skin development. Proc Natl Acad Sci U S A 106:498–502PubMedCentralPubMedGoogle Scholar
  78. 78.
    Cheloufi S, Dos Santos CO, Chong MM et al (2010) A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465:584–589PubMedCentralPubMedGoogle Scholar
  79. 79.
    Yang JS, Maurin T, Robine N et al (2010) Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci U S A 107:15163–15168PubMedCentralPubMedGoogle Scholar
  80. 80.
    Babiarz JE, Ruby JG, Wang Y et al (2008) Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev 22:2773–2785PubMedGoogle Scholar
  81. 81.
    Berezikov E, Chung WJ, Willis J et al (2007) Mammalian mirtron genes. Mol Cell 28:328–336PubMedCentralPubMedGoogle Scholar
  82. 82.
    Yang JS, Lai EC (2011) Alternative miRNA biogenesis pathways and the interpretation of core miRNA pathway mutants. Mol Cell 43:892–903PubMedCentralPubMedGoogle Scholar
  83. 83.
    van Kouwenhove M, Kedde M, Agami R (2011) MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat Rev Cancer 11:644–656PubMedGoogle Scholar
  84. 84.
    Hagan JP, Piskounova E, Gregory RI (2009) Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 16:1021–1025PubMedCentralPubMedGoogle Scholar
  85. 85.
    Kawahara Y, Zinshteyn B, Chendrimada TP et al (2007) RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep 8:763–769PubMedCentralPubMedGoogle Scholar
  86. 86.
    Stefani G, Slack FJ (2008) Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol 9:219–230PubMedGoogle Scholar
  87. 87.
    Kumar MS, Lu J, Mercer KL et al (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 39:673–677PubMedGoogle Scholar
  88. 88.
    Kumar MS, Pester RE, Chen CY et al (2009) Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev 23:2700–2704PubMedGoogle Scholar
  89. 89.
    Lambertz I, Nittner D, Mestdagh P et al (2010) Monoallelic but not biallelic loss of Dicer1 promotes tumorigenesis in vivo. Cell Death Differ 17:633–641PubMedCentralPubMedGoogle Scholar
  90. 90.
    Paroo Z, Ye X, Chen S et al (2009) Phosphorylation of the human microRNA-generating complex mediates MAPK/Erk signaling. Cell 139:112–122PubMedCentralPubMedGoogle Scholar
  91. 91.
    Melo SA, Ropero S, Moutinho C et al (2009) A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function. Nat Genet 41:365–370PubMedGoogle Scholar
  92. 92.
    Garre P, Perez-Segura P, Diaz-Rubio E et al (2010) Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer. Nat Genet 42:817–818; author reply 818PubMedGoogle Scholar
  93. 93.
    Valastyan S, Weinberg RA (2010) Metastasis suppression: a role of the Dice(r). Genome Biol 11:141PubMedCentralPubMedGoogle Scholar
  94. 94.
    Newman MA, Thomson JM, Hammond SM (2008) Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14:1539–1549PubMedGoogle Scholar
  95. 95.
    Piskounova E, Viswanathan SR, Janas M et al (2008) Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. J Biol Chem 283:21310–21314PubMedGoogle Scholar
  96. 96.
    Rybak A, Fuchs H, Smirnova L et al (2008) A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol 10:987–993PubMedGoogle Scholar
  97. 97.
    Viswanathan SR, Daley GQ, Gregory RI (2008) Selective blockade of microRNA processing by Lin28. Science 320:97–100PubMedCentralPubMedGoogle Scholar
  98. 98.
    Viswanathan SR, Powers JT, Einhorn W et al (2009) Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 41:843–848PubMedCentralPubMedGoogle Scholar
  99. 99.
    Viswanathan SR, Daley GQ (2010) Lin28: a microRNA regulator with a macro role. Cell 140:445–449PubMedGoogle Scholar
  100. 100.
    Fukuda T, Yamagata K, Fujiyama S et al (2007) DEAD-box RNA helicase subunits of the Drosha complex are required for processing of rRNA and a subset of microRNAs. Nat Cell Biol 9:604–611PubMedGoogle Scholar
  101. 101.
    Suzuki HI, Yamagata K, Sugimoto K et al (2009) Modulation of microRNA processing by p53. Nature 460:529–533PubMedGoogle Scholar
  102. 102.
    Davis BN, Hilyard AC, Lagna G et al (2008) SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454(7200):56–61PubMedCentralPubMedGoogle Scholar
  103. 103.
    Trabucchi M, Briata P, Garcia-Mayoral M et al (2009) The RNA-binding protein KSRP promotes the biogenesis of a subset of microRNAs. Nature 459:1010–1014PubMedCentralPubMedGoogle Scholar
  104. 104.
    Melo SA, Moutinho C, Ropero S et al (2010) A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 18:303–315PubMedGoogle Scholar
  105. 105.
    Ender C, Meister G (2010) Argonaute proteins at a glance. J Cell Sci 123:1819–1823PubMedGoogle Scholar
  106. 106.
    Parker JS (2010) How to slice: snapshots of Argonaute in action. Silence 1:3PubMedCentralPubMedGoogle Scholar
  107. 107.
    Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110PubMedGoogle Scholar
  108. 108.
    Linsley PS, Schelter J, Burchard J et al (2007) Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol 27:2240–2252PubMedCentralPubMedGoogle Scholar
  109. 109.
    Zhao Y, Ransom JF, Li A et al (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317PubMedGoogle Scholar
  110. 110.
    Bagga S, Bracht J, Hunter S et al (2005) Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell 122:553–563PubMedGoogle Scholar
  111. 111.
    Lim LP, Lau NC, Garrett-Engele P et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773PubMedGoogle Scholar
  112. 112.
    Baek D, Villen J, Shin C et al (2008) The impact of microRNAs on protein output. Nature 455(7209):64–71PubMedCentralPubMedGoogle Scholar
  113. 113.
    Selbach M, Schwanhausser B, Thierfelder N et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455(7209):58–63PubMedGoogle Scholar
  114. 114.
    Grimson A, Farh KK, Johnston WK et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105PubMedCentralPubMedGoogle Scholar
  115. 115.
    Hausser J, Landthaler M, Jaskiewicz L et al (2009) Relative contribution of sequence and structure features to the mRNA binding of Argonaute/EIF2C-miRNA complexes and the degradation of miRNA targets. Genome Res 19:2009–2020PubMedGoogle Scholar
  116. 116.
    Karginov FV, Conaco C, Xuan Z et al (2007) A biochemical approach to identifying microRNA targets. Proc Natl Acad Sci U S A 104:19291–19296PubMedCentralPubMedGoogle Scholar
  117. 117.
    Krützfeldt J, Rajewsky N, Braich R et al (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689PubMedGoogle Scholar
  118. 118.
    Landthaler M, Gaidatzis D, Rothballer A et al (2008) Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA 14:2580–2596PubMedGoogle Scholar
  119. 119.
    Guo H, Ingolia NT, Weissman JS et al (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466:835–840PubMedCentralPubMedGoogle Scholar
  120. 120.
    Mu P, Han YC, Betel D et al (2009) Genetic dissection of the miR-17 92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev 23:2806–2811PubMedGoogle Scholar
  121. 121.
    Wu S, Huang S, Ding J et al (2010) Multiple microRNAs modulate p21Cip1/Waf1 expression by directly targeting its 3′ untranslated region. Oncogene 29:2302–2308PubMedGoogle Scholar
  122. 122.
    Krek A, Grun D, Poy MN et al (2005) Combinatorial microRNA target predictions. Nat Genet 37:495–500PubMedGoogle Scholar
  123. 123.
    Chin LJ, Ratner E, Leng S 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 68:8535–8540PubMedCentralPubMedGoogle Scholar
  124. 124.
    Jiang S, Zhang HW, Lu MH et al (2010) MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Res 70:3119–3127PubMedGoogle Scholar
  125. 125.
    Takamizawa J, Konishi H, Yanagisawa K et al (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64:3753–3756PubMedGoogle Scholar
  126. 126.
    Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579PubMedCentralPubMedGoogle Scholar
  127. 127.
    Mayr C, Bartel DP (2009) Widespread shortening of 3′ UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138:673–684PubMedCentralPubMedGoogle Scholar
  128. 128.
    Poliseno L, Salmena L, Zhang J et al (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465:1033–1038PubMedCentralPubMedGoogle Scholar
  129. 129.
    Bhattacharyya SN, Habermacher R, Martine U et al (2006) Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125:1111–1124PubMedGoogle Scholar
  130. 130.
    Kim HH, Kuwano Y, Srikantan S et al (2009) HuR recruits let-7/RISC to repress c-Myc expression. Genes Dev 23:1743–1748PubMedGoogle Scholar
  131. 131.
    Kedde M, Strasser MJ, Boldajipour B et al (2007) RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131:1273–1286PubMedGoogle Scholar
  132. 132.
    Kedde M, van Kouwenhove M, Zwart W et al (2010) A Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nat Cell Biol 12:1014–1020PubMedGoogle Scholar
  133. 133.
    Volinia S, Galasso M, Costinean S et al (2010) Reprogramming of miRNA networks in cancer and leukemia. Genome Res 20:589–599PubMedGoogle Scholar
  134. 134.
    Mestdagh P, Lefever S, Pattyn F et al (2011) The microRNA body map: dissecting microRNA function through integrative genomics. Nucleic Acids Res 39(20):e136PubMedCentralPubMedGoogle Scholar
  135. 135.
    Keller A, Leidinger P, Bauer A et al (2011) Toward the blood-borne miRNome of human diseases. Nat Methods 8(10):841–843PubMedGoogle Scholar
  136. 136.
    Calin GA, Cimmino A, Fabbri M et al (2008) MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 105:5166–5171PubMedCentralPubMedGoogle Scholar
  137. 137.
    Roush S, Slack FJ (2008) The let-7 family of microRNAs. Trends Cell Biol 18:505–516PubMedGoogle Scholar
  138. 138.
    Peter ME (2009) Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 8:843–852PubMedCentralPubMedGoogle Scholar
  139. 139.
    Osada H, Takahashi T (2011) let-7 and miR-17-92: small-sized major players in lung cancer development. Cancer Sci 102:9–17PubMedGoogle Scholar
  140. 140.
    O’Day E, Lal A (2010) MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res 12:201PubMedCentralPubMedGoogle Scholar
  141. 141.
    Aqeilan RI, Calin GA, Croce CM (2010) miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ 17:215–220PubMedGoogle Scholar
  142. 142.
    Finnerty JR, Wang WX, Hebert SS et al (2010) The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol 402:491–509PubMedCentralPubMedGoogle Scholar
  143. 143.
    Mendell JT (2008) miRiad roles for the miR-17-92 cluster in development and disease. Cell 133:217–222PubMedCentralPubMedGoogle Scholar
  144. 144.
    Uziel T, Karginov FV, Xie S et al (2009) The miR-17 92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma. Proc Natl Acad Sci U S A 106:2812–2817PubMedCentralPubMedGoogle Scholar
  145. 145.
    Poliseno L, Salmena L, Riccardi L et al (2010) Identification of the miR-106b∼25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 3:ra29PubMedCentralPubMedGoogle Scholar
  146. 146.
    Jazbutyte V, Thum T (2010) MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets 11:926–935PubMedGoogle Scholar
  147. 147.
    Sander S, Bullinger L, Klapproth K et al (2008) MYC stimulates EZH2 expression by repression of its negative regulator miR-26a. Blood 112:4202–4212PubMedGoogle Scholar
  148. 148.
    Kota J, Chivukula RR, O’Donnell KA et al (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137:1005–1017PubMedCentralPubMedGoogle Scholar
  149. 149.
    Visone R, Pallante P, Vecchione A et al (2007) Specific microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 26:7590–7595PubMedGoogle Scholar
  150. 150.
    Kim H, Huang W, Jiang X et al (2010) Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci U S A 107:2183–2188PubMedCentralPubMedGoogle Scholar
  151. 151.
    Cole KA, Attiyeh EF, Mosse YP et al (2008) A functional screen identifies miR-34a as a candidate neuroblastoma tumor suppressor gene. Mol Cancer Res 6:735–742PubMedCentralPubMedGoogle Scholar
  152. 152.
    Li N, Fu H, Tie Y et al (2009) miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 275:44–53PubMedGoogle Scholar
  153. 153.
    Gregory PA, Bracken CP, Bert AG et al (2008) MicroRNAs as regulators of epithelial-mesenchymal transition. Cell Cycle 7:3112–3118PubMedGoogle Scholar
  154. 154.
    Nakada C, Matsuura K, Tsukamoto Y et al (2008) Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J Pathol 216:418–427PubMedGoogle Scholar
  155. 155.
    Du Y, Xu Y, Ding L et al (2009) Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. J Gastroenterol 44:556–561PubMedGoogle Scholar
  156. 156.
    Adam L, Zhong M, Choi W et al (2009) miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res 15:5060–5072PubMedGoogle Scholar
  157. 157.
    Bendoraite A, Knouf EC, Garg KS et al (2009) Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol Oncol 116:117–125PubMedCentralPubMedGoogle Scholar
  158. 158.
    Park SM, Gaur AB, Lengyel E et al (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22:894–907PubMedGoogle Scholar
  159. 159.
    Hu X, Macdonald DM, Huettner PC et al (2009) A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecol Oncol 114:457–464PubMedGoogle Scholar
  160. 160.
    Gandellini P, Folini M, Longoni N (2009) miR-205 Exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 69:2287–2295PubMedGoogle Scholar
  161. 161.
    Schaefer A, Jung M, Mollenkopf HJ et al (2010) Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer 126:1166–1176PubMedGoogle Scholar
  162. 162.
    Wiklund ED, Bramsen JB, Hulf T et al (2011) Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer 128:1327–1334PubMedGoogle Scholar
  163. 163.
    Iorio MV, Ferracin M, Liu CG et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070PubMedGoogle Scholar
  164. 164.
    Wu H, Zhu S, Mo YY (2009) Suppression of cell growth and invasion by miR-205 in breast cancer. Cell Res 19:439–448PubMedCentralPubMedGoogle Scholar
  165. 165.
    Feber A, Xi L, Luketich JD et al (2008) MicroRNA expression profiles of esophageal cancer. J Thorac Cardiovasc Surg 135:255–260; discussion 260PubMedCentralPubMedGoogle Scholar
  166. 166.
    Iorio MV, Visone R, Di Leva G et al (2007) MicroRNA signatures in human ovarian cancer. Cancer Res 67:8699–8707PubMedGoogle Scholar
  167. 167.
    Negrini M, Calin GA (2008) Breast cancer metastasis: a microRNA story. Breast Cancer Res 10:203PubMedCentralPubMedGoogle Scholar
  168. 168.
    Ferretti E, De Smaele E, Po A et al (2009) MicroRNA profiling in human medulloblastoma. Int J Cancer 124:568–577PubMedGoogle Scholar
  169. 169.
    Laios A, O’Toole S, Flavin R et al (2008) Potential role of miR-9 and miR-223 in recurrent ovarian cancer. Mol Cancer 7:35PubMedCentralPubMedGoogle Scholar
  170. 170.
    Ma L, Young J, Prabhala H et al (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12:247–256PubMedCentralPubMedGoogle Scholar
  171. 171.
    Sun Y, Wu J, Wu SH et al (2009) Expression profile of microRNAs in c-Myc induced mouse mammary tumors. Breast Cancer Res Treat 118:185–196PubMedGoogle Scholar
  172. 172.
    Kumar MS, Erkeland SJ, Pester RE et al (2008) Suppression of non-small cell lung tumor development by the let-7 microRNA family. Proc Natl Acad Sci 105:3903–3908PubMedGoogle Scholar
  173. 173.
    Xiao C, Srinivasan L, Calado DP et al (2008) Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol 9:405–414PubMedCentralPubMedGoogle Scholar
  174. 174.
    Medina PP, Nolde M, Slack FJ (2010) OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467:86–90PubMedGoogle Scholar
  175. 175.
    Costinean S, Zanesi N, Pekarsky Y et al (2006) Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci U S A 103:7024–7029PubMedCentralPubMedGoogle Scholar
  176. 176.
    O’Connell RM, Rao DS, Chaudhuri AA et al (2008) Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 205:585–594PubMedCentralPubMedGoogle Scholar
  177. 177.
    Hurst DR, Edmonds MD, Welch DR (2009) Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res 69:7495–7498PubMedCentralPubMedGoogle Scholar
  178. 178.
    Camps C, Buffa FM, Colella S et al (2008) hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res 14:1340–1348PubMedGoogle Scholar
  179. 179.
    Foekens JA, Sieuwerts AM, Smid M et al (2008) Four miRNAs associated with aggressiveness of lymph node-negative, estrogen receptor-positive human breast cancer. Proc Natl Acad Sci 105:13021–13026PubMedGoogle Scholar
  180. 180.
    Friedman RC, Farh KK, Burge CB et al (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedGoogle Scholar
  181. 181.
    Valastyan S, Benaich N, Chang A et al (2009) Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis. Genes Dev 23:2592–2597PubMedGoogle Scholar
  182. 182.
    Cano A, Nieto MA (2008) Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends Cell Biol 18:357–359PubMedGoogle Scholar
  183. 183.
    Yu F, Yao H, Zhu P et al (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123PubMedGoogle Scholar
  184. 184.
    Lewis MA, Quint E, Glazier AM et al (2009) An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet 41:614–618PubMedCentralPubMedGoogle Scholar
  185. 185.
    Mencia A, Modamio-Hoybjor S, Redshaw N et al (2009) Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet 41:609–613PubMedGoogle Scholar
  186. 186.
    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 71:357–364PubMedGoogle Scholar
  187. 187.
    de Pontual L, Yao E, Callier P (2011) Germline deletion of the miR-17 approximately 92 cluster causes skeletal and growth defects in humans. Nat Genet 43(10):1026–1030PubMedCentralPubMedGoogle Scholar
  188. 188.
    Calin GA, Ferracin M, Cimmino A et al (2005) A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 353:1793–1801PubMedGoogle Scholar
  189. 189.
    Raveche ES, Salerno E, Scaglione BJ et al (2007) Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice. Blood 109:5079–5086PubMedGoogle Scholar
  190. 190.
    Chi SW, Zang JB, Mele A et al (2009) Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460:479–486PubMedCentralPubMedGoogle Scholar
  191. 191.
    Hafner M, Landthaler M, Burger L et al (2010) Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141:129–141PubMedCentralPubMedGoogle Scholar
  192. 192.
    Johnson CD, Esquela-Kerscher A, Stefani G et al (2007) The let-7 MicroRNA represses cell proliferation pathways in human cells. Cancer Res 67:7713–7722PubMedGoogle Scholar
  193. 193.
    Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198PubMedGoogle Scholar
  194. 194.
    Esau C, Kang X, Peralta E et al (2004) MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 279:52361–52365PubMedGoogle Scholar
  195. 195.
    Krutzfeldt J, Kuwajima S, Braich R et al (2007) Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic Acids Res 35:2885–2892PubMedCentralPubMedGoogle Scholar
  196. 196.
    Elmen J, Lindow M, Silahtaroglu A et al (2008) Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res 36:1153–1162PubMedCentralPubMedGoogle Scholar
  197. 197.
    Esau C, Davis S, Murray SF et al (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3:87–98PubMedGoogle Scholar
  198. 198.
    Elmen J, Lindow M, Schutz S et al (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–899PubMedGoogle Scholar
  199. 199.
    Ebert MS, Sharp PA (2010) MicroRNA sponges: progress and possibilities. RNA 16:2043–2050PubMedGoogle Scholar
  200. 200.
    Lanford RE, Hildebrandt-Eriksen ES, Petri A et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327:198–201PubMedCentralPubMedGoogle Scholar
  201. 201.
    Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431:343–349PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Thalia A. Farazi
    • 1
  • Jessica I. Hoell
    • 1
  • Pavel Morozov
    • 1
  • Thomas Tuschl
    • 1
  1. 1.Howard Hughes Medical Institute, Laboratory of RNA Molecular BiologyThe Rockefeller UniversityNew YorkUSA

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