Immune Netw.  2011 Jun;11(3):135-154. 10.4110/in.2011.11.3.135.

MicroRNAs in Human Diseases: From Cancer to Cardiovascular Disease

• Ha TY

• KMID: 2150701
• DOI: http://doi.org/10.4110/in.2011.11.3.135

Abstract

The great discovery of microRNAs (miRNAs) has revolutionized current cell biology and medical science. miRNAs are small conserved non-coding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region of specific messenger RNAs for degradation or translational repression. New members of the miRNA family are being discovered on a daily basis and emerging evidence has demonstrated that miRNAs play a major role in a wide range of developmental process including cell proliferation, cell cycle, cell differentiation, metabolism, apoptosis, developmental timing, neuronal cell fate, neuronal gene expression, brain morphogenesis, muscle differentiation and stem cell division. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, psychiatric and neurological diseases, cardiovascular disease, and autoimmune disease. Interestingly, in addition, miRNA deficiencies or excesses have been correlated with a number of clinically important diseases ranging from cancer to myocardial infarction. miRNAs can repress the gene translation of hundreds of their targets and are therefore well-positioned to target a multitude of cellular mechanisms. As a consequence of extensive participation in normal functions, it is quite logical to ask the question if abnormalities in miRNAs should have importance in human diseases. Great discoveries and rapid progress in the past few years on miRNAs provide the hope that miRNAs will in the near future have a great potential in the diagnosis and treatment of many diseases. Currently, an explosive literature has focussed on the role of miRNA in human cancer and cardiovascular disease. In this review, I briefly summarize the explosive current studies about involvement of miRNA in various human cancers and cardiovascular disease.

Keyword

MicroRNAs; Human disease; Cancer; Heart disease

MeSH Terms

3' Untranslated Regions
Apoptosis
Autoimmune Diseases
Brain
Cardiovascular Diseases
Cell Cycle
Cell Differentiation
Cell Proliferation
Gene Expression
Heart Diseases
Homeostasis
Humans
Logic
MicroRNAs
Morphogenesis
Muscles
Myocardial Infarction
Neurons
Repression, Psychology
RNA, Messenger
RNA, Untranslated
Stem Cells
3' Untranslated Regions
MicroRNAs
RNA, Messenger
RNA, Untranslated

Figure

• 

  Figure 1 Modes of gene regulation by miRNAs. Diverse role of miRNAs, such as mRNA degradation, inhibition of translation, histone modification, and DNA methylation. miRNAs not only regulate gene expression at the post-transcriptional level, but they are also capable of modifying transcription (For the details, see Text).

• 

  Figure 2 Biological and cellular functions of miRNAs. miRNAs subserve multiple fundamental biological roles. Various miRNAs may interact with thousands of different mRNA targets. Post-transcriptional RNA editing may change mRNA target specificity (For the details, see Text).

• 

  Figure 3 miRNAs function as both tumor suppressor (including metastasis suppressor miRNA), and oncogene in breast cancer (For the details, see Text).

• 

  Figure 4 MicroRNAs are altered or induced by environmental chemicals, drugs and dietary components through epigenetic mechanisms and genetic polymorphisms including protein or miRNA genes. Dietary components potentially influence fundamental cellular processes involved in carcinogenesis and psychiatric disorders, including apoptosis, cell cycle control, angiogenesis, inflammation and DNA repair. These alteration can be caused by various mechanisms, including deletion, amplifications or mutations involving miRNA loci, epigenetic silencing or dysregulation of transcription factors that target specific mRNA. Targeting miRNAs may provide insight into the common and unique pathways and mechanisms of the treatment. Elucidating more miRNAs and predicted targets may reveal novel therapies that modify plasticity cascades to restore function (For the details, see Text).

Reference

1. O'Neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol. 2011; 11:163–175. PMID: 21331081.

2. O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 2010; 10:111–122. PMID: 20098459.

3. Baltimore D, Boldin MP, O'Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008; 9:839–845. PMID: 18645592.

4. Slaby O, Svoboda M, Michalek J, Vyzula R. MicroRNAs in colorectal cancer: translation of molecular biology into clinical application. Mol Cancer. 2009; 8:102. PMID: 19912656.

5. Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature. 2011; 469:336–342. PMID: 21248840.

6. Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, Qin YW, Jing Q. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010; 31:659–666. PMID: 20159880.

7. Miller BH, Wahlestedt C. MicroRNA dysregulation in psychiatric disease. Brain Res. 2010; 1338:89–99. PMID: 20303342.

8. Belver L, de Yébenes VG, Ramiro AR. MicroRNAs prevent the generation of autoreactive antibodies. Immunity. 2010; 33:713–722. PMID: 21093320.

9. Caporali A, Meloni M, Völlenkle C, Bonci D, Sala-Newby GB, Addis R, Spinetti G, Losa S, Masson R, Baker AH, Agami R, le Sage C, Condorelli G, Madeddu P, Martelli F, Emanueli C. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. 2011; 123:282–291. PMID: 21220732.

10. Maes OC, Chertkow HM, Wang E, Schipper HM. MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders. Curr Genomics. 2009; 10:154–168. PMID: 19881909.

11. Tili E, Michaille JJ, Calin GA. Expression and function of micro-RNAs in immune cells during normal or disease state. Int J Med Sci. 2008; 5:73–79. PMID: 18392144.

12. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, Taccioli C, Volinia S, Liu CG, Alder H, Calin GA, Ménard S, Croce CM. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007; 67:8699–8707. PMID: 17875710.

13. Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010; 466:835–840. PMID: 20703300.

14. Perera RJ, Ray A. MicroRNAs in the search for understanding human diseases. BioDrugs. 2007; 21:97–104. PMID: 17402793.

15. Ha TY. The Role of MicroRNAs in Regulatory T Cells and in the Immune Response. Immune Netw. 2011; 11:11–41. PMID: 21494372.

16. Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W, Cui Q. An analysis of human microRNA and disease associations. PLoS One. 2008; 3:e3420. PMID: 18923704.

17. Garofalo M, Condorelli G, Croce CM. MicroRNAs in diseases and drug response. Curr Opin Pharmacol. 2008; 8:661–667. PMID: 18619557.

18. Tomankova T, Petrek M, Kriegova E. Involvement of microRNAs in physiological and pathological processes in the lung. Respir Res. 2010; 11:159. PMID: 21092244.

19. Pallante P, Visone R, Croce CM, Fusco A. Deregulation of microRNA expression in follicular-cell-derived human thyroid carcinomas. Endocr Relat Cancer. 2010; 17:F91–F104. PMID: 19942715.

20. Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008; 455:58–63. PMID: 18668040.

21. Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008; 455:64–71. PMID: 18668037.

22. Germain RN, Meier-Schellersheim M, Nita-Lazar A, Fraser ID. Systems biology in immunology: a computational modeling perspective. Annu Rev Immunol. 2011; 29:527–585. PMID: 21219182.

23. Lu LF, Liston A. MicroRNA in the immune system, microRNA as an immune system. Immunology. 2009; 127:291–298. PMID: 19538248.

24. Liston A, Linterman M, Lu LF. MicroRNA in the adaptive immune system, in sickness and in health. J Clin Immunol. 2010; 30:339–346. PMID: 20191314.

25. Schetter AJ, Heegaard NH, Harris CC. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis. 2010; 31:37–49. PMID: 19955394.

26. Yu Z, Willmarth NE, Zhou J, Katiyar S, Wang M, Liu Y, McCue PA, Quong AA, Lisanti MP, Pestell RG. microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc Natl Acad Sci U S A. 2010; 107:8231–8236. PMID: 20406904.

27. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, Tang DG. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011; 17:211–215. PMID: 21240262.

28. Navarro A, Gaya A, Martinez A, Urbano-Ispizua A, Pons A, Balagué O, Gel B, Abrisqueta P, Lopez-Guillermo A, Artells R, Montserrat E, Monzo M. MicroRNA expression profiling in classic Hodgkin lymphoma. Blood. 2008; 111:2825–2832. PMID: 18089852.

29. Contu R, Latronico MV, Condorelli G. Circulating micro-RNAs as potential biomarkers of coronary artery disease: a promise to be fulfilled? Circ Res. 2010; 107:573–574. PMID: 20814026.

30. Qian L, Van Laake LW, Huang Y, Liu S, Wendland MF, Srivastava D. miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes. J Exp Med. 2011; 208:549–560. PMID: 21383058.

31. Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R Jr, Chen A, Hornstein E. miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A. 2010; 107:13111–13116. PMID: 20616011.

32. Beveridge NJ, Tooney PA, Carroll AP, Gardiner E, Bowden N, Scott RJ, Tran N, Dedova I, Cairns MJ. Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. Hum Mol Genet. 2008; 17:1156–1168. PMID: 18184693.

33. Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008; 28:1213–1223. PMID: 18234899.

34. Tili E, Michaille JJ, Costinean S, Croce CM. MicroRNAs, the immune system and rheumatic disease. Nat Clin Pract Rheumatol. 2008; 4:534–541. PMID: 18728632.

35. De Santis G, Ferracin M, Biondani A, Caniatti L, Rosaria Tola M, Castellazzi M, Zagatti B, Battistini L, Borsellino G, Fainardi E, Gavioli R, Negrini M, Furlan R, Granieri E. Altered miRNA expression in T regulatory cells in course of multiple sclerosis. J Neuroimmunol. 2010; 226:165–171. PMID: 20637509.

36. Leeper NJ, Cooke JP. MicroRNA and mechanisms of impaired angiogenesis in diabetes mellitus. Circulation. 2011; 123:236–238. PMID: 21220736.

37. Pandey AK, Agarwal P, Kaur K, Datta M. MicroRNAs in diabetes: tiny players in big disease. Cell Physiol Biochem. 2009; 23:221–232. PMID: 19471090.

38. Fulci V, Scappucci G, Sebastiani GD, Giannitti C, Franceschini D, Meloni F, Colombo T, Citarella F, Barnaba V, Minisola G, Galeazzi M, Macino G. miR-223 is overexpressed in T-lymphocytes of patients affected by rheumatoid arthritis. Hum Immunol. 2010; 71:206–211. PMID: 19931339.

39. Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010; 10:849–859. PMID: 21107346.

40. Sonkoly E, Pivarcsi A. Advances in microRNAs: implications for immunity and inflammatory diseases. J Cell Mol Med. 2009; 13:24–38. PMID: 19175698.

41. Yi R, Fuchs E. MicroRNA-mediated control in the skin. Cell Death Differ. 2010; 17:229–235. PMID: 19609273.

42. Chatzikyriakidou A, Voulgari PV, Georgiou I, Drosos AA. The role of microRNA-146a (miR-146a) and its target IL-1R-associated kinase (IRAK1) in psoriatic arthritis susceptibility. Scand J Immunol. 2010; 71:382–385. PMID: 20500689.

43. Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, Solway J, Gern JE, Lemanske RF, Nicolae D, Ober C. Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Hum Genet. 2007; 81:829–834. PMID: 17847008.

44. Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc Natl Acad Sci U S A. 2009; 106:18704–18709. PMID: 19843690.

45. Polikepahad S, Knight JM, Naghavi AO, Oplt T, Creighton CJ, Shaw C, Benham AL, Kim J, Soibam B, Harris RA, Coarfa C, Zariff A, Milosavljevic A, Batts LM, Kheradmand F, Gunaratne PH, Corry DB. Proinflammatory role for let-7 microRNAS in experimental asthma. J Biol Chem. 2010; 285:30139–30149. PMID: 20630862.

46. Li Y, Chan EY, Li J, Ni C, Peng X, Rosenzweig E, Tumpey TM, Katze MG. MicroRNA expression and virulence in pandemic influenza virus-infected mice. J Virol. 2010; 84:3023–3032. PMID: 20071585.

47. Witwer KW, Sisk JM, Gama L, Clements JE. MicroRNA regulation of IFN-beta protein expression: rapid and sensitive modulation of the innate immune response. J Immunol. 2010; 184:2369–2376. PMID: 20130213.

48. Belair C, Darfeuille F, Staedel C. Helicobacter pylori and gastric cancer: possible role of microRNAs in this intimate relationship. Clin Microbiol Infect. 2009; 15:806–812. PMID: 19702585.

49. Liu X, Wang T, Wakita T, Yang W. Systematic identification of microRNA and messenger RNA profiles in hepatitis C virus-infected human hepatoma cells. Virology. 2010; 398:57–67. PMID: 20006370.

50. Zhang GL, Li YX, Zheng SQ, Liu M, Li X, Tang H. Suppression of hepatitis B virus replication by microRNA-199a-3p and microRNA-210. Antiviral Res. 2010; 88:169–175. PMID: 20728471.

51. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004; 116:281–297. PMID: 14744438.

52. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009; 11:228–234. PMID: 19255566.

53. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009; 10:126–139. PMID: 19165215.

54. Kim VN. Small RNAs: classification, biogenesis, and function. Mol Cells. 2005; 19:1–15. PMID: 15750334.

55. Boyd SD. Everything you wanted to know about small RNA but were afraid to ask. Lab Invest. 2008; 88:569–578. PMID: 18427554.

56. Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A. Identification of mammalian microRNA host genes and transcription units. Genome Res. 2004; 14:1902–1910. PMID: 15364901.

57. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006; 103:2257–2261. PMID: 16461460.

58. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006; 6:857–866. PMID: 17060945.

59. Shenouda SK, Alahari SK. MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev. 2009; 28:369–378. PMID: 20012925.

60. Slezak-Prochazka I, Durmus S, Kroesen BJ, van den Berg A. MicroRNAs, macrocontrol: regulation of miRNA processing. RNA. 2010; 16:1087–1095. PMID: 20423980.

61. Ambros V. The functions of animal microRNAs. Nature. 2004; 431:350–355. PMID: 15372042.

62. Hwang HW, Mendell JT. MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 2006; 94:776–780. PMID: 16495913.

63. Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005; 132:4653–4662. PMID: 16224045.

64. Di Leva G, Calin GA, Croce CM. MicroRNAs: fundamental facts and involvement in human diseases. Birth Defects Res C Embryo Today. 2006; 78:180–189. PMID: 16847883.

65. Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010; 9:775–789. PMID: 20885409.

66. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–674. PMID: 21376230.

67. Soifer HS, Rossi JJ, Saetrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther. 2007; 15:2070–2079. PMID: 17878899.

68. Lynam-Lennon N, Maher SG, Reynolds JV. The roles of microRNA in cancer and apoptosis. Biol Rev Camb Philos Soc. 2009; 84:55–71. PMID: 19046400.

69. Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007; 302:1–12. PMID: 16989803.

70. Hernando E. microRNAs and cancer: role in tumorigenesis, patient classification and therapy. Clin Transl Oncol. 2007; 9:155–160. PMID: 17403626.

71. Osaki M, Takeshita F, Ochiya T. MicroRNAs as biomarkers and therapeutic drugs in human cancer. Biomarkers. 2008; 13:658–670. PMID: 19096960.

72. Gebeshuber CA, Zatloukal K, Martinez J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep. 2009; 10:400–405. PMID: 19247375.

73. Hunsberger JG, Austin DR, Chen G, Manji HK. MicroRNAs in mental health: from biological underpinnings to potential therapies. Neuromolecular Med. 2009; 11:173–182. PMID: 19544012.

74. Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Curr Opin Pediatr. 2009; 21:243–251. PMID: 19663042.

75. Saini S, Majid S, Dahiya R. Diet, microRNAs and prostate cancer. Pharm Res. 2010; 27:1014–1026. PMID: 20221895.

76. Marsit CJ, Eddy K, Kelsey KT. MicroRNA responses to cellular stress. Cancer Res. 2006; 66:10843–10848. PMID: 17108120.

77. Shin S, Cha HJ, Lee EM, Lee SJ, Seo SK, Jin HO, Park IC, Jin YW, An S. Alteration of miRNA profiles by ionizing radiation in A549 human non-small cell lung cancer cells. Int J Oncol. 2009; 35:81–86. PMID: 19513554.

78. Lovis P, Roggli E, Laybutt DR, Gattesco S, Yang JY, Widmann C, Abderrahmani A, Regazzi R. Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction. Diabetes. 2008; 57:2728–2736. PMID: 18633110.

79. Gueta K, Molotski N, Gerchikov N, Mor E, Savion S, Fein A, Toder V, Shomron N, Torchinsky A. Teratogen-induced alterations in microRNA-34, microRNA-125b and micro-RNA-155 expression: correlation with embryonic p53 genotype and limb phenotype. BMC Dev Biol. 2010; 10:20. PMID: 20170545.

80. Yang N, Coukos G, Zhang L. MicroRNA epigenetic alterations in human cancer: one step forward in diagnosis and treatment. Int J Cancer. 2008; 122:963–968. PMID: 18098137.

81. Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res. 2006; 66:1277–1281. PMID: 16452179.

82. Melkamu T, Zhang X, Tan J, Zeng Y, Kassie F. Alteration of microRNA expression in vinyl carbamate-induced mouse lung tumors and modulation by the chemopreventive agent indole-3-carbinol. Carcinogenesis. 2010; 31:252–258. PMID: 19748927.

83. Nelson PT, Wang WX, Rajeev BW. MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol. 2008; 18:130–138. PMID: 18226108.

84. Ha TY. The role of regulatory T cells in cancer. Immune Netw. 2009; 9:209–235. PMID: 20157609.

85. Liston A, Lu LF, O'Carroll D, Tarakhovsky A, Rudensky AY. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J Exp Med. 2008; 205:1993–2004. PMID: 18725526.

86. Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT, Bluestone JA. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med. 2008; 205:1983–1991. PMID: 18725525.

87. Cobb BS, Hertweck A, Smith J, O'Connor E, Graf D, Cook T, Smale ST, Sakaguchi S, Livesey FJ, Fisher AG, Merkenschlager M. A role for Dicer in immune regulation. J Exp Med. 2006; 203:2519–2527. PMID: 17060477.

88. Croce CM. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 2009; 10:704–714. PMID: 19763153.

89. Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, Croce CM. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 2007; 179:5082–5089. PMID: 17911593.

90. Ventura A, Jacks T. MicroRNAs and cancer: short RNAs go a long way. Cell. 2009; 136:586–591. PMID: 19239879.

91. Jazbutyte V, Thum T. MicroRNA-21: from cancer to cardiovascular disease. Curr Drug Targets. 2010; 11:926–935. PMID: 20415649.

92. Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL, Morgan DL, Postier RG, Brackett DJ, Schmittgen TD. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 2007; 120:1046–1054. PMID: 17149698.

93. Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005; 65:7065–7070. PMID: 16103053.

94. Waldman SA, Terzic A. Applications of microRNA in cancer: Exploring the advantages of miRNA. Clin Transl Sci. 2009; 2:248–249. PMID: 20443899.

95. Waldman SA, Terzic A. A study of microRNAs in silico and in vivo: diagnostic and therapeutic applications in cancer. FEBS J. 2009; 276:2157–2164. PMID: 19250312.

96. Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008; 451:147–152. PMID: 18185580.

97. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011; 470:548–553. PMID: 21326202.

98. Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, Goggins MG, Mendell JT, Maitra A. Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology. 2009; 9:293–301. PMID: 19407485.

99. Szafranska AE, Davison TS, John J, Cannon T, Sipos B, Maghnouj A, Labourier E, Hahn SA. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007; 26:4442–4452. PMID: 17237814.

100. Zhang Y, Li M, Wang H, Fisher WE, Lin PH, Yao Q, Chen C. Profiling of 95 microRNAs in pancreatic cancer cell lines and surgical specimens by real-time PCR analysis. World J Surg. 2009; 33:698–709. PMID: 19030927.

101. Toyota M, Suzuki H, Sasaki Y, Maruyama R, Imai K, Shinomura Y, Tokino T. Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res. 2008; 68:4123–4132. PMID: 18519671.

102. Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 2009; 58:1375–1381. PMID: 19201770.

103. Wang CJ, Zhou ZG, Wang L, Yang L, Zhou B, Gu J, Chen HY, Sun XF. Clinicopathological significance of microRNA-31, -143 and -145 expression in colorectal cancer. Dis Markers. 2009; 26:27–34. PMID: 19242066.

104. Nishida N, Yokobori T, Mimori K, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Kuwano H, Mori M. MicroRNA miR-125b is a prognostic marker in human colorectal cancer. Int J Oncol. 2011; 38:1437–1443. PMID: 21399871.

105. Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X. Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer. 2010; 127:118–126. PMID: 19876917.

106. Negrini M, Nicoloso MS, Calin GA. MicroRNAs and cancer--new paradigms in molecular oncology. Curr Opin Cell Biol. 2009; 21:470–479. PMID: 19411171.

107. Wang QZ, Xu W, Habib N, Xu R. Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy. Curr Cancer Drug Targets. 2009; 9:572–594. PMID: 19519323.

108. Jiang L, Huang Q, Zhang S, Zhang Q, Chang J, Qiu X, Wang E. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells. BMC Cancer. 2010; 10:318. PMID: 20569443.

109. Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009; 4:199–227. PMID: 18817506.

110. Saito Y, Suzuki H, Hibi T. The role of microRNAs in gastrointestinal cancers. J Gastroenterol. 2009; 44(Suppl 19):18–22. PMID: 19148788.

111. Yao Y, Suo AL, Li ZF, Liu LY, Tian T, Ni L, Zhang WG, Nan KJ, Song TS, Huang C. MicroRNA profiling of human gastric cancer. Mol Med Report. 2009; 2:963–970. PMID: 21475928.

112. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B. Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A. 2008; 105:3945–3950. PMID: 18308931.

113. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004; 101:2999–3004. PMID: 14973191.

114. Inomata M, Tagawa H, Guo YM, Kameoka Y, Takahashi N, Sawada K. MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. Blood. 2009; 113:396–402. PMID: 18941111.

115. Kluiver J, Poppema S, de Jong D, Blokzijl T, Harms G, Jacobs S, Kroesen BJ, van den Berg A. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol. 2005; 207:243–249. PMID: 16041695.

116. Bullrich F, Fujii H, Calin G, Mabuchi H, Negrini M, Pekarsky Y, Rassenti L, Alder H, Reed JC, Keating MJ, Kipps TJ, Croce CM. Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene. Cancer Res. 2001; 61:6640–6648. PMID: 11559527.

117. Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM. MicroRNA 29b functions in acute myeloid leukemia. Blood. 2009; 114:5331–5341. PMID: 19850741.

118. Mantovani A, Romero P, Palucka AK, Marincola FM. Tumour immunity: effector response to tumour and role of the microenvironment. Lancet. 2008; 371:771–783. PMID: 18275997.

119. Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009; 137:1005–1017. PMID: 19524505.

120. Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab. 2008; 93:1600–1608. PMID: 18270258.

121. Guo LM, Pu Y, Han Z, Liu T, Li YX, Liu M, Li X, Tang H. MicroRNA-9 inhibits ovarian cancer cell growth through regulation of NF-kappaB1. FEBS J. 2009; 276:5537–5546. PMID: 19702828.

122. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 2008; 110:13–21. PMID: 18589210.

123. Bonci D, Coppola V, Musumeci M, Addario A, Giuffrida R, Memeo L, D'Urso L, Pagliuca A, Biffoni M, Labbaye C, Bartucci M, Muto G, Peschle C, De Maria R. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 2008; 14:1271–1277. PMID: 18931683.

124. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, Iuliano R, Palumbo T, Pichiorri F, Roldo C, Garzon R, Sevignani C, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005; 353:1793–1801. PMID: 16251535.

125. Zaman MS, Chen Y, Deng G, Shahryari V, Suh SO, Saini S, Majid S, Liu J, Khatri G, Tanaka Y, Dahiya R. The functional significance of microRNA-145 in prostate cancer. Br J Cancer. 2010; 103:256–264. PMID: 20588276.

126. Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, Sunakozaka H, Sakai Y, Horimoto K, Kaneko S. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology. 2009; 49:1098–1112. PMID: 19173277.

127. Zhao H, Wang D, Du W, Gu D, Yang R. MicroRNA and leukemia: tiny molecule, great function. Crit Rev Oncol Hematol. 2010; 74:149–155. PMID: 19520590.

128. Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation. 2010; 121:1022–1032. PMID: 20194875.

129. Barringhaus KG, Zamore PD. MicroRNAs: regulating a change of heart. Circulation. 2009; 119:2217–2224. PMID: 19398677.

130. Chu CY, Rana TM. Small RNAs: regulators and guardians of the genome. J Cell Physiol. 2007; 213:412–419. PMID: 17674365.

131. Latronico MV, Condorelli G. MicroRNAs and cardiac pathology. Nat Rev Cardiol. 2009; 6:419–429. PMID: 19434076.

132. Corsten MF, Dennert R, Jochems S, Kuznetsova T, Devaux Y, Hofstra L, Wagner DR, Staessen JA, Heymans S, Schroen B. Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet. 2010; 3:499–506. PMID: 20921333.

133. Fichtlscherer S, De Rosa S, Fox H, Schwietz T, Fischer A, Liebetrau C, Weber M, Hamm CW, Röxe T, Müller-Ardogan M, Bonauer A, Zeiher AM, Dimmeler S. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010; 107:677–684. PMID: 20595655.

134. Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N. Plasma miR-208 as a biomarker of myocardial injury. Clin Chem. 2009; 55:1944–1949. PMID: 19696117.

135. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008; 105:10513–10518. PMID: 18663219.

136. Latronico MV, Catalucci D, Condorelli G. Emerging role of microRNAs in cardiovascular biology. Circ Res. 2007; 101:1225–1236. PMID: 18063818.

137. Ikeda S, Kong SW, Lu J, Bisping E, Zhang H, Allen PD, Golub TR, Pieske B, Pu WT. Altered microRNA expression in human heart disease. Physiol Genomics. 2007; 31:367–373. PMID: 17712037.

138. van Rooij E, Marshall WS, Olson EN. Toward microRNA-based therapeutics for heart disease: the sense in antisense. Circ Res. 2008; 103:919–928. PMID: 18948630.

139. Yang Y, Ago T, Zhai P, Abdellatif M, Sadoshima J. Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7. Circ Res. 2011; 108:305–313. PMID: 21183740.

140. Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Côté J, Simard MJ, Bonnet S. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011; 208:535–548. PMID: 21321078.

141. Abdellatif M. The role of microRNA-133 in cardiac hypertrophy uncovered. Circ Res. 2010; 106:16–18. PMID: 20056941.