MicroRNA: Small Molecules of Great Significance

VN Aushev

N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Vasilii Nikolaevich Aushev, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-17-64; e-mail: vaushev@gmail.com

For citation: Aushev VN. MicroRNA: Small Molecules of Great Significance. Clinical oncohematology. 2015;8(1):1–12 (In Russ).


ABSTRACT

Background. MicroRNAs were first discovered as antisense transcripts in Caenorhabditis elegans nematodes, where they inhibited expression of genes containing complementary sequences in mRNAs. Therefore, these molecules, along with the short interfering microRNAs are main mediators of RNA interference, which is a universal mechanism of regulation of the expression.

Results. MicroRNAs are small molecules transcribed from genomic DNA, undergoing further processing and exported to the cytoplasm. They can be a part of protein-coding transcripts or may be transcribed from non-coding areas. Primary processing can also be realized either by the specialized enzyme complex, or as a part of standard mRNA splicing. After exporting to the cytoplasm, intermediate RNA product undergoes final processing resulting in formation of an active RNA-protein complex capable of binding to complementary sequences of target mRNAs. Ultimate effect of such binding is the suppression of translation from the target mRNA; the latter can often be split due to the RNase activity of the complex.

Conclusions. Several thousand microRNAs are encoded in human genome, forming a large regulatory network involved in various signaling pathways and cellular processes. Malfunction of microRNA regulation are typical for a wide range of diseases and all types of malignancies. MicroRNAs are of great importance in oncology, including oncohematology as perspective cancer biomarkers and potential therapeutic agents. Involvement of some microRNAs in the development of a broad range of hematopoietic diseases has been demonstrated to date. In a number of cases it is recommended to use these molecules for molecular diagnosing and for determining prognosis of the disease.


Keywords: microRNA, regulation of expression, tumor biomarkers.

Received: July 16, 2014

Accepted: October 7, 2014

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REFERENCES

  1. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12(11):847–65. doi: 10.1038/nrd4140.
  2. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843–54. doi: 10.1016/0092-8674(93)90529-y.
  3. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75(5):855–62. doi: 10.1016/0092-8674(93)90530-4.
  4. Lee R, Feinbaum R, Ambros V. A short history of a short RNA. Cell. 2004;116(2 Suppl):S89–S92. doi: 10.1016/s0092-8674(04)00035-2.
  5. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31. doi: 10.1038/nrg1379.
  6. Reinhart BJ, Slack FJ, Basson M, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000;403(6772):901–6. doi: 10.1038/35002607.
  7. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of Novel Genes Coding for Small Expressed RNAs. Science. 2001;294(5543):853–8. doi: 10.1126/science.1064921.
  8. Lau NC, Lim LP, Weinstein EG, et al. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science. 2001;294(5543):858–62. doi: 10.1126/science.1065062.
  9. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of Novel Genes Coding for Small Expressed RNAs. Science. 2001;294(5543):855–8. doi: 10.1126/science.1064921.
  10. Calin GA, Dumitru CD, Shimizu M, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99(24):15524–9.
  11. Ambros V. A uniform system for microRNA annotation. RNA. 2003;9(3):277–9. doi: 10.1261/rna.2183803.
  12. Griffiths-Jones S, Grocock RJ, van Dongen S, et al. miRBase: microRNA sequences, targets and gene nomenclature. Nucl Acids Res. 2006;34(Database issue):D140–4. doi: 10.1093/nar/gkj112.
  13. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucl Acids Res. 2011;39(Database issue):D152–7. doi: 10.1093/nar/gkq1027.
  14. Lei EP, Silver PA. Protein and RNA export from the nucleus. Dev Cell. 2002;2(3):261–72. doi: 10.1016/s1534-5807(02)00134-x.
  15. Behm-Ansmant I, Rehwinkel J, Doerks T, et al. mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev. 2006;20(14):1885–98. doi: 10.1101/gad.1424106.
  16. Nishihara T, Zekri L, Braun JE, et al. miRISC recruits decapping factors to miRNA targets to enhance their degradation. Nucl Acids Res. 2013;41(18):8692–705. doi: 10.1093/nar/gkt619.
  17. Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318(5858):1931–4. doi: 10.1126/science.1149460.
  18. Wilson RC, Doudna JA. Molecular mechanisms of RNA interference. Ann Rev Biophys. 2013;42:217–39. doi: 10.1146/annurev-biophys-083012-130404.
  19. Friedman RC, Farh KK, Burge CB, et al. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105. doi: 10.1101/gr.082701.108.
  20. Cobb BS, Hertweck A, Smith J, et al. A role for Dicer in immune regulation. J Exp Med. 2006;203(11):2519–27. doi: 10.1084/jem.20061692.
  21. O’Carroll D, Mecklenbrauker I, Das PP, et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 2007;21(16):1999–2004. doi: 10.1101/gad.1565607.
  22. Felli N, Fontana L, Pelosi E, et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA. 2005;102(50):18081–6. doi: 10.1073/pnas.0506216102.
  23. Wang Q, Huang Z, Xue H, et al. MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood. 2008;111(2):588–95. doi: 10.1182/blood-2007-05-092718.
  24. Elton TS, Selemon H, Elton SM, et al. Regulation of the MIR155 host gene in physiological and pathological processes. Gene. 2013;532(1):1–12. doi: 10.1016/j.gene.2012.12.009.
  25. Dagan LN, Jiang X, Bhatt S, et al. miR-155 regulates HGAL expression and increases lymphoma cell motility. Blood. 2012;119(2):513–20. doi: 10.1182/blood-2011-08-370536.
  26. Teng G, Hakimpour P, Landgraf P, et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008;28(5):621–9. doi: 10.1016/j.immuni.2008.03.015.
  27. Bissels U, Bosio A, Wagner W. MicroRNAs are shaping the hematopoietic landscape. Haematologica. 2012;97(2):160–7. doi: 10.3324/haematol.2011.051730.
  28. Listowski MA, Heger E, Boguslawska DM, et al. microRNAs: fine tuning of erythropoiesis. Cell Mol Biol Lett. 2013;18(1):34–46. doi: 10.2478/s11658-012-0038-z.
  29. Lawrie CH. MicroRNAs in hematological malignancies. Blood Rev. 2013;27(3):143–54. doi: 10.1016/j.blre.2013.04.002.
  30. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102(39):13944–9. doi: 10.1073/pnas.0506654102.
  31. Fabbri M, Bottoni A, Shimizu M, et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA. 2011;305(1):59–67. doi: 10.1001/jama.2010.1919.
  32. Pekarsky Y, Santanam U, Cimmino A, et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res. 2006;66(24):11590–3. doi: 10.1158/0008-5472.can-06-3613.
  33. Starczynowski DT, Morin R, McPherson A, et al. Genome-wide identification of human microRNAs located in leukemia-associated genomic alterations. Blood. 2011;117(2):595–607. doi: 10.1182/blood-2010-03-277012.
  34. Starczynowski DT, Kuchenbauer F, Argiropoulos B, et al. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med. 2010;16(1):49–58. doi: 10.1038/nm.2054.
  35. Bousquet M, Quelen C, Rosati R, et al. Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation. J Exp Med. 2008;205(11):2499–506. doi: 10.1084/jem.20080285.
  36. Chapiro E, Russell LJ, Struski S, et al. A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia. 2010;24(7):1362–4. doi: 10.1038/leu.2010.93.
  37. Bousquet M, Harris MH, Zhou B, et al. MicroRNA miR-125b causes leukemia. Proc Natl Acad Sci USA. 2010;107(50):21558–63. doi: 10.1073/pnas.1016611107.
  38. Agirre X, Jimenez-Velasco A, San Jose-Eneriz E, et al. Down-regulation of hsa-miR-10a in chronic myeloid leukemia CD34+ cells increases USF2-mediated cell growth. Mol Cancer Res. 2008;6(12):1830–40. doi: 10.1158/1541-7786.mcr-08-0167.
  39. Bueno MJ, Perez de Castro I, Gomez de Cedron M, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008;13(6):496–506. doi: 10.1016/j.ccr.2008.04.018.
  40. Venturini L, Battmer K, Castoldi M, et al. Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells. Blood. 2007;109(10):4399–405. doi: 10.1182/blood-2006-09-045104.
  41. Xu C, Fu H, Gao L, et al. BCR-ABL/GATA1/miR-138 mini circuitry contributes to the leukemogenesis of chronic myeloid leukemia. Oncogene. 2014:33(1):44–54. doi: 10.1038/onc.2012.557.
  42. Mi S, Lu J, Sun M, et al. MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proc Natl Acad Sci USA. 2007;104(50):19971–6. doi: 10.1073/pnas.0709313104.
  43. Schotte D, De Menezes RX, Akbari Moqadam F, et al. MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica. 2011;96(5):703–11. doi: 10.3324/haematol.2010.026138.
  44. Magrath I. Epidemiology: clues to the pathogenesis of Burkitt lymphoma. Br J Haematol. 2012;156(6):744–56. doi: 10.1111/j.1365-2141.2011.09013.x.
  45. Dorsett Y, McBride KM, Jankovic M, et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity. 2008;28(5):630–8. doi: 10.1016/j.immuni.2008.04.002.
  46. Costinean S, Zanesi N, Pekarsky Y, et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci USA. 2006;103(18):7024–9. doi: 10.1073/pnas.0602266103.
  47. Kluiver J, Poppema S, de Jong D, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol. 2005;207(2):243–9. doi: 10.1002/path.1825.
  48. Eis PS, Tam W, Sun L, et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci USA. 2005;102(10):3627–32. doi: 10.1073/pnas.0500613102.
  49. Lawrie CH, Soneji S, Marafioti T, et al. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer. 2007;121(5):1156–61. doi: 10.1002/ijc.22800.
  50. O’Connell RM, Chaudhuri AA, Rao DS, et al. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc Natl Acad Sci USA. 2009;106(17):7113–8. doi: 10.1073/pnas.0902636106.
  51. Yamanaka Y, Tagawa H, Takahashi N, et al. Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood. 2009;114(15):3265–75. doi: 10.1182/blood-2009-06-222794.
  52. Pedersen IM, Otero D, Kao E, et al. Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med. 2009;1(5):288–95. doi: 10.1002/emmm.200900028.
  53. O’Connell RM, Rao DS, Chaudhuri AA, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205(3):585–94. doi: 10.1084/jem.20072108.
  54. Roehle A, Hoefig KP, Repsilber D, et al. MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas. Br J Haematol. 2008;142(5):732–44. doi: 10.1111/j.1365-2141.2008.07237.x.
  55. Lawrie CH, Chi J, Taylor S, et al. Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma. J Cell Mol Med. 2009;13(7):1248–60. doi: 10.1111/j.1582-4934.2008.00628.x.
  56. Pichiorri F, Suh SS, Ladetto M, et al. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci USA. 2008;105(35):12885–90. doi: 10.1073/pnas.0806202105.
  57. Loffler D, Brocke-Heidrich K, Pfeifer G, et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood. 2007;110(4):1330–3.
  58. Wang X, Li C, Ju S, et al. Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation. Leuk Lymphoma. 2011;52(10):1991–8. doi: 10.3109/10428194.2011.591004.
  59. Dimopoulos K, Gimsing P, Gronbaek K. Aberrant microRNA expression in multiple myeloma. Eur J Haematol. 2013;91(2):95–105. doi: 10.1111/ejh.12124.
  60. Chen RW, Bemis LT, Amato CM, et al. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma. Blood. 2008;112(3):822–9. doi: 10.1182/blood-2008-03-142182.
  61. Deshpande A, Pastore A, Deshpande AJ, et al. 3¢UTR mediated regulation of the cyclin D1 proto-oncogene. Cell Cycle. 2009;8(21):3592–600. doi: 10.4161/cc.8.21.9993.
  62. Rao E, Jiang C, Ji M, et al. The miRNA-17 approximately 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia. 2012;26(5):1064–72. doi: 10.1038/leu.2011.305.
  63. Van Vlierberghe P, De Weer A, Mestdagh P, et al. Comparison of miRNA profiles of microdissected Hodgkin/Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells reveals a distinct subset of differentially expressed miRNAs. Br J Haematol. 2009;147(5):686–90. doi: 10.1111/j.1365-2141.2009.07909.x.
  64. Calin GA, Liu CG, Sevignani C, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proc Natl Acad Sci USA. 2004;101(32):11755–60. doi: 10.1073/pnas.0404432101.
  65. Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353(17):1793–801. doi: 10.1056/nejmoa050995.
  66. Moussay E, Palissot V, Vallar L, et al. Determination of genes and microRNAs involved in the resistance to fludarabine in vivo in chronic lymphocytic leukemia. Mol Cancer. 2010;9(1):115. doi: 10.1186/1476-4598-9-115.
  67. Li Z, Lu J, Sun M, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA. 2008;105(40):15535–40. doi: 10.1073/pnas.0808266105.
  68. Jongen-Lavrencic M, Sun SM, Dijkstra MK, et al. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111(10):5078–85. doi: 10.1182/blood-2008-01-133355.
  69. Maki K, Yamagata T, Sugita F, et al. Aberrant expression of MIR9 indicates poor prognosis in acute myeloid leukaemia. Br J Haematol. 2012;158(2):283–5. doi: 10.1111/j.1365-2141.2012.09118.x.
  70. Ishida M, Selaru FM. miRNA-Based Therapeutic Strategies. Curr Anesth Rep. 2013;1(1):63–70. doi: 10.1007/s40139-012-0004-5.
  71. Czauderna F, Fechtner M, Dames S, et al. Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. Nucl Acids Res. 2003;31(11):2705–16. doi: 10.1093/nar/gkg393.
  72. Davis S, Propp S, Freier SM, et al. Potent inhibition of microRNA in vivo without degradation. Nucl Acids Res. 2009;37(1):70–7. doi: 10.1093/nar/gkn904.
  73. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685–94. doi: 10.1056/nejmoa1209026.
  74. Qiu Z, Dai Y. Roadmap of miR-122-related clinical application from bench to bedside. Expert Opin Invest Drugs. 2014;23(3):347–55. doi: 10.1517/13543784.2014.867327.
  75. Di Martino MT, Campani V, Misso G, et al. In Vivo Activity of MiR-34a Mimics Delivered by Stable Nucleic Acid Lipid Particles (SNALPs) against Multiple Myeloma. PloS One. 2014;9(2):e90005. doi: 10.1371/journal.pone.0090005.
  76. Velu CS, Chaubey A, Phelan JD, et al. Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity. J Clin Invest. 2014;124(1):222–36. doi: 10.1172/jci66005.
  77. Huang X, Schwind S, Yu B, et al. Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res. 2013;19(9):2355–67. doi: 10.1158/1078-0432.CCR-12-3191.
  78. Gong JN, Yu J, Lin HS, et al. The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia. Cell Death Differ. 2014;21(1):100–12. doi: 10.1038/cdd.2013.133.
  79. Ito M, Teshima K, Ikeda S, et al. MicroRNA-150 inhibits tumor invasion and metastasis by targeting the chemokine receptor CCR6 in advanced cutaneous T-cell lymphoma. Blood. 2014;123:1499–511. doi: 10.1182/blood-2013-09-527739.