Seminars in Oncology
Volume 38, Issue 6 , Pages 721-723, December 2011

MicroRNAs and Cancer: Introduction

The Ohio State University Comprehensive Cancer Center, Columbus, OH

Article Outline

 

MicroRNAs (miRNAs) are endogenous small noncoding RNAs of 18 to 24 nucleotides in length that regulate gene expression in animals and plants.1 Evolutionary conserved, miRNAs bind to the 3′ untranslated regions (3′ UTRs) of messenger RNAs (mRNA) and induce degradation or protein translation inhibition.1 This fascinating mechanism of gene regulation where a small RNA controls the translation and stability of a larger RNA (mRNA) was discovered by the laboratories of Victor Ambros and Gary Ruvkun in 1993 while investigating temporal gene expression control in nematodes.2, 3 Many years later, multiple reports established that miRNAs regulate critical cell processes such as cell division, development, metabolism, and death.4, 5, 6, 7 Remarkably, miRNAs can target large numbers of mRNAs (average 500 targets) and frequently a single mRNA can be targeted by multiple miRNAs.8, 9, 10, 11 Despite having a widespread role in gene regulation (it is estimated that miRNAs regulate about 60% of all genes), miRNAs are very few.12 There are approximately 1,048 human miRNAs described in the last version of miRBase (a public database of published miRNA sequences and annotation, www.mirbase.org). About 50% of these miRNAs are transcribed from introns or exons of known noncoding or protein-coding genes, while the other 50% are transcribed from miRNA genes that are located far away from previously annotated genes.12 Remarkably, about 30% to 40% of all mammalian miRNAs are localized very close to each other (≤10 kb) and are transcribed together in clusters.12 Independent of their genomic location, miRNAs are transcribed by polymerase II into an initial miRNA precursor called pri-miRNA, which subsequently is processed by the ribonuclease DROSHA complex into a precursor of about 70 to 100 nucleotides called pre-miRNA (Figure 1).13, 14 This precursor is then exported to the cytoplasm by exportin 5, where it undergoes further processing by the ribonuclease DICER into a mature 18- to 24-nucleotide double-strand miRNA.15, 16 While the active or mature strand is retained in the RNA-induced silencing complex (RISC), the passenger strand is removed and degraded. The active strand will recognize complementarity sequences in the target mRNA and guide the RISC–miRNA complex to induce degradation and protein translational inhibition of the target mRNA.1, 17 The specificity is dictated by the degree of base complementarities between the positions 2 to 8 of the mature miRNA (also known as the seed) with the 3′ UTR of target mRNAs.1, 17, 18 When the mature miRNA seeds have perfect complementarities to the target mRNA, there is mRNA degradation. In contrast, if there is not perfect miRNA–mRNA complementarity, post-translational inhibition occurs.1, 17, 18 Overall, the net result is target protein downregulation (Figure 1). However, there have been also situations where miRNAs can bind to the 5′ UTR of mRNAs and instead activate transcription.19

  • View full-size image.
  • Figure 1. 

    MicroRNA biogenesis. (a) miRNAs are transcribed by RNA polymerase II (pol II) into long primary miRNA transcripts of variable size (pri-miRNA), which are recognized and cleaved in the nucleus by the RNase III enzyme Drosha, resulting in a hairpin precursor form called pre-miRNA. (b) Pre-miRNA is exported from the nucleus to the cytoplasm by exportin 5 and is further processed by another RNase enzyme called Dicer (c), which produces a transient 19- to 24-nucleotide duplex. Only one strand of the miRNA duplex (mature miRNA) is incorporated into a large protein complex called RISC (RNA-induced silencing complex). (d) The mature miRNA leads RISC to cleave the mRNA or induce translational repression, depending on the degree of complementarity between the miRNA and its target.

Reproduced from Garzon et al.27

Once miRNAs were established as critical regulators of cell processes, researchers started to investigate whether miRNA expression is deregulated in disease and whether this deregulation causes disease or facilitates its development or progression. In 2002, our group reported that two miRNAs, miR-15a and miR-16-1, were downregulated in a subset of chronic lymphocytic leukemia (CLL) patients.20 This was the first evidence that a miRNA was deregulated in cancer. Interestingly, both miR-15a and miR-16-1 were located in chromosome 13q34, a genomic region that is commonly deleted in CLL and thought to harbor a potent tumor-suppressor.21 Future work by our group and others confirmed this tumor-suppressor activity and the critical role of these miRNAs in CLL pathogenesis by showing that selective loss of miR-15a-16-1 expression in mice causes CLL.22, 23 Following these startling discoveries and taking advantage of novel high-throughput expression platforms such as microarrays, a systematic investigation of miRNA profiling was performed in almost every cancer known to man. As a result, it become evident that miRNA expression is deregulated widely in solid tumors and hematologic malignancies.24, 25, 26 Further studies implicated miRNAs in the initiation and progression of cancer.26 In this issue of Seminars in Oncology, experts in the field will review and discuss the current literature relevant to the role of miRNAs in the pathogenesis, diagnosis, prognosis, and treatment of the most common cancers. Potential applications and pitfalls will be discussed as well.

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References 

  1. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233
  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;75:843–854
  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;75:855–862
  4. Carleton M, Cleary MA, Linsley PS. MicroRNAs and cell cycle regulation. Cell Cycle. 2007;6:2127–2132
  5. Harfe BD. MicroRNAs in vertebrate development. Curr Opin Genet Dev. 2005;15:410–415
  6. Boehm M, Slack FJ. MicroRNA control of lifespan and metabolism. Cell Cycle. 2005;5:837–840
  7. Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290–1297
  8. Lewis B, Shih I, Jones-Rhoades M, Bartel D, Burge C. Prediction of mammalian microRNA targets. Cell. 2003;115:787–798
  9. Krek D, Grün D, Poy MN, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500
  10. Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–D153
  11. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105
  12. Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ. miRBase: tools for microRNA genomics. Nucleic Acids Res. 2008;36:D154–D158
  13. Lee Y, Kim M, Han J, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–4060
  14. Lee Y, Ahn C, Han J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415–419
  15. Bohnsack MT, Czaplinski K, Gorlich D. Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of premiRNAs. RNA. 2004;10:185–191
  16. Hammond S, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000;404:293–329
  17. Thimmaiah P, Chendrimada GR, Kumaraswamy E, et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005;436:740–744
  18. Hutvanger G, Zamore PD. A microRNA in a multiple-turnover RNAi enxyme complex. Science. 2002;297:2056–2060
  19. Ørom UA, Nielsen FN, Lund AH. MicroRNA-10a Binds the 5' UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008;4:460–471
  20. Bullrich F, Fujii H, Calin G, et al. 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
  21. Calin GA, Dumitru C, 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 U S A. 2002;99:15524–15529
  22. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2006;102:13944–13949
  23. Klein U, Lia M, Crespo M, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell. 2010;17:28–40
  24. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838
  25. Volinia S, Calin G, Liu CG, et al. A microRNA expression signature in human solid tumors defines cancer targets. Proc Natl Acad Sci U S A. 2006;103:2257–2261
  26. Garzon R, Calin GA, Croce CM. MiRNAs as oncogenes and tumor suppressors. Annu Rev Med. 2009;60:167–179
  27. Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNAs expression and function in cancer. Trends Mol Med. 2006;12:580–587

PII: S0093-7754(11)00216-8

doi:10.1053/j.seminoncol.2011.08.008

Seminars in Oncology
Volume 38, Issue 6 , Pages 721-723, December 2011

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