Skip to main content
Log in

Mikro-RNA in der Uroonkologie

Neue Hoffnungen für die Diagnostik und Therapie von Tumoren?

MicroRNA in uro-oncology

New hope for the diagnosis and treatment of tumors?

  • Übersichten
  • Published:
Der Urologe Aims and scope Submit manuscript

Zusammenfassung

Mikro-RNA (miRNA) sind nicht kodierende RNA, die grundlegende zelluläre Prozesse steuern, aber auch mit Krebsmerkmalen assoziiert sind. Ziel dieses Artikels ist es, Grundzüge der Biogenese und Funktion von miRNA sowie ihre Bedeutung in der Tumorentwicklung, insbesondere in der Uroonkologie zu beschreiben. Zu diesem Zweck wurde eine PubMed-Literaturrecherche durchgeführt. Bis März 2009 erschienen ca. 4500 Publikationen über miRNA. Expressionsstudien in Karzinomen und funktionelle Analysen belegen ihre besondere Rolle in der Kanzerogenese, ihr Potenzial als diagnostische und prognostische Marker sowie als Zielstruktur für neue Therapeutika. In der Uroonkologie wurden bisher nur wenige miRNA-Studien veröffentlicht. Tumorspezifische miRNA-Expressionen wurden zwar für urologische Karzinome nachgewiesen, widersprüchliche Daten zeigen jedoch, dass hier die Forschung noch am Anfang steht. Eine systematische Aufklärung charakteristischer miRNA-Anomalien könnte in Zukunft sowohl die Diagnostik als auch die Therapie urologischer Tumoren entscheidend verbessern helfen.

Abstract

MicroRNAs (miRNAs) are non-coding RNAs that regulate basic cellular processes and are associated with cancer characteristics. The aim of this review is to summarize the principles of miRNA biogenesis and function and to describe their contribution to tumor development, especially in uro-oncology. Therefore a PubMed search was conducted. Up to March 2009 approximately 4,500 miRNA-related articles were cited in this database. Studies of miRNA expression and functional analyses prove their impact in carcinogenesis and their potential as diagnostic or prognostic markers or as novel therapeutic targets. Only a few miRNA-related studies have been published in uro-oncology so far. Although tumor-specific miRNA expression has been shown for urological neoplasms, the contradicting data show that miRNA research is still in its infancy in this field. A systematic elucidation of characteristic miRNA abnormalities could decisively improve diagnostics as well as therapy of urological tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Abbreviations

3’-UTR:

untranslatierter Bereich der mRNA

BAK1:

BCL2-antagonist/killer 1; zur BCL2-Familie gehörig

BCL2:

B-cell CLL/lymphoma 2

Bim:

apoptoseregulierendes Protein der BCL2-Familie

CD44:

CD44 molecule (Indian blood group)

CpG:

Dinukleotidsequenz Cytosin-Phosphatdiester-Guanin

DNA:

Desoxyribonukleinsäure

E2F1:

E2F-Transkriptionsfaktor 1

E2F3:

E2F-Transkriptionsfaktor 3

EZH2:

enhancer of zeste homolog 2 (Drosophila)

GENIM4:

gem (nuclear organelle) associated protein 4

HMGA2:

high mobility group AT-hook 2

Hsa-miR:

Homo sapiens mikro-RNA

LNCaP:

Prostatakarzinomzelllinie

MeSH:

„medical subject headings“ der Datenbank PubMed

miRISC:

MiRNA induced silencing complex

miRNA:

Mikro-RNA

mRNA:

Messenger-RNA

p21/WAF1:

zyklinabhängiger Kinaseinhibitor p21

p27kip :

zyklinabhängiger Kinaseinhibitor p27

p53:

Tumorsuppressorgen p53

PC3:

Prostatakarzinomzelllinie

Pre-miRNA:

Vorläufer-miRNA

Pri-miRNA:

Primäre miRNA

RASV12:

RAS-Onkogen

RNA:

Ribonukleinsäure

ROCK1:

Proteinkinase (rho-associated, coiled-coil containing protein kinase 1)

RT-PCR:

reverse Transkriptase-Polymerase-Kettenreaktion

SOX4:

SRY (sex determining region Y)-box 4

Literatur

  1. Ambs S, Prueitt RL, Yi M et al (2008) Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 68: 6162–6170

    Article  PubMed  CAS  Google Scholar 

  2. Berezikov E, Guryev V, van de Belt J et al (2005) Phylogenetic shadowing and computational identification of human microRNA genes. Cell 120: 21–24

    Article  PubMed  CAS  Google Scholar 

  3. Bonci D, Coppola V, Musumeci M et al (2008) The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 14: 1271–1277

    Article  PubMed  CAS  Google Scholar 

  4. Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6: 857–866

    Article  PubMed  CAS  Google Scholar 

  5. Calin GA, Croce CM (2006) MicroRNA-cancer connection: the beginning of a new tale. Cancer Res 66: 7390–7394

    Article  PubMed  CAS  Google Scholar 

  6. 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 USA 99: 15524–15529

    Article  PubMed  CAS  Google Scholar 

  7. Chan JA, Krichevsky AM, Kosik KS (2005) MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res 65: 6029–6033

    Article  PubMed  CAS  Google Scholar 

  8. Cowland JB, Hother C, Gronbaek K (2007) MicroRNAs and cancer. APMIS 115: 1090–1106

    Article  PubMed  CAS  Google Scholar 

  9. Dutta KK, Zhong Y, Liu YT et al (2007) Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer Sci 98: 1845–1852

    Article  PubMed  CAS  Google Scholar 

  10. Duursma AM, Kedde M, Schrier M et al (2008) miR-148 targets human DNMT3b protein coding region. RNA 14: 872–877

    Article  PubMed  CAS  Google Scholar 

  11. Ebert MS, Neilson JR, Sharp PA (2007) MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 4: 721–726

    Article  PubMed  CAS  Google Scholar 

  12. Esquela-Kerscher A, Slack FJ (2006) Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 6: 259–269

    Article  PubMed  CAS  Google Scholar 

  13. Fabbri M (2008) MicroRNAs and cancer epigenetics. Curr Opin Investig Drugs 9: 583–590

    PubMed  CAS  Google Scholar 

  14. Fabbri M, Ivan M, Cimmino A et al (2007) Regulatory mechanisms of microRNAs involvement in cancer. Expert Opin Biol Ther 7: 1009–1019

    Article  PubMed  CAS  Google Scholar 

  15. Fontana L, Fiori ME, Albini S et al (2008) Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS ONE 3: e2236

    Article  PubMed  Google Scholar 

  16. Fujita Y, Kojima K, Hamada N et al (2008) Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun 377: 114–119

    Article  PubMed  CAS  Google Scholar 

  17. Galardi S, Mercatelli N, Giorda E et al (2007) miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem 282: 23716–23724

    Article  PubMed  CAS  Google Scholar 

  18. Gillis AJ, Stoop HJ, Hersmus R et al (2007) High-throughput microRNAome analysis in human germ cell tumours. J Pathol 213: 319–328

    Article  PubMed  CAS  Google Scholar 

  19. Gottardo F, Liu CG, Ferracin M et al (2007) Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 25: 387–392

    PubMed  CAS  Google Scholar 

  20. Horikawa Y, Wood CG, Yang H et al (2008) Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma. Clin Cancer Res 14: 7956–7962

    Article  PubMed  CAS  Google Scholar 

  21. Huang Q, Gumireddy K, Schrier M et al (2008) The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 10: 202–210

    Article  PubMed  CAS  Google Scholar 

  22. Iorio MV, Ferracin M, Liu CG et al (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65: 7065–7070

    Article  PubMed  CAS  Google Scholar 

  23. Josson S, Sung SY, Lao K et al (2008) Radiation modulation of MicroRNA in prostate cancer cell lines. Prostate 68: 1599–1606

    Article  PubMed  CAS  Google Scholar 

  24. Jung M, Mollenkopf H-J, Grimm C et al (2009) MicroRNA profiling of clear cell renal cell cancer identifies a robust signature to define renal malignancy. J Cell Mol Med (doi: 10.1111/j.1582–4934.2009.00705.x)

    Google Scholar 

  25. Kort EJ, Farber L, Tretiakova M et al (2008) The E2F3-Oncomir-1 axis is activated in Wilms‘ tumor. Cancer Res 68: 4034–4038

    Article  PubMed  CAS  Google Scholar 

  26. Krutzfeldt J, Rajewsky N, Braich R et al (2005) Silencing of microRNAs in vivo with ‚antagomirs’. Nature 438: 685–689

    Article  PubMed  Google Scholar 

  27. Lamy P, Andersen CL, Dyrskjot L et al (2006) Are microRNAs located in genomic regions associated with cancer? Br J Cancer 95: 1415–1418

    Article  PubMed  CAS  Google Scholar 

  28. Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21: 1025–1030

    Article  PubMed  CAS  Google Scholar 

  29. Lee YS, Kim HK, Chung S et al (2005) Depletion of human micro-RNA miR-125b reveals that it is critical for the proliferation of differentiated cells but not for the down-regulation of putative targets during differentiation. J Biol Chem 280: 16635–16641

    Article  PubMed  CAS  Google Scholar 

  30. Lewis BP, Burge CB, Bartel DP (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120: 15–20

    Article  PubMed  CAS  Google Scholar 

  31. Lim LP, Lau NC, Garrett-Engele P et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433: 769–773

    Article  PubMed  CAS  Google Scholar 

  32. Lin SL, Chiang A, Chang D, Ying SY (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14: 417–424

    Article  PubMed  CAS  Google Scholar 

  33. Lindow M, Gorodkin J (2007) Principles and limitations of computational microRNA gene and target finding. DNA Cell Biol 26: 339–351

    Article  PubMed  CAS  Google Scholar 

  34. Looijenga LH, Gillis AJ, Stoop H et al (2007) Relevance of microRNAs in normal and malignant development, including human testicular germ cell tumours. Int J Androl 30: 304–314

    Article  PubMed  CAS  Google Scholar 

  35. Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435: 834–838

    Article  PubMed  CAS  Google Scholar 

  36. Mattie MD, Benz CC, Bowers J et al (2006) Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer 5: 24

    Article  PubMed  Google Scholar 

  37. Mercatelli N, Coppola V, Bonci D et al (2008) The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice. PLoS ONE 3: e4029

    Article  PubMed  Google Scholar 

  38. Mishra PJ, Mishra PJ, Banerjee D, Bertino JR (2008) MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics. Cell Cycle 7: 853–858

    PubMed  CAS  Google Scholar 

  39. Mitchell PS, Parkin RK, Kroh EM et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105: 10513–10518

    Article  PubMed  CAS  Google Scholar 

  40. Murakami Y, Yasuda T, Saigo K et al (2006) Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 25: 2537–2545

    Article  PubMed  CAS  Google Scholar 

  41. Musiyenko A, Bitko V, Barik S (2008) Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells. J Mol Med 86: 313–322

    Article  PubMed  CAS  Google Scholar 

  42. 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: 418–427

    Article  PubMed  CAS  Google Scholar 

  43. Novotny GW, Nielsen JE, Sonne SB et al (2007) Analysis of gene expression in normal and neoplastic human testis: new roles of RNA. Int J Androl 30: 316–326

    Article  PubMed  CAS  Google Scholar 

  44. Ozen M, Creighton CJ, Ozdemir M, Ittmann M (2008) Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 27: 1788–1793

    Article  PubMed  CAS  Google Scholar 

  45. Pillai RS, Bhattacharyya SN, Filipowicz W (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 17: 118–126

    Article  PubMed  CAS  Google Scholar 

  46. Porkka KP, Pfeiffer MJ, Waltering KK et al (2007) MicroRNA expression profiling in prostate cancer. Cancer Res 67: 6130–6135

    Article  PubMed  CAS  Google Scholar 

  47. Prueitt RL, Yi M, Hudson RS et al (2008) Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate 68: 1152–1164

    Article  PubMed  CAS  Google Scholar 

  48. Ruvkun G (2001) Molecular biology. Glimpses of a tiny RNA world. Science 294: 797–799

    Article  PubMed  CAS  Google Scholar 

  49. Saito Y, Friedman JM, Chihara Y et al (2009) Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. Biochem Biophys Res Commun 379: 726–731

    Article  PubMed  CAS  Google Scholar 

  50. 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: 435–443

    Article  PubMed  CAS  Google Scholar 

  51. Schaefer A, Jung M, Kristiansen G et al (2009) MicroRNAs and cancer: current state and future perspectives in urologic oncology. Urol Oncol (Epub ahead of print, doi:10.1016/j.urolonc.2008.10.021)

  52. Scharer CD, McCabe CD, li-Seyed M et al (2009) Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. Cancer Res 69: 709–717

    Article  PubMed  CAS  Google Scholar 

  53. Schetter AJ, Leung SY, Sohn JJ et al (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299: 425–436

    Article  PubMed  CAS  Google Scholar 

  54. Schmittgen TD (2008) Part B--microRNAs: microRNA methods. Methods 44: 1–2

    Article  PubMed  CAS  Google Scholar 

  55. Shi XB, Tepper CG, Vere White RW (2008) MicroRNAs and prostate cancer. J Cell Mol Med 12: 1456–1465

    Article  PubMed  CAS  Google Scholar 

  56. Shi XB, Xue L, Yang J et al (2007) An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci USA 104: 19983–19988

    Article  PubMed  CAS  Google Scholar 

  57. Tang G, Tang X, Mendu V et al (2008) The art of microRNA: various strategies leading to gene silencing via an ancient pathway. Biochim Biophys Acta 1779: 655–662

    PubMed  CAS  Google Scholar 

  58. Tong AW, Fulgham P, Jay C et al (2009) MicroRNA profile analysis of human prostate cancers. Cancer Gene Ther 16: 206–216

    PubMed  CAS  Google Scholar 

  59. Varambally S, Cao Q, Mani RS et al (2008) Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322: 1695–1699

    Article  PubMed  CAS  Google Scholar 

  60. Volinia S, Calin GA, Liu CG et al (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261

    Article  PubMed  CAS  Google Scholar 

  61. Voorhoeve PM, le Sage C, Schrier M et al (2006) A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124: 1169–1181

    Article  PubMed  CAS  Google Scholar 

  62. Weiler J, Hunziker J, Hall J (2006) Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? Gene Ther 13: 496–502

    Article  PubMed  CAS  Google Scholar 

  63. Yang H, Dinney CP, Ye Y et al (2008) Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. Cancer Res 68: 2530–2537

    Article  PubMed  CAS  Google Scholar 

  64. Yu SL, Chen HY, Chang GC et al (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13: 48–57

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung hin: Die Arbeit enthält aktualisierte Angaben aus einer Übersicht der Autoren, die in der Zeitschrift Urologic Oncology erscheint (Epub ahead of print, December 29, 2008; doi:10.1016/j.urolonc.2008.10.021). Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K. Jung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schaefer, A., Jung, M., Kristiansen, G. et al. Mikro-RNA in der Uroonkologie. Urologe 48, 877–885 (2009). https://doi.org/10.1007/s00120-009-2010-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00120-009-2010-8

Schlüsselwörter

Keywords

Navigation