MicroRNAs in Prostate Cancer: A Possible Role as Novel Biomarkers and Therapeutic Targets?

Chapter

Abstract

Eradication of advanced prostate cancer still represents an unsolved clinical problem, making the development of alternative treatment approaches highly desirable. Understanding the molecular alterations that distinguish the non-progressive from progressive disease will allow the identification of novel biomarkers for improved staging and prognostication, and will also provide mechanistic information to facilitate treatment selection and design of novel therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression. Recent findings indicate that miRNAs are deregulated in human tumors, suggesting a potential role for these molecules in the pathogenesis of cancer. Thus far, only a limited number of studies have investigated miRNA expression in prostate cancer. Results indicate that miRNA expression profiles may distinguish carcinoma from non-neoplastic specimens and further classify tumors according to androgen dependence. In addition, a prognostic significance has been attributed to specific miRNAs as predictors of clinical recurrence following radical prostatectomy. These findings, together with the documented possibility to detect cancer-related miRNAs in blood and core biopsies, open a window on the possibility to utilize them as novel biomarkers. For a handful of miRNAs, functional investigation has also been pursued in prostate cancer experimental models to establish the rationale for the development of miRNA-based therapies. However, a better understanding of the role exerted by specific miRNAs in the onset and progression of prostate cancer is needed, as is a precise definition of their targets relevant to the disease, before translating these molecules into the clinical setting.

Keywords

Benign Prostatic Hyperplasia Radical Prostatectomy miRNA Expression Gleason Score miRNA Expression Profile 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Ambs S, Prueitt RL, Yi M, et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 2008;68:6162–70.CrossRefPubMedGoogle Scholar
  2. Andriole GL, Crawford ED, Grubb RL 3rd, et al. PLCO project team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310–9.CrossRefPubMedGoogle Scholar
  3. Bonci D, Coppola V, Musumeci M, et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med. 2008;14:1271–7.CrossRefPubMedGoogle Scholar
  4. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66.CrossRefPubMedGoogle Scholar
  5. Chen X, Gong J, Zeng H, et al. MicroRNA145 targets BNIP3 and suppresses prostate cancer progression. Cancer Res. 2010;70:2728–38.CrossRefPubMedGoogle Scholar
  6. Cimmino A, Calin GA, Fabbri M, Iorio MV, et al. MiR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA. 2005;102:13944–9.CrossRefPubMedGoogle Scholar
  7. Cortez MA, Calin GA. MicroRNA identification in plasma and serum: a new tool to diagnose and monitor diseases. Expert Opin Biol Ther. 2009;9:703–11.CrossRefPubMedGoogle Scholar
  8. Creighton CJ, Nagaraja AK, Hanash SM, et al. A bioinformatics tool for linking gene expression profiling results with public databases of microRNA target predictions. RNA. 2008;14:2290–6.CrossRefPubMedGoogle Scholar
  9. Damber JE, Aus G. Prostate cancer. Lancet. 2008;371:1710–21.CrossRefPubMedGoogle Scholar
  10. Deberardinis RJ, Sayed N, Ditsworth D, et al. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18:54–61.CrossRefPubMedGoogle Scholar
  11. Dong Q, Meng P, Wang T, et al. MicroRNA let-7a inhibits proliferation of human prostate cancer cells in vitro and in vivo by targeting E2F2 and CCND2. PLoS One. 2010;5:e10147.Google Scholar
  12. Elmen J, Thonberg H, Ljungberg K, et al. Locked nucleic acid (LNA) mediated improvements in siRNA stability and functionality. Nucleic Acids Res. 2005;33:439–47.CrossRefPubMedGoogle Scholar
  13. Folini M, Gandellini P, Longoni N, et al. MiR-21: an oncomir on strike in prostate cancer. Mol Cancer. 2010;9:12.Google Scholar
  14. Fontana L, Fiori ME, Albini S, et al. Antagomir-17-5pabolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS One. 2008;3:e2236.Google Scholar
  15. Fujita Y, Kojima K, Hamada N, et al. Effects of miR-34a on cell growth and chemoresistance in prostate cancer PC3 cells. Biochem Biophys Res Commun. 2008;377:114–9.CrossRefPubMedGoogle Scholar
  16. Fujita Y, Kojima K, Ohhashi R, et al. MiR-148a attenuates paclitaxel-resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating MSK1 expression. J Biol Chem. 2010;285:19076–84.Google Scholar
  17. Galardi S, Mercatelli N, Giorda E, et al. MiR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 2007;282:23716–24.CrossRefPubMedGoogle Scholar
  18. Gandellini P, Folini M, Longoni N, et al. MiR-205 exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res. 2009b;69:2287–95.CrossRefPubMedGoogle Scholar
  19. Gandellini P, Folini M, Zaffaroni N. Towards the definition of prostate cancer-related microRNAs: where are we now? Trends Mol Med. 2009a;15:381–90.CrossRefPubMedGoogle Scholar
  20. Gandellini P, Folini M, Zaffaroni N. Emerging role of microRNAs in prostate cancer: implications for personalized medicine. Discov Med. 2010;9:212–8.PubMedGoogle Scholar
  21. Gao P, Tchernyshyov I, Chang TC, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5.CrossRefPubMedGoogle Scholar
  22. Hagman Z, Larne O, Edsjö A, et al. MiR-34c is down regulated in prostate cancer and exerts tumor suppressive functions. Int J Cancer. 2010;127:2768–76.PubMedGoogle Scholar
  23. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedGoogle Scholar
  24. Kong D, Li Y, Wang Z, Banerjee et al. MiR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells 2009;27:1712–21.CrossRefPubMedGoogle Scholar
  25. Krichevsky AM, Gabriely G. MiR-21: a small multi-faceted RNA. J Cell Mol Med. 2009;13:39–53.CrossRefPubMedGoogle Scholar
  26. Krützfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.CrossRefPubMedGoogle Scholar
  27. Leite KR, Sousa-Canavez JM, Reis ST, et al. Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis. Urol Oncol. 2010. doi:10.1016/j.urolonc.2009.02.002.Google Scholar
  28. Li J, Smyth P, Flavin R, et al. Comparison of miRNA expression patterns using total RNA extracted from matched samples of formalin-fixed paraffin-embedded (FFPE) cells and snap frozen cells. BMC Biotechnol. 2007;7:36.Google Scholar
  29. Lin SL, Chiang A, Chang D, et al. Loss of miR-146a function in hormone-refractory prostate cancer. RNA. 2008;14:417–24.CrossRefPubMedGoogle Scholar
  30. Lodes MJ, Caraballo M, Suciu D, et al. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One. 2009;4:e6229.Google Scholar
  31. Lodygin D, Tarasov V, Epanchintsev A, et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle. 2008;7:2591–600.CrossRefPubMedGoogle Scholar
  32. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.CrossRefPubMedGoogle Scholar
  33. Mattie MD, Benz CC, Bowers J, et al. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer. 2006;5:24.Google Scholar
  34. McNamara JO 2nd, Andrechek ER, Wang Y, et al. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol. 2006;24:1005–15.CrossRefPubMedGoogle Scholar
  35. Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–8.CrossRefPubMedGoogle Scholar
  36. Musiyenko A, Bitko V, Barik S. 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. 2008;86:313–22.CrossRefPubMedGoogle Scholar
  37. Ozen M, Creighton CJ, Ozdemir M, et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene. 2008;27:1788–93.CrossRefPubMedGoogle Scholar
  38. Poliseno L, Salmena L, Riccardi L, et al. 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. 2010;3:ra29.Google Scholar
  39. Porkka KP, Pfeiffer MJ, Waltering KK, et al. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67:6130–5.CrossRefPubMedGoogle Scholar
  40. Prueitt RL, Yi M, Hudson RS, et al. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate. 2008;68:1152–64.CrossRefPubMedGoogle Scholar
  41. Schaefer A, Jung M, Mollenkopf HJ, et al. Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer. 2010;126:1166–76.PubMedGoogle Scholar
  42. Schröder FH, Hugosson J, Roobol MJ, et al. ERSPC investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320–8.CrossRefPubMedGoogle Scholar
  43. Shi XB, Xue L, Yang J, et al. An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells. Proc Natl Acad Sci USA. 2007;104:19983–8.CrossRefPubMedGoogle Scholar
  44. Spahn M, Kneitz S, Scholz CJ, et al. Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer. 2010; 127:394–403.PubMedGoogle Scholar
  45. Stenvang J, Silahtaroglu AN, Lindow M, et al. The utility of LNA in microRNA-based cancer diagnostics and therapeutics. Semin Cancer Biol. 2008;8:89–102.CrossRefGoogle Scholar
  46. Sylvestre Y, De Guire V, Querido E, et al. An E2F/miR-20a autoregulatory feedback loop. J Biol Chem. 2007;282:2135–43.CrossRefPubMedGoogle Scholar
  47. Szczyrba J, Löprich E, Wach S, et al. The microRNA profile of prostate carcinoma obtained by deep sequencing. Mol Cancer Res. 2010;8:529–38.CrossRefPubMedGoogle Scholar
  48. Takeshita F, Patrawala L, Osaki M, et al. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther. 2010;18:181–7.CrossRefPubMedGoogle Scholar
  49. Tong AW, Fulgham P, Jay C, et al. MicroRNA profile analysis of human prostate cancers. Cancer Gene Ther. 2009;16:206–16.PubMedGoogle Scholar
  50. Varambally S, Cao Q, Mani RS, et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–9.CrossRefPubMedGoogle Scholar
  51. Varambally S, Dhanasekaran SM, Zhou M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.CrossRefPubMedGoogle Scholar
  52. Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 2006;103:2257–61.CrossRefPubMedGoogle Scholar
  53. Weidhaas JB, Babar I, Nallur SM, et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res. 2007;67:11111–6.CrossRefPubMedGoogle Scholar
  54. Wu H, Mo YY. Targeting miR-205 in breast cancer. Expert Opin Ther Targets. 2009;13:1439–48.CrossRefPubMedGoogle Scholar
  55. Yang K, Handorean AM, Iczkowski KA. MicroRNAs 373 and 520c are downregulated in prostate cancer, suppress CD44 translation and enhance invasion of prostate cancer cells in vitro. Int J Clin Exp Pathol. 2009;2:361–9.PubMedGoogle Scholar
  56. Yang Y, Chaerkady R, Beer MA, et al. Identification of miR-21 targets in breast cancer cells using a quantitative proteomic approach. Proteomics. 2009;9:1374–84.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Netherlands 2011

Authors and Affiliations

  • Paolo Gandellini
    • 1
  • Marco Folini
    • 2
  • Nadia Zaffaroni
    • 2
  1. 1.Molecular Pharmacology Unit, Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  2. 2.Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly

Personalised recommendations