Skip to main content

Advertisement

SpringerLink
Log in

Profiling of circulating microRNAs for prostate cancer biomarker discovery

  • Clinical Research
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Prostate cancer (PC) is the most frequent cancer in men in the Western world. Currently, serum prostate-specific antigen levels and digital rectal examinations are used to indicate the need for diagnostic prostate biopsy, but lack in specificity and sensitivity. Thus, many men undergo unnecessary biopsy, and better and less invasive tools for PC detection are needed. Furthermore, whereas aggressive PC should be treated immediately to prevent dissemination, indolent PC often does not progress and overtreatment should be avoided. Currently, the best predictors of aggressiveness are Gleason score and T-stage of the primary PC. Better tools to assess PC aggressiveness could aid in treatment decisions. Recently, circulating miRNAs have been suggested as potential new biomarkers for PC with diagnostic and prognostic potential. Here, to identify new serum miRNA biomarker candidates for PC, we performed genome-wide miRNA profiling of serum samples from 13 benign prostatic hyperplasia (BPH) control patients and 31 PC patients. Furthermore, we carefully reviewed the literature on circulating miRNA biomarkers for PC. Our results confirmed the de-regulation of miR-141 and miR-375, two of the most well-documented candidate miRNA markers for PC. Moreover, we identified several new potential serum miRNA markers for PC and developed three novel and highly specific (100 %) miRNA candidate marker panels able to identify 84 % of all PC patients (miR-562/miR-210/miR-501-3p/miR-375/miR-551b), 80 % of patients with disseminated PC when compared to BPH patients (let-7a*/miR-210/miR-562/miR-616), and 75 % of disseminated PC patients when compared to localized PC patients (miR-375/miR-708/miR-1203/miR-200a), demonstrating high potential of serum miRNAs for diagnosing and staging of PC.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46(4):765–81. doi:10.1016/j.ejca.2009.12.014.

    Article  CAS  PubMed  Google Scholar 

  2. Hoogendam A, Buntinx F, de Vet HC. The diagnostic value of digital rectal examination in primary care screening for prostate cancer: a meta-analysis. Family Practice. 1999;16(6):621–6.

    Article  CAS  PubMed  Google Scholar 

  3. Glaser AP, Novakovic K, Helfand BT. The impact of prostate biopsy on urinary symptoms, erectile function, and anxiety. Current Urol Reports. 2012;13(6):447–54. doi:10.1007/s11934-012-0277-6.

    Article  Google Scholar 

  4. Wolters T, van der Kwast TH, Vissers CJ, Bangma CH, Roobol M, Schroder FH, et al. False-negative prostate needle biopsies: frequency, histopathologic features, and follow-up. The Am J Surg Pathol. 2010;34(1):35–43. doi:10.1097/PAS.0b013e3181c3ece9.

    Article  PubMed  Google Scholar 

  5. Albertsen PC. Treatment of localized prostate cancer: when is active surveillance appropriate? Nature Rev Clin Oncol. 2010;7(7):394–400. doi:10.1038/nrclinonc.2010.63.

    Article  Google Scholar 

  6. Healy NA, Heneghan HM, Miller N, Osborne CK, Schiff R, Kerin MJ. Systemic miRNAs as potential biomarkers for malignancy. Int J Cancer. 2012;131(10):2215–22. doi:10.1002/ijc.27642.

    Article  CAS  PubMed  Google Scholar 

  7. Zhou L, Zhao YP, Liu WJ, Dong J, Chen WY, Zhang TP, et al. Circulating microRNAs in cancer: diagnostic and prognostic significance. Expert Rev of Anticancer Ther. 2012;12(2):283–8. doi:10.1586/era.11.197.

    Article  CAS  Google Scholar 

  8. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006. doi:10.1038/cr.2008.282.

    Article  CAS  PubMed  Google Scholar 

  9. Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22(3):125–32. doi:10.1016/j.tcb.2011.12.001.

    Article  CAS  PubMed  Google Scholar 

  10. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009;19(2):43–51. doi:10.1016/j.tcb.2008.11.003.

    Article  CAS  PubMed  Google Scholar 

  11. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nature Rev Immunol. 2002;2(8):569–79. doi:10.1038/nri855.

    CAS  Google Scholar 

  12. Ratajczak J, Wysoczynski M, Hayek F, Janowska-Wieczorek A, Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia. 2006;20(9):1487–95. doi:10.1038/sj.leu.2404296.

    Article  CAS  PubMed  Google Scholar 

  13. Simons M, Raposo G. Exosomes—vesicular carriers for intercellular communication. Current Opinion in Cell Biol. 2009;21(4):575–81. doi:10.1016/j.ceb.2009.03.007.

    Article  CAS  Google Scholar 

  14. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13(4):423–33. doi:10.1038/ncb2210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108(12):5003–8. doi:10.1073/pnas.1019055108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39(16):7223–33. doi:10.1093/nar/gkr254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ma R, Jiang T, Kang X. Circulating microRNAs in cancer: origin, function and application. J Exp Clin Cancer Res: CR. 2012;31:38. doi:10.1186/1756-9966-31-38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A. 2008;105(30):10513–8. doi:10.1073/pnas.0804549105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kelly BD, Miller N, Healy NA, Walsh K, Kerin MJ. A review of expression profiling of circulating microRNAs in men with prostate cancer. BJU Int. 2013;111(1):17–21. doi:10.1111/j.1464-410X.2012.11244.x.

    Article  CAS  PubMed  Google Scholar 

  20. Selth LA, Tilley WD, Butler LM. Circulating microRNAs: macro-utility as markers of prostate cancer? Endocrine-related cancer. 2012;19(4):R99–R113. doi:10.1530/ERC-12-0010.

    Article  CAS  PubMed  Google Scholar 

  21. Andersen CL, Jensen JL, Orntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64(15):5245–50. doi:10.1158/0008-5472.CAN-04-0496.

    Article  CAS  PubMed  Google Scholar 

  22. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22. doi:10.1016/j.ccr.2010.05.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bryant RJ, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, et al. Changes in circulating microRNA levels associated with prostate cancer. British J Cancer. 2012;106(4):768–74. doi:10.1038/bjc.2011.595.

    Article  CAS  Google Scholar 

  24. Brase JC, Johannes M, Schlomm T, Falth M, Haese A, Steuber T, et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer. 2011;128(3):608–16. doi:10.1002/ijc.25376.

    Article  CAS  PubMed  Google Scholar 

  25. Nguyen HC, Xie W, Yang M, Hsieh CL, Drouin S, Lee GS, et al. Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer. Prostate. 2012. doi:10.1002/pros.22572.

    PubMed  PubMed Central  Google Scholar 

  26. Lodes MJ, Caraballo M, Suciu D, Munro S, Kumar A, Anderson B. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS One. 2009;4(7):e6229. doi:10.1371/journal.pone.0006229.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stoppler H, et al. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res. 2011;71(2):550–60. doi:10.1158/0008-5472.CAN-10-1229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang HL, Yang LF, Zhu Y, Yao XD, Zhang SL, Dai B, et al. Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel-based chemotherapy. Prostate. 2011;71(3):326–31. doi:10.1002/pros.21246.

    Article  CAS  PubMed  Google Scholar 

  29. Yaman Agaoglu F, Kovancilar M, Dizdar Y, Darendeliler E, Holdenrieder S, Dalay N, et al. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol : J Int Soc for Oncodevelopmental Biol and Med. 2011;32(3):583–8. doi:10.1007/s13277-011-0154-9.

    Article  CAS  Google Scholar 

  30. Selth LA, Townley S, Gillis JL, Ochnik AM, Murti K, Macfarlane RJ, et al. Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease. Int J Cancer. 2012;131(3):652–61. doi:10.1002/ijc.26405.

    Article  CAS  PubMed  Google Scholar 

  31. Mahn R, Heukamp LC, Rogenhofer S, von Ruecker A, Muller SC, Ellinger J. Circulating microRNAs (miRNA) in serum of patients with prostate cancer. Urology. 2011;77(5):1265 e9-16. doi:10.1016/j.urology.2011.01.020.

    Article  PubMed  Google Scholar 

  32. Heneghan HM, Miller N, Kelly R, Newell J, Kerin MJ. Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. The oncologist. 2010;15(7):673–82. doi:10.1634/theoncologist.2010-0103.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zheng C, Yinghao S, Li J. MiR-221 expression affects invasion potential of human prostate carcinoma cell lines by targeting DVL2. Med Oncol. 2012;29(2):815–22. doi:10.1007/s12032-011-9934-8.

    Article  CAS  PubMed  Google Scholar 

  34. Shen J, Hruby GW, McKiernan JM, Gurvich I, Lipsky MJ, Benson MC, et al. Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer. Prostate. 2012;72(13):1469–77. doi:10.1002/pros.22499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen ZH, Zhang GL, Li HR, Luo JD, Li ZX, Chen GM, et al. A panel of five circulating microRNAs as potential biomarkers for prostate cancer. Prostate. 2012;72(13):1443–52. doi:10.1002/pros.22495.

    Article  CAS  PubMed  Google Scholar 

  36. Jung K. A review of expression profiling of circulating microRNAs in men with prostate cancer. BJU Int. 2013;111(1):3–4. doi:10.1111/j.1464-410X.2012.11257.x.

    Article  CAS  PubMed  Google Scholar 

  37. Olmos D, Brewer D, Clark J, Danila DC, Parker C, Attard G, et al. Prognostic value of blood mRNA expression signatures in castration-resistant prostate cancer: a prospective, two-stage study. The lancet Oncol. 2012;13(11):1114–24. doi:10.1016/S1470-2045(12)70372-8.

    Article  CAS  PubMed  Google Scholar 

  38. Ross RW, Galsky MD, Scher HI, Magidson J, Wassmann K, Lee GS, et al. A whole-blood RNA transcript-based prognostic model in men with castration-resistant prostate cancer: a prospective study. The lancet Oncol. 2012;13(11):1105–13. doi:10.1016/S1470-2045(12)70263-2.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Birgitte Trolle, Conni Sørensen, Nadia Gadeberg Knudsen, Karin Fredborg, and Susanne Skou for excellent technical assistance. The Danish Cancer Biobank is acknowledged for biological material. This study was supported by the Danish Agency for Science, Technology and Innovation, the Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research.

Conflicts of interest

All authors declare that they have no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

    Christa Haldrup, Torben F. Orntoft & Karina D. Sorensen

  2. Division of Molecular and Cellular Medicine, National Cancer Center Research Institute (NCCRI), Tokyo, Japan

    Nobuyoshi Kosaka & Takahiro Ochiya

  3. Department of Urology, Aarhus University Hospital, Aarhus, Denmark

    Michael Borre

  4. Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark

    Soren Høyer

Authors
  1. Christa Haldrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobuyoshi Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takahiro Ochiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Borre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soren Høyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Torben F. Orntoft
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karina D. Sorensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karina D. Sorensen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 753 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haldrup, C., Kosaka, N., Ochiya, T. et al. Profiling of circulating microRNAs for prostate cancer biomarker discovery. Drug Deliv. and Transl. Res. 4, 19–30 (2014). https://doi.org/10.1007/s13346-013-0169-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-013-0169-4

Keywords

Search

Navigation