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The translational potential of microRNAs as biofluid markers of urological tumours

Key Points

  • Several hundred microRNAs (miRNAs) occur in biofluids as free molecules or are secreted in vesicles or bound in a ribonucleoprotein complex

  • The secretion of miRNAs into biofluids is dysregulated in cancer making miRNAs potential noninvasive tumour biomarkers

  • Studies performed on samples from patients with urological carcinomas suggest that miRNAs in whole-blood samples, serum, plasma and urine can be applied as novel diagnostic, prognostic and surveillance biomarkers

  • Inconsistent and contradictory results from studies in bladder, kidney and prostate cancer impede translation of miRNA measurements into routine clinical practice, but a clinically useful signature has been developed for testicular cancer

  • Preanalytical, analytical and postanalytical differences as well as insufficient power and the heterogeneity of studies are the main factors in shortcomings in this research field

  • Prospective, multicentre studies that consider all these deficiencies in their design are necessary to assess the real clinical benefit of miRNA measurements in the biofluids of patients with urological carcinomas

Abstract

MicroRNAs (miRNAs) are secreted by cells in vesicles, bound in a ribonucleoprotein complex or as free molecules. These miRNA secretion pathways are dysregulated in cancer, making miRNAs attractive candidate molecules for liquid biopsies. A number of studies have investigated the regulation of miRNA secretion into blood and urine and suggested that miRNAs are noninvasive diagnostic, prognostic and surveillance markers in urological carcinomas, and research in this area has increased over the past 5 years. However, methodological and analytical pitfalls exist and require addressing to enable future translation of the laboratory findings regarding miRNAs as biomarkers into clinical practice in bladder cancer, kidney cancer, prostate cancer and testicular cancer.

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Figure 1: Total annual microRNA (miRNA) publications indexed in the PubMed database relating to urological tumours.
Figure 2: The origin of circulating microRNAs (miRNAs).

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References

  1. Schaefer, A., Stephan, C., Busch, J., Yousef, G. M. & Jung, K. Diagnostic, prognostic, and therapeutic implications of miRNAs in urologic tumors. Nat. Rev. Urol. 7, 286–297 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Chen, M., Calin, G. A. & Meng, Q. H. Circulating microRNAs as promising tumor biomarkers. Adv. Clin. Chem. 67, 189–214 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Fabris, L. et al. The potential of microRNAs as prostate cancer biomarkers. Eur. Urol. 70, 312–322 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fedorko, M. et al. MicroRNAs in the pathogenesis of renal cell carcinoma and their diagnostic and prognostic utility as cancer biomarkers. Int. J. Biol. Markers 31, e26–e37 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Filella, X. & Foj, L. miRNAs as novel biomarkers in the management of prostate cancer. Clin. Chem. Lab. Med. http://dx.doi.org/10.1515/cclm-2015-1073 (2016).

  6. Junker, K., Heinzelmann, J., Beckham, C., Ochiya, T. & Jenster, G. Extracellular vesicles and their role in urologic malignancies. Eur. Urol. 70, 323–331 (2016).

    Article  PubMed  Google Scholar 

  7. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  8. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

  9. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

  10. Davis, C. F. et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 26, 319–330 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Linehan, W. M. et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N. Engl. J. Med. 374, 135–145 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Weber, J. A. et al. The microRNA spectrum in 12 body fluids. Clin. Chem. 56, 1733–1741 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fuentes-Arderiu, X. What is a biomarker? It's time for a renewed definition. Clin. Chem. Lab. Med. 51, 1689–1690 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Ibrahim, R., Pasic, M. & Yousef, G. M. Omics for personalized medicine: defining the current we swim in. Expert Rev. Mol. Diagn. 16, 719–722 (2016).

    Article  CAS  PubMed  Google Scholar 

  15. Arroyo, J. D. et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D. & Remaley, A. T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, K., Zhang, S., Weber, J., Baxter, D. & Galas, D. J. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 38, 7248–7259 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Franzen, C. A., Blackwell, R. H., Foreman, K. E., Kuo, P. C. & Gupta, G. N. Urinary exosomes: the potential for biomarker utility, intercellular signaling and therapeutics in urological malignancy. J. Urol. 195, 1331–1339 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Iftikhar, H. & Carney, G. E. Evidence and potential in vivo functions for biofluid miRNAs: from expression profiling to functional testing: potential roles of extracellular miRNAs as indicators of physiological change and as agents of intercellular information exchange. Bioessays 38, 367–378 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Mitchell, P. S. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mall, C., Rocke, D. M., Durbin-Johnson, B. & Weiss, R. H. Stability of miRNA in human urine supports its biomarker potential. Biomark. Med. 7, 623–631 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Ostenfeld, M. S. et al. Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res. 74, 5758–5771 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. McDonald, J. S., Milosevic, D., Reddi, H. V., Grebe, S. K. & Algeciras-Schimnich, A. Analysis of circulating microRNA: preanalytical and analytical challenges. Clin. Chem. 57, 833–840 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Kirschner, M. B., van Zandwijk, N. & Reid, G. Cell-free microRNAs: potential biomarkers in need of standardized reporting. Front. Genet. 4, 56 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Farina, N. H. et al. Standardizing analysis of circulating microRNA: clinical and biological relevance. J. Cell. Biochem. 115, 805–811 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mlcochova, H., Hezova, R., Stanik, M. & Slaby, O. Urine microRNAs as potential noninvasive biomarkers in urologic cancers. Urol. Oncol. 32, 41–49 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Ralla, B. et al. Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies. Crit. Rev. Clin. Lab. Sci. 51, 200–231 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Xylinas, E. et al. Urine markers for detection and surveillance of bladder cancer. Urol. Oncol. 32, 222–229 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Netto, G. J. Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat. Rev. Urol. 9, 41–51 (2012).

    Article  CAS  Google Scholar 

  31. Babjuk, M. et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur. Urol. 59, 997–1008 (2011).

    Article  PubMed  Google Scholar 

  32. Knowles, M. A. & Hurst, C. D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer 15, 25–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Rosenberg, E. et al. Predicting progression of bladder urothelial carcinoma using microRNA expression. BJU Int. 112, 1027–1034 (2013).

    CAS  PubMed  Google Scholar 

  34. Hanke, M. et al. A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. Urol. Oncol. 28, 655–661 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Yamada, Y. et al. MiR-96 and miR-183 detection in urine serve as potential tumor markers of urothelial carcinoma: correlation with stage and grade, and comparison with urinary cytology. Cancer Sci. 102, 522–529 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Miah, S. et al. An evaluation of urinary microRNA reveals a high sensitivity for bladder cancer. Br. J. Cancer 107, 123–128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Puerta-Gil, P. et al. miR-143, miR-222, and miR-452 are useful as tumor stratification and noninvasive diagnostic biomarkers for bladder cancer. Am. J. Pathol. 180, 1808–1815 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Snowdon, J., Boag, S., Feilotter, H., Izard, J. & Siemens, D. R. A pilot study of urinary microRNA as a biomarker for urothelial cancer. Can. Urol. Assoc. J. 7, 28–32 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Wang, G. et al. Expression of microRNAs in the urine of patients with bladder cancer. Clin. Genitourin. Cancer 10, 106–113 (2012).

    Article  PubMed  Google Scholar 

  40. Yun, S. J. et al. Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int. J. Oncol. 41, 1871–1878 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, S. M. et al. Cell-Free microRNA-214 from urine as a biomarker for non-muscle-invasive bladder cancer. Korean J. Urol. 54, 791–796 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Mengual, L. et al. Using microRNA profiling in urine samples to develop a non-invasive test for bladder cancer. Int. J. Cancer 133, 2631–2641 (2013).

    CAS  PubMed  Google Scholar 

  43. Shimizu, T. et al. Methylation of a panel of microRNA genes is a novel biomarker for detection of bladder cancer. Eur. Urol. 63, 1091–1100 (2013).

    Article  CAS  PubMed  Google Scholar 

  44. Tölle, A. et al. Identification of microRNAs in blood and urine as tumour markers for the detection of urinary bladder cancer. Oncol. Rep. 30, 1949–1956 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Zhang, D. Z. et al. Cell-free urinary microRNA-99a and microRNA-125b are diagnostic markers for the non-invasive screening of bladder cancer. PLoS ONE 9, e100793 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou, X. et al. Urinary cell-free microRNA-106b as a novel biomarker for detection of bladder cancer. Med. Oncol. 31, 197 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Eissa, S., Habib, H., Ali, E. & Kotb, Y. Evaluation of urinary miRNA-96 as a potential biomarker for bladder cancer diagnosis. Med. Oncol. 32, 413 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Eissa, S., Matboli, M., Essawy, N. O. & Kotb, Y. M. Integrative functional genetic-epigenetic approach for selecting genes as urine biomarkers for bladder cancer diagnosis. Tumour Biol. 36, 9545–9552 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Liu, W. et al. MiRNA-141 and miRNA-200b are closely related to invasive ability and considered as decision-making biomarkers for the extent of PLND during cystectomy. BMC Cancer 15, 92 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Long, J. D. et al. A non-invasive miRNA based assay to detect bladder cancer in cell-free urine. Am. J. Transl Res. 7, 2500–2509 (2015).

    PubMed  PubMed Central  Google Scholar 

  51. Wang, J. et al. Downregulation of urinary cell-free microRNA-214 as a diagnostic and prognostic biomarker in bladder cancer. J. Surg. Oncol. 111, 992–999 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Sapre, N. et al. A urinary microRNA signature can predict the presence of bladder urothelial carcinoma in patients undergoing surveillance. Br. J. Cancer 114, 454–462 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Scheffer, A. R. et al. Circulating microRNAs in serum: novel biomarkers for patients with bladder cancer? World J. Urol. 32, 353–358 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Jiang, X. et al. Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer. Int. J. Cancer 136, 854–862 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Kriebel, S. et al. Analysis of tissue and serum microRNA expression in patients with upper urinary tract urothelial cancer. PLoS ONE 10, e0117284 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Adam, L. et al. Plasma microRNA profiles for bladder cancer detection. Urol. Oncol. 31, 1701–1708 (2013).

    Article  CAS  PubMed  Google Scholar 

  57. Feng, Y. et al. microRNA-99a acts as a tumor suppressor and is down-regulated in bladder cancer. BMC Urol. 14, 50 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Feng, Y. et al. miR-19a acts as an oncogenic microRNA and is up-regulated in bladder cancer. J. Exp. Clin. Cancer Res. 33, 67 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Du, M. et al. Circulating miR-497 and miR-663b in plasma are potential novel biomarkers for bladder cancer. Sci. Rep. 5, 10437 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Armstrong, D. A., Green, B. B., Seigne, J. D., Schned, A. R. & Marsit, C. J. MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. Mol. Cancer 14, 194 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. MacLellan, S. A., MacAulay, C., Lam, S. & Garnis, C. Pre-profiling factors influencing serum microRNA levels. BMC Clin. Pathol. 14, 27 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bossuyt, P. M. et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Clin. Chem. 49, 1–6 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Kirschner, M. B. et al. The impact of hemolysis on cell-free microRNA biomarkers. Front. Genet. 4, 94 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Sun, M. et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur. Urol. 60, 644–661 (2011).

    Article  PubMed  Google Scholar 

  65. von Brandenstein, M. et al. MicroRNA 15a, inversely correlated to PKCα, is a potential marker to differentiate between benign and malignant renal tumors in biopsy and urine samples. Am. J. Pathol. 180, 1787–1797 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Schmitt, J. et al. Treatment-independent miRNA signature in blood of Wilms tumor patients. BMC Genomics 13, 379 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wulfken, L. M. et al. MicroRNAs in renal cell carcinoma: diagnostic implications of serum miR-1233 levels. PLoS ONE 6, e25787 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Redova, M. et al. Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J. Transl Med. 10, 55 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cheng, T. et al. Differential microRNA expression in renal cell carcinoma. Oncol. Lett. 6, 769–776 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhao, A., Li, G., Peoc'h, M., Genin, C. & Gigante, M. Serum miR-210 as a novel biomarker for molecular diagnosis of clear cell renal cell carcinoma. Exp. Mol. Pathol. 94, 115–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Iwamoto, H. et al. Serum miR-210 as a potential biomarker of early clear cell renal cell carcinoma. Int. J. Oncol. 44, 53–58 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Fedorko, M. et al. Combination of miR-378 and miR-210 serum levels enables sensitive detection of renal cell carcinoma. Int. J. Mol. Sci. 16, 23382–23389 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ludwig, N. et al. Circulating serum miRNAs as potential biomarkers for nephroblastoma. Pediatr. Blood Cancer 62, 1360–1367 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Wang, C. et al. A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci. Rep. 5, 7610 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Teixeira, A. L. et al. Higher circulating expression levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol. 35, 4057–4066 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Gamez-Pozo, A. et al. MicroRNA expression profiling of peripheral blood samples predicts resistance to first-line sunitinib in advanced renal cell carcinoma patients. Neoplasia 14, 1144–1152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, K. et al. Comparing the microRNA spectrum between serum and plasma. PLoS ONE 7, e41561 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Youssef, Y. M. et al. Accurate molecular classification of kidney cancer subtypes using microRNA signature. Eur. Urol. 59, 721–730 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Hauser, S. et al. Analysis of serum microRNAs (miR-26a-2*, miR-191, miR-337-3p and miR-378) as potential biomarkers in renal cell carcinoma. Cancer Epidemiol. 36, 391–394 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Friedel, R., Diederichs, F. & Lindena, J. in Advances in Clinical Enzymology (eds Schmidt, E., Schmidt, F. W., Trautschold, I. & Friedel, R.) 70–105 (S. Karger AG, 1979).

    Google Scholar 

  81. Qaseem, A., Barry, M. J., Denberg, T. D., Owens, D. K. & Shekelle, P. Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann. Intern. Med. 158, 761–769 (2013).

    Article  PubMed  Google Scholar 

  82. Dietrich, D. et al. Nucleic acid-based tissue biomarkers of urologic malignancies. Crit. Rev. Clin. Lab. Sci. 51, 173–199 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Ahumada-Tamayo, S. MicroRNA determination in urine for prostate cancer detection in Mexican patients at the Hospital General “Dr. Manuel Gea Gonzalez”. Rev. Mex. Urol. 71, 213–217 (2011).

    Google Scholar 

  84. Bryant, R. J. et al. Changes in circulating microRNA levels associated with prostate cancer. Br. J. Cancer 106, 768–774 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Srivastava, A. et al. MicroRNA profiling in prostate cancer—the diagnostic potential of urinary miR-205 and miR-214. PLoS ONE 8, e76994 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Casanova-Salas, I. et al. Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J. Urol. 192, 252–259 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Haj-Ahmad, T. A., Abdalla, M. A. & Haj-Ahmad, Y. Potential urinary miRNA biomarker candidates for the accurate detection of prostate cancer among benign prostatic hyperplasia patients. J. Cancer 5, 182–191 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sapre, N. et al. Curated microRNAs in urine and blood fail to validate as predictive biomarkers for high-risk prostate cancer. PLoS ONE 9, e91729 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yun, S. J. et al. Urinary microRNAs of prostate cancer: virus-encoded hsv1-miRH18 and hsv2-miR-H9-5p could be valuable diagnostic markers. Int. Neurourol. J. 19, 74–84 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Egidi, M. G. et al. Characterization of kallikreins and microRNAs in urine sediment for the discrimination of prostate cancer from benign prostatic hyperplasia. J. Cancer Sci. Ther. 7, 130–136 (2015).

    CAS  Google Scholar 

  91. Korzeniewski, N. et al. Identification of cell-free microRNAs in the urine of patients with prostate cancer. Urol. Oncol. 33, 16–22 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Stephan, C., Jung, M., Rabenhorst, S., Kilic, E. & Jung, K. Urinary miR-183 and miR-205 do not surpass PCA3 in urine as predictive markers for prostate biopsy outcome despite their highly dysregulated expression in prostate cancer tissue. Clin. Chem. Lab. Med. 53, 1109–1118 (2015).

    CAS  PubMed  Google Scholar 

  93. Santos, J. I. et al. Influence of peripheral whole-blood microRNA-7 and microRNA-221 high expression levels on the acquisition of castration-resistant prostate cancer: evidences from in vitro and in vivo studies. Tumour Biol. 35, 7105–7113 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Leidinger, P. et al. Differential blood-based diagnosis between benign prostatic hyperplasia and prostate cancer: miRNA as source for biomarkers independent of PSA level, Gleason score, or TNM status. Tumour Biol. 37, 10177–10185 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Lodes, M. J. et al. Detection of cancer with serum miRNAs on an oligonucleotide microarray. PLoS ONE 4, e6229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Brase, J. C. et al. Circulating miRNAs are correlated with tumor progression in prostate cancer. Int. J. Cancer 128, 608–616 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Mahn, R. et al. Circulating microRNAs (miRNA) in serum of patients with prostate cancer. Urology 77, 1265.e9–1265.e16 (2011).

    Article  Google Scholar 

  98. Moltzahn, F. et al. Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients. Cancer Res. 71, 550–560 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Selth, L. A. et al. Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease. Int. J. Cancer 131, 652–661 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Zhang, H. L. 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 71, 326–331 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Cheng, H. H. et al. Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia. PLoS ONE 8, e69239 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Egidi, M. G. et al. Circulating microRNAs and kallikreins before and after radical prostatectomy: are they really prostate cancer markers? Biomed Res. Int. 2013, 241780 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nguyen, H. C. et al. Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer. Prostate 73, 346–354 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Selth, L. A. et al. Circulating microRNAs predict biochemical recurrence in prostate cancer patients. Br. J. Cancer 109, 641–650 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhang, H. L. et al. An elevated serum miR-141 level in patients with bone-metastatic prostate cancer is correlated with more bone lesions. Asian J. Androl. 15, 231–235 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Haldrup, C. et al. Profiling of circulating microRNAs for prostate cancer biomarker discovery. Drug Deliv. Transl Res. 4, 19–30 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Kotb, S. et al. Circulating miRNAs 21 and 221 as biomarkers for early diagnosis of prostate cancer. Tumour Biol. 35, 12613–12617 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Singh, P. K. et al. Serum microRNA expression patterns that predict early treatment failure in prostate cancer patients. Oncotarget 5, 824–840 (2014).

    PubMed  PubMed Central  Google Scholar 

  109. Wang, S. Y. et al. miR-19, miR-345, miR-519c-5p serum levels predict adverse pathology in prostate cancer patients eligible for active surveillance. PLoS ONE 9, e98597 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Westermann, A. M. et al. Serum microRNAs as biomarkers in patients undergoing prostate biopsy: results from a prospective multi-center study. Anticancer Res. 34, 665–669 (2014).

    CAS  PubMed  Google Scholar 

  111. Mihelich, B. L., Maranville, J. C., Nolley, R., Peehl, D. M. & Nonn, L. Elevated serum microRNA levels associate with absence of high-grade prostate cancer in a retrospective cohort. PLoS ONE 10, e0124245 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sun, X. et al. Prognostic implications of tissue and serum levels of microRNA-128 in human prostate cancer. Int. J. Clin. Exp. Pathol. 8, 8394–8401 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Wach, S. et al. The combined serum levels of miR-375 and urokinase plasminogen activator receptor are suggested as diagnostic and prognostic biomarkers in prostate cancer. Int. J. Cancer 137, 1406–1416 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Agaoglu, F. Y. et al. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumour Biol. 32, 583–588 (2011).

    Article  CAS  Google Scholar 

  115. Gonzales, J. C. et al. Comparison of circulating microRNA 141 to circulating tumor cells, lactate dehydrogenase, and prostate-specific antigen for determining treatment response in patients with metastatic prostate cancer. Clin. Genitourin. Cancer 9, 39–45 (2011).

    Article  PubMed  Google Scholar 

  116. Chen, Z. H. et al. A panel of five circulating microRNAs as potential biomarkers for prostate cancer. Prostate 72, 1443–1452 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Shen, J. et al. Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer. Prostate 72, 1469–1477 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Watahiki, A. et al. Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer. Int. J. Mol. Sci. 14, 7757–7770 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Medina-Villaamil, V. et al. Circulating microRNAs in blood of patients with prostate cancer. Actas Urol. Esp. 38, 633–639 (2014).

    Article  CAS  PubMed  Google Scholar 

  120. Kachakova, D. et al. Combinations of serum prostate-specific antigen and plasma expression levels of let-7c, miR-30c, miR-141, and miR-375 as potential better diagnostic biomarkers for prostate cancer. DNA Cell Biol. 34, 189–200 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kelly, B. D. et al. A circulating microRNA signature as a biomarker for prostate cancer in a high risk group. J. Clin. Med. 4, 1369–1379 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen, H. et al. Evaluation of plasma miR-21 and miR-152 as diagnostic biomarkers for common types of human cancers. J. Cancer 7, 490–499 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Huang, W., Kang, X. L., Cen, S., Wang, Y. & Chen, X. High-level expression of microRNA-21 in peripheral blood mononuclear cells is a diagnostic and prognostic marker in prostate cancer. Genet. Test. Mol. Biomarkers 19, 469–475 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Huang, X. et al. Exosomal miR-1290 and miR-375 as prognostic markers in castration-resistant prostate cancer. Eur. Urol. 67, 33–41 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Xu, S. et al. Downregulation of miR-129 in peripheral blood mononuclear cells is a diagnostic and prognostic biomarker in prostate cancer. Int. J. Clin. Exp. Pathol. 8, 14335–14344 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Li, Z. et al. Exosomal microRNA-141 is upregulated in the serum of prostate cancer patients. OncoTargets Ther. 9, 139–148 (2016).

    CAS  Google Scholar 

  127. Altman, D. G., McShane, L. M., Sauerbrei, W. & Taube, S. E. Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med. 9, e1001216 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Voorhoeve, P. M. et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124, 1169–1181 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Gillis, A. J. et al. High-throughput microRNAome analysis in human germ cell tumours. J. Pathol. 213, 319–328 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Palmer, R. D. et al. Malignant germ cell tumors display common microRNA profiles resulting in global changes in expression of messenger RNA targets. Cancer Res. 70, 2911–2923 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rijlaarsdam, M. A. et al. Identification of known and novel germ cell cancer-specific (embryonic) miRs in serum by high-throughput profiling. Andrology 3, 85–91 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Spiekermann, M. et al. MicroRNA miR-371a-3p in serum of patients with germ cell tumours: evaluations for establishing a serum biomarker. Andrology 3, 78–84 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Syring, I. et al. Circulating serum miRNA (miR-367-3p, miR-371a-3p, miR-372-3p and miR-373-3p) as biomarkers in patients with testicular germ cell cancer. J. Urol. 193, 331–337 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Dieckmann, K. P. et al. MicroRNAs miR-371-3 in serum as diagnostic tools in the management of testicular germ cell tumours. Br. J. Cancer 107, 1754–1760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Murray, M. J. et al. Identification of microRNAs from the miR-371373 and miR-302 clusters as potential serum biomarkers of malignant germ cell tumors. Am. J. Clin. Pathol. 135, 119–125 (2011).

    Article  CAS  PubMed  Google Scholar 

  136. Gillis, A. J. et al. Targeted serum miRNA (TSmiR) test for diagnosis and follow-up of (testicular) germ cell cancer patients: a proof of principle. Mol. Oncol. 7, 1083–1092 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Spiekermann, M., Dieckmann, K. P., Balks, T., Bullerdiek, J. & Belge, G. Is relative quantification dispensable for the measurement of microRNAs as serum biomarkers in germ cell tumors? Anticancer Res. 35, 117–121 (2015).

    CAS  PubMed  Google Scholar 

  138. Ruf, C. G. et al. Small RNAs in the peripheral blood discriminate metastasized from non-metastasized seminoma. Mol. Cancer 13, 47 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mestdagh, P. et al. Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study. Nat. Methods 11, 809–815 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the Foundation of Urologic Research, Berlin, Germany and by a Twinning Research Grant of the Berlin Institute of Health (BIH), Berlin, Germany.

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Correspondence to Klaus Jung.

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AUO No. AH 14/15-MicroRNA

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Fendler, A., Stephan, C., Yousef, G. et al. The translational potential of microRNAs as biofluid markers of urological tumours. Nat Rev Urol 13, 734–752 (2016). https://doi.org/10.1038/nrurol.2016.193

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