MicroRNAs are key regulators of gene expression and play critical roles in both normal physiology and pathology. Recent research has demonstrated that these molecules are present in body fluids, such as serum, plasma, and urine, and can be readily measured using a variety of techniques. More importantly, emerging evidence suggests that circulating or urine miRNAs are useful indicators of disease. Here, we consider the potential utility of such miRNAs as noninvasive biomarkers of prostate cancer, a disease that would benefit substantially from novel diagnostic and prognostic tools. The studies aimed at identifying diagnostic, prognostic, and/or predictive miRNAs for prostate cancer are summarised and reviewed. Finally, practical considerations that will influence the translation of this recent research into clinical implementation are discussed. 1. The Clinical Problem of Prostate Cancer Prostate cancer is the second most common solid tumour in men worldwide and, despite significant advances in early diagnosis and management, it remains a leading cause of cancer-related death in men [1]. Pathological diagnosis of prostate cancer is usually obtained by a transrectal ultrasound-guided biopsy prompted by elevated levels of serum prostate-specific antigen (PSA) and/or an abnormal digital rectal examination (DRE). The use of PSA for the diagnosis of prostate cancer is associated with several clinical issues. PSA is not specific for this malignancy, being elevated in many other conditions including benign prostatic hyperplasia (BPH), urinary retention, prostatitis, trauma, and physical manipulation [2]. Moreover, elevated levels only correlate loosely with disease severity: approximately 30% of people with PSA 5–10 and >50% with PSA > 10 will have prostate cancer [3]. Conversely about 10–15% of people with PSA < 5 will harbour prostate cancer [4]. Perhaps more important than its diagnostic inaccuracy, three large clinical trials have revealed that PSA testing/screening is associated with a high rate of overdiagnosis and overtreatment [5–7]. Prostate cancer is characterised by distinctly unpredictable outcomes from latent, slow growing tumours to aggressive, rapidly lethal tumours. Although much effort has been put into finding biomarkers that would improve diagnosis, the pertinent clinical issue is the detection of aggressive forms of the disease at an early, curable stage. A significant proportion of cases follow an indolent course and may not require curative treatment. In fact, up to 40% of elderly men will harbour cancer within their prostates at autopsy
References
[1]
F. Bray, J.-S. Ren, E. Masuyer, and J. Ferlay, “Global estimates of cancer prevalence for 27 sites in the adult population in 2008,” International Journal of Cancer, vol. 132, no. 5, pp. 1133–1145, 2013.
[2]
J. E. Oesterling, “Prostate specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate,” Journal of Urology, vol. 145, no. 5, pp. 907–923, 1991.
[3]
W. J. Catalona, D. S. Smith, T. L. Ratliff et al., “Measurement of prostate-specific antigen in serum as a screening test for prostate cancer,” The New England Journal of Medicine, vol. 324, no. 17, pp. 1156–1161, 1991.
[4]
I. M. Thompson, D. K. Pauler, P. J. Goodman et al., “Prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0？ng per milliliter,” The New England Journal of Medicine, vol. 350, no. 22, pp. 2239–2346, 2004.
[5]
J. Hugosson, S. Carlsson, G. Aus et al., “Mortality results from the G？teborg randomised population-based prostate-cancer screening trial,” The Lancet Oncology, vol. 11, no. 8, pp. 725–732, 2010.
[6]
F. H. Schr？der, J. Hugosson, M. J. Roobol et al., “Screening and prostate-cancer mortality in a randomized european study,” The New England Journal of Medicine, vol. 360, no. 13, pp. 1320–1328, 2009.
[7]
G. L. Andriole, E. D. Crawford, R. L. Grubb III et al., “Mortality results from a randomized prostate-cancer screening trial,” The New England Journal of Medicine, vol. 360, no. 13, pp. 1310–1319, 2009.
[8]
M. Sánchez-Chapado, G. Olmedilla, M. Cabeza, E. Donat, and A. Ruiz, “Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study,” Prostate, vol. 54, no. 3, pp. 238–247, 2003.
[9]
K. Stamatiou, A. Alevizos, E. Agapitos, and F. Sofras, “Incidence of impalpable carcinoma of the prostate and of non-malignant and precarcinomatous lesions in Greek male population: an autopsy study,” Prostate, vol. 66, no. 12, pp. 1319–1328, 2006.
[10]
P. C. Albertsen, J. A. Hanley, D. F. Gleason, and M. J. Barry, “Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer,” Journal of the American Medical Association, vol. 280, no. 11, pp. 975–980, 1998.
[11]
P. Mufarrij, A. Sankin, G. Godoy, and H. Lepor, “Pathologic outcomes of candidates for active surveillance undergoing radical prostatectomy,” Urology, vol. 76, no. 3, pp. 689–692, 2010.
[12]
G. Attard and J. S. De Bono, “Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients,” Clinical Cancer Research, vol. 17, no. 12, pp. 3867–3875, 2011.
[13]
K. A. Phillips, S. Van Bebber, and A. M. Issa, “Diagnostics and biomarker development: priming the pipeline,” Nature Reviews Drug Discovery, vol. 5, no. 6, pp. 463–469, 2006.
[14]
R. C. Lee, R. L. Feinbaum, and V. Ambros, “The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14,” Cell, vol. 75, no. 5, pp. 843–854, 1993.
[15]
D. P. Bartel, “MicroRNAs: target recognition and regulatory functions,” Cell, vol. 136, no. 2, pp. 215–233, 2009.
[16]
J. Winter, S. Jung, S. Keller, R. I. Gregory, and S. Diederichs, “Many roads to maturity: microRNA biogenesis pathways and their regulation,” Nature Cell Biology, vol. 11, no. 3, pp. 228–234, 2009.
[17]
Y. Lee, C. Ahn, J. Han et al., “The nuclear RNase III Drosha initiates microRNA processing,” Nature, vol. 425, no. 6956, pp. 415–419, 2003.
[18]
E. Lund, S. Güttinger, A. Calado, J. E. Dahlberg, and U. Kutay, “Nuclear export of microRNA precursors,” Science, vol. 303, no. 5654, pp. 95–98, 2004.
[19]
R. Yi, Y. Qin, I. G. Macara, and B. R. Cullen, “Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs,” Genes and Development, vol. 17, no. 24, pp. 3011–3016, 2003.
[20]
R. C. Friedman, K. K. H. Farh, C. B. Burge, and D. P. Bartel, “Most mammalian mRNAs are conserved targets of microRNAs,” Genome Research, vol. 19, no. 1, pp. 92–105, 2009.
[21]
B. P. Lewis, C. B. Burge, and D. P. Bartel, “Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets,” Cell, vol. 120, no. 1, pp. 15–20, 2005.
[22]
A. Kozomara and S. Griffiths-Jones, “MiRBase: integrating microRNA annotation and deep-sequencing data,” Nucleic Acids Research, vol. 39, no. 1, pp. D152–D157, 2011.
[23]
R. Zhang and B. Su, “Small but influential: the role of microRNAs on gene regulatory network and 3′UTR evolution,” Journal of Genetics and Genomics, vol. 36, no. 1, pp. 1–6, 2009.
[24]
G. A. Calin, C. D. Dumitru, M. Shimizu et al., “Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 24, pp. 15524–15529, 2002.
[25]
C. M. Croce, “Causes and consequences of microRNA dysregulation in cancer,” Nature Reviews Genetics, vol. 10, no. 10, pp. 704–714, 2009.
[26]
A. Schaefer, C. Stephan, J. Busch, G. M. Yousef, and K. Jung, “Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors,” Nature Reviews Urology, vol. 7, no. 5, pp. 286–297, 2010.
[27]
R. Ma, T. Jiang, and X. Kang, “Circulating microRNAs in cancer: origin, function and application,” Journal of Experimental and Clinical Cancer Research, vol. 31, no. 1, article 38, 2012.
[28]
Y. Karube, H. Tanaka, H. Osada et al., “Reduced expression of Dicer associated with poor prognosis in lung cancer patients,” Cancer Science, vol. 96, no. 2, pp. 111–115, 2005.
[29]
M. S. Kumar, R. E. Pester, C. Y. Chen et al., “Dicer1 functions as a haploinsufficient tumor suppressor,” Genes and Development, vol. 23, no. 23, pp. 2700–2704, 2009.
[30]
R. Koesters, V. Adams, D. Betts et al., “Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34-p35, and expression,” Genomics, vol. 61, no. 2, pp. 210–218, 1999.
[31]
L. Li, C. Yu, H. Gao, and Y. Li, “Argonaute proteins: potential biomarkers for human colon cancer,” BMC Cancer, vol. 10, article no. 38, 2010.
[32]
D. Qiao, A. M. Zeeman, W. Deng, L. H. J. Looijenga, and H. Lin, “Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas,” Oncogene, vol. 21, no. 25, pp. 3988–3999, 2002.
[33]
J. Lu, G. Getz, E. A. Miska et al., “MicroRNA expression profiles classify human cancers,” Nature, vol. 435, no. 7043, pp. 834–838, 2005.
[34]
M. V. Iorio, M. Ferracin, C. G. Liu et al., “MicroRNA gene expression deregulation in human breast cancer,” Cancer Research, vol. 65, no. 16, pp. 7065–7070, 2005.
[35]
M. V. Iorio, R. Visone, G. Di Leva et al., “MicroRNA signatures in human ovarian cancer,” Cancer Research, vol. 67, no. 18, pp. 8699–8707, 2007.
[36]
P. S. Mitchell, R. K. Parkin, E. M. Kroh et al., “Circulating microRNAs as stable blood-based markers for cancer detection,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 30, pp. 10513–10518, 2008.
[37]
L. A. Selth, S. Townley, J. L. Gillis et al., “Discovery of circulating microRNAs associated with human prostate cancer using a mouse model of disease,” International Journal of Cancer, vol. 131, no. 3, pp. 652–661, 2012.
[38]
S. S. C. Chim, T. K. F. Shing, E. C. W. Hung et al., “Detection and characterization of placental microRNAs in maternal plasma,” Clinical Chemistry, vol. 54, no. 3, pp. 482–490, 2008.
[39]
C. H. Lawrie, S. Gal, H. M. Dunlop et al., “Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma,” British Journal of Haematology, vol. 141, no. 5, pp. 672–675, 2008.
[40]
L. A. Selth, W. D. Tilley, and L. M. Butler, “Circulating microRNAs: macro-utility as markers of prostate cancer?” Endocrine-Related Cancer, vol. 19, no. 4, pp. R99–R113, 2012.
[41]
X. Chen, Y. Ba, L. Ma et al., “Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases,” Cell Research, vol. 18, no. 10, pp. 997–1006, 2008.
[42]
J. D. Arroyo, J. R. Chevillet, E. M. Kroh et al., “Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 5003–5008, 2011.
[43]
H. Valadi, K. Ekstr？m, A. Bossios, M. Sj？strand, J. J. Lee, and J. O. L？tvall, “Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells,” Nature Cell Biology, vol. 9, no. 6, pp. 654–659, 2007.
[44]
K. C. Vickers, B. T. Palmisano, B. M. Shoucri, R. D. Shamburek, and A. T. Remaley, “MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins,” Nature Cell Biology, vol. 13, no. 4, pp. 423–433, 2011.
[45]
J. Skog, T. Würdinger, S. van Rijn et al., “Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers,” Nature Cell Biology, vol. 10, no. 12, pp. 1470–1476, 2008.
[46]
M. A. Cortez, C. Bueso-Ramos, J. Ferdin, G. Lopez-Berestein, A. K. Sood, and G. A. Calin, “MicroRNAs in body fluids-the mix of hormones and biomarkers,” Nature Reviews Clinical Oncology, vol. 8, no. 8, pp. 467–477, 2011.
[47]
Y. Zhang, D. Liu, X. Chen et al., “Secreted monocytic miR-150 enhances targeted endothelial cell migration,” Molecular Cell, vol. 39, no. 1, pp. 133–144, 2010.
[48]
J. A. Weber, D. H. Baxter, S. Zhang et al., “The microRNA spectrum in 12 body fluids,” Clinical Chemistry, vol. 56, no. 11, pp. 1733–1741, 2010.
[49]
M. Hanke, K. Hoefig, H. Merz et al., “A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer,” Urologic Oncology, vol. 28, no. 6, pp. 655–661, 2010.
[50]
N. J. Park, H. Zhou, D. Elashoff et al., “Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection,” Clinical Cancer Research, vol. 15, no. 17, pp. 5473–5477, 2009.
[51]
M. J. Lodes, M. Caraballo, D. Suciu, S. Munro, A. Kumar, and B. Anderson, “Detection of cancer with serum miRNAs on an oligonucleotide microarray,” PLoS ONE, vol. 4, no. 7, Article ID e6229, 2009.
[52]
F. Moltzahn, A. B. Olshen, L. Baehner et al., “Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients,” Cancer Research, vol. 71, no. 2, pp. 550–560, 2011.
[53]
J. C. Brase, M. Johannes, T. Schlomm et al., “Circulating miRNAs are correlated with tumor progression in prostate cancer,” International Journal of Cancer, vol. 128, no. 3, pp. 608–616, 2011.
[54]
J. C. Gonzales, L. M. Fink, O. B. Goodman Jr., J. T. Symanowski, N. J. Vogelzang, and D. C. Ward, “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,” Clinical Genitourinary Cancer, vol. 9, no. 1, pp. 39–45, 2011.
[55]
F. Y. Agaoglu, M. Kovancilar, Y. Dizdar et al., “Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer,” Tumour Biology, vol. 32, no. 3, pp. 583–588, 2011.
[56]
R. Mahn, L. C. Heukamp, S. Rogenhofer, A. Von Ruecker, S. C. Müller, and J. Ellinger, “Circulating microRNAs (miRNA) in serum of patients with prostate cancer,” Urology, vol. 77, no. 5, pp. 1265–e9, 2011.
[57]
R. J. Bryant, T. Pawlowski, J. W. F. Catto et al., “Changes in circulating microRNA levels associated with prostate cancer,” British Journal of Cancer, vol. 106, no. 4, pp. 768–774, 2012.
[58]
H. C. N. Nguyen, W. Xie, M. Yang et al., “Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer,” Prostate, vol. 73, no. 4, pp. 346–354, 2013.
[59]
Z.-H. Chen, G.-L. Zhang, H.-R. Li et al., “A panel of five circulating microRNAs as potential biomarkers for prostate cancer,” Prostate, vol. 72, no. 13, pp. 1443–1452, 2012.
[60]
C. Zheng, S. Yinghao, and J. Li, “MiR-221 expression affects invasion potential of human prostate carcinoma cell lines by targeting DVL2,” Medical Oncology, vol. 29, no. 2, pp. 815–822, 2012.
[61]
J. Shen, G. W. Hruby, J. M. McKiernan et al., “Dysregulation of circulating microRNAs and prediction of aggressive prostate cancer,” Prostate, vol. 72, no. 13, pp. 1469–1477, 2012.
[62]
I. Sanders, S. Holdenrieder, G. Walgenbach-Brünagel et al., “Evaluation of reference genes for the analysis of serum miRNA in patients with prostate cancer, bladder cancer and renal cell carcinoma,” International Journal of Urology, vol. 19, no. 11, pp. 1017–1025, 2012.
[63]
J. C. Brase, D. Wuttig, R. Kuner, and H. Sültmann, “Serum microRNAs as non-invasive biomarkers for cancer,” Molecular Cancer, vol. 9, article no. 306, 2010.
[64]
H. L. Zhang, L. F. Yang, Y. Zhu 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, vol. 71, no. 3, pp. 326–331, 2011.
[65]
D. Hessels, J. M. T. Klein Gunnewiek, I. Van Oort et al., “DD -based molecular urine analysis for the diagnosis of prostate cancer,” European Urology, vol. 44, no. 1, pp. 8–16, 2003.
[66]
J. Szczyrba, E. L？prich, S. Wach et al., “The microRNA profile of prostate carcinoma obtained by deep sequencing,” Molecular Cancer Research, vol. 8, no. 4, pp. 529–538, 2010.
[67]
H. Cheng, L. Zhang, D. E. Cogdell et al., “Circulating plasma MiR-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis,” PLoS One, vol. 6, no. 3, Article ID e17745, 2011.
[68]
L. M. Li, Z. B. Hu, Z. X. Zhou et al., “Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma,” Cancer Research, vol. 70, no. 23, pp. 9798–9807, 2010.
[69]
R. Duttagupta, R. Jiang, J. Gollub, R. C. Getts, and K. W. Jones, “Impact of cellular miRNAs on circulating miRNA biomarker signatures,” PLoS One, vol. 6, no. 6, Article ID e20769, 2011.
[70]
J. S. McDonald, D. Milosevic, H. V. Reddi, S. K. Grebe, and A. Algeciras-Schimnich, “Analysis of circulating microRNA: preanalytical and analytical challenges,” Clinical Chemistry, vol. 57, no. 6, pp. 833–840, 2011.
[71]
M. B. Kirschner, S. C. Kao, J. J. Edelman et al., “Haemolysis during sample preparation alters microRNA content of plasma,” PLoS One, vol. 6, no. 9, Article ID e24145, 2011.
[72]
L. J. Sokoll, W. Ellis, P. Lange et al., “A multicenter evaluation of the PCA3 molecular urine test: pre-analytical effects, analytical performance, and diagnostic accuracy,” Clinica Chimica Acta, vol. 389, no. 1-2, pp. 1–6, 2008.
[73]
E. M. Kroh, R. K. Parkin, P. S. Mitchell, and M. Tewari, “Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR),” Methods, vol. 50, no. 4, pp. 298–301, 2010.
[74]
L. W. Lee, S. Zhang, A. Etheridge et al., “Complexity of the microRNA repertoire revealed by next-generation sequencing,” RNA, vol. 16, no. 11, pp. 2170–2180, 2010.
[75]
B. M. Ryan, A. I. Robles, and C. C. Harris, “Genetic variation in microRNA networks: the implications for cancer research,” Nature Reviews Cancer, vol. 10, no. 6, pp. 389–402, 2010.
[76]
Z. Huang, D. Huang, S. Ni, Z. Peng, W. Sheng, and X. Du, “Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer,” International Journal of Cancer, vol. 127, no. 1, pp. 118–126, 2010.
[77]
B. M. Bolstad, R. A. Irizarry, M. ？strand, and T. P. Speed, “A comparison of normalization methods for high density oligonucleotide array data based on variance and bias,” Bioinformatics, vol. 19, no. 2, pp. 185–193, 2003.
[78]
A. Deo, J. Carlsson, and A. Lindl？f, “How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays,” Journal of Bioinformatics and Computational Biology, vol. 9, no. 6, pp. 795–812, 2011.
[79]
Y. J. Hua, K. Tu, Z. Y. Tang, Y. X. Li, and H. S. Xiao, “Comparison of normalization methods with microRNA microarray,” Genomics, vol. 92, no. 2, pp. 122–128, 2008.
[80]
S. Pradervand, J. Weber, J. Thomas et al., “Impact of normalization on miRNA microarray expression profiling,” RNA, vol. 15, no. 3, pp. 493–501, 2009.
[81]
M. S. Pepe, R. Etzioni, Z. Feng et al., “Phases of biomarker development for early detection of cancer,” Journal of the National Cancer Institute, vol. 93, no. 14, pp. 1054–1061, 2001.
[82]
R. Simon, M. D. Radmacher, K. Dobbin, and L. M. McShane, “Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification,” Journal of the National Cancer Institute, vol. 95, no. 1, pp. 14–18, 2003.
