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  • Original Article
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Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

Oncogene volume 31, pages 978–991 (2012)Cite this article

Abstract

Prostate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in Western countries. Current clinical and pathological methods are limited in the prediction of postoperative outcome. It is becoming increasingly evident that small non-coding RNA (ncRNA) species are associated with the development and progression of this malignancy. To assess the diversity and abundance of small ncRNAs in PCa, we analyzed the composition of the entire small transcriptome by Illumina/Solexa deep sequencing. We further analyzed the microRNA (miRNA) expression signatures of 102 fresh-frozen patient samples during PCa progression by miRNA microarrays. Both platforms were cross-validated by quantitative reverse transcriptase–PCR. Besides the altered expression of several miRNAs, our deep sequencing analyses revealed strong differential expression of small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs). From microarray analysis, we derived a miRNA diagnostic classifier that accurately distinguishes normal from cancer samples. Furthermore, we were able to construct a PCa prognostic predictor that independently forecasts postoperative outcome. Importantly, the majority of miRNAs included in the predictor also exhibit high sequence counts and concordant differential expression in Illumina PCa samples, supported by quantitative reverse transcriptase–PCR. Our findings provide miRNA expression signatures that may serve as an accurate tool for the diagnosis and prognosis of PCa.

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References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berezikov E, Thuemmler F, van Laake LW, Kondova I, Bontrop R, Cuppen E et al. (2006). iversity of microRNAs in human and chimpanzee brain. Nat Genet 38: 1375–1377.

    Article  CAS  PubMed  Google Scholar 

  • Bin Hafeez B, Adhami VM, Asim M, Siddiqui IA, Bhat KM, Zhong W et al. (2009). Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin Cancer Res 15: 452–459.

    Article  CAS  PubMed  Google Scholar 

  • Brameier M, Herwig A, Reinhardt R, Walter L, Gruber J . (2011). Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Res 39: 675–686.

    Article  CAS  PubMed  Google Scholar 

  • Care A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P et al. (2007). MicroRNA-133 controls cardiac hypertrophy. Nat Med 13: 613–618.

    Article  CAS  PubMed  Google Scholar 

  • Catto JW, Alcaraz A, Bjartell AS, De Vere White R, Evans CP, Fussel S et al. (2011). MicroRNA in prostate, bladder, and kidney cancer: a systematic review. Eur Urol 59: 671–681.

    Article  CAS  PubMed  Google Scholar 

  • Chiosea S, Jelezcova E, Chandran U, Acquafondata M, McHale T, Sobol RW et al. (2006). Up-regulation of dicer, a component of the microRNA machinery, in prostate adenocarcinoma. Am J Pathol 169: 1812–1820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coppola V, De Maria R, Bonci D . (2010). MicroRNAs and prostate cancer. Endocr Relat Cancer 17: F1–17.

    Article  CAS  PubMed  Google Scholar 

  • Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S et al. (2008). Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 68: 5049–5058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dong X-Y, Rodriguez C, Guo P, Sun X, Talbot JT, Zhou W et al. (2008). SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer. Hum Mol Genet 17: 1031 .

    Article  CAS  PubMed  Google Scholar 

  • Ender C, Krek A, Friedländer MR, Beitzinger M, Weinmann L, Chen W et al. (2008). A human snoRNA with microRNA-like functions. Mol Cell 32: 519–528.

    Article  CAS  PubMed  Google Scholar 

  • Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P . (2007). Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18: 581–592.

    Article  CAS  PubMed  Google Scholar 

  • Gandellini P, Folini M, Longoni N, Pennati M, Binda M, Colecchia M et al. (2009). miR-205 exerts tumor-suppressive functions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res 69: 2287–2295.

    Article  CAS  PubMed  Google Scholar 

  • Gillies JK, Lorimer IAJ . (2007). Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle 6: 2005–2009.

    Article  CAS  PubMed  Google Scholar 

  • Git A, Dvinge H, Salmon-Divon M, Osborne M, Kutter C, Hadfield J et al. (2010). Systematic comparison of microarray profiling, real-time PCR, and next-generation sequencing technologies for measuring differential microRNA expression. RNA 16: 991–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke XS, Qu Y, Rostad K, Li WC, Lin B, Halvorsen OJ et al. (2009). Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis. PLoS One 4: e4687.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kishore S, Stamm S . (2006). The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311: 230–232.

    Article  CAS  PubMed  Google Scholar 

  • Lee JT, Lehmann BD, Terrian DM, Chappell WH, Stivala F, Libra M et al. (2008). Targeting prostate cancer based on signal transduction and cell cycle pathways. Cell Cycle 15: 1745–1762.

    Article  Google Scholar 

  • Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D et al. (2005). MicroRNA expression profiles classify human cancers. Nature 435: 834–838.

    Article  CAS  PubMed  Google Scholar 

  • Majid S, Dar AA, Saini S, Yamamura S, Hirata H, Tanaka Y et al. (2010). MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 116: 5637–5649.

    Article  CAS  PubMed  Google Scholar 

  • Marberger M . (2009). Prostate cancer 2008: challenges in diagnosis and management. Eur Urol, Supplements 8: 89–96.

    Article  Google Scholar 

  • Marshall L, White RJ . (2008). Non-coding RNA production by RNA polymerase III is implicated in cancer. Nat Rev Cancer 8: 911–914.

    Article  CAS  PubMed  Google Scholar 

  • Mattick JS, Makunin IV . (2006). Non-coding RNA. Hum Mol Genet 15 (Spec No 1): R17–R29.

    Article  CAS  PubMed  Google Scholar 

  • Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ . (2003). Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1: 882–891.

    CAS  PubMed  Google Scholar 

  • Morin RD, O'Connor MD, Griffith M, Kuchenbauer F, Delaney A, Prabhu AL et al. (2008). Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res 18: 610–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mukherjee R, McGuinness DH, McCall P, Underwood MA, Seywright M, Orange C et al. (2011). Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer. Br J Cancer 104: 1920–1928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Paronetto MP, Farini D, Sammarco I, Maturo G, Vespasiani G, Geremia R et al. (2004). Expression of a truncated form of the c-Kit tyrosine kinase receptor and activation of Src kinase in human prostatic cancer. Am J Pathol 164: 1243–1251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TLJ, Visakorpi T . (2007). MicroRNA expression profiling in prostate cancer. Cancer Res 67: 6130–6135.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radmacher MD, McShane LM, Simon R . (2002). A paradigm for class prediction using gene expression profiles. J Comput Biol 9: 505–511.

    Article  CAS  PubMed  Google Scholar 

  • Reis EM, Nakaya HI, Louro R, Canavez FC, Flatschart AV, Almeida GT et al. (2004). Antisense intronic non-coding RNA levels correlate to the degree of tumor differentiation in prostate cancer. Oncogene 23: 6684–6692.

    Article  CAS  PubMed  Google Scholar 

  • Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH et al. (2009). miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res 69: 7165–7169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Royo H, Bortolin ML, Seitz H, Cavaillé J . (2006). Small non-coding RNAs and genomic imprinting. Cytogenet and Genome Res 113: 99–108.

    Article  CAS  Google Scholar 

  • Schaefer A, Jung M, Mollenkopf H-J, Wagner I, Stephan C, Jentzmik F et al. (2010). Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma. Int J Cancer 126: 1166–1176.

    CAS  PubMed  Google Scholar 

  • Shi X-B, Xue L, Yang J, Ma A-H, Zhao J, Xu M 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  CAS  PubMed  PubMed Central  Google Scholar 

  • Simon R, Radmacher MD, Dobbin K, McShane LM . (2003). Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. J Natl Cancer Inst 95: 14–18.

    Article  CAS  PubMed  Google Scholar 

  • Spahn M, Kneitz S, Scholz CJ, Stenger N, Rudiger T, Strobel P et al. (2010). Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence. Int J Cancer 127: 394–403.

    CAS  PubMed  Google Scholar 

  • Sun T, Wang Q, Balk S, Brown M, Lee GS, Kantoff P . (2009). The role of microRNA-221 and microRNA-222 in androgen-independent prostate cancer cell lines. Cancer Res 69: 3356–3363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szczyrba J, Loprich E, Wach S, Jung V, Unteregger G, Barth S et al. (2010). The microRNA profile of prostate carcinoma obtained by deep sequencing. Mol Cancer Res 8: 529–538.

    Article  CAS  PubMed  Google Scholar 

  • Taft RJ, Glazov EA, Lassmann T, Hayashizaki Y, Carninci P, and Mattick JS et al. (2009). Small RNAs derived from snoRNAs. RNA 15: 1233–1240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Volinia S, Calin GA, Liu C-G, Ambs S, Cimmino A, Petrocca F et al. (2006). A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103: 2257–2261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, Latonen LM et al. (2011). Androgen regulation of micro-RNAs in prostate cancer. Prostate 71 (6): 604–614.

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Bian C, Yang Z, Bo Y, Li J, Zeng L et al. (2009). miR-145 inhibits breast cancer cell growth through RTKN. Int J Oncol 34: 1461–1466.

    CAS  PubMed  Google Scholar 

  • Wiklund ED, Bramsen JB, Hulf T, Dyrskjot L, Ramanathan R, Hansen TB et al. (2010). Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer 128: 1327–1334.

    Article  Google Scholar 

  • Willenbrock H, Salomon J, Sokilde R, Barken KB, Hansen TN, Nielsen FC et al. (2009). Quantitative miRNA expression analysis: comparing microarrays with next-generation sequencing. RNA 15: 2028–2034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wit E, Linsen SEV, Cuppen E, Berezikov E . (2009). Repertoire and evolution of miRNA genes in four divergent nematode species. Genome Res 19: 2064–2074.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wright GW, Simon RM . (2003). A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics 19: 2448–2455.

    Article  CAS  PubMed  Google Scholar 

  • Zhao J-J, Lin J, Yang H, Kong W, He L, Ma X et al. (2008). MicroRNA-221/222 negatively regulates estrogen receptor{alpha} and is associated with tamoxifen resistance in breast cancer. J Biol Chem 283: 31079–31086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Theo van der Kwast for histo-pathological examination of patient samples. We also thank Mark Wildhagen for providing the coded clinical data. We acknowledge the European Community's Seventh Framework Program (FP7/2007-2013), grant agreement No HEALTH-F2-2007-201438, the Academy of Finland; Cancer Society of Finland; Reino Lahtikari Foundation; Sigrid Juselius Foundation; and the Medical Research Fund of Tampere University Hospital for their support.

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Author notes

  1. E S Martens-Uzunova and S E Jalava: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands

    E S Martens-Uzunova, N F Dits, C H Bangma & G Jenster

  2. Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland

    S E Jalava & T Visakorpi

  3. Department of Pathology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands

    G J L H van Leenders & J Trapman

  4. Exiqon A/S, Vedbaek, Denmark

    S Møller & T Litman

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  1. E S Martens-Uzunova
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Correspondence to G Jenster.

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Competing interests

Dr Litman and Dr Møller have been employed by Exiqon A/S and own stocks in that company. The remaining authors declare no conflict of interest.

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Martens-Uzunova, E., Jalava, S., Dits, N. et al. Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene 31, 978–991 (2012). https://doi.org/10.1038/onc.2011.304

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