UroToday - The related review summarizes the current state of microRNA (miRNA) research in urology and gives an outlook on potential diagnostic and therapeutic value of miRNAs.

miRNAs are short non-coding RNAs which play a crucial role in posttranscriptional gene regulation. So far, very few miRNA related articles have been published in uro-oncology (22 for prostate, 4 for kidney, 3 for bladder and 6 for testis). Although cancer specific expression patterns of miRNAs are shown, data are limited and partially inconsistent. For prostate cancer, only four studies compared miRNA expression by microarray analyses in more than 10 samples. While Ozen et al. [1] observed an overall downregulation of miRNAs, the other 3 studies [2-4] identified both up- and down-regulated miRNAs. Comparison of these 3 studies reveals no accordance of miRNA regulation. Some miRNAs even showed opposite expression patterns. Further, only few microarray data were validated in RT-PCR analyses with similar discrepancies. For other urological tumors data are even more limited.

Association of miRNA expression with clinical data is also sparse. In prostate cancer, only two miRNAs were identified which are differentially expressed in tumors with Gleason >7 [5]. It was further observed that androgen-responsibility played a major role for miRNA expression [3]. For kidney and bladder cancer no significant changes in miRNA expression were found for tumor stage, grade or histotype [6].

Especially for the application of miRNAs in therapy, their targets have to be identified. Target research is still in its infancy in uro-oncology but regulation of known oncogenes or tumor-supressor genes by miRNAs has been shown. Validated miRNA targets are for example p27 [7] in prostate cancer or E2F3 [8] in kidney cancer.

Despite of the sparse data in urological tumors, the utilisation of miRNAs as biomarkers has been shown in other cancer types. Lu et al. [9] developed a miRNA based classifier and identified 12 out of 17 poorly classified carcinomas correctly, whereas an mRNA based classifier identified only 1 sample correctly. First successful studies of miRNAs in the blood of patient with prostate cancer support the feasibility of miRNAs as diagnostic, prognostic, and predictive markers [10].

Identification of altered miRNA expression, as well as their targets, provides new opportunities for therapeutic strategies. Studies regarding therapeutic utilisation of miRNAs yielded encouraging results. It was demonstrated that antisense oligonucleotides termed "antagomirs" can specifically reduce miRNA expression and successfully inhibit tumor growth [11]. Alternatively, transfection of synthetic miRNAs ("agomirs") could knock-down expression of oncogenes [12]. Another promising approach seems to be "miRNA sponges". These sponges are RNAs expressed by transgenes which competitively bind to miRNA targets thereby de-repressing them [13]. As many miRNAs where shown to be regulated by epigenetic mechanisms, epigenetic drugs could also regulate miRNA expression. For example, miR-127 is down-regulated by methylation of CpG islands in bladder cancer. Treatment with epigenetic drugs lead to up-regulation of miR-127 resulting in decreased tumor proliferation [14].

In conclusion, the current knowledge shows that miRNA research in uro-oncology is still in its infancy but nevertheless the available data indicate the great potential of miRNAs in diagnostic and therapy.

References:

[1] Ozen M, Creighton CJ, Ozdemir M, Ittmann M. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 2008;27:1788-93.
[2] 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.
[3] Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res 2007;67:6130-5.
[4] Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A 2006;103:2257-61.
[5] Lin SL, Chiang A, Chang D, Ying SY. Loss of mir-146a function in hormone-refractory prostate cancer. RNA 2008;14:417-24.
[6] Gottardo F, Liu CG, Ferracin M, et al. Micro-RNA profiling in kidney and bladder cancers. Urol Oncol 2007;25:387-92.
[7] 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.
[8] Dutta KK, Zhong Y, Liu YT, et al. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer Sci 2007;98:1845-52.
[9] Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 2005;435:834-8.
[10] Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008;105:10513-8.
[11] Fontana L, Fiori ME, Albini S, et al. Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM. PLoS ONE 2008;3:e2236.
[12] Takamizawa J, Konishi H, Yanagisawa K, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004;64:3753-6.
[13] Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007;4:721-6.
[14] Saito Y, Liang G, Egger G, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006;9:435-43.

Annika Schaefer1,2, Monika Jung1, Carsten Stephan1, Glen Kristiansen3 and Klaus Jung1,2 as part of Beyond the Abstract on UroToday.

1 Department of Urology, University Hospital Charité, University Medicine Berlin, Schumannstr. 20/21, 10117 Berlin, Germany

2 Berlin Institute for Urologic Research and Foundation of Urologic Research, Robert-Koch-Platz 7, 10115 Berlin, Germany

3 Department of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland

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