Abstract
With ∼30 000 deaths annually in the United States, prostate cancer (PCa) is a major oncologic disease. Here we show that the microRNAs miR-130a, miR-203 and miR-205 jointly interfere with the two major oncogenic pathways in prostate carcinoma and are downregulated in cancer tissue. Using transcriptomics we show that the microRNAs repress several gene products known to be overexpressed in this cancer. Argonaute 2 (AGO2) co-immunoprecipitation, reporter assays and western blot analysis demonstrate that the microRNAs directly target several components of the mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signaling pathways, among those several AR coregulators and HRAS (Harvey rat sarcoma viral oncogene homolog), and repress signaling activity. Both pathways are central for the development of the primary tumor and in particular the progression to its incurable castration-resistant form. Reconstitution of the microRNAs in LNCaP PCa cells induce morphological changes, which resemble the effect of androgen deprivation, and jointly impair tumor cell growth by induction of apoptosis and cell cycle arrest. We therefore propose that these microRNAs jointly act as tumor suppressors in prostate carcinoma and might interfere with progression to castration resistance.
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Acknowledgements
We thank Stephan Schreiber, Anne-Sophie Krakovic, Yvonne Kullnick, Sabina Christ, Kathrin Jäger, Rudolf Ascherl and Christine Schumann for technical assistance and Catherine Davis for proof-reading. We thank Gunter Meister and colleagues for providing AGO2 antibodies. This work was supported in part by the Medical Faculty of the University of Leipzig through funding of the Interdisciplinary Center for Clinical Research and a formel.1 grant ‘Sequence and functional analysis of non-coding RNA in prostate carcinoma’, the European Framework Programme 6 Project SYNLET (EC contract number 043312), by the Initiative and Networking Fund one of the Helmholtz Association (VH-NG-738) and by LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, which was funded by means of the European Social Fund and the Free State of Saxony.
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Boll, K., Reiche, K., Kasack, K. et al. MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene 32, 277–285 (2013). https://doi.org/10.1038/onc.2012.55
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DOI: https://doi.org/10.1038/onc.2012.55
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