ECTS Abstracts (2015) 1 P129

miR-25 and miR-21 regulate prostate cancer invasiveness by attenuation of notch-TGF-[beta] crosstalk and self-renewal markers

Eugenio Zoni1, Marjan van de Merbel1, Geertje van der Horst1, Jayant Rane2, Tapio Visakorpi3, Ewa Snaar4, Norman Maitland2 & Gabri van der Pluijm1

1Department of Urology, Leiden University Medical Center, Leiden, The Netherlands; 2YCR Cancer Research Unit, dept. Biology, York, UK; 3University of Tampere, Institute of Medical Technology, Tampere, Finland; 4University of Leiden, Department of Biology, Leiden, The Netherlands.

Altered microRNA (miR) expression is associated with tumour formation and progression of various solid cancers. A major challenge in miR profiling of bulk tumours is represented by the heterogeneity of the subpopulations of cells that constitute the organ and tumour tissue. We analysed the expression of miRs in a subpopulation of bone metastasis-initiating stem/progenitor-like cells in human prostate cancer (PCSC) and compared with more differentiated cancer cells. In PC-3M-Pro4Luc2 and C4-2B prostate cancer cell lines and clinical prostate cancer specimens we identified that miR-25 and miR-21 expression in PCSCs was low/absent and steadily increased during their differentiation into cells with a luminal epithelial phenotype. Functional studies revealed that overexpression of miR-25 in prostate cancer cell lines and selected subpopulation of highly metastatic/ tumourigenic cells (ALDHhigh) strongly affected the invasive cytoskeleton reducing migration in vitro, while overexpression of miR-21 reduced the size of ALDHhigh subpopulation. Additionally, miR-25 overexpression dramatically decreased the expression of Notch1 and Jagged1, critically involved in aetiology of skeletal metastasis, together with other Notch downstream targets in prostate cancer cells, while miR-21 downregulated self-renewal markers. Moreover, we found that miR-25 decreased TGF-β signaling in human prostate cancer cells and that miR-25 overexpression blocks the induction of Jagged1 driven by TGF-β. In line with these observations, we further demonstrate that miR-25 can act as a tumour suppressor in highly metastatic PCSCs by direct functional interaction with the 3′UTR of pro-invasive α6 and αv- integrins. Finally, we show here for the first time, that miR-25 can reduce metastasis by blocking the extravasation of human prostate cancer cells in vivo. Taken together, our observations suggest that miR-21 and miR-25 are key regulators of invasiveness in human prostate cancer through direct interactions with αv- and α6 integrins & Notch1 expression.

Disclosure: The authors declared no competing interests. The research leading to these results has received funding from the FP7 Marie Curie ITN under grant agreement n°264817 - BONE-NET and Grant from Prostate Action UK.

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