miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo

BMC Cancer

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[1] 0000 0001 0726 5157, grid.5734.5, Urology Research Laboratory, Department for BioMedical Research, University of Bern, Bern, Switzerland;0000 0001 0726 5157, grid.5734.5, Urology Research Laboratory, Department for BioMedical Research, University of Bern, Bern, Switzerland;0000 0004 0479 0855, grid.411656.1, Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland;0000 0001 2312 1970, grid.5132.5, IBL, University of Leiden, Leiden, the Netherlands;Department of Urology and Paediatric Urology, University Medical Center of Würzburg, Würzburg, Germany;Urology Center Zürich, Clinic Hirslanden, Zürich, Switzerland;0000 0001 2187 5445, grid.5718.b, Department of Urology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany;

关键词: Prostate cancer;    miR-221-5p;    Proliferation;    Migration;    Tumor suppressor miRNA;   

DOI  :  10.1186/s12885-019-5819-6

来源: publisher

【 摘 要 】

BackgroundDespite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa.MethodsmiRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4–2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth.ResultsAnalysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa.ConclusionsTogether these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.

【 授权许可】

CC BY