Kiener, Mirjam; Chen, Lanpeng; Krebs, Markus; Grosjean, Joël; Klima, Irena; Kalogirou, Charis; Riedmiller, Hubertus; Kneitz, Burkhard; Thalmann, George; Snaar-Jagalska, Ewa; Spahn, Martin; Kruithof-de Julio, Marianna; Zoni, Eugenio (2019). miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo. BMC cancer, 19(1), p. 627. BioMed Central 10.1186/s12885-019-5819-6
|
Text
Tha_miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo_18072019.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (2MB) | Preview |
BACKGROUND
Despite 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.
METHODS
miRNA 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.
RESULTS
Analysis 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.
CONCLUSIONS
Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.
Actions (login required)
 |
Edit item |