TY  - JOUR
A1  - Kiener, Mirjam
A1  - Chen, Lanpeng
A1  - Krebs, Markus
A1  - Grosjean, Joȅl
A1  - Klima, Irena
A1  - Kalogirou, Charis
A1  - Riedmiller, Hubertus
A1  - Kneitz, Burkhard
A1  - Thalmann, George N.
A1  - Snaar-Jagalska, Ewa
A1  - Spahn, Martin
A1  - Kruithof-de Julio, Marianna
A1  - Zoni, Eugenio
T1  - miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo
JF  - BMC Cancer
N2  - 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.
KW  - prostate cancer
KW  - miR-221-5p
KW  - proliferation
KW  - migration
KW  - tumor suppressor miRNA
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325762
VL  - 19
ER  -