Journal Article

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

Kiener, Mirjam, Chen, Lanpeng, Krebs, Markus, Kruithof-de Julio, Marianna, Zoni, Eugenio, Grosjean, Joël, Thalmann, George N., Kalogirou, Charis, Kneitz, Burkhard, Spahn, Martin, Klima, Irena, Snaar-Jagalska, Ewa, Riedmiller, Hubertus

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Androgens / Biochemistry / Biomedical and Life Sciences / Biomedicine / Cancer cells / Cancer metastasis / Cancer Research / Cancer treatment / Care and treatment / Cell and molecular biology / Control / Death / Development and progression / Gene expression / Genes / Health Promotion and Disease Prevention / Laboratory rats / Medicine/Public Health / MicroRNA / Migration / miR-221-5p / Oncology / Proliferation / Prostate cancer / Research Article / RNA / Surgical Oncology / Tumor suppressor miRNA / Tumors