Abstract
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.
Highlights
Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men
MicroRNAs are 19-25 nt long small noncoding RNAs that modulate a multitude of biological processes by negative regulation of their target mRNAs [11, 12]. miRNAs are encoded in introns or separate genes [13,14,15] and transcribed into a long primary transcript, which is cut by Drosha/DGCR8 complex into the ~ 70 nucleotide long precursor miRNA
To evaluate whether the differential expression of Epithelial-to-mesenchymal transition (EMT) markers in miR-221-5p transfected cells correlates with functional changes, we studied the effect of miR221-5p on migration by transwell migration assay
Summary
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. MiR-221-5p alterations have been reported in PCa. Prostate cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of cancer-related death in European men [1]. Androgen deprivation therapy (ADT) is often applied as adjuvant treatment for radiotherapy or to treat advanced, hormone sensitive tumors [4] but most patients will develop castration-resistant PCa (CRPC) and progress to metastatic disease, which comprises the most lethal phase of PCa [2]. It is encoded in a gene cluster together with miR-222 on the short arm of the X chromosome. miR-221/− 222 are transcribed together into the pri-miRNA, which is further processed to mature miR-221-3p and the passenger miR-221-5p to regulate gene expression [22]
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