MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets

Jayant K Rane; Mauro Scaravilli; Antti Ylipää; Davide Pellacani; Vincent M Mann; Matthew S Simms; Matti Nykter; Anne T Collins; Tapio Visakorpi; Norman J Maitland

doi:10.1016/j.eururo.2014.09.005

MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets

Eur Urol. 2015 Jan;67(1):7-10. doi: 10.1016/j.eururo.2014.09.005. Epub 2014 Sep 16.

Authors

Affiliations

¹ YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, UK.
² University of Tampere and Tampere University Hospital, BioMediTech, Molecular Biology of Prostate Cancer Group, Tampere, Finland.
³ University of Tampere and Tampere University Hospital, BioMediTech, Molecular Biology of Prostate Cancer Group, Tampere, Finland; Department of Signal Processing, Tampere University of Technology, Tampere, Finland.
⁴ YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, UK; Terry Fox Laboratory, Eaves Lab, BC Cancer Research Centre, Vancouver, BC, Canada.
⁵ Hull York Medical School, University of Hull, Hull, East Yorkshire, UK; Department of Urology, Castle Hill Hospital, Cottingham, East Yorkshire, UK.
⁶ YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, UK; Hull York Medical School, University of Hull, Hull, East Yorkshire, UK. Electronic address: n.j.maitland@york.ac.uk.

PMID: 25234358
DOI: 10.1016/j.eururo.2014.09.005

Abstract

MicroRNA (miRNA) expression profiles were generated from prostate epithelial subpopulations enriched from patient-derived benign prostatic hyperplasia (n=5), Gleason 7 treatment-naive prostate cancer (PCa) (n=5), and castration-resistant PCa (CRPC) (n=3). Microarray expression was validated in an independent patient cohort (n=10). Principal component analysis showed that miRNA expression is clustered by epithelial cell phenotype, regardless of pathologic status. We also discovered concordance between the miRNA expression profiles of unfractionated epithelial cells from CRPCs, human embryonic stem cells (SCs), and prostate epithelial SCs (both benign and malignant). MiR-548c-3p was chosen as a candidate miRNA from this group to explore its usefulness as a CRPC biomarker and/or therapeutic target. Overexpression of miR-548c-3p was confirmed in SCs (fivefold, p<0.05) and in unfractionated CRPCs (1.8-fold, p<0.05). Enforced overexpression of miR-548c-3p in differentiated cells induced stemlike properties (p<0.01) and radioresistance (p<0.01). Reanalyses of published studies further revealed that miR-548c-3p is significantly overexpressed in CRPC (p<0.05) and is associated with poor recurrence-free survival (p<0.05), suggesting that miR-548c-3p is a functional biomarker for PCa aggressiveness. Our results validate the prognostic and therapeutic relevance of miRNAs for PCa management while demonstrating that resolving cell-type and differentiation-specific differences is essential to obtain clinically relevant miRNA expression profiles.

Patient summary: We report microRNA (miRNA) expression profiles of epithelial cell fractions from the human prostate, including stem cells. miR-548c-3p was revealed as a functional biomarker for prostate cancer progression. The evaluation of miR-548c-3p in a larger patient cohort should yield information on its clinical usefulness.

Keywords: Biomarker; Castration-resistant prostate cancer; MicroRNA; Stem cells.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics*
Disease-Free Survival
Epithelial Cells
Gene Expression Profiling*
Humans
Male
MicroRNAs / genetics*
Neoplastic Stem Cells*
Oligonucleotide Array Sequence Analysis
Phenotype
Prostatic Hyperplasia / genetics*
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / genetics*
Prostatic Neoplasms, Castration-Resistant / pathology
Radiation Tolerance / genetics
Up-Regulation

Substances

Biomarkers, Tumor
MIRN548 microRNA, human
MicroRNAs