title: MicroRNA expression profile of primary prostate cancer stem cells as a source of biomarkers and therapeutic targets.
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.
  
  
  RESULTS
  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.
authors.affiliation: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, UK.
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Rane
authors.affiliation: University of Tampere and Tampere University Hospital, BioMediTech, Molecular Biology of Prostate Cancer Group, Tampere, Finland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Scaravilli
authors.affiliation: 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.
authors.forename: Antti
authors.initials: A
authors.lastname: Ylipää
authors.affiliation: 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.
authors.forename: Davide
authors.initials: D
authors.lastname: Pellacani
authors.affiliation: Hull York Medical School, University of Hull, Hull, East Yorkshire, UK; Department of Urology, Castle Hill Hospital, Cottingham, East Yorkshire, UK.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Mann
authors.affiliation: Hull York Medical School, University of Hull, Hull, East Yorkshire, UK; Department of Urology, Castle Hill Hospital, Cottingham, East Yorkshire, UK.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Simms
authors.affiliation: 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.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: YCR Cancer Research Unit, Department of Biology, University of York, York, North Yorkshire, UK.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Collins
authors.affiliation: University of Tampere and Tampere University Hospital, BioMediTech, Molecular Biology of Prostate Cancer Group, Tampere, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.affiliation: 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.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Maitland
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D004847:Epithelial Cells; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011470:Prostatic Hyperplasia / Q000235:genetics*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C561887:MIRN548 microRNA, human; D035683:MicroRNAs
keywords: Biomarker; Castration-resistant prostate cancer; MicroRNA; Stem cells