title: miR-145 suppress the androgen receptor in prostate cancer cells and correlates to prostate cancer prognosis.
abstract: Androgen signalling through the androgen receptor (AR) is essential for prostate cancer initiation, progression and transformation to the lethal castration-resistant state. The aim of this study was to characterize the mechanisms by which miR-145 deregulation contribute to prostate cancer progression. The miR-145 levels, measured by quantitative reverse transcription-polymerase chain reaction, were found to inversely correlate with occurrence of metastases, survival and androgen deprivation therapy response in a well-characterized prostate cancer cohort. Introduction of ectopic miR-145 in prostate cancer cells generated an inhibitory effect on the AR at both transcript and protein levels as well as its activity and downstream targets prostate-specific antigen (PSA), kallikrein-related peptidase 2 and TMPRSS2. The regulation was shown to be mediated by direct binding using Ago2-specific immunoprecipitation, but there was also indication of synergetic AR activation. These findings were verified in clinical prostate specimens by demonstrating inverse correlations between miR-145 and AR expression as well as serum PSA levels. In addition, miR-145 was found to regulate androgen-dependent cell growth in vitro. Our findings put forward novel possibilities of therapeutic intervention, as miR-145 potentially could decrease both the stem cells and the AR expressing bulk of the tumour and hence reduce the transformation to the deadly castration-resistant form of prostate cancer.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Medicon Village 404, 22381 Lund, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Larne
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Medicon Village 404, 22381 Lund, Sweden.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Hagman
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Medicon Village 404, 22381 Lund, Sweden, Department of Surgery (Urology), Clinical Laboratories, Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK and.
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.affiliation: Department of Clinical Sciences and.
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.affiliation: Center for Molecular Pathology, Lund University, Lund, Sweden Present address: Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Edsjö
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Medicon Village 404, 22381 Lund, Sweden, yvonne.ceder@med.lu.se.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ceder
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007610:Kallikreins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: C410798:AR protein, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; C000595667:KLK2 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D017430:Prostate-Specific Antigen