title: miR-183 in prostate cancer cells positively regulates synthesis and serum levels of prostate-specific antigen.
abstract: BACKGROUND
  Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood.
  
  
  OBJECTIVE
  To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA.
  
  
  METHODS
  Reporter assays with PSA and KLK2 3' untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts.
  
  
  METHODS
  RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis.
  
  
  CONCLUSIONS
  Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3' UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression.
  
  
  CONCLUSIONS
  The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings.
  
  
  RESULTS
  These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer.
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Larne
authors.affiliation: Current affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland; Medical Biotechnology, VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Östling
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
authors.forename: Benedikta S
authors.initials: BS
authors.lastname: Haflidadóttir
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Hagman
authors.affiliation: Current affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland; Medical Biotechnology, VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Aakula
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Division of Molecular Toxicology, Institute of Environmental Medicine/Institutet för miljömedicin (IMM), Karolinska Institutet, Solna, Sweden.
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.affiliation: Current affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.affiliation: Centre for Molecular Pathology, Lund University, Malmö, Sweden; Current affiliation: Sahlgrenska Cancer Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Edsjö
authors.affiliation: Department of Clinical Medicine, Urology, Division of Urological Cancers, Lund University, Malmö, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden; Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
authors.forename: Hans
authors.initials: H
authors.lastname: Lilja
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lundwall
authors.affiliation: Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden; Department of Laboratory Medicine, Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: Yvonne.Ceder@med.lu.se.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ceder
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D045744:Cell Line, Tumor; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007610:Kallikreins / Q000097:blood* / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D060787:Neoplasm Grading; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D040081:Protein Array Analysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C533449:MIRN183 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C000595667:KLK2 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: Diagnosis; MicroRNAs; Prostate cancer; Prostate-specific Antigen; miR-183