title: The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladder cancer.
abstract: BACKGROUND
  Upregulation of the proto-oncogene plasminogen activator inhibitor-1 (PAI-1) is a common hallmark of various solid tumours, but the mechanisms controlling its expression are not fully understood.
  
  
  METHODS
  We investigate microRNAs (miRNAs) regulating PAI-1 in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1-T4 tumours using expression microarrays and qRT-PCR. The prognostic implications of PAI-1 deregulation are established by tissue microarray staining of non-muscle-invasive bladder tumours. MicroRNA repression of PAI-1 is assayed by ectopic miRNA expression, argonaute immunoprecipitation and luciferase assays.
  
  
  RESULTS
  We found that the miR-143/-145 cluster is downregulated in all stages of bladder cancer and inversely correlated with PAI-1 expression. Mature miR-143 and miR-145 are coordinately expressed, and both directly target the PAI-1 3'UTR, leading to reduced PAI-1 mRNA and protein levels. Furthermore, we show that PAI-1 and miR-145 levels may serve as useful prognostic markers for non-muscle-invasive bladder tumours for which accurate progressive outcome is currently difficult to predict.
  
  
  CONCLUSIONS
  This report provides the first evidence for direct miRNA regulation of PAI-1 in bladder cancer. We also demonstrate mRNA co-targeting by a cluster of non-family miRNAs, and suggest miR-145 and PAI-1 as clinically relevant biomarkers in bladder cancer.
authors: Department of Molecular Biology, Aarhus University, C.F. Møllers Allé Build, 1130, Aarhus C 8000, Denmark.
authors: S B
authors: SB
authors: Villadsen
authors: J B
authors: JB
authors: Bramsen
authors: M S
authors: MS
authors: Ostenfeld
authors: E D
authors: ED
authors: Wiklund
authors: N
authors: N
authors: Fristrup
authors: S
authors: S
authors: Gao
authors: T B
authors: TB
authors: Hansen
authors: T I
authors: TI
authors: Jensen
authors: M
authors: M
authors: Borre
authors: T F
authors: TF
authors: Ørntoft
authors: L
authors: L
authors: Dyrskjøt
authors: J
authors: J
authors: Kjems
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D017931:DNA Primers; C000715470:MAS1 protein, human; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger