title: MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.
abstract: BACKGROUND
  Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool.
  
  
  METHODS
  Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs.
  
  
  RESULTS
  MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and--to a lesser extent--mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively.
  
  
  CONCLUSIONS
  MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.
authors: Department of Medical Oncology, Erasmus University Medical Center - Erasmus MC Cancer Institute, Dr Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
authors: C M M
authors: CM
authors: Gits
authors: P F
authors: PF
authors: van Kuijk
authors: M B E
authors: MB
authors: Jonkers
authors: A W M
authors: AW
authors: Boersma
authors: W F
authors: WF
authors: van Ijcken
authors: A
authors: A
authors: Wozniak
authors: R
authors: R
authors: Sciot
authors: P
authors: P
authors: Rutkowski
authors: P
authors: P
authors: Schöffski
authors: T
authors: T
authors: Taguchi
authors: R H J
authors: RH
authors: Mathijssen
authors: J
authors: J
authors: Verweij
authors: S
authors: S
authors: Sleijfer
authors: M
authors: M
authors: Debiec-Rychter
authors: E A C
authors: EA
authors: Wiemer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D005810:Multigene Family; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D035683:MicroRNAs; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit
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