MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours

Caroline Gits, Patricia van Kuijk, Moniek Jonkers, Ton Boersma, Wilfred van Ijcken, A Wozniak, R Sciot, P Rutkowski, P Schoffski, T Taguchi, RHJ Mathijssen, Jaap Verweij, Stefan Sleijfer, M Debiec-Rychter, Erik Wiemer

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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 a Conclusion: 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.
Original languageUndefined/Unknown
Pages (from-to)1625-1635
Number of pages11
JournalBritish Journal of Cancer
Volume109
Issue number6
DOIs
Publication statusPublished - 2013

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