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- Title
MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.
- Authors
Gits, C M M; van Kuijk, P F; Jonkers, M B E; Boersma, A W M; van Ijcken, W F; Wozniak, A; Sciot, R; Rutkowski, P; Schöffski, P; Taguchi, T; Mathijssen, R H J; Verweij, J; Sleijfer, S; Debiec-Rychter, M; Wiemer, E A C
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Publication
British Journal of Cancer, 2013, Vol 109, Issue 6, p1625
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/bjc.2013.483