Universität zu Köln

Ihle, Michaela Angelika, Trautmann, Marcel ORCID: 0000-0002-5842-1196, Kuenstlinger, Helen, Huss, Sebastian, Heydt, Carina, Fassunke, Jana, Wardelmann, Eva, Bauer, Sebastian ORCID: 0000-0001-5949-8120, Schildhaus, Hans-Ulrich, Buettner, Reinhard and Merkelbach-Bruse, Sabine (2015). miRNA-221 and miRNA-222 induce apoptosis via the KIT/AKT signalling pathway in gastrointestinal stromal tumours. Mol. Oncol., 9 (7). S. 1421 - 1434. HOBOKEN: WILEY. ISSN 1878-0261

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Abstract

Aberrantly expressed microRNAs (miRNAs) are involved in many diseases including cancer. In gastrointestinal stromal tumours (GISTs) expression of miR-221 and miR-222 is reduced compared to control tissue and other sarcomas but the functional effects of this downregulation are not fully understood. This study aimed at evaluating the miR-221 and miR-222 expression profiles in different GIST subtypes and the functional role of these miRNAs. Expression of miR-221 and miR-222 was analysed in six KIT exon 9 and three KIT exon 11 mutated and nine wildtype GISTs by qPCR. Viability and apoptosis were examined in three different, KIT positive GIST cell lines (GIST882, GIST-T1 and GIST48) after overexpression of these miRNAs. The modulation of KIT and the PI3K/AKT pathways was determined by Western blot. Wildtype and KIT mutated GISTs revealed reduced miRNA expression compared to adequate control tissue. miRNA expression was lower for wildtype compared to mutated GISTs. Transient transfection of miR-221 and miR-222 reduced viability and induced apoptosis by inhibition of KIT expression and its phosphorylation and activation of caspases 3 and 7 in all three GIST cell lines. p-AKT, AKT and BCL2 expression was reduced after miRNA transfection whereas only slight influence on p-MTOR, MTOR and BCL2L11 (BIM) was detected. Our results demonstrate that miR-221 and miR-222 which are downregulated in wildtype and mutated GISTs, induce apoptosis in vitro by a signalling cascade involving KIT, AKT and BCL2. Therefore, overexpression of these miRNAs seems to functionally counteract oncogenic signalling pathways in GIST. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ihle, Michaela Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Trautmann, Marcel UNSPECIFIED orcid.org/0000-0002-5842-1196 UNSPECIFIED Kuenstlinger, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Heydt, Carina UNSPECIFIED UNSPECIFIED UNSPECIFIED Fassunke, Jana UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Bauer, Sebastian UNSPECIFIED orcid.org/0000-0001-5949-8120 UNSPECIFIED Schildhaus, Hans-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-398214
DOI:	10.1016/j.molonc.2015.03.013
Journal or Publication Title:	Mol. Oncol.
Volume:	9
Number:	7
Page Range:	S. 1421 - 1434
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1878-0261
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PDGFRA MUTATIONS; DOWN-REGULATION; MICRORNA GENES; UP-REGULATION; CANCER CELLS; KIT; IMATINIB; EXPRESSION; MIR-222; PROLIFERATION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39821