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

doi:10.1038/bjc.2013.483

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

73 Citations (Scopus)

3 Downloads (Pure)

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.

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 language	English
Pages (from-to)	1625-1635
Number of pages	11
Journal	British Journal of Cancer
Volume	109
Issue number	6
DOIs	https://doi.org/10.1038/bjc.2013.483
Publication status	Published - 17 Sept 2013

Research programs

EMC MGC-02-13-02
EMC MM-03-86-01
EMC MM-03-86-08

Access to Document

10.1038/bjc.2013.483Licence: CC BY-NC

007815.pdfFinal published version, 2.04 MBLicence: CC BY-NC

http://hdl.handle.net/1765/41609

Cite this

Gits, C., van Kuijk, P., Jonkers, M., Boersma, T., van Ijcken, W., Wozniak, A., Sciot, R., Rutkowski, P., Schoffski, P., Taguchi, T., Mathijssen, RHJ., Verweij, J., Sleijfer, S., Debiec-Rychter, M., & Wiemer, E. (2013). MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours. British Journal of Cancer, 109(6), 1625-1635. https://doi.org/10.1038/bjc.2013.483

@article{e3b12f30b5794b969e74daa10fd9e9ab,

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.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.",

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

year = "2013",

month = sep,

day = "17",

doi = "10.1038/bjc.2013.483",

language = "English",

volume = "109",

pages = "1625--1635",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "6",

}

Gits, C, van Kuijk, P, Jonkers, M, Boersma, T , van Ijcken, W, Wozniak, A, Sciot, R, Rutkowski, P, Schoffski, P, Taguchi, T, Mathijssen, RHJ , Verweij, J , Sleijfer, S, Debiec-Rychter, M & Wiemer, E 2013, 'MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours', British Journal of Cancer, vol. 109, no. 6, pp. 1625-1635. https://doi.org/10.1038/bjc.2013.483

TY - JOUR

T1 - MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours

AU - Gits, Caroline

AU - van Kuijk, Patricia

AU - Jonkers, Moniek

AU - Boersma, Ton

AU - van Ijcken, Wilfred

AU - Wozniak, A

AU - Sciot, R

AU - Rutkowski, P

AU - Schoffski, P

AU - Taguchi, T

AU - Mathijssen, RHJ

AU - Verweij, Jaap

AU - Sleijfer, Stefan

AU - Debiec-Rychter, M

AU - Wiemer, Erik

PY - 2013/9/17

Y1 - 2013/9/17

N2 - 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.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.

AB - 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.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.

U2 - 10.1038/bjc.2013.483

DO - 10.1038/bjc.2013.483

M3 - Article

C2 - 23969726

SN - 0007-0920

VL - 109

SP - 1625

EP - 1635

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 6

ER -

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

Abstract

Research programs

Access to Document

Fingerprint

Cite this