Molenaar, Jan J., Domingo-Fernandez, Raquel, Ebus, Marli E., Lindner, Sven, Koster, Jan ORCID: 0000-0002-0890-7585, Drabek, Ksenija, Mestdagh, Pieter, van Sluis, Peter, Valentijn, Linda J., van Nes, Johan ORCID: 0000-0001-7691-1431, Broekmans, Marloes, Haneveld, Franciska, Volckmann, Richard, Bray, Isabella, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Spruessel, Annika, Thor, Theresa, Kieckbusch, Kristina, Klein-Hitpass, Ludger, Fischer, Matthias, Vandesompele, Jo ORCID: 0000-0001-6274-0184, Schramm, Alexander ORCID: 0000-0001-7670-7529, van Noesel, Max M., Varesio, Luigi, Speleman, Frank, Eggert, Angelika ORCID: 0000-0003-3476-8184, Stallings, Raymond L., Caron, Huib N., Versteeg, Rogier ORCID: 0000-0001-7172-0388 and Schulte, Johannes H. (2012). LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genet., 44 (11). S. 1199 - 1207. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

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Abstract

LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Molenaar, Jan J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domingo-Fernandez, RaquelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ebus, Marli E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koster, JanUNSPECIFIEDorcid.org/0000-0002-0890-7585UNSPECIFIED
Drabek, KsenijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mestdagh, PieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Sluis, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valentijn, Linda J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Nes, JohanUNSPECIFIEDorcid.org/0000-0001-7691-1431UNSPECIFIED
Broekmans, MarloesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haneveld, FranciskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Volckmann, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bray, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDorcid.org/0000-0002-3388-3482UNSPECIFIED
Spruessel, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thor, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kieckbusch, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein-Hitpass, LudgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vandesompele, JoUNSPECIFIEDorcid.org/0000-0001-6274-0184UNSPECIFIED
Schramm, AlexanderUNSPECIFIEDorcid.org/0000-0001-7670-7529UNSPECIFIED
van Noesel, Max M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varesio, LuigiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speleman, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggert, AngelikaUNSPECIFIEDorcid.org/0000-0003-3476-8184UNSPECIFIED
Stallings, Raymond L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caron, Huib N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Versteeg, RogierUNSPECIFIEDorcid.org/0000-0001-7172-0388UNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-480629
DOI: 10.1038/ng.2436
Journal or Publication Title: Nature Genet.
Volume: 44
Number: 11
Page Range: S. 1199 - 1207
Date: 2012
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COPY NUMBER DEFECTS; TUMOR-SUPPRESSOR; CELL-PROLIFERATION; PROMOTES TRANSFORMATION; RISK STRATIFICATION; MIRNA EXPRESSION; MESSENGER-RNA; IN-VIVO; N-MYC; MICRORNAMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48062

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