@article{9eb36fd76ee94864b904d125c1166d7d,
title = "LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression",
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.",
keywords = "Animals, Cell Differentiation, DNA-Binding Proteins/genetics, Gene Expression Regulation, Neoplastic, Gene Silencing, Humans, Mice, Mice, Transgenic, MicroRNAs/genetics, N-Myc Proto-Oncogene Protein, Neuroblastoma/genetics, Nuclear Proteins/genetics, Oncogene Proteins/genetics, RNA-Binding Proteins, Signal Transduction",
author = "Molenaar, {Jan J} and Raquel Domingo-Fern{\'a}ndez and Ebus, {Marli E} and Sven Lindner and Jan Koster and Ksenija Drabek and Pieter Mestdagh and {van Sluis}, Peter and Valentijn, {Linda J} and {van Nes}, Johan and Marloes Broekmans and Franciska Haneveld and Richard Volckmann and Isabella Bray and Lukas Heukamp and Annika Spr{\"u}ssel and Theresa Thor and Kristina Kieckbusch and Ludger Klein-Hitpass and Matthias Fischer and Jo Vandesompele and Alexander Schramm and {van Noesel}, {Max M} and Luigi Varesio and Frank Speleman and Angelika Eggert and Stallings, {Raymond L} and Caron, {Huib N} and Rogier Versteeg and Schulte, {Johannes H}",
note = "Funding Information: We kindly thank A. Odersky, L. Schild, I. van der Ploeg, E. Dolman, T. Eleveld and L. Bate Eya for excellent technical assistance. The research reported in this manuscript was supported by grants from the Villa Joep Foundation, Kinderen Kankervrij (KiKa), the Tom Vo{\^u}te Fund and the Netherlands Cancer Foundation. R.L.S. was a recipient of grants from the Science Foundation Ireland (07/IN.1/B1776), the Children{\textquoteright}s Medical and Research Foundation and the US National Institutes of Health (5R01CA127496). A.E. is funded by the European Union (ENCCA: EU Seventh Framework Programme, Network of Excellence 261474; ASSET: EU Seventh Framework Programme, CP 259348). Support was also provided by the National Genome Research Network (NGFNplus (Germany); PKN-01GS0894-6 to J.H.S., A.E. and A.S.) and the German Cancer Aid (grant 108941 to J.H.S. and A.E.).",
year = "2012",
month = oct,
doi = "10.1038/ng.2436",
language = "English",
volume = "44",
pages = "1199--206",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "11",
}