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.
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands. j.j.molenaar@amc.uva.nl
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.forename: Raquel
authors.initials: R
authors.lastname: Domingo-Fernández
authors.forename: Marli E
authors.initials: ME
authors.lastname: Ebus
authors.forename: Sven
authors.initials: S
authors.lastname: Lindner
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Ksenija
authors.initials: K
authors.lastname: Drabek
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Peter
authors.initials: P
authors.lastname: van Sluis
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Valentijn
authors.forename: Johan
authors.initials: J
authors.lastname: van Nes
authors.forename: Marloes
authors.initials: M
authors.lastname: Broekmans
authors.forename: Franciska
authors.initials: F
authors.lastname: Haneveld
authors.forename: Richard
authors.initials: R
authors.lastname: Volckmann
authors.forename: Isabella
authors.initials: I
authors.lastname: Bray
authors.forename: Lukas
authors.initials: L
authors.lastname: Heukamp
authors.forename: Annika
authors.initials: A
authors.lastname: Sprüssel
authors.forename: Theresa
authors.initials: T
authors.lastname: Thor
authors.forename: Kristina
authors.initials: K
authors.lastname: Kieckbusch
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein-Hitpass
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Stallings
authors.forename: Huib N
authors.initials: HN
authors.lastname: Caron
authors.forename: Rogier
authors.initials: R
authors.lastname: Versteeg
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human