LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Jan J Molenaar; Raquel Domingo-Fernández; Marli E Ebus; Sven Lindner; Jan Koster; Ksenija Drabek; Pieter Mestdagh; Peter van Sluis; Linda J Valentijn; Johan van Nes; Marloes Broekmans; Franciska Haneveld; Richard Volckmann; Isabella Bray; Lukas Heukamp; Annika Sprüssel; Theresa Thor; Kristina Kieckbusch; Ludger Klein-Hitpass; Matthias Fischer; Jo Vandesompele; Alexander Schramm; Max M van Noesel; Luigi Varesio; Frank Speleman; Angelika Eggert; Raymond L Stallings; Huib N Caron; Rogier Versteeg; Johannes H Schulte

doi:10.1038/ng.2436

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Jan J Molenaar
, Raquel Domingo-Fernández
, Marli E Ebus
, Sven Lindner
, Jan Koster
, Ksenija Drabek
, Pieter Mestdagh
, Peter van Sluis
, Linda J Valentijn
, Johan van Nes
, Marloes Broekmans
, Franciska Haneveld
, Richard Volckmann
, Isabella Bray
, Lukas Heukamp
, Annika Sprüssel
, Theresa Thor
, Kristina Kieckbusch
, Ludger Klein-Hitpass
, Matthias Fischer

Jo Vandesompele, Alexander Schramm, Max M van Noesel, Luigi Varesio, Frank Speleman, Angelika Eggert, Raymond L Stallings, Huib N Caron, Rogier Versteeg, Johannes H Schulte

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

343 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1199-206
Number of pages	8
Journal	Nature Genetics
Volume	44
Issue number	11
DOIs	https://doi.org/10.1038/ng.2436
Publication status	Published - Oct 2012
Externally published	Yes

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

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10.1038/ng.2436

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Molenaar, J. J., Domingo-Fernández, R., Ebus, M. E., Lindner, S., Koster, J., Drabek, K., Mestdagh, P., van Sluis, P., Valentijn, L. J., van Nes, J., Broekmans, M., Haneveld, F., Volckmann, R., Bray, I., Heukamp, L., Sprüssel, A., Thor, T., Kieckbusch, K., Klein-Hitpass, L., ... Schulte, J. H. (2012). LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genetics, 44(11), 1199-206. https://doi.org/10.1038/ng.2436

@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",

}

Molenaar, JJ, Domingo-Fernández, R, Ebus, ME, Lindner, S, Koster, J, Drabek, K, Mestdagh, P, van Sluis, P, Valentijn, LJ, van Nes, J, Broekmans, M, Haneveld, F, Volckmann, R, Bray, I, Heukamp, L, Sprüssel, A, Thor, T, Kieckbusch, K, Klein-Hitpass, L, Fischer, M, Vandesompele, J, Schramm, A, van Noesel, MM, Varesio, L, Speleman, F, Eggert, A, Stallings, RL, Caron, HN, Versteeg, R & Schulte, JH 2012, 'LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression', Nature Genetics, vol. 44, no. 11, pp. 1199-206. https://doi.org/10.1038/ng.2436

TY - JOUR

T1 - LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

AU - Molenaar, Jan J

AU - Domingo-Fernández, Raquel

AU - Ebus, Marli E

AU - Lindner, Sven

AU - Koster, Jan

AU - Drabek, Ksenija

AU - Mestdagh, Pieter

AU - van Sluis, Peter

AU - Valentijn, Linda J

AU - van Nes, Johan

AU - Broekmans, Marloes

AU - Haneveld, Franciska

AU - Volckmann, Richard

AU - Bray, Isabella

AU - Heukamp, Lukas

AU - Sprüssel, Annika

AU - Thor, Theresa

AU - Kieckbusch, Kristina

AU - Klein-Hitpass, Ludger

AU - Fischer, Matthias

AU - Vandesompele, Jo

AU - Schramm, Alexander

AU - van Noesel, Max M

AU - Varesio, Luigi

AU - Speleman, Frank

AU - Eggert, Angelika

AU - Stallings, Raymond L

AU - Caron, Huib N

AU - Versteeg, Rogier

AU - Schulte, Johannes H

N1 - 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 Voûte 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’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.).

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation

KW - DNA-Binding Proteins/genetics

KW - Gene Expression Regulation, Neoplastic

KW - Gene Silencing

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - MicroRNAs/genetics

KW - N-Myc Proto-Oncogene Protein

KW - Neuroblastoma/genetics

KW - Nuclear Proteins/genetics

KW - Oncogene Proteins/genetics

KW - RNA-Binding Proteins

KW - Signal Transduction

UR - https://www.scopus.com/pages/publications/84868210731

U2 - 10.1038/ng.2436

DO - 10.1038/ng.2436

M3 - Article

C2 - 23042116

SN - 1061-4036

VL - 44

SP - 1199

EP - 1206

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Abstract

Keywords

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