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

Nature Genetics volume 44, pages 1199–1206 (2012)Cite this article

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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.

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Figure 1: Amplification and overexpression of LIN28B in poor-prognosis neuroblastoma.
Figure 2: LIN28B silencing results in growth inhibition and neuronal differentiation.
Figure 3: The LIN28B–let-7–MYCN axis in neuroblastoma.
Figure 4: LIN28B drives malignant transformation.
Figure 5: Lin28b drives neuroblastoma in vivo.

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Acknowledgements

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.).

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Authors and Affiliations

  1. Department of Oncogenomics, Academic Medical Center, Amsterdam, The Netherlands

    Jan J Molenaar, Marli E Ebus, Jan Koster, Ksenija Drabek, Peter van Sluis, Linda J Valentijn, Johan van Nes, Marloes Broekmans, Franciska Haneveld, Richard Volckmann, Huib N Caron & Rogier Versteeg

  2. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

    Raquel Domingo-Fernández, Isabella Bray & Raymond L Stallings

  3. National Children's Research Centre, Dublin, Ireland

    Raquel Domingo-Fernández, Isabella Bray & Raymond L Stallings

  4. Department of Pediatric Oncology and Haematology, Children's Hospital Essen, Essen, Germany

    Sven Lindner, Annika Sprüssel, Theresa Thor, Kristina Kieckbusch, Alexander Schramm, Angelika Eggert & Johannes H Schulte

  5. Center for Medical Genetics, Ghent University, Ghent, Belgium

    Pieter Mestdagh, Jo Vandesompele & Frank Speleman

  6. Institute of Pathology, University Hospital Cologne, Cologne, Germany

    Lukas Heukamp

  7. Institute of Cell Biology, University Hospital Essen, Essen, Germany

    Ludger Klein-Hitpass

  8. Department of Pediatric Oncology and Hematology, Children's Hospital, University of Cologne, Cologne, Germany

    Matthias Fischer

  9. Department of Pediatric Oncology/Hematology, Erasmus Medical Centre–Sophia Children's Hospital, Rotterdam, The Netherlands

    Max M van Noesel

  10. Laboratory of Molecular Biology, Gaslini Institute, Genoa, Italy

    Luigi Varesio

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  1. Jan J Molenaar
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Contributions

J.J.M. and J.H.S. contributed to project coordination, data analysis and preparation of the manuscript. R.D.-F. and R.L.S. performed experiments and data analysis and contributed to preparation of the manuscript. J.K. and R. Volckmann performed analysis of bioinformatics data. M.E.E., S.L., K.D., P.M., P.v.S., J.v.N., M.B., I.B., L.J.V., F.H., K.K. and L.K.-H. conducted wet-lab experiments and data analysis. L.H., A. Sprüssel, T.T. and J.V. performed studies of the in vivo models. M.M.v.N., L.V., F.S. and M.F. contributed and/or organized samples and their accompanying clinical data. A. Schramm, A.E., H.N.C. and R. Versteeg supervised the project and contributed to the preparation of the manuscript.

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Correspondence to Jan J Molenaar.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–24 and Supplementary Tables 1–5 and 7 (PDF 6833 kb)

Supplementary Table 6

Regulated genes after LIN28B and/or MYCN over-expression in JoMa1 cells (XLS 236 kb)

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Molenaar, J., Domingo-Fernández, R., Ebus, M. et al. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nat Genet 44, 1199–1206 (2012). https://doi.org/10.1038/ng.2436

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