LIN28B Induces Neuroblastoma and Enhances MYCN Levels Via Let-7 Suppression

Overview

Journal Nat Genet

Specialty Genetics

Date 2012 Oct 9

PMID 23042116

Citations 222

Authors

Jan J Molenaar

Raquel Domingo-Fernandez

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 Sprussel

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Polyamine Inhibition with DFMO: Shifting the Paradigm in Neuroblastoma Therapy.

Schramm J, Sholler C, Menachery L, Vazquez L, Saulnier Sholler G J Clin Med. 2025; 14(4).

PMID: 40004600 PMC: 11856405. DOI: 10.3390/jcm14041068.

Molecular mechanism and therapeutic strategies for embryonal tumors with multilayered rosettes in children (Review).

Lv W, Gao J, Guo X Mol Clin Oncol. 2025; 22(3):30.

PMID: 39926370 PMC: 11803348. DOI: 10.3892/mco.2025.2825.

Emerging Trends in Neuroblastoma Diagnosis, Therapeutics, and Research.

Sharma R, Yadav J, Bhat S, Musayev A, Myrzagulova S, Sharma D Mol Neurobiol. 2025; .

PMID: 39804528 DOI: 10.1007/s12035-024-04680-w.

Rapid-onset cancer.

Bilger A, Lambert P Tumour Virus Res. 2025; 19:200312.

PMID: 39755235 PMC: 11764593. DOI: 10.1016/j.tvr.2024.200312.

Cell-based assay to detect small molecules restoring levels of let-7 miRNAs.

Szewczyk S, Buckley B, Chernov M, Wang X, Pathak S, Yeger H Am J Cancer Res. 2024; 14(10):4772-4787.

PMID: 39553217 PMC: 11560832. DOI: 10.62347/MBLD9480.

References

Polesskaya A, Cuvellier S, Naguibneva I, Duquet A, Moss E, Harel-Bellan A . Lin-28 binds IGF-2 mRNA and participates in skeletal myogenesis by increasing translation efficiency. Genes Dev. 2007; 21(9):1125-38. PMC: 1855237. DOI: 10.1101/gad.415007. View

Helland A, Anglesio M, George J, Cowin P, Johnstone C, House C . Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One. 2011; 6(4):e18064. PMC: 3076323. DOI: 10.1371/journal.pone.0018064. View

Heo I, Joo C, Cho J, Ha M, Han J, Kim V . Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 2008; 32(2):276-84. DOI: 10.1016/j.molcel.2008.09.014. View

Johnson C, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D . The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res. 2007; 67(16):7713-22. DOI: 10.1158/0008-5472.CAN-07-1083. View

Molenaar J, Koster J, Zwijnenburg D, van Sluis P, Valentijn L, van der Ploeg I . Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012; 483(7391):589-93. DOI: 10.1038/nature10910. View

Maris J, Hogarty M, Bagatell R, Cohn S . Neuroblastoma. Lancet. 2007; 369(9579):2106-20. DOI: 10.1016/S0140-6736(07)60983-0. View

Mestdagh P, Feys T, Bernard N, Guenther S, Chen C, Speleman F . High-throughput stem-loop RT-qPCR miRNA expression profiling using minute amounts of input RNA. Nucleic Acids Res. 2008; 36(21):e143. PMC: 2588502. DOI: 10.1093/nar/gkn725. View

Loven J, Zinin N, Wahlstrom T, Muller I, Brodin P, Fredlund E . MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma. Proc Natl Acad Sci U S A. 2010; 107(4):1553-8. PMC: 2824410. DOI: 10.1073/pnas.0913517107. View

Roush S, Slack F . The let-7 family of microRNAs. Trends Cell Biol. 2008; 18(10):505-16. DOI: 10.1016/j.tcb.2008.07.007. View

10.

Olsson-Carter K, Slack F . A developmental timing switch promotes axon outgrowth independent of known guidance receptors. PLoS Genet. 2010; 6(8). PMC: 2916846. DOI: 10.1371/journal.pgen.1001054. View

11.

Viswanathan S, Powers J, Einhorn W, Hoshida Y, Ng T, Toffanin S . Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009; 41(7):843-8. PMC: 2757943. DOI: 10.1038/ng.392. View

12.

Viswanathan S, Daley G, Gregory R . Selective blockade of microRNA processing by Lin28. Science. 2008; 320(5872):97-100. PMC: 3368499. DOI: 10.1126/science.1154040. View

13.

Lee Y, Jeon K, Lee J, Kim S, Kim V . MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 2002; 21(17):4663-70. PMC: 126204. DOI: 10.1093/emboj/cdf476. View

14.

Fieuw A, Kumps C, Schramm A, Pattyn F, Menten B, Antonacci F . Identification of a novel recurrent 1q42.2-1qter deletion in high risk MYCN single copy 11q deleted neuroblastomas. Int J Cancer. 2011; 130(11):2599-606. DOI: 10.1002/ijc.26317. View

15.

Schulte J, Horn S, Otto T, Samans B, Heukamp L, Eilers U . MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int J Cancer. 2007; 122(3):699-704. DOI: 10.1002/ijc.23153. View

16.

Valentijn L, Koppen A, van Asperen R, Root H, Haneveld F, Versteeg R . Inhibition of a new differentiation pathway in neuroblastoma by copy number defects of N-myc, Cdc42, and nm23 genes. Cancer Res. 2005; 65(8):3136-45. DOI: 10.1158/0008-5472.CAN-04-2469. View

17.

Molenaar J, Koster J, Ebus M, van Sluis P, Westerhout E, De Preter K . Copy number defects of G1-cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis. Genes Chromosomes Cancer. 2011; 51(1):10-9. DOI: 10.1002/gcc.20926. View

18.

Mestdagh P, Van Vlierberghe P, De Weer A, Muth D, Westermann F, Speleman F . A novel and universal method for microRNA RT-qPCR data normalization. Genome Biol. 2009; 10(6):R64. PMC: 2718498. DOI: 10.1186/gb-2009-10-6-r64. View

19.

Heukamp L, Thor T, Schramm A, De Preter K, Kumps C, De Wilde B . Targeted expression of mutated ALK induces neuroblastoma in transgenic mice. Sci Transl Med. 2012; 4(141):141ra91. DOI: 10.1126/scitranslmed.3003967. View

20.

Rybak A, Fuchs H, Smirnova L, Brandt C, Pohl E, Nitsch R . A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nat Cell Biol. 2008; 10(8):987-93. DOI: 10.1038/ncb1759. View