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Nature. 2016 Jul 14;535(7611):246-51. doi: 10.1038/nature18632. Epub 2016 Jul 6.

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.

Author information

1
Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
2
Department of Pediatric Oncology, University Hospital Köln, Köln 50937, Germany.
3
Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, USA.
4
Department of Pathology, Boston Children's Hospital, Boston Massachusetts 02215, USA.
5
Department of Biological Engineering, Massachusetts Institute of Technology, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
6
Stem Cell Transplantation Program, Dana Farber Cancer Institute &Boston Children's Hospital, Boston, Massachusetts 02115, USA.
7
Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
8
Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.

Abstract

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.

Comment in

PMID:
27383785
PMCID:
PMC4947006
DOI:
10.1038/nature18632
[Indexed for MEDLINE]
Free PMC Article

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