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Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Author

Listed:
  • John T. Powers

    (Boston Children’s Hospital)

  • Kaloyan M. Tsanov

    (Boston Children’s Hospital)

  • Daniel S. Pearson

    (Boston Children’s Hospital)

  • Frederik Roels

    (University Hospital Köln)

  • Catherine S. Spina

    (Wyss Institute for Biologically Inspired Engineering)

  • Richard Ebright

    (Boston Children’s Hospital)

  • Marc Seligson

    (Boston Children’s Hospital)

  • Yvanka de Soysa

    (Boston Children’s Hospital)

  • Patrick Cahan

    (Boston Children’s Hospital)

  • Jessica Theißen

    (University Hospital Köln)

  • Ho-Chou Tu

    (Boston Children’s Hospital)

  • Areum Han

    (Boston Children’s Hospital)

  • Kyle C. Kurek

    (Boston Children’s Hospital)

  • Grace S. LaPier

    (Boston Children’s Hospital)

  • Jihan K. Osborne

    (Boston Children’s Hospital)

  • Samantha J. Ross

    (Boston Children’s Hospital)

  • Marcella Cesana

    (Boston Children’s Hospital)

  • James J. Collins

    (Wyss Institute for Biologically Inspired Engineering
    Massachusetts Institute of Technology, Broad Institute of MIT and Harvard)

  • Frank Berthold

    (University Hospital Köln)

  • George Q. Daley

    (Boston Children’s Hospital
    Stem Cell Transplantation Program, Dana Farber Cancer Institute & Boston Children’s Hospital
    Harvard Medical School
    Harvard Stem Cell Institute)

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.

Suggested Citation

  • John T. Powers & Kaloyan M. Tsanov & Daniel S. Pearson & Frederik Roels & Catherine S. Spina & Richard Ebright & Marc Seligson & Yvanka de Soysa & Patrick Cahan & Jessica Theißen & Ho-Chou Tu & Areum , 2016. "Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma," Nature, Nature, vol. 535(7611), pages 246-251, July.
    • Handle: RePEc:nat:nature:v:535:y:2016:i:7611:d:10.1038_nature18632
    DOI: 10.1038/nature18632
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