Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

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 Han, Kyle C. Kurek, Grace S. LaPier, Jihan K. Osborne, Samantha J. Ross, Marcella Cesana, James J. Collins, Frank Berthold and George Q. Daley ()
Additional contact information
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
Frank Berthold: University Hospital Köln
George Q. Daley: Boston Children’s Hospital

Nature, 2016, vol. 535, issue 7611, 246-251

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature18632

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