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, George Q. Daley

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)246-251
Number of pages6
JournalNature
Volume535
Issue number7611
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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