Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Chromosome Deletion
  • Female
  • Gene Amplification / genetics*
  • Gene Deletion
  • Genes, Neoplasm / genetics
  • Humans
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Models, Genetic
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics*
  • Neuroblastoma / pathology
  • Nuclear Proteins / genetics*
  • Oncogene Proteins / genetics*
  • RNA-Binding Proteins / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • 3' Untranslated Regions
  • LIN28B protein, human
  • MYCN protein, human
  • MicroRNAs
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human