Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1

Genes Dev. 2018 Aug 1;32(15-16):996-1007. doi: 10.1101/gad.313783.118. Epub 2018 Jul 19.


Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor pleomorphic adenoma gene 1 (PLAG1) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress PLAG1 through copy number alterations, and PLAG1 expression correlates with prognosis in Wilms tumors. PLAG1 overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, PLAG1 transactivates insulin-like growth factor 2 (IGF2), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.

Keywords: IGF2; PLAG1; Wilms tumor; kidney; microRNA processing; pediatric cancer.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA Copy Number Variations
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor II / biosynthesis*
  • Kidney / metabolism
  • Mice
  • MicroRNAs / metabolism*
  • Mutation*
  • RNA Processing, Post-Transcriptional
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Wilms Tumor / genetics*
  • Wilms Tumor / metabolism
  • Wilms Tumor / pathology


  • DNA-Binding Proteins
  • IGF2 protein, human
  • MIRN16 microRNA, human
  • MIRN34 microRNA, human
  • MicroRNAs
  • PLAG1 protein, human
  • Transcription Factors
  • Insulin-Like Growth Factor II
  • TOR Serine-Threonine Kinases