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

Kenneth Chen, Emily K. Stroup, Albert Budhipramono, Dinesh Rakheja, Diana Nichols-Vinueza, Lin Xu, Sarai H. Stuart, Abhay A. Shukla, Claudette Fraire, Joshua T Mendell, James F Amatruda

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)996-1007
Number of pages12
JournalGenes and Development
Volume32
Issue number15-16
DOIs
StatePublished - Aug 1 2018

Fingerprint

Wilms' Tumor Genes
Pleomorphic Adenoma
Wilms Tumor
Somatomedins
MicroRNAs
Mutation
Genes
Growth
Oncogenes
Carcinogenesis
Transcription Factors
Kidney
Gene Expression

Keywords

  • IGF2
  • Kidney
  • nicroRNA processing
  • Pediatric cancer
  • PLAG1
  • Wilms tumor

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Mutations in microRNA processing genes in wilms tumors derepress the IGF2 regulator PLAG1. / Chen, Kenneth; Stroup, Emily K.; Budhipramono, Albert; Rakheja, Dinesh; Nichols-Vinueza, Diana; Xu, Lin; Stuart, Sarai H.; Shukla, Abhay A.; Fraire, Claudette; Mendell, Joshua T; Amatruda, James F.

In: Genes and Development, Vol. 32, No. 15-16, 01.08.2018, p. 996-1007.

Research output: Contribution to journalArticle

Chen, K, Stroup, EK, Budhipramono, A, Rakheja, D, Nichols-Vinueza, D, Xu, L, Stuart, SH, Shukla, AA, Fraire, C, Mendell, JT & Amatruda, JF 2018, 'Mutations in microRNA processing genes in wilms tumors derepress the IGF2 regulator PLAG1', Genes and Development, vol. 32, no. 15-16, pp. 996-1007. https://doi.org/10.1101/gad.313783.118
Chen, Kenneth ; Stroup, Emily K. ; Budhipramono, Albert ; Rakheja, Dinesh ; Nichols-Vinueza, Diana ; Xu, Lin ; Stuart, Sarai H. ; Shukla, Abhay A. ; Fraire, Claudette ; Mendell, Joshua T ; Amatruda, James F. / Mutations in microRNA processing genes in wilms tumors derepress the IGF2 regulator PLAG1. In: Genes and Development. 2018 ; Vol. 32, No. 15-16. pp. 996-1007.
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