Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1
- Kenneth S. Chen1,2,
- Emily K. Stroup1,
- Albert Budhipramono1,
- Dinesh Rakheja1,3,
- Diana Nichols-Vinueza1,
- Lin Xu1,4,
- Sarai H. Stuart1,
- Abhay A. Shukla1,
- Claudette Fraire1,
- Joshua T. Mendell5,6 and
- James F. Amatruda1,2,5,7
- 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 2Margaret Gill Center for Cancer and Blood Disorders, Children's Health, Dallas, Texas 75390, USA;
- 3Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 4Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas 75290, USA;
- 5Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 6Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 7Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
- Corresponding author: james.amatruda{at}utsouthwestern.edu
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.313783.118.
- Received March 3, 2018.
- Accepted June 5, 2018.
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