Journal
GENES & DEVELOPMENT
Volume 32, Issue 15-16, Pages 996-1007Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.313783.118
Keywords
IGF2; PLAG1; Wilms tumor; kidney; microRNA processing; pediatric cancer
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Funding
- Alex's Lemonade Stand Foundation Young Investigator grant
- Damon Runyon-Sohn Pediatric Cancer Research Fellowship [DRSG 4P-13]
- National Institutes of Health [K08CA207849, P50CA196516, R35CA197311]
- NATIONAL CANCER INSTITUTE [R35CA197311, K08CA207849, P50CA196516] Funding Source: NIH RePORTER
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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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