期刊
MOLECULAR ONCOLOGY
卷 11, 期 4, 页码 405-421出版社
WILEY
DOI: 10.1002/1878-0261.12044
关键词
AKT; KRAS; Wilms tumor; beta-catenin
类别
资金
- Vander-bilt-Ingram Cancer Center
- TJ Martell Foundation
- Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation
- CTSA Grant [5UL1 RR024975-03]
- Vanderbilt-Ingram Cancer Center [P30 CA68485]
- Vanderbilt Vision Center [P30 EY08126]
- NIH/NCRR [G20 RR030956]
- [K08 CA113452]
- [P30 DK079341]
- [1R03CA182063-01A1]
- [1I01BX002196]
- [RO1-DK083187]
- [RO1-DK075594]
- [R01-DK066921]
Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/beta-catenin signaling. We previously showed that coordinate activation of Ras and beta-catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with b-catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.
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