Journal
ONCOTARGET
Volume 7, Issue 31, Pages 49435-49449Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10356
Keywords
beta-catenin; PI3K; ras; thyroid cancer
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Funding
- Ministerio de Economia y Competitividad of Spain [SAF2013-44709-R]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Instituto de Salud Carlos III (ISCIII) [RD12/0036/0030]
- Comunidad de Madrid [S2011/BMD-2328]
- Fundacion Espanola contra el Cancer (AECC) [GCB14142311CRES]
- FPU fellowship from the Ministerio de Economia y Competitividad
- AECC [GCB14142311CRES]
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Mutations in beta-catenin are traditionally described as late events in thyroid cancer progression. However, the functional implications of beta-catenin dysregulation in the context of tumor initiating events remain unclear. The aim of this work was to investigate whether the two main oncogenic drivers in thyroid cancer, RAS and BRAF, could activate the Wnt/beta-catenin pathway. Expression of HRAS(V12) but not BRAF(V600E) in thyroid cells induced beta-catenin nuclear localization, increased beta-catenin-dependent transcriptional activity and inhibited GSK3 beta. In a panel of human thyroid cancer cell lines representative of the main genetic events in thyroid cancer, beta-catenin activation was highly dependent on PI3K/AKT activity through its phosphorylation at S552, but not on MAPK. Silencing of beta-catenin expression in cell lines led to a dramatic reduction in proliferation due to an induction of senescence, which was concordant with a reduction in tumor size in nude mice. Moreover, beta-catenin silencing suppressed the expression of EMT-related genes and reduced the invasive capacity of the tumor cells. In conclusion, this work demonstrates that RAS-driven tumors induce PI3K/AKT-dependent beta-catenin activation.
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