title: β-catenin signaling is required for RAS-driven thyroid cancer through PI3K activation.
abstract: Mutations in β-catenin are traditionally described as late events in thyroid cancer progression. However, the functional implications of β-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/β-catenin pathway. Expression of HRASV12 but not BRAFV600E in thyroid cells induced β-catenin nuclear localization, increased β-catenin-dependent transcriptional activity and inhibited GSK3β. In a panel of human thyroid cancer cell lines representative of the main genetic events in thyroid cancer, β-catenin activation was highly dependent on PI3K/AKT activity through its phosphorylation at S552, but not on MAPK. Silencing of β-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, β-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 β-catenin activation.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Sastre-Perona
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain.|Servicio de Endocrinología, Hospital Universitario de Móstoles, Madrid, Spain.
authors.forename: Garcilaso
authors.initials: G
authors.lastname: Riesco-Eizaguirre
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Zaballos
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D004789:Enzyme Activation; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
keywords: PI3K; RAS; thyroid cancer; β-catenin