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Cited by 51Wnt/β-catenin signaling in development and cancerThyroid Cancer Diagnosis and TreatmentThyroid Disorders and Treatments

ß-catenin signaling is required for RAS-driven thyroid cancer through PI3K activation

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Sastre-Perona, Ana, Riesco-Eizaguirre, Garcilaso, Zaballos, Miguel A., Santisteban, Pilar·2016·Oncotarget
DOI 10.18632/oncotarget.10356PMC PMC5226519
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Abstract

// Ana Sastre-Perona 1 , Garcilaso Riesco-Eizaguirre 1, 2 , Miguel A. Zaballos 1 , Pilar Santisteban 1 1 Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain 2 Servicio de Endocrinología, Hospital Universitario de Móstoles, Madrid, Spain Correspondence to: Pilar Santisteban, email: psantisteban@iib.uam.es Keywords: β-catenin, PI3K, RAS, thyroid cancer Received: December 10, 2015 Accepted: June 16, 2016 Published: June 30, 2016 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 HRAS V12 but not BRAF V600E 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.

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  • Upregulation of pioneer developmental organizers such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, and BCL6 is reported downstream of BRAF/MAPK-driven tumor.

    “Even upregulation of pioneer developmental organizers, such as SOX2, KLF4, β-catenin, SNAIL-1, c-MYC, TBX3, BCL6, et al., are reported downstream of BRAF/MAPK-driven tumor, the pathways causing lineage reprogramming are not clear12,15,30–36.”

    From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [35]

    The Results section ('RAS but not BRAF induces Wnt/β-catenin activation in thyroid cells'; page unavailable) reports that only HRAS increased nuclear β-catenin, although both HRAS and BRAF caused a minor increase in total levels. The Abstract and Discussion attribute substantial β-catenin activation to RAS and PI3K/AKT, not BRAF/MAPK. The paper therefore makes a contrary point about the β-catenin component of the cited claim; it does not establish the other listed factors as downstream of BRAF/MAPK. (LLM, conf=0.88)

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Authors
Sastre-Perona, A., Riesco-Eizaguirre, G., Zaballos, M. A., & Santisteban, P.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas (CSIC) y Universidad Autónoma de Madrid (UAM), Madrid, Spain
Corresponding author
Santisteban, Pilar
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-06-30
Volume
7
Issue
31
Pages
49435-49449
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.10356
PMC
PMC5226519
OpenAlex
W2469417466
Cited by
51
References
1
Citations by year
2025: 3 · 2024: 3 · 2023: 11 · 2022: 4 · 2021: 7 · 2020: 2 · 2019: 8 · 2018: 9 · 2017: 4
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders
  • University of Kansas
  • Comunidad de Madrid (S2011/BMD-2328)
  • Ministerio de Economía y Competitividad
  • Instituto de Salud Carlos III (RD12/0036/0030)
  • European Regional Development Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Keywords
β-catenin signaling, Ras, PI3K/Akt signaling, thyroid cancer, Wnt/β-catenin signaling, BRAF V600E mutation, GSK3β, senescence, epithelial-mesenchymal transition, tumor invasion, oncogenic drivers
MeSH terms
Animals, Enzyme Activation, Female, HeLa Cells, Humans, Mice, Nude, Neoplasm Invasiveness, Phosphorylation, Thyroid Neoplasms, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, ras Proteins, Phosphatidylinositol 3-Kinases, Gene Silencing, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, beta Catenin, Mice, HEK293 Cells, Wnt Signaling Pathway

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