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Crosstalk between Wnt/beta-catenin and PI3K/Akt signaling pathway in thyroid cancer

AutorSastre-Perona, Ana ; Riesco-Eizaguirre, Garcilaso; Santisteban, Pilar
Fecha de publicación2013
CitaciónETA 2013
ResumenMutations in beta-catenin (beta-cat) have been described as a late event in thyroid cancer. Nevertheless, increasing evidences have shown the involvement of this pathway in the earliest stages of thyroid tumor progression since it is activated by the RET/PTC rearrangements. The aim of this work was to study the activation of the Wnt/beta-cat canonical pathway in tumor cells carrying RAS (H/N/K), BRAF mutations and PTEN deletions, genetic events that are known to be involved in thyroid cancer initiation. Expression of HRAS in thyroid cells, but not BRAF, induced beta-cat nuclear localization increasing beta-cat -dependent transcriptional activity through its phosphorylation at S552. In parallel there is an increase of GSK3beta inhibition when HRAS was expressed. We also found nuclear localization, transcriptional activation and S552 phosphorylation of beta-cat in a set of human thyroid cancer cell lines carrying RAS mutations and PTEN deletion. In these cell lines, beta-cat signaling is dependent on PI3K/Akt activity, but not on MAPK, indicating a differential role of these signaling pathways in beta-cat regulation. The knock-down of beta-cat expression in these cells leads to a dramatic reduction in cell proliferation due to an induction of senescence, which is concordant with a reduction in tumor formation in nude mice. Silencing of beta-cat also induces a down-regulation of EMT-related genes, decreasing the invasive capacity of the tumor cells. Furthermore preliminary results showed that beta-cat is involved in metastasis formation in an orthotopic model of mouse thyroid cancer. In conclusion this work describes a novel mechanism of beta-cat stabilization in thyroid tumor cells, dependent on Akt activity but not on MAPK, and demonstrates that beta-cat has a functional role in cell proliferation and EMT being a potential therapeutic target in thyroid cancer.
DescripciónResumen del trabajo presentado al 37th Annual Meeting of the European Thyroid Association, celebrado en Leiden (Holanda) del 7 al 11 de septiembre de 2013.
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