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

Ana Sastre-Perona,Garcilaso Riesco-Eizaguirre,Miguel A Zaballos,Pilar Santisteban

doi:10.18632/oncotarget.10356

Abstract

Mutations in ß-catenin are traditionally described as late events in thyroid cancer progression. However, the functional implications of ß-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/ß-catenin pathway. Expression of HRASV12 but not BRAFV600E in thyroid cells induced ß-catenin nuclear localization, increased ß-catenin-dependent transcriptional activity and inhibited GSK3ß. In a panel of human thyroid cancer cell lines representative of the main genetic events in thyroid cancer, ß-catenin activation was highly dependent on PI3K/AKT activity through its phosphorylation at S552, but not on MAPK. Silencing of ß-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, ß-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 ß-catenin activation.

Highlights

The most recent advances in thyroid cancer research emerge from an increased understanding of the mechanisms that control thyroid cell proliferation and differentiation, and the associated signal transduction pathways [1]
We investigated whether the Wnt/β-catenin pathway was active in the earliest steps of thyroid tumorigenesis driven by RAS and BRAF, the two main oncogenes in thyroid cancer [28]
As β-catenin stabilization is due in part to GSK3β inhibition, we examined GSK3β phosphorylation at Ser9

Summary

Introduction

The most recent advances in thyroid cancer research emerge from an increased understanding of the mechanisms that control thyroid cell proliferation and differentiation, and the associated signal transduction pathways [1]. Thyroid cancer progression to PDC and ATC involves additional mutations that stimulate other cell signaling pathways, such as p53 and Wnt/β-catenin [12]. This latter pathway is constitutively activated in 50% of PDC and ATC due to mutations in β-catenin and Axin genes [13,14,15]. These mutations impair normal β-catenin degradation, resulting in its accumulation in the cytoplasm and nucleus of tumor cells, and activation of target genes involved in biological functions essential for carcinogenesis [15,16,17,18,19]

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