The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells

Rosa Marina Melillo, Maria Domenica Castellone, Valentina Guarino, Valentina De Falco, Anna Maria Cirafici, Giuliana Salvatore, Fiorina Caiazzo, Fulvio Basolo, Riccardo Giannini, Mogens Kruhoffer, Torben Orntoft, Alfredo Fusco, Massimo Santoro

Research output: Contribution to journalArticlepeer-review

Abstract

In papillary thyroid carcinomas (PTCs), rearrangements of the RET receptor (RET/PTC) and activating mutations in the BRAF or RAS oncogenes are mutually exclusive. Here we show that the 3 proteins function along a linear oncogenic signaling cascade in which RET/PTC induces RAS-dependent BRAF activation and RAS- and BRAF-dependent ERK activation. Adoptive activation of the RET/PTC-RAS-BRAF axis induced cell proliferation and Matrigel invasion of thyroid follicular cells. Gene expression profiling revealed that the 3 oncogenes activate a common transcriptional program in thyroid cells that includes upregulation of the CXCL1 and CXCL10 chemokines, which in turn stimulate proliferation and invasion. Thus, motile and mitogenic properties are intrinsic to transformed thyroid cells and are governed by an epistatic oncogenic signaling cascade.

Original languageEnglish
Pages (from-to)1068-1081
Number of pages14
JournalJournal of Clinical Investigation
Volume115
Issue number4
DOIs
Publication statusPublished - Apr 2005

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells'. Together they form a unique fingerprint.

Cite this