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- Title
The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells.
- Authors
Melillo, Rosa Marina; Castellone, Maria Domenica; Guarino, Valentina; Falco, Valentina de; Cirafici, Anna Maria; Salvatore, Giuliana; Caiazzo, Fiorina; Basolo, Fulvio; Giannini, Riccardo; Kruhoffer, Mogens; Orntoft, Torben; Fusco, Aifredo; Santoro, Massimo; De Falco, Valentina; Fusco, Alfredo
- 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.
- Subjects
THYROID cancer; CANCER cells; ONCOGENES; CANCER genetics; CELL proliferation; GENE expression; PROTEIN metabolism; ANIMALS; BIOCHEMISTRY; CANCER invasiveness; CELL lines; CELL physiology; CELLULAR signal transduction; CYTOKINES; GENES; GROWTH factors; PHENOMENOLOGY; PROTEIN-tyrosine kinases; PROTEINS; RATS; RESEARCH evaluation; THYROID gland; THYROID gland tumors; TRANSFERASES; PHENOTYPES; GENE expression profiling
- Publication
Journal of Clinical Investigation, 2005, Vol 115, Issue 4, p1068
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI200522758