The RET/PTC-RAS-BRAF linear signaling cascade mediates the motile and mitogenic phenotype of thyroid cancer cells.
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.
Melillo
Rosa Marina
RM
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR G. Salvatore, Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II, Naples, Italy.
Castellone
Maria Domenica
MD
Guarino
Valentina
V
De Falco
Valentina
V
Cirafici
Anna Maria
AM
Salvatore
Giuliana
G
Caiazzo
Fiorina
F
Basolo
Fulvio
F
Giannini
Riccardo
R
Kruhoffer
Mogens
M
Orntoft
Torben
T
Fusco
Alfredo
A
Santoro
Massimo
M
D000818:Animals; D019898:Autocrine Communication; D002460:Cell Line; D049109:Cell Proliferation; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion; D010641:Phenotype; D011505:Protein-Tyrosine Kinases; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000502:physiology*; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
C475829:CXCL1 protein, human; C114753:CXCL10 protein, human; D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins