Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior. (copyright) 2005 by The National Academy of Sciences of the USA.
|Titolo:||Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene|
|Autori interni:||MANTOVANI, ALBERTO|
|Parole Chiave:||article; cancer invasion; controlled study; gene activation; gene expression; gene rearrangement; human cell; human; inflammation; malignant transformation; oncogene ret; priority journal; receptor upregulation; thyroid cell; thyroid papillary carcinoma; L selectin; cell adhesion molecule; chemokine CCL20; chemokine receptor CXCR4; chemokine; granulocyte colony stimulating factor; granulocyte macrophage colony stimulating factor; interleukin 1beta; interleukin 8; metalloproteinase; monocyte chemotactic protein 1; protein Ret; protein tyrosine kinase; stromal cell derived factor 1; unclassified drug; urokinase receptor|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||11-ott-2005|
|Digital Object Identifier (DOI):||10.1073/pnas.0503039102|
|Appare nelle tipologie:||01 - Articolo su periodico|