Induction of a Proinflammatory Program in Normal Human Thyrocytes by the RET/PTC1 Oncogene

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2005-10, Vol.102 (41), p.14825-14830
Main Authors: Maria Grazia Borrello, Luisella Alberti, Andrew Fischer, Debora Degl'Innocenti, Cristina Ferrario, Gariboldi, Manuela, Federica Marchesi, Paola Allavena, Greco, Angela, Paola Collini, Silvana Pilotti, Giuliana Cassinelli, Paola Bressan, Laura Fugazzola, Mantovani, Alberto, Pierotti, Marco A.
Format: Article
Language:English
Subjects:
Biological Sciences
Blotting, Western
Cell growth
Cell Movement - physiology
Cells, Cultured
Chemokines
Cytokines
Cytokines - metabolism
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation - genetics
Gene Rearrangement - genetics
Genes
Humans
Inflammation
Inflammation - genetics
Inflammation - metabolism
L-Selectin - metabolism
Metalloproteases - metabolism
Microarray Analysis
Molecules
Oncogenes
Pathology
Polymerase Chain Reaction
Proto-Oncogene Proteins c-ret - genetics
Proto-Oncogene Proteins c-ret - metabolism
Receptors
Receptors, Cytokine - metabolism
Thyroid cancer
Thyroid gland
Thyroid Gland - cytology
Thyroid Gland - metabolism
Thyroid Neoplasms - genetics
Thyroid Neoplasms - metabolism
Tumors
Urokinase-Type Plasminogen Activator - metabolism
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Summary: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 uroki-nase-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, MB, 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0503039102