Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene

Maria Grazia Borrello, Luisella Alberti, Andrew Fischer, Debora Degl'Innocenti, Cristina Ferrario, Manuela Gariboldi, Federica Marchesi, Paola Allavena, Angela Greco, Paola Collini, Silvana Pilotti, Giuliana Cassinelli, Paola Bressan, Laura Fugazzola, Alberto Mantovani, Marco A. Pierotti

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)14825-14830
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number41
DOIs
Publication statusPublished - Oct 11 2005

Keywords

  • Chemokines
  • Gene expression
  • Inflammation
  • Papillary thyroid carcinoma

ASJC Scopus subject areas

  • Genetics
  • General

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