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 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.
Borrello
Maria Grazia
MG
Departments of Experimental Oncology, Research Units 3 and 14, and Pathology, Istituto Nazionale Tumori, 20133 Milan, Italy.
Alberti
Luisella
L
Fischer
Andrew
A
Degl'innocenti
Debora
D
Ferrario
Cristina
C
Gariboldi
Manuela
M
Marchesi
Federica
F
Allavena
Paola
P
Greco
Angela
A
Collini
Paola
P
Pilotti
Silvana
S
Cassinelli
Giuliana
G
Bressan
Paola
P
Fugazzola
Laura
L
Mantovani
Alberto
A
Pierotti
Marco A
MA
D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D019041:L-Selectin / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D016207:Cytokines; D018121:Receptors, Cytokine; D019041:L-Selectin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D045726:Metalloproteases; D014568:Urokinase-Type Plasminogen Activator