Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas.
To identify genes involved in the transformation of thyroid follicular cells, we explored, using DNA oligonucleotide microarrays, the transcriptional response of PC Cl3 rat thyroid epithelial cells to the ectopic expression of the RET/PTC oncogenes. We found that RET/PTC was able to induce the expression of CXCR4, the receptor for the chemokine CXCL12/SDF-1alpha/beta. We observed that CXCR4 expression correlated with the transforming ability of the oncoprotein and depended on the integrity of the RET/PTC-RAS/ERK signaling pathway. We found that CXCR4 was expressed in RET/PTC-positive human thyroid cancer cell lines, but not in normal thyroid cells. Furthermore, we found CXCR4 expression in human thyroid carcinomas, but not in normal thyroid samples by immunohistochemistry. Since CXCR4 has been recently implicated in tumor proliferation, motility and invasiveness, we asked whether treatment with SDF-1alpha was able to induce a biological response in thyroid cells. We observed that SDF-1alpha induced S-phase entry and survival of thyroid cells. Invasion through a reconstituted extracellular matrix was also supported by SDF-1alpha and inhibited by a blocking antibody to CXCR4. Taken together, these results suggest that human thyroid cancers bearing RET/PTC rearrangements may use the CXCR4/SDF-1alpha receptor-ligand pathway to proliferate, survive and migrate.
Castellone
Maria D
MD
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR G Salvatore, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, 80131 Naples, Italy.
Guarino
Valentina
V
De Falco
Valentina
V
Carlomagno
Francesca
F
Basolo
Fulvio
F
Faviana
Pinuccia
P
Kruhoffer
Mogens
M
Orntoft
Torben
T
Russell
John P
JP
Rothstein
Jay L
JL
Fusco
Alfredo
A
Santoro
Massimo
M
Melillo
Rosa Marina
RM
D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism; D002470:Cell Survival; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000502:physiology*; D016196:S Phase; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases