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Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas

Oncogene volume 23, pages 5958–5967 (2004)Cite this article

Abstract

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-1α/β. 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-1α was able to induce a biological response in thyroid cells. We observed that SDF-1α induced S-phase entry and survival of thyroid cells. Invasion through a reconstituted extracellular matrix was also supported by SDF-1α 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-1α receptor–ligand pathway to proliferate, survive and migrate.

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Acknowledgements

We are indebted to JA Fagin for the PC-PTC1-inducible cells and to CJ Marshall for the BRAF expression plasmid. We are also grateful to F Curcio for the P5 primary thyroid culture and to JM Hershman for the BHP2-7, BHP7-13, BHP10-13, BHP5-16, BHP14-9 and BHP17-10 cell lines. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Progetto Strategico Oncologia of the CNR/MIUR, the Italian Ministero per l'Istruzione, Università e Ricerca Scientifica (MIUR), the BioGeM s.c.ar.l. (Biotecnologia e Genetica Molecolare nel Mezzogiorno d'Italia) and the Italian Ministero della Salute. VG was a fellow of Biogem s.c.a.r.l.

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Authors and Affiliations

  1. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR ‘G Salvatore’, Naples, 80131, Italy

    Maria D Castellone, Valentina Guarino, Valentina De Falco, Francesca Carlomagno, Alfredo Fusco, Massimo Santoro & Rosa Marina Melillo

  2. Dipartimento di oncologia, Pisa, Italy

    Fulvio Basolo & Pinuccia Faviana

  3. Department of Clinical Biochemistry, Molecular Diagnostic Laboratory, Aarhus University Hospital, Skejby, Aarhus, Denmark

    Mogens Kruhoffer & Torben Orntoft

  4. Departments of Microbiology/Immunology and Otolaryngology-Head and neck surgery, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, PA, USA

    John P Russell & Jay L Rothstein

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  1. Maria D Castellone
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Correspondence to Rosa Marina Melillo.

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Castellone, M., Guarino, V., De Falco, V. et al. Functional expression of the CXCR4 chemokine receptor is induced by RET/PTC oncogenes and is a common event in human papillary thyroid carcinomas. Oncogene 23, 5958–5967 (2004). https://doi.org/10.1038/sj.onc.1207790

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