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Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells

Oncogene volume 23, pages 2188–2196 (2004)Cite this article

Abstract

Papillary thyroid carcinomas are characterized by rearrangements of the RET receptor tyrosine kinase generating RET/PTC oncogenes. Here we show that osteopontin (OPN), a secreted glycoprotein, is a major RET/PTC-induced transcriptional target in PC Cl 3 thyroid follicular cells. OPN upregulation depended on the integrity of the RET/PTC kinase and tyrosines Y1015 and Y1062, two major RET/PTC autophosphorylation sites. RET/PTC also induced a strong overexpression of CD44, a cell surface signalling receptor for OPN. Upregulation of CD44 was dependent on RET/PTC Y1062, as well. Constitutive OPN overexpression or treatment with exogenous recombinant OPN sharply increased proliferation, Matrigel invasion and spreading in collagen gels of RET/PTC-transformed PC Cl 3 cells. These effects were impaired by the treatment of PC Cl 3-RET/PTC cells with OPN- and CD44-locking antibodies. Thus, RET/PTC signalling triggers an autocrine loop involving OPN and CD44 that sustains proliferation and invasion of transfomed PC Cl 3 thyrocytes.

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Acknowledgements

We thank J Fagin for RET/PTC inducible cells and F Carlomagno for ZD6474 experiment. This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC), the EC grant FIGH-CT1999-CHIPS, the Progetto Strategico Oncologia of the CNR/MIUR, grants from the Ministero per l'Istruzione, Università e Ricerca Scientifica (MIUR) and the Ministero della Salute. VG was recipient of a fellowship of the BioGeM s.c.ar.l. (Biotecnologia e Genetica Molecolare nel Mezzogiorno d'Italia).

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Authors and Affiliations

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

    Maria Domenica Castellone, Angela Celetti, Valentina Guarino, Anna Maria Cirafici, Alfredo Fusco, Rosa Marina Melillo & Massimo Santoro

  2. Dipartimento di Oncologia, Pisa, Italy

    Fulvio Basolo & Riccardo Giannini

  3. Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin, Candiolo (TO), Italy

    Enzo Medico

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

    Mogens Kruhoffer & Torben F Orntoft

  5. Dipartimento di Patologia e Medicina Sperimentale e Clinica, University of Udine, Italy

    Francesco Curcio

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  1. Maria Domenica Castellone
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Correspondence to Massimo Santoro.

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Castellone, M., Celetti, A., Guarino, V. et al. Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells. Oncogene 23, 2188–2196 (2004). https://doi.org/10.1038/sj.onc.1207322

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