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Osteopontin Is Overexpressed in Human Papillary Thyroid Carcinomas and Enhances Thyroid Carcinoma Cell Invasiveness

Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Richerche (V.G., G.S., M.D.C., A.M.C., V.D.F., A.C., R.M.M., M.S.), Naples, Italy; and Dipartimento di Oncologia, Università di Pisa (P.F., R.G., F.B.), Pisa, Italy

Address all correspondence and requests for reprints to: Dr. Massimo Santoro, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università di Napoli Federico II, via S. Pansini 5, 80131 Naples, Italy. E-mail: masantor{at}unina.it.

Context: The transmembrane glycoprotein CD44v6 is overexpressed in most papillary thyroid carcinomas (PTC). We previously reported that osteopontin (OPN), a secreted glycoprotein that functions as a ligand for CD44v6, is overexpressed in thyrocytes transformed by the RET/PTC oncogene.

Objective: In this study we asked whether OPN is overexpressed in human PTC samples, and whether its expression correlates with clinical and histological features of the tumors. Furthermore, we wanted to establish the functional role of the CD44-OPN axis in thyroid tumorigenesis.

Design: Thyroid samples from 117 patients who had undergone surgical resection of the thyroid gland for benign or malignant lesions were collected. OPN and CD44 expressions were evaluated by immunohistochemistry with specific monoclonal antibodies. OPN expression was correlated with different PTC histological variants, lymph node metastasis, and PTC size.

Results: In this study we show that OPN is overexpressed in human PTCs with respect to normal thyroid tissue, follicular adenomas, and multinodular goiters (P < 0.05). The prevalence and intensity of OPN staining were significantly correlated with the presence of lymph node metastases (P = 0.0091) and tumor size (P = 0.0001). We also show that treatment of human PTC cells with recombinant exogenous OPN stimulated Matrigel invasion and activated the ERK and V-AKT murine thymoma viral oncogene homolog 1/protein kinase B; signaling pathways. Blockage of anti-CD44 antibodies prevented these effects.

Conclusions: Given its prevalence and its correlation with aggressive features of human PTCs, we suggest that OPN might be used as a diagnostic and prognostic marker for these tumors. Furthermore, given the role of the OPN-CD44v6 axis in PTC cells, we suggest that CD44 and/or OPN may be molecular targets for therapeutic intervention in aggressive PTCs.

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