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TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

Oncogene volume 30, pages 3011–3023 (2011)Cite this article

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Abstract

Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

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Acknowledgements

We thank Drs Daniele Lecis, Francesca Miccichè and Anna De Filippo for providing reagents and advice for the detection of soluble TNFα and ALCAM, and Mrs Cristina Mazzadi for secretarial help. This work was supported by AIRC grant N.4472, ACC, Ministry of Health and Progetto Strategico Istituzionale (PSI) 5xmille, 2008.

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Authors and Affiliations

  1. Molecular Mechanisms Unit, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    M C Anania, C Miranda, M G Vizioli, S Pagliardini, M G Borrello & A Greco

  2. Functional Genomics Core Facility, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    M Sensi

  3. Human Tumors Immunobiology Unit, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    M Sensi

  4. Department of Veterinary Pathology, Faculty of Veterinary Medicine, Università degli Studi di Milano, Milan, Italy

    E Radaelli

  5. Mouse & Animal Pathology Lab, Fondazione Filarete, Milan, Italy

    E Radaelli

  6. Molecular Pharmacology Unit, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    E Favini & R Supino

  7. Department of Experimental Oncology and Molecular Medicine, Chemoprevention Unit, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    L Cleris & F Formelli

  8. Scientific Directorate, IRCCS Foundation–Istituto Nazionale dei Tumori, Milan, Italy

    M A Pierotti

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Correspondence to A Greco.

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Anania, M., Sensi, M., Radaelli, E. et al. TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene 30, 3011–3023 (2011). https://doi.org/10.1038/onc.2011.18

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  • DOI: https://doi.org/10.1038/onc.2011.18

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