1. ¹Operative Unit 'Molecular Mechanisms of Cancer Growth and Progression', Department of Experimental Oncology, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy
2. ²IFOM Foundation (The Firc Institute for Molecular Oncology Foundation), Milan, Italy
3. ³Department of Pathology, Experimental Molecular Pathology, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy
4. ⁴Operative Unit 'Chemoprevention', Department of Experimental Oncology, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy
5. ⁵Scientific Direction, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy

Correspondence: Dr A Greco, PhD, Operative Unit 'Molecular Mechanisms of Cancer Growth and Progression', Department of Experimental Oncology Fondazione IRCCS 'Istituto Nazionale dei Tumori', Via G Venezian, 1, Milan 20133, Italy. E-mail: angela.greco@istitutotumori.mi.it

Received 6 November 2007; Revised 25 January 2008; Accepted 29 January 2008; Published online 10 March 2008.

Abstract

The molecular pathogenesis of tumors arising from the thyroid follicular epithelial cells, including papillary (PTC) and follicular thyroid carcinoma (FTC), is only partially understood, and the role of tumor suppressor genes has not yet been assessed. The metallothionein (MT) gene family encodes a class of metal-binding proteins involved in several cellular processes, and their expression is often deregulated in human tumors. Recently, downregulation of MT gene expression in PTC has been reported, suggesting a possible oncosuppressor role of this gene family in the pathogenesis of thyroid tumors. To further explore this possibility, we performed expression and functional studies. Analysis of microarray data of thyroid tumors of different histologic types showed that several MT genes were downregulated with respect to normal tissue. The microarray data were corroborated by quantitative PCR experiments, showing downregulation of MTs in PTC and FTC, but to a greater extent in papillary carcinoma. The expression of MTs was also investigated at the protein level by immunohistochemistry; the results were consistent with the microarray data, showing general downregulation in tumor samples, which was more evident in PTC. The functional consequence of MT downregulation was addressed employing an experimental model made of the PTC-derived K1 cell line in which MT1G expression is repressed by promoter methylation. Restoration of MT1G expression by cDNA transfection affected growth rate and in vivo tumorigenicity of K1 cells, indicating an oncosuppressor role for MT1G in thyroid papillary tumorigenesis.