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Hepatocyte Growth Factor Receptor, Matrix Metalloproteinase-11, Tissue Inhibitor of Metalloproteinase-1, and Fibronectin Are Up-Regulated in Papillary Thyroid Carcinoma

A cDNA and Tissue Microarray Study

Departments of Oncology [V-M. W., S. H., H. J.] and Pathology [K. F.] and Laboratory of Medical Genetics, Helsinki University Central Hospital, and the Department of Medical Genetics, Haartman Institute [E. K., S. K.], FIN-00029 Helsinki, Finland

Purpose: To screen and validate the global gene expression in papillary thyroid carcinoma (PTC) using cDNA expression arrays and immunohistochemistry on tumor tissue microarrays in an attempt to find genes that may be of importance in the molecular pathogenesis and malignant progression of PTC.

Experimental Design: Eighteen PTC tissue specimens were compared with three morphologically normal thyroid specimens by applying Atlas Human Cancer 1.2 Array membranes printed with cDNAs of 1176 human genes involved in cancer. Results for selected genes were confirmed by reverse transcription-PCR. Protein expression of selected genes was further studied using a tissue microarray consisting of 107 PTCs and compared with histologically normal thyroid tissue samples.

Results: By cDNA arrays, two genes [c-MET and matrix metalloproteinase (MMP)-11] were expressed only in tumor tissue, where they were present in >50% of cases. Ten genes [macrophage inhibitory cytokine-1, CGD, fibronectin (FN), hypoxia-inducible factor 1, Fc--receptor -chain, lactate dehydrogenase A, HLA-DBP1, AH receptor, tissue inhibitor of metalloproteinase (TIMP-1), and glycyl-tRNA-synthetase] were found to be up-regulated >2-fold in 40–100% of cancers, whereas 9 genes (GADD153, polykystic kidney disease-1, CYR61, DPC4, HBA1, gravin, DLG3, protein tyrosine phosphatase , and heterochromatin protein 1 homologue-) were down-regulated to <50% of their normal levels in 40–94% of cases. Conventional reverse transcription-PCR gave consistent results with the cDNA array findings for all four genes selected to be studied (c-MET, FN, TIMP-1, and GADD153). Immunohistochemistry for three selected proteins, FN, MMP-11, and TIMP-1, showed positive staining in 81, 87, and 68% of the tumor samples, respectively.

Conclusions: Several novel and previously undetected tumor promoting/inhibiting genes may be of importance in the molecular pathogenesis and malignant progression of PTC. Transcription of these genes may result in overexpression of proteins, such as c-MET, MMP-11, TIMP-1, and FN, which may contribute to the pathogenesis of PTC.

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