Abstract
Met protein is a tyrosine kinase receptor for hepatocyte growth factor (HGF). c-Met has morphogenic, mitogenic, and motogenic properties and is overexpressed in many solid tumors. We studied c-met mRNA and protein expression in papillary thyroid carcinomas and nonneoplastic thyroid tissue. The c-met mRNA was detected in all biopsies by reverse transcriptase-polymerase chain reaction and by hybridization of complex cDNA probes to a c-met-specific DNA fragment in a dot blot array. Immunohistochemistry on fresh frozen biopsies showed Met protein localized along the basal cell membrane of normal thyrocytes in 32 of 35 nonneoplastic thyroid tissue specimens, sometimes associated with weak cytoplasmic reactivity but without apical cell membrane staining. In papillary carcinomas an increased Met protein expression was seen, comprising a cytoplasmic (33 of 49) and apical cell membrane (24 of 49) immunoreactivity, whereas only 1 of 49 biopsies showed basal cell membrane staining. A 145-kDa Met-specific band was detected by Western immunoblotting on protein extracts from papillary carcinomas. The tight junction protein zona occludens-1 (ZO-1), studied by immunohistochemistry, was weakly expressed along the apical cell membrane in 10 nonneoplastic biopsies. In contrast, increased and cytoplasmic/apical membranous ZO-1 immunostaining was seen in 11 of 15 papillary carcinomas. Nuclear ZO-1 staining was present in a few papillary carcinomas with partial dedifferentiation. The concomitant overexpression and subcellular redistribution of Met and ZO-1 proteins indicate a change in cell polarity in papillary carcinomas compared to nonneoplastic thyroid tissue. These observations may reflect an important feature of the tumorigenesis of papillary thyroid carcinomas. No significant association was found between semiquantitative immunohistochemical assessment of Met protein and clinical parameters in papillary carcinoma patients.
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