MITOGENIC, DEDIFFERENTIATING, AND SCATTERING EFFECTS OF HEPATOCYTE GROWTH-FACTOR ON DOG THYROID-CELLS

Hepatocyte growth factor (HGF)/scatter factor (SF) is a potent mitogen ic factor or motility factor in different cells, acting through the ty rosine kinase receptor encoded by the met protooncogene. In the presen t work, we demonstrate the powerful mitogenic activity of this growth factor on dog thyroid cells in primary culture. This effect, maximal a t 50 ng/ml, was superior to those of other thyroid mitogenic agents, s uch as TSH, forskolin, and epidermal growth factor (EGF). HGF inhibite d both TSH- and forskolin-stimulated iodide uptake (a thyroid-specific differentiation marker) in the same way as EGF. However, as with basi c fibroblast growth factor, this dedifferentiating action appeared onl y during the growing phase concomitantly with the enhanced proliferati on. HGF treatment also markedly decreased TSH receptor and thyroglobul in messenger RNA levels, two other markers of differentiated thyrocyte s. Besides its proliferative and dedifferentiating effects, HGF enhanc ed the motility of the cultured thyroid cells. Concerning the mechanis m of its action, we showed that HGF had no effect on basal cAMP levels , but like EGF and 12-O-tetradecanoyl-phorbol 13-acetate, it induced t he rapid tyrosine phosphorylation of mitogen-activated protein kinases p42 and p44. These data establish HGF as the strongest mitogenic agen t for dog thyroid cells and may explain the important role of met onco gene expression in human thyroid tumors.