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

Hepatocyte growth factor (HGF)/scatter factor (SF) is a potent mitogenic factor or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the met protooncogene. In the present work, we demonstrate the powerful mitogenic activity of this growth factor on dog thyroid cells in primary culture. This effect, maximal at 50 ng/ml, was superior to those of other thyroid mitogenic agents, such as TSH, forskolin, and epidermal growth factor (EGF). HGF inhibited both TSH- and forskolin-stimulated iodide uptake (a thyroid-specific differentiation marker) in the same way as EGF. However, as with basic fibroblast growth factor, this dedifferentiating action appeared only during the growing phase concomitantly with the enhanced proliferation. HGF treatment also markedly decreased TSH receptor and thyroglobulin messenger RNA levels, two other markers of differentiated thyrocytes. Besides its proliferative and dedifferentiating effects, HGF enhanced the motility of the cultured thyroid cells. Concerning the mechanism 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 the rapid tyrosine phosphorylation of mitogen-activated protein kinases p42 and p44. These data establish HGF as the strongest mitogenic agent for dog thyroid cells and may explain the important role of met oncogene expression in human thyroid tumors.