Autocrine stimulation by osteopontin plays a pivotal role in the expression of the mitogenic and invasive phenotype of RET/PTC-transformed thyroid cells.

Papillary thyroid carcinomas are characterized by re- arrangements of the RET receptor tyrosine kinase generatingRET/PTConcogenes.Hereweshowthat osteopontin (OPN), a secreted glycoprotein, is a major RET/PTC-induced transcriptional target in PC Cl 3 thyroidfollicularcells.OPNupregulationdependedon the integrity of the RET/PTC kinase and tyrosines Y1015 and Y1062, two major RET/PTC autophosphorylation sites.RET/PTCalsoinducedastrongoverexpressionof CD44, a cell surface signalling receptor for OPN. Upregulation of CD44 was dependent on RET/PTC Y1062,aswell.ConstitutiveOPNoverexpressionor treatment with exogenous recombinant OPN sharply increased proliferation, Matrigel invasion and spreading in collagen gels of RET/PTC-transformed PC Cl 3 cells. These effects were impaired by the treatment of PC Cl 3-RET/PTC cells with OPN- and CD44-blocking anti- bodies.Thus,RET/PTCsignallingtriggersanautocrine loop involving OPN and CD44 that sustains proliferation and invasion of transfomed PC Cl 3 thyrocytes.