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

Papillary thyroid carcinomas are characterized by rearrangements of the RET receptor tyrosine kinase generating RET/ PTC oncogenes. Here we show that osteopontin ( OPN), a secreted glycoprotein, is a major RET/ PTC- induced transcriptional target in PC Cl 3 thyroid follicular cells. OPN upregulation depended on the integrity of the RET/ PTC kinase and tyrosines Y1015 and Y1062, two major RET/ PTC autophosphorylation sites. RET/ PT C also induced a strong overexpression of CD44, a cell surface signalling receptor for OPN. Upregulation of CD44 was dependent on RET/ PTC Y1062, as well. Constitutive OPN overexpression or 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 antibodies. Thus, RET/ PTC signalling triggers an autocrine loop involving OPN and CD44 that sustains proliferation and invasion of transfomed PC Cl 3 thyrocytes.