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 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/PTC 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-locking antibodies. Thus, RET/PTC signalling triggers an autocrine loop involving OPN and CD44 that sustains proliferation and invasion of transfomed PC Cl 3 thyrocytes.
Dipartimento di Biologia e Patologia Cellulare e Molecolare, University Federico II c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
Maria Domenica
MD
Castellone
Angela
A
Celetti
Valentina
V
Guarino
Anna Maria
AM
Cirafici
Fulvio
F
Basolo
Riccardo
R
Giannini
Enzo
E
Medico
Mogens
M
Kruhoffer
Torben F
TF
Orntoft
Francesco
F
Curcio
Alfredo
A
Fusco
Rosa Marina
RM
Melillo
Massimo
M
Santoro
D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D009361:Neoplasm Invasiveness; D053495:Osteopontin; D010641:Phenotype; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014443:Tyrosine / Q000378:metabolism
D024042:Collagen Type I; D004338:Drug Combinations; D018960:Hyaluronan Receptors; D007797:Laminin; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin; C059485:matrigel; D014443:Tyrosine; D003094:Collagen; D004247:DNA; D020794:Receptor Protein-Tyrosine Kinases