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

Maria Domenica Castellone, Angela Celetti, Valentina Guarino, Anna Maria Cirafici, Fulvio Basolo, Riccardo Giannini, Enzo Medico, Mogens Kruhoffer, Torben F. Orntoft, Francesco Curcio, Alfredo Fusco, Rosa Marina Melillo, Massimo Santoro

Research output: Contribution to journalArticlepeer-review

Abstract

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-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.

Original languageEnglish
Pages (from-to)2188-2196
Number of pages9
JournalOncogene
Volume23
Issue number12
DOIs
Publication statusPublished - Mar 18 2004

Keywords

  • Carcinoma
  • Kinase
  • Motility
  • Ras
  • Thyroid
  • Tyrosine

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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