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

Oncogene. 2004 Mar 18;23(12):2188-96. doi: 10.1038/sj.onc.1207322.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Papillary / genetics
  • Carcinoma, Papillary / metabolism*
  • Carcinoma, Papillary / pathology*
  • Cell Division
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • Collagen / metabolism
  • Collagen Type I / metabolism
  • DNA / biosynthesis
  • Drug Combinations
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hyaluronan Receptors / metabolism
  • Laminin / metabolism
  • Neoplasm Invasiveness
  • Osteopontin
  • Phenotype
  • Phosphorylation
  • Protein Structure, Tertiary
  • Proteoglycans / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Recombinant Proteins / metabolism
  • Sialoglycoproteins / metabolism*
  • Signal Transduction
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology*
  • Tyrosine / metabolism

Substances

  • Collagen Type I
  • Drug Combinations
  • Hyaluronan Receptors
  • Laminin
  • Proteoglycans
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • SPP1 protein, human
  • Sialoglycoproteins
  • Osteopontin
  • matrigel
  • Tyrosine
  • Collagen
  • DNA
  • Receptor Protein-Tyrosine Kinases