title: Pituitary tumor transforming gene (PTTG) stimulates thyroid cell proliferation via a vascular endothelial growth factor/kinase insert domain receptor/inhibitor of DNA binding-3 autocrine pathway.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) exerts its biological effects by binding to the tyrosine kinase receptors VEGF receptor type 1 (VEGFR1/Flt-1) and VEGFR2 (Flk-1/KDR). Kinase insert domain receptor (KDR) is the critical receptor controlling proliferation and migration of endothelial cells and has been shown to be expressed in some nonendothelial cells. We recently reported that the proangiogenic pituitary tumor transforming gene (PTTG) stimulates VEGF and up-regulates inhibitor of DNA binding-3 (ID3), an important gene in VEGF-dependent angiogenesis.
  
  
  OBJECTIVE
  Our objective was to test whether VEGF, ID3, and KDR confer a PTTG-mediated effect on thyroid cell growth.
  
  
  METHODS
  Gene expression, MAPK stimulation, and cell proliferation were assessed in follicular thyroid cancer FTC133 cells. Gene expression and clinical associations were determined in 21 normal and 38 tumorous thyroid specimens (nine follicular and 29 papillary).
  
  
  RESULTS
  ID3 correlated with VEGF mRNA expression in our series of thyroid cancers, which also showed up-regulated KDR mRNA. Stimulation of FTC133 cells with exogenous VEGF enhanced ID3 expression, which could be abrogated by the KDR-specific inhibitor ZM323881, suggesting that VEGF regulation of ID3 is KDR dependent. PTTG significantly correlated with KDR mRNA expression in our thyroid cancer cohort and up-regulated KDR and VEGF expression in FTC133 cells. Finally, cells transfected with PTTG demonstrated increased cell proliferation and phosphorylation of MAPK, which was abrogated by ZM323881.
  
  
  CONCLUSIONS
  We report the presence of a VEGF/KDR/ID3-dependent autocrine pathway in FTC133 thyroid cells. By up-regulating both VEGF and KDR expression, we propose a novel PTTG-mediated proliferative pathway that may be critical to thyroid cancer growth and progression.
authors.affiliation: Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: D S
authors.initials: DS
authors.lastname: Kim
authors.forename: J A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: K
authors.initials: K
authors.lastname: Boelaert
authors.forename: M C
authors.initials: MC
authors.lastname: Eggo
authors.forename: J C
authors.initials: JC
authors.lastname: Watkinson
authors.forename: C J
authors.initials: CJ
authors.lastname: McCabe
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000378:metabolism; D019898:Autocrine Communication; D002291:Carcinoma, Papillary / Q000378:metabolism; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D019899:Paracrine Communication; D010766:Phosphorylation; D064249:Securin; D013961:Thyroid Gland / Q000378:metabolism / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D006133:Growth Substances; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D064249:Securin; D042461:Vascular Endothelial Growth Factor A; C578002:pituitary tumor-transforming protein 1, human; C075640:ID3 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases