Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling Academic Article uri icon


MeSH Major

  • Disease Progression
  • Epithelial-Mesenchymal Transition
  • MAP Kinase Signaling System
  • Mitogen-Activated Protein Kinases
  • Proto-Oncogene Proteins B-raf
  • Thyroid Neoplasms
  • Transforming Growth Factor beta


  • Mice with thyroid-specific expression of oncogenic BRAF (Tg-Braf) develop papillary thyroid cancers (PTCs) that are locally invasive and have well-defined foci of poorly differentiated thyroid carcinoma (PDTC). To investigate the PTC-PDTC progression, we performed a microarray analysis using RNA from paired samples of PDTC and PTC collected from the same animals by laser capture microdissection. Analysis of eight paired samples revealed a profound deregulation of genes involved in cell adhesion and intracellular junctions, with changes consistent with an epithelial-mesenchymal transition (EMT). This was confirmed by immunohistochemistry, as vimentin expression was increased and E-cadherin lost in PDTC compared with adjacent PTC. Moreover, PDTC stained positively for phospho-Smad2, suggesting a role for transforming growth factor (TGF)β in mediating this process. Accordingly, TGFβ-induced EMT in primary cultures of thyroid cells from Tg-Braf mice, whereas wild-type thyroid cells retained their epithelial features. TGFβ-induced Smad2 phosphorylation, transcriptional activity and induction of EMT required mitogen-activated protein kinase (MAPK) pathway activation in Tg-Braf thyrocytes. Hence, tumor initiation by oncogenic BRAF renders thyroid cells susceptible to TGFβ-induced EMT, through a MAPK-dependent process.

publication date

  • July 14, 2011



  • Academic Article



  • eng

PubMed Central ID

  • PMC3136543

Digital Object Identifier (DOI)

  • 10.1038/onc.2011.44

PubMed ID

  • 21383698

Additional Document Info

start page

  • 3153

end page

  • 62


  • 30


  • 28