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

J. A. Knauf, M. A. Sartor, M. Medvedovic, E. Lundsmith, M. Ryder, M. Salzano, Y. E. Nikiforov, T. J. Giordano, R. A. Ghossein, J. A. Fagin

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119 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3153-3162
Number of pages10
JournalOncogene
Volume30
Issue number28
DOIs
StatePublished - Jul 14 2011

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Keywords

  • BRAF
  • TGFΒ
  • epithelialmesenchymal transition
  • thyroid

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Knauf, J. A., Sartor, M. A., Medvedovic, M., Lundsmith, E., Ryder, M., Salzano, M., Nikiforov, Y. E., Giordano, T. J., Ghossein, R. A., & Fagin, J. A. (2011). Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling. Oncogene, 30(28), 3153-3162. https://doi.org/10.1038/onc.2011.44