Open AccessProgression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGFβ signaling
Author(s) -
Jeffrey A. Knauf,
Maureen A. Sartor,
Mario Medvedovic,
Emma T. Lundsmith,
Mabel Ryder,
Marcella Salzano,
Yuri E. Nikiforov,
Thomas J. Giordano,
Ronald Ghossein,
James A. Fagin
Publication year - 2011
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2011.44
Subject(s) - epithelial–mesenchymal transition , biology , cancer research , laser capture microdissection , thyroid cancer , vimentin , transforming growth factor , thyroid carcinoma , mapk/erk pathway , tumor progression , thyroid , kinase , cancer , pathology , metastasis , immunohistochemistry , endocrinology , gene expression , microbiology and biotechnology , immunology , medicine , gene , genetics , biochemistry
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.