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 language | English (US) |
|---|---|
| Pages (from-to) | 3153-3162 |
| Number of pages | 10 |
| Journal | Oncogene |
| Volume | 30 |
| Issue number | 28 |
| DOIs | |
| State | Published - Jul 14 2011 |
| Externally published | Yes |
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Keywords
- BRAF
- epithelialmesenchymal transition
- TGFΒ
- thyroid
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling. / 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.
In: Oncogene, Vol. 30, No. 28, 14.07.2011, p. 3153-3162.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling
AU - Knauf, J. A.
AU - Sartor, M. A.
AU - Medvedovic, M.
AU - Lundsmith, E.
AU - Ryder, M.
AU - Salzano, M.
AU - Nikiforov, Y. E.
AU - Giordano, T. J.
AU - Ghossein, R. A.
AU - Fagin, J. A.
PY - 2011/7/14
Y1 - 2011/7/14
N2 - 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.
AB - 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.
KW - BRAF
KW - epithelialmesenchymal transition
KW - TGFΒ
KW - thyroid
UR - http://www.scopus.com/inward/record.url?scp=79960381628&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79960381628&partnerID=8YFLogxK
U2 - 10.1038/onc.2011.44
DO - 10.1038/onc.2011.44
M3 - Article
C2 - 21383698
AN - SCOPUS:79960381628
VL - 30
SP - 3153
EP - 3162
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 28
ER -