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

Research output: Contribution to journalArticle

116 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Transforming Growth Factors
Thyroid Neoplasms
Phosphotransferases
Thyroid Gland
Mitogen-Activated Protein Kinases
Laser Capture Microdissection
Primary Cell Culture
Vimentin
Cadherins
Microarray Analysis
Cell Adhesion
Immunohistochemistry
Phosphorylation
RNA
Papillary Thyroid cancer
Genes
Neoplasms

Keywords

  • BRAF
  • epithelialmesenchymal transition
  • TGFΒ
  • thyroid

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Knauf, J. A., Sartor, M. A., Medvedovic, M., Lundsmith, E., Ryder, M., Salzano, M., ... 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

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 journalArticle

Knauf, JA, Sartor, MA, Medvedovic, M, Lundsmith, E, Ryder, M, Salzano, M, Nikiforov, YE, Giordano, TJ, Ghossein, RA & Fagin, JA 2011, 'Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling', Oncogene, vol. 30, no. 28, pp. 3153-3162. https://doi.org/10.1038/onc.2011.44
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. / Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling. In: Oncogene. 2011 ; Vol. 30, No. 28. pp. 3153-3162.
@article{8ab3eecdf827424d82c8d1ba574797c8,
title = "Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFΒ signaling",
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.",
keywords = "BRAF, epithelialmesenchymal transition, TGFΒ, thyroid",
author = "Knauf, {J. A.} and Sartor, {M. A.} and M. Medvedovic and E. Lundsmith and M. Ryder and M. Salzano and Nikiforov, {Y. E.} and Giordano, {T. J.} and Ghossein, {R. A.} and Fagin, {J. A.}",
year = "2011",
month = "7",
day = "14",
doi = "10.1038/onc.2011.44",
language = "English (US)",
volume = "30",
pages = "3153--3162",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "28",

}

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 -