V600EBRAF promotes invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a Snail-dependent mechanism

Baquero, Pablo; Sánchez-Hernández, Irene; Jiménez-Mora, Eva; Orgaz, José L.; Jiménez, Benilde; Chiloeches, Antonio

doi:10.1016/j.canlet.2013.02.033

Cited by 52 publications

(57 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There have been previous reports that BRAF (V600E) mutation stimulates migration and invasion of thyroid cancer cells, through the increased expression of EMT-related markers via a MEK/ERK-dependent mechanism and that these processes together with tumor proliferation can be inhibited by BRAF inhibitor PLX4720 treatment [40, 41]. This however, may not always be the case, as has been demonstrated in this present study.…”

Section: Discussionsupporting

confidence: 47%

Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Byeon

Yang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, β-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.

show abstract

Section: Discussionsupporting

confidence: 47%

Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Byeon

Yang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…In agreement, we found enhanced expression of the Snail family of EMT inducers (including Snail and Slug) and TGF-β1, TGF-β3, and TGF-βRII in the murine papillary thyroid carcinoma samples as shown in previous studies (13, 35, 44). Recent work has also demonstrated that thyroid cancer, which developed in BRAF V600E mice were susceptible to TGF-β1 induced EMT (25) and BRAF V600E promoted invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a Snail-dependent mechanism (45). We also demonstrated that TGF-β1 or over-expression of Snail dramatically increased the mesenchymal marker vimentin and stem cell markers in thyroid cancer cells derived from BRAF V600E mice.…”

Section: Discussionmentioning

confidence: 99%

Stemness is Derived from Thyroid Cancer Cells

Bonnefond

Morshed

et al. 2014

Front. Endocrinol.

View full text Add to dashboard Cite

Background: One hypothesis for thyroid cancer development is its derivation from thyroid cancer stem cells (CSCs). Such cells could arise via different paths including from mutated resident stem cells within the thyroid gland or via epithelial to mesenchymal transition (EMT) from malignant cells since EMT is known to confer stem-like characteristics. Furthermore, EMT is a critical process for epithelial tumor progression, local invasion, and metastasis formation. In addition, stemness provides cells with therapeutic resistance and is the likely cause of tumor recurrence. However, the relevance of EMT and stemness in thyroid cancer progression has not been extensively studied.Methods: To examine the status of stemness in thyroid papillary cancer, we employed a murine model of thyroid papillary carcinoma and examined the expression of stemness and EMT using qPCR and histochemistry in mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre). This construct is only activated at the time of thyroid peroxidase (TPO) expression in differentiating thyroid cells and cannot be activated by undifferentiated stem cells, which do not express TPO.Results: There was decreased expression of thyroid-specific genes such as Tg and NIS and increased expression of stemness markers, such as Oct4, Rex1, CD15, and Sox2 in the thyroid carcinoma tissue from 6-week-old BRAFV600E mice indicating the dedifferentiated status of the cells and the fact that stemness was derived in this model from differentiated thyroid cells. The decreased expression of the epithelial marker E-cadherin and increased EMT regulators including Snail, Slug, and TGF-β1 and TGF-β3, and the mesenchymal marker vimentin demonstrated the simultaneous progression of EMT and the CSC-like phenotype. Stemness was also found in a cancer thyroid cell line (named Marca cells) derived from one of the murine tumors. In this cell line, we also found that overexpression of Snail caused up-regulation of vimentin expression and up-regulation of stemness markers Oct4, Rex1, and CD15, with enhanced migration ability of the cells. We also showed that TGF-β1 was able to induce Snail and vimentin expression in the Marca cell thyroid cancer line, indicating the induction of EMT in these cells, and this induction of EMT and stemness was significantly inhibited by celastro a natural inhibitor of neoplastic cells.Conclusion: Our findings support our earlier hypothesis that stemness in thyroid cancer is derived via EMT rather than from resident thyroid stem cells. In mice with a thyroid-specific knock-in of oncogenic Braf (LSL-Braf(V600E)/TPO-Cre), the neoplastic changes were dependent on thyroid cell differentiation and the onset of stemness must have been derived from differentiated thyroid epithelial cells. Furthermore, celastrol suppressed TGF-β1 induced EMT in thyroid cancer cells and may have therapeutic potential.

show abstract

“…23 Other investigators have demonstrated the implication of different cell adhesion molecules in thyroid cancer progression. 24, 25 Buitrago et al 24 showed that intercellular adhesion molecule-1 turned out to be upregulated in PTC, both as gene expression and as protein immunohistochemical expression. Moreover, this up-regulated molecule correlated with aggressive tumor features such as BRAF V600E mutation, extrathyroidal extension, and lymph node metastasis.…”

Section: Discussionmentioning

confidence: 97%

E-selectin expression and BRAF status in papillary thyroid carcinomas: Correlation with clinicopathologic features

Miccoli

Torregrossa

Borrelli

et al. 2014

Surgery

View full text Add to dashboard Cite

V600EBRAF promotes invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a Snail-dependent mechanism

Cited by 52 publications

References 47 publications

Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Stemness is Derived from Thyroid Cancer Cells

E-selectin expression and BRAF status in papillary thyroid carcinomas: Correlation with clinicopathologic features

Contact Info

Product

Resources

About