(V600E)BRAF promotes invasiveness of thyroid cancer cells by decreasing E-cadherin expression through a Snail-dependent mechanism

BRAF is a main oncogene in human thyroid cancer. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with BRAF inhibitor PLX4720 decreases migration and invasion in thyroid cancer cells expressing oncogenic (V600E)BRAF through a MEK/ERK-dependent mechanism, since tr...

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Bibliographic Details
Published in:Cancer letters 2013-07, Vol.335 (1), p.232-241
Main Authors: Baquero, Pablo, Sánchez-Hernández, Irene, Jiménez-Mora, Eva, Orgaz, Jose L, Jiménez, Benilde, Chiloeches, Antonio
Format: Article
Language:English
Subjects:
Antigens, CD
Butadienes - pharmacology
Cadherins - genetics
Cadherins - metabolism
Carcinoma - metabolism
Carcinoma - pathology
Carcinoma, Papillary
Cell Line, Tumor
Cell Movement
Gene Expression
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Indoles - pharmacology
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - metabolism
Mutation, Missense
Neoplasm Invasiveness
Nitriles - pharmacology
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - metabolism
RNA, Small Interfering - genetics
Snail Family Transcription Factors
Sulfonamides - pharmacology
Thyroid Cancer, Papillary
Thyroid Neoplasms - metabolism
Thyroid Neoplasms - pathology
Transcription Factors - metabolism
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Summary:BRAF is a main oncogene in human thyroid cancer. Here, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with BRAF inhibitor PLX4720 decreases migration and invasion in thyroid cancer cells expressing oncogenic (V600E)BRAF through a MEK/ERK-dependent mechanism, since treatment with the MEK inhibitor U0126 exerts the same effect. Moreover, over-expression of (V600E)BRAF increases migration and invasion of wild-type BRAF thyroid cells. Using the same strategies, we demonstrate that these effects are mediated by upregulation of the transcriptional repressor Snail with a concomitant decrease of its target E-cadherin, both hallmarks of EMT. These results reveal a novel (V600E)BRAF-induced mechanism in thyroid tumours progression and provides a rationale for using the PLX4720 inhibitor to target (V600E)BRAF signalling to effectively control progression of thyroid cancer.
ISSN:1872-7980
DOI:10.1016/j.canlet.2013.02.033