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

Abstract

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.

• Authors: Pablo Baquero, Irene Sánchez-Hernández, Eva Jiménez-Mora, Jose L Orgaz, Benilde Jiménez, Antonio Chiloeches
• Journal: Cancer letters (Cancer Lett) Vol. 335 Issue 1 Pg. 232-41 (Jul 10 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23435375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antigens, CD
• Butadienes
• CDH1 protein, human
• Cadherins
• Indoles
• Nitriles
• PLX 4720
• RNA, Small Interfering
• Snail Family Transcription Factors
• Sulfonamides
• Transcription Factors
• U 0126
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase Kinases

Topics

• Antigens, CD
• Butadienes (pharmacology)
• Cadherins (genetics, metabolism)
• Carcinoma (metabolism, 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, metabolism)
• Mutation, Missense
• Neoplasm Invasiveness
• Nitriles (pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics)
• Snail Family Transcription Factors
• Sulfonamides (pharmacology)
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (metabolism, pathology)
• Transcription Factors (metabolism)