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

Cancer Lett. 2013 Jul 10;335(1):232-41. doi: 10.1016/j.canlet.2013.02.033. Epub 2013 Feb 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • 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