BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor kappaB activation

Endocrinology. 2006 Dec;147(12):5699-707. doi: 10.1210/en.2006-0400. Epub 2006 Sep 7.


The BRAFV600E mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAFV600E are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAFV600E, we developed two different cell culture models: 1) doxycycline-inducible BRAFV600E-expressing clonal line derived from human thyroid cancer WRO cells originally harboring wild-type BRAF; 2) WRO, KTC-3, and NPA cells infected with an adenovirus vector carrying BRAFV600E. BRAFV600E expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAFV600E-overexpressing cells also showed an increase of nuclear factor kappaB (NF-kappaB) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappaB pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-kappaB inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAFV600E activates not only MAPK but also NF-kappaB signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappaB may provide a new therapeutic modality for thyroid cancers with BRAFV600E.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Papillary / genetics*
  • Carcinoma, Papillary / pathology*
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Humans
  • I-kappa B Proteins / metabolism
  • Inhibitor of Apoptosis Proteins / metabolism
  • MAP Kinase Signaling System
  • Mutation, Missense
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness*
  • Protein Denaturation
  • Proto-Oncogene Proteins B-raf / genetics*
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology*
  • Transfection
  • Tumor Cells, Cultured


  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • NF-KappaB Inhibitor alpha
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf