Journal
ENDOCRINOLOGY
Volume 147, Issue 12, Pages 5699-5707Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2006-0400
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The BRAF(V600E) mutation is closely linked to tumorigenesis and malignant phenotype of papillary thyroid cancer. Signaling pathways activated by BRAF(V600E) are still unclear except a common activation pathway, MAPK cascade. To investigate the possible target of BRAF(V600E), we developed two different cell culture models: 1) doxycycline-inducible BRAF(V600E) 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 BRAF(V600E). BRAF(V600E) expression induced ERK phosphorylation and cyclin D1 expression in these cells. The BRAF(V600E)-overexpressing cells also showed an increase of nuclear factor kappa B (NF-kappa B) DNA-binding activity, resulting in up-regulation of antiapoptotic c-IAP-1, c-IAP-2, and X-linked inhibitor of apoptosis. Furthermore, BRAF(V600E) expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-kappa B pathway. Increased invasive ability by BRAF(V600E) expression was significantly inhibited by a specific NF-kappa B inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAF(V600E) activates not only MAPK but also NF-kappa B signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-kappa B may provide a new therapeutic modality for thyroid cancers with BRAF(V600E).
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