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Endocrinology. 2006 Dec;147(12):5699-707. Epub 2006 Sep 7.

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

Author information

1
Department of Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki University Hospital, 852-8523, Japan.

Abstract

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.

PMID:
16959844
DOI:
10.1210/en.2006-0400
[Indexed for MEDLINE]

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