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BRAF^V600E Promotes Invasiveness of Thyroid Cancer Cells through Nuclear Factor B Activation

Department of Molecular Medicine (I.P., H.N., N.M., A.P., I.S., S.Y.), Department of International Health and Radiation Research (V.S., S.Y.), and Department of Medical Gene Technology (Y.N.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan; Takashi Nagai International Hibakusha Medical Center (A.O., S.Y.), Nagasaki University Hospital, Nagasaki 852-8501, Japan; Department of Applied Chemistry (K.U.), Faculty of Science and Technology, Keio University, Yokohama 223-0061, Japan; and The Research Institute of Personalized Health Sciences (D.S.), Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan

Address all correspondence and requests for reprints to: Hiroyuki Namba, M.D., Ph.D., Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: namba{at}net.nagasaki-u.ac.jp.

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 B (NF-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-B pathway. Increased invasive ability by BRAF^V600E expression was significantly inhibited by a specific NF-B inhibitor, racemic dehydroxymethylepoxyquinomicin. These data indicate that BRAF^V600E activates not only MAPK but also NF-B signaling pathway in human thyroid cancer cells, leading to an acquisition of apoptotic resistance and promotion of invasion. Inactivation of NF-B may provide a new therapeutic modality for thyroid cancers with BRAF^V600E.

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