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Submitted on March 28, 2006
Accepted on August 28, 2006
B Activation
Department of Molecular Medicine, Department of International Health and Radiation Research, Department of Medical Gene Technology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523; Takashi Nagai International Hibakusha Medical Center, Nagasaki University Hospital, Nagasaki 852-8501; Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223-0061, The Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido 061-0293, Japan
* To whom correspondence should be addressed. E-mail: namba{at}net.nagasaki-u.ac.jp.
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 NF-
B DNA-binding activity, resulting in up-regulation of anti-apoptotic c-IAP-1, c-IAP-2 and XIAP. Furthermore, BRAFV600E expression also induced the expression of matrix metalloproteinase and cell invasion into matrigel through NF-B pathway. Increased invasive ability by BRAFV600E expression was significantly inhibited by a specific NF-B inhibitor, DHMEQ.
These data indicate that BRAFV600E 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 BRAFV600E.
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