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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5118-5129.
Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2007-09-110635.
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NEOPLASIA
Overexpressed NF- B–inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells
Yasunori Saitoh1,
Norio Yamamoto1,
M. Zahidunnabi Dewan1,
Haruyo Sugimoto1,
Vicente J. Martinez Bruyn1,
Yuki Iwasaki1,
Katsuyoshi Matsubara1,
Xiaohua Qi1,
Tatsuya Saitoh2,
Issei Imoto3,
Johji Inazawa3,
Atae Utsunomiya4,
Toshiki Watanabe5,
Takao Masuda6,
Naoki Yamamoto1,7, and
Shoji Yamaoka1
1 Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo;
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita;
3 Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo;
4 Department of Hematology, Imamura Bun-in Hospital, Kagoshima;
5 Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo;
6 Department of Immunotherapeutics, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo; and
7 AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
The nuclear factor- B (NF-B) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-B is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-B–inducing kinase (NIK) is overexpressed at the pretranslational level in adult T-cell leukemia (ATL) and Hodgkin Reed-Sternberg cells (H-RS) that do not express viral regulatory proteins. The overexpression of NIK causes cell transformation in rat fibroblasts, which is abolished by a super-repressor form of IB . Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-B and NF-B–dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/ cnull mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-B activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.
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