Overexpressed NF-κB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells
Overexpressed NF-κB-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells
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DOI：
10.1182/blood-2007-09-110635
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发表时间：
2008-05-15
期刊：
影响因子：
20.3
通讯作者：
Yamaoka, Shoji
中科院分区：
文献类型：
--
作者：
Saitoh, Yasunori;Yamamoto, Norio;Yamaoka, Shoji
核因子-κ B（nuclear factor-kappa B）转录因子通过抑制细胞凋亡和促进肿瘤细胞生长在肿瘤的发生发展中起重要作用。然而，NF-κ B B在特定癌细胞中被组成性激活的确切机制在很大程度上仍然未知。在我们目前的研究中，我们现在报告说，NF-κ B诱导激酶（NIK）在翻译前水平在成人T细胞白血病（ATL）和霍奇金Reed-Sternberg细胞（H-RS），不表达病毒调节蛋白。NIK的过表达引起大鼠成纤维细胞的细胞转化，其被I κ B α的超阻遏物形式消除。值得注意的是，通过RNA干扰消除ATL细胞中的NIK降低了NF-κ B的DNA结合活性和NF-κ B依赖性转录活性，并有效地抑制了NOD/SCID/γ c（null）小鼠中的肿瘤生长。这些结果表明，NIK的表达失调在ATL和H-RS细胞中的组成性NF-κ B活化中起关键作用，并且还表明NIK是癌症治疗的有吸引力的分子靶点。
The nuclear factor-kappa B (NF-kappa 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-kappa B is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-kappa 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 I kappa B alpha.. Notably, depletion of NIK in ATL cells by RNA interference reduces the DNA-binding activity of NF-kappa B and NF-kappa B-dependent transcriptional activity, and efficiently suppresses tumor growth in NOD/SCID/gamma c(null) mice. These results indicate that the deregulated expression of NIK plays a critical role in constitutive NF-kappa B activation in ATL and H-RS cells, and suggest also that NIK is an attractive molecular target for cancer therapy.