Ikappa B Kinaseβ/Nuclear Factor-κB Activation Controls the Development of Liver Metastasis by Way of Interleukin-6 Expression
Ikappa B Kinaseβ/Nuclear Factor-κB Activation Controls the Development of Liver Metastasis by Way of Interleukin-6 Expression
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DOI：
10.1002/hep.23199
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发表时间：
2009-12-01
期刊：
影响因子：
13.5
通讯作者：
Omata, Masao
中科院分区：
文献类型：
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作者：
Maeda, Shin;Hikiba, Yohko;Omata, Masao
核因子-kappaB在调节先天免疫反应、细胞凋亡、炎症和肿瘤发生等方面发挥着重要作用。脾内注射肺癌细胞系LLC可诱导肝转移，观察到肝组织中核因子-kappaB的活化。为了探讨IKK复合体的关键蛋白Ikappa B激酶β(IKKβ)和核因子-kappa B的激活在肿瘤转移中的作用，我们将LLC细胞注射到肝细胞特异性IKKβ基因敲除小鼠(IKKβ(Delta Hep))、全肝基因敲除小鼠(IKKβ(Delta L+H))和对照小鼠(IKKβ(F/F))中。与IKKβ(Delta Hep)和IKK Beta(F/F)小鼠相比，IKKβ(Delta L+H)小鼠发生肝转移的肝脏重量和转移灶显著减少。此外，脾内注射LLC可诱导IKKβ(F/F)小鼠IL-6和IL-1β的信使核糖核酸表达，而IKKβ(Delta L+H)小鼠IL-6和IL-1β的表达较低。IL-6(-/-)小鼠和用抗IL-6受体抗体治疗的小鼠肿瘤转移程度较轻，表明IL-6与肝转移有关。结论：IKKβ/NF-kappaB的激活通过IL-6的表达控制肝转移的发生，是抗肿瘤药物开发的潜在靶点。(《肝病》2009；50：1851-1860。)
Nuclear factor kappaB (NF-kappa B) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF-kappa B activation in the liver was observed after intrasplenic administration of a lung carcinoma cell line, LLC, which induces liver metastasis. To explore the role of Ikappa B kinase beta (IKK beta), which is the critical kinase of the IKK complex, and NF-kappa B activation in metastasis, we injected LLC cells into hepatocyte-specific IKK beta knockout mice (Ikk beta(Delta hep)), whole-liver knockout (Ikk beta(Delta L+H)) mice, and control (Ikk beta(F/F)) mice. Ikk beta(Delta L+H) mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikk beta(Delta hep) and Ikk beta(F/F) mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)-6 and IL-1 beta in Ikk beta(F/F) mice, whereas these genes were less expressed in Ikk beta(Delta L+H) mice. IL-6(-/-) mice and treatment with anti-IL-6 receptor antibody showed a lesser degree of metastatic tumor, indicating that IL-6 is associated with liver metastasis. Conclusion: Collectively, these observations suggest that IKK beta/NF-kappa B activation controls the development of liver metastasis byway of IL-6 expression and is a potential target for the development of antimetastatic drugs. (HEPATOLOGY 2009;50:1851-1860.)