Maeda Shin, Hikiba Yohko, Sakamoto Kei, Nakagawa Hayato, Hirata Yoshihiro, Hayakawa Yoku, Yanai Ayako, Ogura Keiji, Karin Michael, Omata Masao
Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
Hepatology. 2009 Dec;50(6):1851-60. doi: 10.1002/hep.23199.
Nuclear factor kappaB (NF-kappaB) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF-kappaB 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 (IKKbeta), which is the critical kinase of the IKK complex, and NF-kappaB activation in metastasis, we injected LLC cells into hepatocyte-specific IKKbeta knockout mice (Ikkbeta(Deltahep)), whole-liver knockout (Ikkbeta(DeltaL+H)) mice, and control (Ikkbeta(F/F)) mice. Ikkbeta(DeltaL+H) mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikkbeta(Deltahep) and Ikkbeta(F/F) mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)-6 and IL-1beta in Ikkbeta(F/F) mice, whereas these genes were less expressed in Ikkbeta(DeltaL+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.
Collectively, these observations suggest that IKKbeta/NF-kappaB activation controls the development of liver metastasis by way of IL-6 expression and is a potential target for the development of antimetastatic drugs.
核因子κB（NF-κB）在先天性免疫反应、细胞凋亡、炎症和肿瘤发生的调节中起重要作用。在脾内注射诱导肝转移的肺癌细胞系LLC后，观察到肝脏中NF-κB的激活。为了探究IKK复合物的关键激酶IKKβ以及NF-κB激活在转移中的作用，我们将LLC细胞注射到肝细胞特异性IKKβ基因敲除小鼠（Ikkbeta(Deltahep)）、全肝基因敲除（Ikkbeta(DeltaL+H)）小鼠和对照（Ikkbeta(F/F)）小鼠体内。与Ikkbeta(Deltahep)和Ikkbeta(F/F)小鼠相比，Ikkbeta(DeltaL+H)小鼠发生肝转移，肝脏重量显著降低，转移灶数量减少。此外，脾内注射LLC诱导Ikkbeta(F/F)小鼠中白细胞介素（IL）-6和IL-1β的信使核糖核酸（mRNA）表达，而这些基因在Ikkbeta(DeltaL+H)小鼠中表达较少（程度较低）。IL-6基因敲除小鼠和用抗IL-6受体抗体治疗显示转移瘤程度较轻，表明IL-6与肝转移有关。
总体而言，这些观察结果表明IKKβ/NF-κB激活通过IL-6表达控制肝转移的发展，是抗转移药物开发的潜在靶点。
