Ikappa B kinaseβ/nuclear factor‐κB activation controls the development of liver metastasis by way of interleukin‐6 expression

Nuclear factor kappaB (NF‐κB) plays an important role in the regulation of innate immune responses, apoptosis, inflammation, and oncogenesis. NF‐κB 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 (IKKβ), which is the critical kinase of the IKK complex, and NF‐κB activation in metastasis, we injected LLC cells into hepatocyte‐specific IKKβ knockout mice (IkkβΔhep), whole‐liver knockout (IkkβΔL+H) mice, and control (IkkβF/F) mice. IkkβΔL+H mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to IkkβΔhep and IkkβF/F mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)‐6 and IL‐1β in IkkβF/F mice, whereas these genes were less expressed in IkkβΔL+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 IKKβ/NF‐κB activation controls the development of liver metastasis by way of IL‐6 expression and is a potential target for the development of antimetastatic drugs. (HEPATOLOGY 2009.)

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