Author(s): Maeda S, Hikiba Y, Sakamoto K, Nakagawa H, Hirata Y,
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Abstract 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. CONCLUSION: 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.
This article was published in Hepatology
and referenced in Journal of Cancer Science & Therapy