Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression.
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.


CONCLUSIONS
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.
Maeda
Shin
S
Department of Gastroenterology, University of Tokyo, Tokyo, Japan. shinmaeda2-gi@umin.ac.jp
Hikiba
Yohko
Y
Sakamoto
Kei
K
Nakagawa
Hayato
H
Hirata
Yoshihiro
Y
Hayakawa
Yoku
Y
Yanai
Ayako
A
Ogura
Keiji
K
Karin
Michael
M
Omata
Masao
M
D000818:Animals; D049109:Cell Proliferation; D051550:I-kappa B Kinase / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000209:etiology; D010455:Peptides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D015850:Interleukin-6; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D051550:I-kappa B Kinase