title: Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression.
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.
  
  
  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.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Tokyo, Japan. shinmaeda2-gi@umin.ac.jp
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Ayako
authors.initials: A
authors.lastname: Yanai
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: 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
chemical_list: 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