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Ikappa B kinaseβ/nuclear factor‐κB activation controls the development of liver metastasis by way of interleukin‐6 expression
Author(s) -
Maeda Shin,
Hikiba Yohko,
Sakamoto Kei,
Nakagawa Hayato,
Hirata Yoshihiro,
Hayakawa Yoku,
Yanai Ayako,
Ogura Keiji,
Karin Michael,
Omata Masao
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23199
Subject(s) - iκb kinase , metastasis , cancer research , kinase , knockout mouse , nf κb , carcinogenesis , biology , hepatology , inflammation , medicine , immunology , cancer , microbiology and biotechnology , receptor
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 ( Ikk β Δ hep ), whole‐liver knockout ( Ikk β Δ L+H ) mice, and control ( Ikk β F/F ) mice. Ikk β Δ L+H mice developed liver metastasis with significantly lower liver weights and fewer metastatic foci compared to Ikk β Δ hep and Ikk β F/F mice. Furthermore, intrasplenic LLC injection induced the messenger RNA (mRNA) expression of interleukin (IL)‐6 and IL‐1β in Ikk β F/F mice, whereas these genes were less expressed in Ikk β Δ L+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. (H EPATOLOGY 2009.)