TAK1 suppresses a NEMO-dependent but NF-kB-independent pathway to liver cancer

K. Bettermann, M. Vucur, J. Haybaeck, C. Koppe, J. Janssen, F. Heymann, A. Weber, R. Weiskirchen, C. Liedtke, N. Gassler, M.R. Müller, R. de Vos, M.J. Wolf, Y. Boege, G.M. Seleznik, N. Zeller, D. Erny, T. Fuchs, S. Zoller, S. CairoM.A. Buendia, M. Prinz, S. Akira, F. Tacke, M. Heikenwalder, C. Trautwein, T. Luedde

Research output: Contribution to journalArticleAcademicpeer-review

170 Citations (Scopus)

Abstract

The MAP3-kinase TGF-ß-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-¿B in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-¿B-independent functions of the I¿B-kinase (IKK)-subunit NF-¿B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-¿B-independent function of NEMO in parenchymal liver cells.
Original languageEnglish
Pages (from-to)481-496
JournalCancer Cell
Volume17
Issue number5
DOIs
Publication statusPublished - 2010

Keywords

  • hepatocellular-carcinoma
  • chemical hepatocarcinogenesis
  • protein-kinases
  • activation
  • mice
  • inflammation
  • injury
  • cell
  • jnk
  • hepatocytes

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