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

Cancer Cell. 2010 May 18;17(5):481-96. doi: 10.1016/j.ccr.2010.03.021.

Abstract

The MAP3-kinase TGF-beta-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-kappaB 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-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Transformation, Neoplastic
  • Hyperplasia
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms, Experimental / metabolism*
  • Liver Neoplasms, Experimental / pathology
  • MAP Kinase Kinase Kinases / physiology*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • Necrosis

Substances

  • Intracellular Signaling Peptides and Proteins
  • NEMO protein, mouse
  • NF-kappa B
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7

Associated data

  • GEO/GSE19105