RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer

Cancer Cell. 2017 Jan 9;31(1):94-109. doi: 10.1016/j.ccell.2016.11.009. Epub 2016 Dec 22.

Abstract

Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.

Keywords: HCC; NF-κB; RIP1; RIP3; RIPK3; apoptosis; cIAP-1; caspase-8; hepatocarcinogenesis; necroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 8 / metabolism
  • Hepatocytes / physiology
  • Humans
  • Liver Neoplasms / etiology*
  • Liver Neoplasms / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / physiology
  • Proteasome Endopeptidase Complex / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology*
  • TNF Receptor-Associated Factor 2 / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • NF-kappa B
  • PSMD2 protein, human
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8
  • Proteasome Endopeptidase Complex