Hepatocyte Necrosis Induced by Oxidative Stress and IL-1α Release Mediate Carcinogen-Induced Compensatory Proliferation and Liver Tumorigenesis

Toshiharu Sakurai, Guobin He, Atsushi Matsuzawa, Guann Yi Yu, Shin Maeda, Gary Hardiman, Michael Karin

Research output: Contribution to journalArticlepeer-review

347 Citations (Scopus)

Abstract

Hepatocyte IκB kinase β (IKKβ) inhibits hepatocarcinogenesis by suppressing accumulation of reactive oxygen species (ROS) and liver damage, whereas JNK1 activation promotes ROS accumulation, liver damage, and carcinogenesis. We examined whether hepatocyte p38α, found to inhibit liver carcinogenesis, acts similarly to IKKβ in control of ROS metabolism and cell death. Hepatocyte-specific p38α ablation enhanced ROS accumulation and liver damage, which were prevented upon administration of an antioxidant. In addition to elevated ROS accumulation, hepatocyte death, augmented by loss of either IKKβ or p38α, was associated with release of IL-1α. Inhibition of IL-1α action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1α release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.

Original languageEnglish
Pages (from-to)156-165
Number of pages10
JournalCancer Cell
Volume14
Issue number2
DOIs
Publication statusPublished - 2008 Aug 12
Externally publishedYes

Keywords

  • CELLBIO
  • HUMDISEASE
  • SIGNALING

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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