Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.

Abstract:

:Hepatocyte I kappaB kinase beta (IKK beta) 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 p38 alpha, found to inhibit liver carcinogenesis, acts similarly to IKK beta in control of ROS metabolism and cell death. Hepatocyte-specific p38 alpha 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 IKK beta or p38 alpha, was associated with release of IL-1 alpha. Inhibition of IL-1 alpha action or ablation of its receptor inhibited carcinogen-induced compensatory proliferation and liver tumorigenesis. IL-1 alpha release by necrotic hepatocytes is therefore an important mediator of liver tumorigenesis.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Sakurai T,He G,Matsuzawa A,Yu GY,Maeda S,Hardiman G,Karin M

doi

10.1016/j.ccr.2008.06.016

subject

Has Abstract

pub_date

2008-08-12 00:00:00

pages

156-65

issue

2

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(08)00226-2

journal_volume

14

pub_type

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