期刊
CELL REPORTS
卷 4, 期 4, 页码 776-790出版社
CELL PRESS
DOI: 10.1016/j.celrep.2013.07.035
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资金
- German Cancer Aid (Deutsche Krebshilfe) [110043]
- ERC [ERC-2007-Stg/208237-Luedde-Med3-Aachen]
- German Research Foundation [SFB-TRR57/P06, SFB-TR36]
- EMBO Young Investigator Program
- Interdisciplinary Centre for Clinical Research BIOMAT Aachen
- Ernst Jung Foundation Hamburg
- medical faculty of the RWTH Aachen
- Helmholtz Foundation
- Hofschneider Foundation
- Helmholtz Alliance Preclinical Comprehensive Center
- ERC Starting Grant (LiverCancerMechanisms)
- Deutsche Stiftung Herzforschung [12/12]
For years, the term apoptosis was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent necroptosis represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and non-parenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.
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