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Status |
Public on Apr 01, 2013 |
Title |
Programmed necrosis and apoptosis differentially regulate cancer development and biliary homeostasis in the liver |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
For years, the term apoptosis was used synonymously for programmed cell death. However, it was recently discovered that programmed necrosis – dependent on the kinases Receptor-Interacting-Protein-Kinase (RIP)1 and RIP3 (also called necroptosis) – represents a major programmed cell-death pathway in development and immunity. At present, the functions of necroptosis in hepatitis, liver cancer development and biliary disease are unclear. Here we show that in mice with chronic hepatitis due to conditional ablation of TGF-beta-activated kinase1 (TAK1) in liver parenchymal cells (LPC), both apoptotic and necroptotic signaling pathways are activated. Strikingly, only Caspase-8-dependent apoptosis promotes spontaneous liver cancer development, while in contrast LPC necroptosis inhibits hepatic tumourigenesis. The tumour-promoting effect of apoptosis results from an induction of strong compensatory proliferation of LPC, linked with the paracrine action of growth factors like Insulin-like growth factor-2 (IGF-2) not induced by necroptosis. In addition to prevention of HCC development, induction of necroptosis leads to massive cholestasis and hyperbilirubinemia, resulting from an insufficient ductular reaction and biliary regeneration from the hepatic stem cell niche as a response to chronic hepatitis. These results indicate previously undefined distinctive functions of apoptosis and programmed necrosis in controlling cancer development and cholestasis in the liver with important implications for future therapeutic strategies in chronic liver disease.
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Overall design |
8 samples were analysed. We compared groups of 4 Tak1/Caspase8 LPC double knockout mice and 4 Tak1 LPC-KO/Rip3-/- mice to detect genes differentially regulated by apoptotic and necrotic signalling pathways.
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Contributor(s) |
Denecke B, Lüdde T, Janssen J |
Citation missing |
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Submission date |
Jul 30, 2012 |
Last update date |
Jun 06, 2013 |
Contact name |
Bernd Denecke |
E-mail(s) |
bernd.denecke@rwth-aachen.de
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Phone |
+49 241 8089918
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Organization name |
RWTH Aachen University
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Department |
IZKF Aachen
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Street address |
Pauwelsstrasse 30
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City |
Aachen |
State/province |
NRW |
ZIP/Postal code |
52074 |
Country |
Germany |
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Platforms (1) |
GPL10740 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [probe set (exon) version] |
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Samples (8)
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Relations |
BioProject |
PRJNA171577 |