Molecular analysis of the role of Caspase-8 during liver regeneration and tumorigenesis

Binding of the cytokine TNF-alpha to TNF-Receptor 1 mediates pleiotropic effects via two different signaling complexes. Complex-I triggers activation of NF-kappaB and activation of c-Jun N-terminal kinases (JNK) leading to inflammation and/ or cell proliferation, whereas complex-II induces apoptosis through Caspase-8. TNF signaling is crucial for the priming phase of liver regeneration following partial hepatectomy (PH) which directly contributes to gene activation of Cyclin D via NF-kappaB, c-Jun/ AP-1 and E2F1. The aim of the present study was to investigate the consequences of Caspase-8 deletion for TNF signaling during liver regeneration and termination as well as the role of Caspase-8 for initiation and development of hepatocellular carcinoma. Consequently, animals expressing Caspase-8 (f/f) on a regular level or mice deleted (delta) in Caspase-8 were generated to define the role of Caspase-8 during TNF-mediated signaling and subjected to 2/3 PH. Cessation of liver regeneration was observed in the same manner in both genotypes at equal time points clearly indicating that the function of Caspase-8 is dispensable for the process of termination. Surprisingly, animals with deleted Caspase-8 were more prone to TNF-mediated NF-kappaB and c-Jun/ AP-1 activation due to advantageous formation of complex-I subsequently leading to earlier onset of cell cycle progression. For the characterization of Casp8deltahep mice in genetic models of hepatocarcinogenesis, a standardized protocol for the application of magnetic resonance imaging (MRI) on genetically modified mice was established. Using this technique and conventional methods it was demonstrated that concomitant Caspase-8 ablation and c-myc over-expression in murine livers (Casp8deltahepalb-myctg) caused delayed tumor development but accelerated progression of HCC when compared to alb-myctg mice. These findings provide strong evidence for a protective function of Caspase-8 in hepatocellular carcinogenesis. In summary, it was demonstrated that Caspase-8 mediates not only pro-apoptotic, but also non-apoptotic functions as it contributes to the proper assembly of TNF- complex-I formation. Thus, ablation of Caspase-8 results in aberrant complex-I formation and subsequently accelerated NF-kappaB and JNK activation eventually leading to earlier Cyclin D expression and induction of cell cycle activity.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2009

Author dc:creator

• Freimuth, Julia

Contributors dc:contributor

• Liedtke, Christian

• info:eu-repo/classification/ddc/610
• Apoptosis
• Leberresektion
• Regeneration
• NMR-Tomographie
• Medizin
• Magnetresonanztomographie
• MRT
• Hepatozelluläres Karzinom
• magnetic resonance imaging
• MRI
• Hepatocellular carcinoma

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-113712%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51420