| Popis: |
Caspase-8 (Casp8) is the apical protease essential for the initiation of extrinsic apoptosis via activation of a caspase cascade. A role of Casp8 for preventing Hepatocellular Carcinoma (HCC) has been postulated. However, several studies revealed tumor suppressive, but also tumor promoting properties of Casp8 depending on the tissue environment. Therefore, the aim of this study was to investigate if Casp8 acts as tumor suppressor in the chemical model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis using conditional, hepatocyte-specific Casp8 knockout (Casp8Deltahepa) mice. Using a model of DEN-induced acute liver injury, it was demonstrated that loss of Casp8 did not substantially affect the immediate reaction towards genotoxic acute liver damage. However, the start of compensatory proliferation was slightly accelerated in Casp8Deltahepa mice hinting at a shortened phase of DNA-repair in these animals. Interestingly, loss of Casp8 was not associated with reduced liver apoptosis after acute DEN treatment demonstrating that liver damage in the DEN model is Casp8-independent. In further studies, a low-dose DEN model was applied to induce HCC in Casp8Deltahepa mice and wild type controls (Casp8f/f). 24 weeks after HCC induction, the frequency and size of dysplastic liver lesions were similar in Casp8f/f and Casp8Deltahepa mice demonstrating that Casp8 does not prevent tumor initiation in the DEN model. However, 40 weeks after DEN treatment HCC progression was substantially enhanced in Casp8Deltahepa mice as measured by increase tumor number and size. Detailed analysis revealed that Casp8Deltahepa mice showed increased hepatic inflammation and accelerated NF-KappaB-activation after DEN treatment. Moreover, loss of Casp8 in advanced HCC resulted in decreased levels of the cell cycle inhibitors p21 and p27. Finally, an induction of the putative tumor stem cell marker CD133+ was demonstrated in Casp8Deltahepa mice which was significantly correlated with an up-regulation of the poorly characterized factor DMBT1 (Deleted in Malignant Brain Tumor 1). In summary, the present study highlights novel, non-apoptotic properties of Casp8 for the suppression of liver tumors potentially by regulating cell cycle inhibition, hepatic stem cell- and NF-KappaB-activation. Accordingly, therapeutical inhibition of Casp8 in hepatitis patients – which is currently tested in clinical trials – should be handled carefully as it could increase the risk of hepatocarcinogenesis. |
