[HTML][HTML] Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

H Ehlken, S Krishna-Subramanian… - Cell Death & …, 2014 - nature.com
H Ehlken, S Krishna-Subramanian, L Ochoa-Callejero, V Kondylis, NE Nadi, BK Straub…
Cell Death & Differentiation, 2014nature.com
Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis
triggered by viruses or toxic substances causing hepatocyte death, inflammation and
compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate
cell death and inflammation and are implicated in liver disease and cancer. Liver
parenchymal cell-specific ablation of NEMO/IKKγ, a subunit of the IκB kinase (IKK) complex
that is essential for the activation of canonical NF-κB signalling, sensitized hepatocytes to …
Abstract
Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKγ, a subunit of the IκB kinase (IKK) complex that is essential for the activation of canonical NF-κB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMO-deficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.
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