title: Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.
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.
authors: 1] Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany [2] University Medical Center Hamburg-Eppendorf, Hamburg D-20246, Germany.
authors: H
authors: H
authors: Ehlken
authors: Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany.
authors: S
authors: S
authors: Krishna-Subramanian
authors: 1] Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany [2] Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logroño, Spain.
authors: L
authors: L
authors: Ochoa-Callejero
authors: Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany.
authors: V
authors: V
authors: Kondylis
authors: Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany.
authors: N E
authors: NE
authors: Nadi
authors: Institute of Pathology, University Hospital Heidelberg, INF 224, 69120 Heidelberg, Germany.
authors: B K
authors: BK
authors: Straub
authors: Institute of Pathology, University Hospital Heidelberg, INF 224, 69120 Heidelberg, Germany.
authors: P
authors: P
authors: Schirmacher
authors: Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London, 72 Huntley Street, WC1E 6BT London, UK.
authors: H
authors: H
authors: Walczak
authors: B.S.R.C. Alexander Fleming, 34 Fleming Street, Vari 16672, Greece.
authors: G
authors: G
authors: Kollias
authors: Institute for Genetics, Center for Molecular Medicine (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Strasse 26, Cologne D-50931, Germany.
authors: M
authors: M
authors: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D006505:Hepatitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D053218:Receptors, Death Domain; D047888:Receptors, Tumor Necrosis Factor, Type I; D051550:I-kappa B Kinase