ArticleCell death and differentiation2014
Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.
Article in Cell death and differentiation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- FADD Activation in Hepatocellular Carcinoma Potentiates CD8+ T-cell Responses and Sensitizes to Immune Checkpoint Inhibitors.Cancer research · 2025Article
- IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.Nature communications · 2024Article
- Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.Virchows Archiv : an international journal of pathology · 2023Article
- Apoptotic cell death in disease-Current understanding of the NCCD 2023.Cell death and differentiation · 2023Review
- Regulation of apoptosis by ubiquitination in liver cancer.American journal of cancer research · 2023Review
- FADD as a key molecular player in cancer progression.Molecular medicine (Cambridge, Mass.) · 2022Review
- p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation.Cancers · 2022Article
- Review
- LUBAC Suppresses IL-21-Induced Apoptosis in CD40-Activated Murine B Cells and Promotes Germinal Center B Cell Survival and the T-Dependent Antibody Response.Frontiers in immunology · 2021Article
- Renal proximal tubular NEMO plays a critical role in ischemic acute kidney injury.JCI insight · 2020Article
- RIPK1 and death receptor signaling drive biliary damage and early liver tumorigenesis in mice with chronic hepatobiliary injury.Cell death and differentiation · 2019Article
- Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer-from Tumor Development to Therapeutic Implications.Cancers · 2019Review
- Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease.Cell death & disease · 2019Article
- Review
- Exploitation of Apoptotic Regulation in Cancer.Frontiers in immunology · 2018Review
- Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis.The Journal of clinical investigation · 2017Article
- The Linear ubiquitin chain assembly complex acts as a liver tumor suppressor and inhibits hepatocyte apoptosis and hepatitis.Hepatology (Baltimore, Md.) · 2017Article
- NF-κB Members Left Home: NF-κB-Independent Roles in Cancer.Biomedicines · 2017Review
- The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2.Molecular cell · 2017Article
- RIPK1 protects from TNF-α-mediated liver damage during hepatitis.Cell death & disease · 2016Article
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 3 countries.
Funding
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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