Open AccessDisruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease
Author(s) -
Francisco Javier Cubero,
Marius Maximilian Woitok,
Miguel Eugenio Zoubek,
Alain de Bruin,
Maximilian Hatting,
Christian Trautwein
Publication year - 2019
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/s41419-019-1391-x
Subject(s) - fas ligand , carcinogenesis , hepatocyte , inflammation , apoptosis , medicine , fas receptor , immunology , liver injury , cancer research , liver disease , tumor necrosis factor alpha , pathology , biology , cancer , programmed cell death , biochemistry , in vitro
Fas Ligand (FasL) and Fas (APO-1/CD95) are members of the TNFR superfamily and may trigger apoptosis. Here, we aimed to elucidate the functional role of Fas signaling in an experimental model of chronic liver disease, the hepatocyte-specific NEMO knockout (NEMO Δhepa ) mice. We generated NEMO Δhepa /Fas lpr mice, while NEMO Δhepa , NEMO f/f as well as Fas lpr animals were used as controls, and characterized their phenotype during liver disease progression. Liver damage was evaluated by serum transaminases, histological, immunofluorescence procedures, and biochemical and molecular biology techniques. Proteins were detected by western Blot, expression of mRNA by RT-PCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Fas lpr mutation in NEMO Δhepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMO Δhepa mice. Moreover, NEMO Δhepa /Fas lpr animals elicited significantly decreased parameters of liver fibrosis, such as Collagen IA1, MMP2, and TIMP1, and reduced proinflammatory macrophages and cytokine expression. At 52 weeks of age, NEMO Δhepa /Fas lpr exhibited less malignant growth as evidenced by reduced HCC burden associated with a significantly decreased number of nodules and LW/BW ratio and decreased myeloid populations. Deletion of TNFR1 further reduced tumor load of 52-weeks-old NEMO Δhepa /Fas lpr mice. The functionality of FasL/Fas might affect inflammation-driven tumorigenesis in an experimental model of chronic liver disease. These results help to develop alternative therapeutic approaches and extend the limitations of tumor therapy against HCC.