| First Author | Cubero FJ | Year | 2019 |
| Journal | Cell Death Dis | Volume | 10 |
| Issue | 2 | Pages | 115 |
| PubMed ID | 30737368 | Mgi Jnum | J:294543 |
| Mgi Id | MGI:6453639 | Doi | 10.1038/s41419-019-1391-x |
| Citation | Cubero FJ, et al. (2019) Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease. Cell Death Dis 10(2):115 |
| abstractText | 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(Deltahepa)) mice. We generated NEMO(Deltahepa) /Fas(lpr) mice, while NEMO(Deltahepa), 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(Deltahepa) mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMO(Deltahepa) mice. Moreover, NEMO(Deltahepa)/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(Deltahepa)/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(Deltahepa)/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. |
