TY - JOUR
T1 - Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease
AU - Javier Cubero, Francisco
AU - Woitok, Marius Maximilian
AU - Zoubek, Miguel E.
AU - de Bruin, Alain
AU - Hatting, Maximilian
AU - Trautwein, Christian
N1 - Funding Information:
This work was supported by the IZKF, the START-Program of the Faculty of Medicine #691405, RWTH Aachen), the DFG TR285-10/1, the German Krebshilfe Grant Nr. 361209 and the MINECO Retos SAF2016-78711, EXOHEP-CM S2017/ BMD-3727, AMMF 2018/117 and ERAB EA 18/14 and COST Action CA17112. F.J. C. is a Ramón y Cajal Researcher (RYC-2014-15242) and a Gilead Liver Research Scholar 2018. We are grateful to the Department of Human and Veterinary Anatomy and Embryology at the Complutense University School of Medicine for their continuous support.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/2/8
Y1 - 2019/2/8
N2 - 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 Delta hepa) mice. We generated NEMO Delta hepa/Fas(lpr) mice, while NEMO.hepa, NEMOf/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 RTPCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Fas(lpr) mutation in NEMO Delta hepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMO Delta hepa mice. Moreover, NEMO Delta hepa/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 Delta hepa/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 Delta hepa/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.
AB - 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 Delta hepa) mice. We generated NEMO Delta hepa/Fas(lpr) mice, while NEMO.hepa, NEMOf/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 RTPCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Fas(lpr) mutation in NEMO Delta hepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMO Delta hepa mice. Moreover, NEMO Delta hepa/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 Delta hepa/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 Delta hepa/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.
KW - HEPATOCELLULAR-CARCINOMA
KW - DEATH RECEPTORS
KW - FAS RECEPTOR
KW - MICE
KW - APOPTOSIS
KW - EXPRESSION
KW - CELLS
KW - HEPATITIS
KW - MECHANISM
KW - NECROSIS
U2 - 10.1038/s41419-019-1391-x
DO - 10.1038/s41419-019-1391-x
M3 - Article
SN - 2041-4889
VL - 10
SP - 1
EP - 12
JO - Cell Death & Disease
JF - Cell Death & Disease
IS - 2
M1 - 115
ER -