title: Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation.
abstract: Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(Δhep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(Δhep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(Δhep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(Δhep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(Δhep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(Δhep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wree
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Johnson
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California-San Diego, La Jolla, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Font-Burgada
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Povero
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California-San Diego, La Jolla, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Pediatrics, University of California-San Diego, La Jolla, CA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D015850:Interleukin-6; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D004052:Diethylnitrosamine; D006861:Hydrogen Peroxide; D002251:Carbon Tetrachloride