title: Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice.
abstract: Hepatocellular carcinoma (HCC) is a devastating consequence of chronic inflammatory liver diseases. The goal of this study was to investigate whether Toll-like receptor 4 (TLR4) activity contributes to HCC initiation and progression in mice. A mouse model of diethylnitrosamine (DEN)-induced HCC was generated with wild-type and TLR4 mutant mice, and the development and progression of HCC and senescent responses were assessed using morphologic, immunological, and biochemical criteria. We found that genetic or pharmacologic blocking of TLR4 increased susceptibility to DEN-induced HCC carcinogenesis and progression, which was indicated by increases in number of tumor nodules, tumor volume, and animal death. The enhanced HCC was associated with a broad-spectrum reduction of immune response to DEN liver injury, as indicated by decreases in the liver-infiltrating F4/80+ macrophages, the apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase/NF-κB and IRF3 signaling activities, and the expression of inflammatory cytokines. Suppressed immune networks resulted in a halt of cellular senescence induction in TLR4 mutant liver tissue, which promoted proliferation and suppressed programmed cell death. Moreover, TLR4 mutation resulted in a suppressed capacity of DNA repair due to a decrease in TLR4-medicated expression of DNA repair proteins Ku70/80 in liver tissue and cells. Isotopic expression of Ku70 in TLR4 mutant mice restored senescence and interrupted the positive feedback loop of DNA damage and oxidative stress, which reversed TLR4 mutation-deteriorated HCC carcinogenesis and progression.
  
  
  CONCLUSIONS
  TLR4 plays an integrated defense role against HCC carcinogenesis by enhancing the expression and function of DNA repair protein Ku70. Our studies provide novel insight into TLR4 activity in the regulation of HCC tumorigenesis, which may be useful for the prevention of HCC development.
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China.
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Wang
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Lv
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Yu
authors.forename: Su
authors.initials: S
authors.lastname: Mi
authors.forename: Jiaping
authors.initials: J
authors.lastname: Wang
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D000072200:Ku Autoantigen; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004052:Diethylnitrosamine; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen