title: Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in Toll-like receptor 2-deficient mice.
abstract: Hepatocellular carcinoma (HCC) is a complication at the endstage of chronic inflammatory liver diseases with dismal prognosis. Targeting of Toll-like receptor (TLR) 2 attenuates tumor metastases; we hypothesized that blocking TLR2 might also play a crucial role in reducing hepatocarcinogenesis. Surprisingly, we found that the genetic deletion of TLR2 increased susceptibility to diethylnitrosamine (DEN), a genotoxic carcinogen that can induce HCC. Indeed, TLR2-deficient mice showed a significant increase in carcinogenesis and progression of HCC as indicated by increases in tumor nodule size, tumor volume, and animal death. The enhanced susceptibility to DEN-induced HCC was associated with a broad-spectrum reduction in the immune response to DEN-induced liver injury. We found that TLR2 deficiency caused a decrease in the infiltration of macrophages and an attenuation of apoptosis signal regulating kinase 1 (ASK1) / p38 mitogen-activated protein kinase (p38 MAPK) / nuclear factor kappa B (NF-κB) signaling, which led to a decrease in the expression of interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1α/β, IL-6, and Cxcl-2 as well as suppression of autophagy flux and increases in oxidative stress and p62 aggregation in liver tissue. The defects in immune networks resulted in suppressed p21- and p16/pRb-dependent senescence, which caused an increase in proliferation and a decrease in apoptotic and autophagy-associated cell death in mouse livers. Restoring cellular senescence and autophagy flux by treating TLR2-deficient mice with IFN-γ, a T helper 1 (Th1) cytokine and positive modulator of senescence and autophagy, could attenuate the carcinogenesis and progression of HCC associated with TLR2-deficient animals.
  
  
  CONCLUSIONS
  The loss of immune networks supporting cellular senescence and autophagy flux is attributed to enhanced susceptibility to DEN-induced hepatocellular carcinogenesis and progression in TLR2-deficient mice. These findings may be used to prevent the development of liver cancer.
authors.affiliation: 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, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Hongzhen
authors.initials: H
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Lv
authors.forename: Jianfei
authors.initials: J
authors.lastname: Xue
authors.forename: Zhuo-Wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D004052:Diethylnitrosamine; D018450:Disease Progression; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C490981:Gtf2h1 protein, mouse; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D004052:Diethylnitrosamine; D007371:Interferon-gamma; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse