Document Detail


TLR4 activity protects against hepatocellular tumorigenesis and progression via regulating the expression of DNA repair protein Ku70(1).
MedLine Citation:
PMID:  23299825     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hepatocellular carcinoma (HCC) is a devastating consequence of chronic inflammatory liver diseases. We recently find that inhibition of TLR4 promotes tumor metastases. We aimed to investigate whether 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 by 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 the increases in tumor nodules, tumor volume and animal death. The enhanced HCC 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 ASK1/p38 MAPK/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 mouse 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 insights into understanding of TLR4 activity in the regulation of HCC tumorigenesis which may be useful for the prevention of HCC development. (HEPATOLOGY 2013.).
Authors:
Ziyan Wang; Jun Yan; Heng Lin; Fang Hua; Xiaoxing Wang; Hanzhi Liu; Xiaoxi Lv; Jiaojiao Yu; Su Mi; Jiaping Wang; Zhuo-Wei Hu;
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-8
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
Affiliation:
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 1 Xian Nong Tan St. Beijing 100050, People's Republic of China.
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