| Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents. | |
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MedLine Citation:
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PMID: 20803560 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation. CONCLUSION: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC. |
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Authors:
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Le-Xing Yu; He-Xin Yan; Qiong Liu; Wen Yang; Hong-Ping Wu; Wei Dong; Liang Tang; Yan Lin; Ya-Qin He; Shan-Shan Zou; Chao Wang; Hui-Lu Zhang; Guang-Wen Cao; Meng-Chao Wu; Hong-Yang Wang |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 52 ISSN: 1527-3350 ISO Abbreviation: Hepatology Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-29 Completed Date: 2010-10-18 Revised Date: 2011-09-09 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 1322-33 Citation Subset: IM |
Affiliation:
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International Cooperation Laboratory on Signal Transduction, Liver Centre of SMMU, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Carcinogens / pharmacology* Carcinoma, Hepatocellular / etiology*, pathology Cell Proliferation / drug effects Diethylnitrosamine / toxicity Intestines / microbiology Lipopolysaccharides / blood, pharmacology* Liver Cirrhosis / complications Liver Neoplasms / etiology* Male Mice NF-kappa B / antagonists & inhibitors Neomycin / pharmacology Polymyxin B / pharmacology Rats Reactive Oxygen Species / pharmacology Toll-Like Receptor 4 / physiology* |
| Chemical | |
Reg. No./Substance:
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0/Carcinogens; 0/Lipopolysaccharides; 0/NF-kappa B; 0/Reactive Oxygen Species; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 4; 1404-04-2/Neomycin; 1404-26-8/Polymyxin B; 55-18-5/Diethylnitrosamine |
| Comments/Corrections | |
Comment In:
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Hepatology. 2011 Aug;54(2):745; author reply 745-6
[PMID:
21563198
]
Hepatology. 2011 Mar;53(3):1069 [PMID: 20967824 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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