Document Detail

The role of innate immunity in the pathogenesis of preneoplasia in drug-induced chronic hepatitis based on a mouse model.
MedLine Citation:
PMID:  21820428     Owner:  NLM     Status:  MEDLINE    
Innate immunity factors such as conversion of the 26S proteasome to form the immunoproteasome and the Toll-like receptor signaling pathways are activated in chronic hepatitis induced by the carcinogenic drug DDC. Over time, preneoplastic hepatocyte phenotypes appear in the liver parenchyma. These changed hepatocytes expand in number because they have a growth advantage over normal hepatocytes when responding to chronic liver injury. The changed hepatocytes can be identified using immunofluorescent antibodies to preneoplastic cells e.g. FAT10/UbD, A2 macroglobulin, glutathione transpeptidase, alpha fetoprotein, glycipan 3, FAS, and gamma glutamyl transpeptidase. The formation of the preneoplastic cells occurs concomitant with activation of the Toll-like receptor signaling pathways and the transformation of the 26S proteasome to form the immunoproteasome. This transformation is in response to interferon stimulating response element on the promoter of the FAT10/UbD gene. NFκB, Erk, p38 and Jnk are also up regulated. Specific inhibitors block these responses in vitro in a mouse tumor cell line exposed to interferon gamma. Mallory-Denk bodies form in these preneoplastic cells, because of the depletion of the 26S proteasome due to formation of the immunoproteasome. Thus, MDB forming cells are also markers of the preneoplastic hepatocytes. The UbD positive preneoplastic cells regress when the liver injury induced chronic hepatitis subsides. When the drug DDC is refed to mice and chronic hepatitis is activated, the preneoplastic cell population expands and Mallory-Denk bodies rapidly reform. This response is remembered by the preneoplastic cells for at least four months indicating that an epigenetic cellular memory has formed in the preneoplastic cells. This proliferative response is prevented by feeding methyl donors such as S-adenosylmethionine or betaine. Drug feeding reduces the methylation of H(3) K4, 9, and 27 and this response is prevented by feeding the methyl donors. After 8 to 15months of drug withdrawal in mice the preneoplastic liver cells persist as single or small clusters of cells in the liver lobules. Multiple liver tumors form, some of which are hepatocellular carcinomas. The tumors immunostain positively for the same preneoplastic markers as the preneoplastic cells. Similar cells are identified in human cirrhosis and hepatocellular carcinoma indicating the relevance of the drug model described here to the preneoplastic changes associated with human chronic hepatitis and hepatocellular carcinoma.
S W French; F Bardag-Gorce; B A French; J Li; J Oliva
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2011-07-28
Journal Detail:
Title:  Experimental and molecular pathology     Volume:  91     ISSN:  1096-0945     ISO Abbreviation:  Exp. Mol. Pathol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-18     Completed Date:  2012-01-23     Revised Date:  2014-09-09    
Medline Journal Info:
Nlm Unique ID:  0370711     Medline TA:  Exp Mol Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  653-9     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Carcinoma, Hepatocellular / etiology,  immunology
Cell Transformation, Neoplastic
Disease Models, Animal
Drug-Induced Liver Injury, Chronic / complications,  immunology*,  pathology*
Hepatocytes / pathology
Immunity, Innate*
Liver Neoplasms / etiology,  immunology
Mice, Inbred C3H
Precancerous Conditions / immunology*
Grant Support

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