Abstract
AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1β, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.
Highlights
Many human cancers such as those affecting the liver are etiologically related to processes of inflammation and/or chronic infection
We show that AIRmax male mice are highly susceptible and AIRmin mice are resistant to urethane-induced development of hepatocellular carcinoma whereas females from both strains are resistant
This phenotype was confirmed by the treatment of mice with the tobacco-related nitrosamine N-nitrosodiethylamine (NDEA or DEN), a typical genotoxic chemical carcinogen that forms DNA adducts after bioactivation by P450 isozymes, including cytochrome P450 2E1 in the liver [18, 19]
Summary
Many human cancers such as those affecting the liver are etiologically related to processes of inflammation and/or chronic infection. Human hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality and the seventh in terms of cancer incidence worldwide [1]. The incidence of HCC varies widely according to racial and ethnic groups and to geographic location, as a result of the influence of genetic factors and of regional variations in exposure to risk factors [2]. Among the most important risk factors of liver cancer are hepatitis B, chronic hepatitis. Environmental toxins and dietary factors, diabetes mellitus, nonalcoholic fatty liver disease, alpha-1 antitrypsin deficiency, and autoimmune hepatitis are all associated with increased risk for HCC [3]. The incidence of HCC is approximately three times higher in men than in women, and most of the experimental models confirm this sex difference [4]
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