Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response

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.

Pycard and BC017158 Candidate Genes of Irm1 Locus Modulate Inflammasome Activation for IL-1β Production

“…AIRmax mice are resistant and AIRmin are susceptible to the development of lung tumors induced by the carcinogen urethane ( 18 ). On the other hand, AIRmax are susceptible and AIRmin are resistant to developing liver tumors ( 19 ). We then analyzed the possible role of Pycard genotypes in the behavior of the AIRmin sublines carrying WT or mutated gene alleles.…”

“…Besides their central role in inflammasomes for cytokine release, ASC specks can be released to the extracellular space, accumulate in inflamed tissues and can be internalized by surrounding inflammatory cells inducing inflammation chronicity or amplification, therefore worsening the disease or contributing to cure (26,27). The AIRmax and AIRmin mouse lines differ in natural resistance to infections, to the induction of autoimmune diseases and chemical carcinogenesis as well as in tissue repair capacity (18,19,(28)(29)(30)(31)(32)(33)(34). These phenotypes might be influenced by the differential Irm1 locus-dependent inflammasome activation between the two lines described here.…”

“…These are preliminary results and further in-depth studies of the actual interference of the mutation in the formation of specks are required. Our hypothesis was based in studies of other groups that clearly demonstrated the importance of residues in interface 1 of the PYD protein domain for filament formation ( 17 – 19 ). A deficient formation of ASC specks in AIRmin could explain a lower activation of Caspase-1, and a decreased release of IL-1β by stimulated cells.…”

“…These phenotypes might be influenced by the differential Irm1 locus-dependent inflammasome activation between the two lines described here. In fact, AIRmin mice bearing the AIRmax Pycard allele (AIRmin Pycard C/C ) were more resistant to the development of lung adenocarcinomas and more susceptible to developing hepatocarcinomas than AIRmin Pycard T/T , following the behavior of AIRmax mice ( 11 , 19 ).…”

Genetic Predisposition to Hepatocellular Carcinoma

“…Similar model could be applied to human hepatocarcinogenesis, accordingly to population research. Comparative functional genetics studies identified the best-fit of mouse [ 74 ] and rat [ 75 , 76 , 77 ] models of hepatocarcinogenesis. The supervised hierarchical analysis of the 6,132 genes, common to rat and human liver, showed that DNs and HCCs of BN rats, and F344 DNs cluster with human HCCB, and F344 DNs and HCCs cluster with HCCP ( Figure 9 ).…”