296 Role of Sphingosine Kinase-2 in Acetaminophen-Induced Liver Injury

Abstract

suppressor gene (TSG) promoters and 3 MINT loci using quantitative assays. Fractional allelic loss (FAL), which is representative for CIN, was calculated using 400 microsatellite markers in a subset of 110 tumors. The association between hypomethylation of repetitive DNA elements and FAL was compared with that between hypermethylation of TSGs and FAL. Prominent hypomethylation at repetitive DNA elements was detected in well-differentiated tumors with progressive decrease in methylation levels with the de-differentiation of tumors. Hierarchical clustering analysis using methylation levels of repetitive DNA sequences as well as TSGs/MINT loci was performed to classify HCCs carrying progressive global hypomethylation or extensive regional hypermethylation. HCCs with progressive hypomethylation showed significantly higher FAL scores than HCCs with mild hypomethylataion in both the well-differentiated HCCs as well as moderately or poorly-differentiated tumors (p = 0.0015 for well-differentiated tumors and p = 0.0270 in poorly-differentiated tumors). Multivariate analysis, using several clinicopathological factors as covariables, revealed that the category of progressive hypomethylation and non-cirrhotic background livers were independent factors that associated with high FAL score (p = 0.0265 for progressed hypomethylation and p = 0.0021 for non-cirrhotic liver). On the other hand, no relationship was observed between extensive hypermethylation on TSGs/MINT loci and FAL. The significant association between progressive hypomethylation on repetitive DNA sequences and CIN suggests that global hypomethylation might trigger development of CIN during HCC formation, particularly for the cancers that occur in the background of non-cirrhotic liver disease.