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Background  C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified.    Methods  We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation in spontaneous liver tumors of C3H mice. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database.    Results  We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including  Mst1r ,  Slpi  and  Extl1 . The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of  Mst1r  in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of  Mst1r  and  Slpi  are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of  Mst1r  and  Slpi,  are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC.    Conclusions  Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for  Mst1r  and  Slpi , which may be applied not only to mouse HCC but also to human HCC.    Electronic supplementary material  The online version of this article (10.1186/s12885-018-4221-0) contains supplementary material, which is available to authorized users.

bmc cancer

The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes