MAPK regulates the immune responses in liver cirrhosis and hepatocellular carcinoma

Abstract Liver diseases causes approximately 2 million death per year worldwide. Aberrant apoptosis is associated with the progression of liver fibrosis and cirrhosis, even for hepatocellular carcinoma (HCC). HCC is one of major causes of cancer death worldwide due to high heterogeneity and recurrence. Immune scores could be used to link HCC disease-free survival and to identify several microenvironment-related genes. MAPK signaling plays an important role in liver fibrogenesis and HCC. ERK activation is associated with aggressive HCC, resulting in short overall survival. In this study, the immune responses of liver fibrosis and HCC mediated by ERK signaling were investigated. Both WT and Erk2 deficient mice were fed with choline-deficient diet to induce liver cirrhosis. Erk2 deficient livers have less degree of liver cirrhosis than WT livers. Our preliminary data suggested there was a significant increasement in the percentages of regulatory T cells in Erk2 deficient splenocytes. The percentages of follicular T cells were similar in WT and Erk2 deficient splenocytes. However, there was no significant differences in Erk2 deficient hepatic CD4 T cells for regulatory T cells and follicular T cells. In addition, Egr1 is one of ERK signaling downstream transcription factors. In HCC, there were about 10-fold differences in gene expression in the Egr1high and Egr1low group and the differential gene expression was identified. In hepatotoxicity, there was about more than 100 genes involved in HCC, 50~70 genes in liver cirrhosis, liver inflammation and liver necrosis/cell death. Therefore, MAPK signaling plays an important role in regulating the immune responses in the liver cirrhosis and HCC progression.