Two Differentially Methylated Region (DMR) Networks in Nonalcoholic Fatty Liver Disease, Viral Hepatitis, and Hepatocellular Carcinoma

Background We previously reported that two differentially methylated region (DMR) networks identified by DMR, and co-methylation analyses are strongly correlated with the fibrosis stages of nonalcoholic fatty liver disease (NAFLD). In the current study, we examined these DMR networks in viral hepatitis and hepatocellular carcinoma (HCC). Methods We performed co-methylation analysis of DMRs using a normal dataset (GSE48325), two NAFLD datasets (JGAS000059 and GSE31803), and two HCC datasets (GSE89852 and GSE56588). Results One DMR network was clearly observed in viral hepatitis and two HCC populations. Methylation levels of genes in this network were higher in viral hepatitis and lower in HCC. Fatty acid binding protein 1 (FABP1), serum/glucocorticoid regulated kinase 2 (SGK2), and hepatocyte nuclear factor 4 α (HNF4A) were potential hub genes in this network. Increased methylation levels of the FABP1 gene deteriorated the protection capacity of hepatocytes from oxidative metabolites in NAFLD and viral hepatitis. The decreased methylation levels of SGK2 facilitated the growth and proliferation of HCC cells. Decreased methylation levels of HNF4A in HCC cells were associated with tumorigenesis. The other DMR network was observed in NAFLD, but not in viral hepatitis or HCC. This second network-included genes involved in transcriptional regulation, cytoskeleton organization, and cellular proliferation, which are specifically related to fibrosis and/or tumorigenesis in NAFLD. Conclusions Our results suggest that one DMR network was associated with fibrosis and tumorigenesis in both NAFLD and viral hepatitis, while the other network was specifically associated with NAFLD progression. FABP1, SGK2, and HNF4A could be possible candidate targets for the prevention and treatment of HCC.

Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure

Background Viral hepatitis E clinically ranges from self-limiting hepatitis to lethal liver failure. Oxidative stress has been shown to mediate hepatic inflammation during HBV-induced liver failure. We investigated whether a biomarker of oxidative stress may be helpful in assessing severity and disease outcomes of patients with HEV-induced liver failure. Methods Clinical data were obtained from patients with HEV-induced acute viral hepatitis (AVH, n = 30), acute liver failure (ALF, n = 17), and acute-on-chronic liver failure (ACLF, n = 36), as well as from healthy controls (HC, n = 30). The SOD and HMGB1 levels were measured in serum by ELISA. HL-7702 cells were cultured and stimulated by serum from HEV-infected patients or by HMGB1; oxidative status was investigated by CellROX and apoptosis was investigated by flow cytometry. Results Patients with HEV-induced liver failure (including ALF and ACLF) showed increased SOD levels compared with HEV-AVH patients and healthy controls. SOD levels > 400 U/mL were associated with a significantly higher risk of mortality in HEV-ALF and HEV-ACLF patients. Serum from HEV-infected patients led to ROS accumulation, HMGB1 secretion, and apoptosis in HL-7702 cells. Antioxidant treatment successfully inhibited HEV-induced HMGB1 secretion, and HMGB1 promoted apoptosis in HL-7702 cells. Conclusion HEV increased oxidative stress in the pathogenesis of HEV-induced hepatic diseases. Early testing of serum SOD may serve as a predictor of both HEV-ALF and HEV-ACLF outcomes. Moreover, development of strategies for modulating oxidative stress might be a potential target for treating HEV-induced liver failure patients.

T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are deeply exhausted, and evidence of dysfunction has also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses [...]

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in “high-risk” patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient’s risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.