Abstract
Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. However, the mechanisms underlying the development of NASH-related HCC is unclear. MUTYH is one of the enzymes that is involved in repair of oxidative DNA damage. The aim of this study was to investigate the association between MUTYH and NASH-related hepatocarcinogenesis. MUTYH wild-type (Mutyh+/+), heterozygous (Mutyh+/−), and MUTYH-null (Mutyh−/−) mice were fed a high-fat high-cholesterol (HFHC) diet or HFHC + high iron diet (20 mice per group) for 9 months. Five of 20 Mutyh−/− mice fed an HFHC + high iron diet developed liver tumors, and they developed more liver tumors than other groups (especially vs. Mutyh+/+ fed an HFHC diet, P = 0.0168). Immunohistochemical analysis revealed significantly higher accumulation of oxidative stress markers in mice fed an HFHC + high iron diet. The gene expression profiles in the non-tumorous hepatic tissues were compared between wild-type mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation.
Highlights
Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is associated with oxidative stress
Regarding role of iron storage in the liver, we have reported that excessive iron is produced in the livers of patients with chronic hepatitis C and hepatitis C virus (HCV)-related hepatocarcinogenesis is strongly associated with oxidative stress[6]
It has been shown that oxidative stress is involved in hepatocarcinogenesis in patients with NASH7,8, the effects of deficiency of enzymes that repair oxidative DNA damage induced by reactive oxygen species (ROS) have not yet been investigated
Summary
Non-alcoholic steatohepatitis (NASH)-related HCC is associated with oxidative stress. The gene expression profiles in the non-tumorous hepatic tissues were compared between wildtype mice that developed no liver tumors and MUTYH-null mice that developed liver tumors. Gene Set Enrichment Analysis identified the involvement of the Wnt/β-catenin signaling pathway and increased expression of c-Myc in MUTYH-null liver. These findings suggest that MUTYH deficiency is associated with hepatocarcinogenesis in patients with NASH with hepatic iron accumulation. Regarding role of iron storage in the liver, we have reported that excessive iron is produced in the livers of patients with chronic hepatitis C and HCV-related hepatocarcinogenesis is strongly associated with oxidative stress[6]. The mechanisms underlying the development of NASH-related HCC remain unclear
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