Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma

SIMPLE SUMMARY: Activation of the Wnt/β-catenin signaling pathway may reduce the efficacy of immune checkpoint inhibitors, which are first-line therapeutic agents for the treatment of hepatocellular carcinoma (HCC). Following gadoxetate-enhanced MRI, HCC lesions may exhibit equal or higher signal intensities in the hepatobiliary phase than normal tissue. Thus, MRI could be used to monitor the therapeutic effect of antitumor agents. In this study, we investigated the relationship between intrahepatic iron overload markers and oxidative stress and activation of the Wnt/β-catenin signaling pathway. We found that for nonalcoholic fatty liver disease-induced HCC, MRI yielded a sensitivity of 57.2% and a specificity of 100%. Serum ferritin > 77.5 ng/mL had a sensitivity of 85.7% and a specificity of 85.7%. We conclude that serum ferritin levels may further improve the accuracy with which activation of Wnt/β-catenin signaling can be predicted. ABSTRACT: We investigated the association between iron overload, oxidative stress (8-oxo-7,8-dihydroguanine: 8-oxo-dG scores), Wnt/β-catenin pathway activation (expression of glutamine synthetase: GS), and tumor hyperintensity in the Gd-EOB-DTPA-enhanced MRI hepatobiliary phase (relative enhancement ratio: RER). This was a retrospective analysis of 94 hepatocellular carcinoma (HCC) patients who underwent surgical resection. In HBV-, HCV-, and alcohol-associated HCC, serum ferritin levels in the high and low RER groups were equivalent. In contrast, ferritin levels were elevated in the ‘high RER’ group of patients with nonalcoholic fatty liver disease (NAFLD)-HCC. As predictors of GS positivity, high RER had a sensitivity of 57.2% and a specificity of 100%. High serum ferritin had a sensitivity of 85.7% and a specificity of 85.7%. All cases with serum ferritin ≥275.5 ng/mL and high RER were 8-oxo-dG- and iron staining-positive. Additionally, GS positivity was seen in all cases with “serum ferritin levels above the upper limits or iron staining-positive” and ‘8-oxo-dG high’ cases. Therefore, combining serum ferritin levels with RER may increase the accuracy with which activated Wnt/β-catenin signaling is predicted in NAFLD-HCC. We suggest that 8-oxo-dG accumulates following increased oxidative stress due to hepatic tissue iron deposition; this may activate Wnt/β-catenin signaling and trigger carcinogenesis.