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

• Published in: Cancers Vol. 14; no. 9; p. 2066
• Main Authors: Hamaguchi, Kota, Miyanishi, Koji, Osuga, Takahiro, Tanaka, Shingo, Ito, Ryo, Sakamoto, Hiroki, Kubo, Tomohiro, Ohnuma, Hiroyuki, Murase, Kazuyuki, Takada, Kohichi, Nagayama, Minoru, Kimura, Yasutoshi, Mizuguchi, Toru, Takemasa, Ichiro, Kato, Junji
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20.04.2022; MDPI
• Subjects: Antibodies; Antitumor activity; Antitumor agents; Carcinogenesis; Ethanol; Fatty liver; Ferritin; Gd-EOB-DTPA-enhanced MRI; Glutamate-ammonia ligase; Glutamine; Hepatocellular carcinoma; Immune checkpoint inhibitors; Iron; iron overload; Liver cancer; Liver diseases; Magnetic resonance imaging; Mutation; nonalcoholic fatty liver disease; Oxidative stress; Patients; serum ferritin; Signal transduction; Tumors; Wnt protein; Wnt/β-catenin signaling pathway; β-Catenin; Japan; Germany; iron overload; immune checkpoint inhibitor; nonalcoholic fatty liver disease; serum ferritin; Wnt/β-catenin signaling pathway; Gd-EOB-DTPA-enhanced MRI; hepatocellular carcinoma
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14092066

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.