Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.
Association between Hepatic Oxidative Stress Related Factors and Activation of Wnt/β-Catenin Signaling in NAFLD-Induced Hepatocellular Carcinoma.
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Wnt/β-连环蛋白信号通路的激活可能会降低免疫检查点抑制剂的疗效，而免疫检查点抑制剂是治疗肝细胞癌 (HCC) 的一线治疗药物。钆塞酸增强 MRI 后，HCC 病变在肝胆期可能表现出与正常组织相同或更高的信号强度。因此，MRI 可用于监测抗肿瘤药物的治疗效果。在本研究中，我们研究了肝内铁超载标志物与氧化应激和 Wnt/β-catenin 信号通路激活之间的关系。我们发现，对于非酒精性脂肪性肝病诱发的 HCC，MRI 的敏感性为 57.2%，特异性为 100%。血清铁蛋白 > 77.5 ng/mL 的敏感性为 85.7%，特异性为 85.7%。我们得出的结论是，血清铁蛋白水平可以进一步提高预测 Wnt/β-连环蛋白信号激活的准确性。我们研究了 Gd-EOB-DTPA 增强 MRI 肝胆期中铁过载、氧化应激（8-oxo-7,8-二氢鸟嘌呤：8-oxo-dG 评分）、Wnt/β-catenin 通路激活（谷氨酰胺合成酶表达：GS）和肿瘤高信号之间的关联（相对增强比：RER）。这是对 94 例接受手术切除的肝细胞癌 (HCC) 患者的回顾性分析。在 HBV、HCV 和酒精相关的 HCC 中，高 RER 组和低 RER 组的血清铁蛋白水平相当。相比之下，非酒精性脂肪性肝病 (NAFLD)-HCC 患者的“高 RER”组铁蛋白水平升高。作为 GS 阳性的预测因子，高 RER 的敏感性为 57.2%，特异性为 100%。高血清铁蛋白的敏感性为 85.7%，特异性为 85.7%。所有血清铁蛋白≥275.5 ng/mL且RER高的病例均为8-oxo-dG-和铁染色阳性。此外，在“血清铁蛋白水平高于上限或铁染色阳性”和“8-oxo-dG 高”病例的所有病例中均出现 GS 阳性。因此，将血清铁蛋白水平与 RER 相结合可能会提高 NAFLD-HCC 中激活的 Wnt/β-连环蛋白信号传导预测的准确性。我们认为，由于肝组织铁沉积导致氧化应激增加，8-oxo-dG 会积累；这可能会激活 Wnt/β-catenin 信号传导并引发癌变。
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. 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.
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