General Surgery Department, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China.
The Eighth Medical Center, Chinese PLA General Hospital, Beijing 100091, China.
Anal Cell Pathol (Amst). 2023 Aug 30;2023:6681065. doi: 10.1155/2023/6681065. eCollection 2023.
The serum selenium level was determined in 45 patients with HBV-positive HCC (HBV-HCC group), 45 patients with chronic hepatitis B virus infection (CHB group), and 45 healthy cases (HC group). The sodium selenite (NaSeO)-treated HepG2.2.15 cells were used to observe the regulatory role of selenium on HBV replication. D-GalN/erastin-added HL7702 was used to determine the regulatory roles of NaSeO on hepatotoxicity or hepatocyte ferroptosis. The wild-type (WT) C57BL/6 mice and HBx-Tg mice were received lipopolysaccharide (LPS)/D-GalN, together with or without NaSeO administration for indicated period. Following euthanasia, the blood and liver tissue samples were collected, and specific markers were evaluated subsequently.
The serum selenium level was downregulated in patients with HBV-positive HCC (HBV-HCC group) (57.2 ± 22.5 g/L vs. 91.8 ± 43.9 g/L, < 0.001), and its higher level could provide a better prognosis in these patients. The treatment using NaSeO, a selenium donor, at high concentration (5 M), suppressed the HBV replication by about 50% in HepG2.2.15 cells ( < 0.001), through promoting apoptotic cell death and inhibiting cellular inhibitor of apoptosis proteins (cIAPs). In addition, low-dose (500 nM) NaSeO could almost totally reversed the hepatotoxicity induced by hepatitis B virus X protein (HBx) ( < 0.001), which were the main causes of HCC in patients. Studies at the cellular levels showed that low-dose NaSeO inhibited the HBx-related hepatotoxicity by blocking ferroptosis, and glutathione peroxidase 4 (GPX4) mediated this regulatory role. Mice model results confirmed that the treatment with NaSeO could mitigated LPS/D-GalN-induced hepatic injury through ferroptosis pathways.
Selenium regulated the dual cell death in different HCC stages via different signaling pathways, which could partly explain the anti-HBV and anti-HCC properties of selenium.
检测 45 例 HBV 阳性 HCC 患者（HBV-HCC 组）、45 例慢性乙型肝炎病毒感染患者（CHB 组）和 45 例健康对照者（HC 组）的血清硒水平。用亚硒酸钠（NaSeO）处理 HepG2.2.15 细胞，观察硒对 HBV 复制的调控作用。用 D-GalN/erastin 处理 HL7702 细胞，观察 NaSeO 对肝毒性或肝细胞铁死亡的调控作用。用野生型（WT）C57BL/6 小鼠和 HBx-Tg 小鼠给予脂多糖（LPS）/D-GalN，并分别给予或不给予 NaSeO 进行相应处理。处死动物后，采集血样和肝组织样本，随后评估特定标志物。
HBV 阳性 HCC 患者（HBV-HCC 组）的血清硒水平降低（57.2±22.5μg/L 比 91.8±43.9μg/L， < 0.001），其高水平可提供更好的预后。高浓度（5μM）亚硒酸钠（一种硒源）处理可使 HepG2.2.15 细胞中的 HBV 复制减少约 50%（ < 0.001），这是通过促进细胞凋亡和抑制细胞凋亡抑制蛋白（cIAPs）实现的。此外，低剂量（500 nM）NaSeO 几乎完全逆转了乙型肝炎病毒 X 蛋白（HBx）诱导的肝毒性（ < 0.001），这是患者发生 HCC 的主要原因。细胞水平研究表明，低剂量 NaSeO 通过阻断铁死亡抑制 HBx 相关的肝毒性，谷胱甘肽过氧化物酶 4（GPX4）介导了这种调节作用。小鼠模型结果证实，NaSeO 治疗可通过铁死亡途径减轻 LPS/D-GalN 诱导的肝损伤。
硒通过不同的信号通路调节不同 HCC 阶段的双重细胞死亡，这部分解释了硒的抗 HBV 和抗 HCC 特性。
