外周血单个核细胞中鼠双微体2甲基化水平降低与乙型肝炎病毒相关肝细胞癌中氧化应激增强相关。

Reduced murine double minute-2 methylation from peripheral blood mononuclear cells correlates with enhanced oxidative stress in hepatitis b virus-related hepatocellular carcinoma.

作者信息

Wang Jing-Wen, Zhu Han-Xu, Zhang Feng, Wang He, Fan Yu-Chen, Han Li-Yan, Wang Kai

机构信息

Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China.

Institute of Hepatology, Shandong University, Jinan, China.

出版信息

Front Microbiol. 2025 May 13;16:1590492. doi: 10.3389/fmicb.2025.1590492. eCollection 2025.

DOI:10.3389/fmicb.2025.1590492

PMID:40432974

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12106469/

Abstract

BACKGROUND

Hepatitis B virus-related hepatocarcinogenesis (HBV-related HCC) involves a variety of causes including oncogene hypomethylation, oxidative stress and HBV itself. Oxidative stress induces an alternation in the DNA methylation status. We aimed to study the relationship between oxidative stress and murine double minute-2 (MDM2) methylation status in HBV-related HCC patients and healthy controls (HCs).

METHODS

A total of 135 patients with HBV-related HCC and 26 healthy controls (HCs) were recruited. The MDM2 methylation status was detected by methylation-specific PCR. The expression of MDM2 mRNA was assessed using quantitative real-time PCR. The plasma malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), nuclear factor erythroid 2-related factor 2 (NRF2), heme Oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were measured by enzyme-linked immunosorbent assay (ELISA). Thirty-six patients with HBV-related HCC and 11 HCs were selected and the serum metabolism was analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS).

RESULTS

Compared with HCs, the MDM2 promoter methylation frequency was significantly decreased in HBV-related HCC. The MDA levels were increased, whereas the GSH, SOD, NRF2, HO-1, and GPX4 levels were decreased in the HBV-related HCC patients relative to HCs. There were 216 differential metabolites between HBV-related HCC and HCs in plasma, which belongs to amino acids, bile acids, fatty acids, phospholipids, and other compounds. The cysteine and methionine metabolism were the most significant metabolic pathways associated with differential metabolites between MDM2 methylated group and MDM2 unmethylated group in HBV-related HCC.

CONCLUSION

Our results suggested that oxidative stress may cause MDM2 hypomethylation, in which cysteine and methionine pathway might play an important role in.

摘要

背景

乙型肝炎病毒相关的肝癌发生（HBV相关HCC）涉及多种原因，包括癌基因低甲基化、氧化应激和HBV本身。氧化应激会导致DNA甲基化状态发生改变。我们旨在研究HBV相关HCC患者和健康对照（HCs）中氧化应激与鼠双微体2（MDM2）甲基化状态之间的关系。

方法

共招募了135例HBV相关HCC患者和26例健康对照（HCs）。通过甲基化特异性PCR检测MDM2甲基化状态。使用定量实时PCR评估MDM2 mRNA的表达。通过酶联免疫吸附测定（ELISA）测量血浆丙二醛（MDA）、超氧化物歧化酶（SOD）、谷胱甘肽（GSH）、核因子红细胞2相关因子2（NRF2）、血红素加氧酶-1（HO-1）和谷胱甘肽过氧化物酶4（GPX4）。选择36例HBV相关HCC患者和11例HCs，通过超高效液相色谱-质谱联用（UHPLC-MS）分析血清代谢情况。

结果

与HCs相比，HBV相关HCC中MDM2启动子甲基化频率显著降低。与HCs相比，HBV相关HCC患者的MDA水平升高，而GSH、SOD、NRF2、HO-1和GPX4水平降低。血浆中HBV相关HCC和HCs之间有216种差异代谢物，属于氨基酸、胆汁酸、脂肪酸、磷脂和其他化合物。半胱氨酸和蛋氨酸代谢是HBV相关HCC中MDM2甲基化组和MDM2未甲基化组之间与差异代谢物相关的最显著代谢途径。