Li Yue-Cui, Hu Wei-Yue, Li Cheng-Hang, Zhang Li-Li, Xu Xiang-Wei, Li Jin, Luo Hong-Xia
Department of Infectious Diseases, The First People's Hospital of Yongkang, Jinhua 321300, Zhejiang Province, China.
World J Gastrointest Surg. 2023 Mar 27;15(3):346-361. doi: 10.4240/wjgs.v15.i3.346.
The relationship between hepatitis B surface antigen (HBsAg)-positive carrier status and liver cancer has been extensively studied. However, the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown. The epigenetic modification of DNA hydroxymethylation is critical in tumor development. Further, 5-hydroxymethylcytosine (5hmC) is an important base for DNA demethylation and epigenetic regulation. It is also involved in the assembly of chromosomes and the regulation of gene expression. However, the mechanism of action of 5hmC in HBsAg-positive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated.
To investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma (HCC) progression from cirrhosis.
Forty HBsAg-positive carriers, forty patients with liver cirrhosis, and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants. Free DNA was extracted using a cf-DNA kit. cfDNA was extracted by 5hmC DNA sequencing for principal component analysis, the expression profiles of the three groups of samples were detected, and the differentially expressed genes (DEGs) modified by hydroxymethylation were screened. Bioinformatic analysis was used to enrich DEGs, such as in biological pathways.
A total of 16455 hydroxymethylated genes were identified. Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients, of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers. Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes, of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis. These genes may have potential loci that are undiscovered or unelucidated, which contribute to the development and progression of liver cancer. Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion. The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2.
The occurrence and development of liver cancer involves multiple genes and pathways, which may be potential targets for preventing hepatitis B carriers from developing liver cancer.
乙肝表面抗原（HBsAg）阳性携带者状态与肝癌之间的关系已得到广泛研究。然而，从HBsAg阳性携带者状态或肝硬化进展为肝癌过程中发生的表观遗传变化尚不清楚。DNA羟甲基化的表观遗传修饰在肿瘤发展中至关重要。此外，5-羟甲基胞嘧啶（5hmC）是DNA去甲基化和表观遗传调控的重要碱基。它还参与染色体组装和基因表达调控。然而，5hmC在HBsAg阳性携带者或发展为肝癌的肝硬化患者中的作用机制尚未完全阐明。
探讨HBsAg阳性携带者及肝硬化进展为肝细胞癌（HCC）的可能表观遗传机制。
选取2020年3月至2021年11月在永康市第一人民医院收治的40例HBsAg阳性携带者、40例肝硬化患者和40例肝癌患者作为研究对象。使用cf-DNA试剂盒提取游离DNA。通过5hmC DNA测序提取cfDNA进行主成分分析，检测三组样本的表达谱，筛选经羟甲基化修饰的差异表达基因（DEGs）。采用生物信息学分析对DEGs进行生物途径等富集分析。
共鉴定出16455个羟甲基化基因。测序结果显示，HBsAg携带者与肝癌患者之间有32个基因存在显著的5hmC修饰差异，其中与HBsAg阳性携带者相比，HCC患者中有30个基因上调，2个基因下调。肝硬化与肝癌患者之间在20个基因中存在显著的5hmC修饰差异，其中与肝硬化患者相比，HCC患者中有17个基因上调，3个基因下调。这些基因可能存在尚未发现或未阐明的潜在位点，它们促进了肝癌的发生和发展。基因本体富集分析和京都基因与基因组百科全书分析表明，差异基因涉及的主要信号通路为胆汁分泌和胰岛素分泌。蛋白质相互作用分析表明，蛋白质-蛋白质相互作用网络中的重要基因是磷酸烯醇式丙酮酸羧激酶和溶质载体家族2。
肝癌的发生发展涉及多个基因和途径，这些可能是预防乙肝携带者发生肝癌的潜在靶点。
