乙型肝炎病毒致肝细胞癌的关键机制及防控策略

谢璐泽; 席雅璇; 曹广文

doi:10.12449/JCH260808

乙型肝炎病毒致肝细胞癌的关键机制及防控策略

DOI: 10.12449/JCH260808

谢璐泽^{1, 2, 3},
席雅璇^{1, 2, 3},
曹广文^{1, 2, 3, , ,}

1.
中国人民解放军海军军医大学流行病学教研室，上海 200433
2.
生物安全防御教育部重点实验室，上海 200433
3.
上海市医学生物防护重点实验室，上海 200433

基金项目:

国家科技重大专项 (2023ZD0500100);

国家自然科学基金面上项目 (82473715);

国家自然科学基金面上项目 (82373671)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：谢璐泽负责查阅文献并撰写论文；席雅璇负责归纳文献并修改论文；曹广文负责指导撰写并修改论文。

详细信息

通信作者:
曹广文， gcao@smmu.edu.cn （ORCID： 0000-0002-8094-1278）

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出版历程
- 收稿日期: 2026-07-02
- 录用日期: 2026-07-22
- 出版日期: 2026-08-25

Key mechanisms of hepatitis B virus-induced hepatocellular carcinoma and related prevention and control strategies

Luze Xie^{1, 2, 3},
Yaxuan Xi^{1, 2, 3},
Guangwen Cao^{1, 2, 3
, ,
,}

1.
Department of Epidemiology，Navy Medical University，Shanghai 200433，China
2.
Key Laboratory of Biological Defense，Ministry of Education，Shanghai 200433，China
3.
Shanghai Key Laboratory of Medical Bioprotection，Shanghai 200433，China

Research funding:

National Science and Technology Major Project (2023ZD0500100);

General Project of National Natural Science Foundation of China (82473715);

General Project of National Natural Science Foundation of China (82373671)

More Information

Corresponding author: Cao Guangwen， gcao@smmu.edu.cn （ORCID： 0000-0002-8094-1278）

摘要

摘要: 乙型肝炎病毒（HBV）慢性感染是肝细胞癌（HCC）的主要原因，其对全球HCC的人群归因分数为57.1%，对中国HCC的人群归因分数为76.1%。阐明HBV致癌的早期分子机制，有助于HCC的精准预防。HBV持续复制、变异、整合及其协同驱动是HBV致癌的主要机制。HBV复制可激活并维持肝脏慢性炎症微环境，为病毒变异累积提供条件；在慢性炎症条件下，炎症因子使载脂蛋白B mRNA编辑酶催化多肽样3B（变异酶）-尿嘧啶-DNA糖基化酶（修复酶）失衡，促进HBV变异和人基因组突变，HBV变异致癌能力增强，炎症微环境可促进变异细胞去分化并获得干性特征；HBV基因组整合可导致端粒酶逆转录酶启动子等“守门人”变异，引发染色体不稳定与表观遗传重编程。HBV复制、变异和整合三大环节在“变异-选择-适应”的进化规律下协同作用，共同推动HCC的发生和发展。HBV高危变异谱、外周血整合片段及端粒酶逆转录酶启动子突变等分子标志物，可指导HCC的抗病毒精准预防、辅助早期筛查与术后复发监测，为完善HCC分层防控策略提供科学依据。
- 乙型肝炎病毒 /
- 癌，肝细胞 /
- 病理过程 /
- 疾病预防
Abstract: Chronic hepatitis B virus （HBV） infection is a major cause of hepatocellular carcinoma （HCC）， with a population-attributable fraction of 57.1% for HCC globally and 76.1% for HCC in China. Identifying the early molecular mechanisms of HBV-driven hepatocarcinogenesis can facilitate precise HCC prevention. Persistent HBV replication， HBV mutation， HBV integration， and the synergistic interplay among them are the main mechanisms of HBV-driven hepatocarcinogenesis. HBV replication activates and sustains a chronic hepatic inflammatory microenvironment， providing conditions for accumulation of viral mutations； under the conditions of chronic inflammation， inflammatory factors cause the imbalance between apolipoprotein B messenger RNA editing enzyme catalytic polypeptide-like 3B and uracil-DNA glycosylase， which promotes HBV mutations and human genomic mutations and enhances the carcinogenic effect of HBV mutations， and the inflammatory microenvironment can promote dedifferentiation of mutated cells and acquisition of stemness； HBV genome integration can cause “gate-keeper” mutations including telomerase reverse transcriptase （TERT） promoter mutation， thereby triggering chromosomal instability and epigenetic reprogramming. The three events of HBV replication， mutation， and integration work synergistically under the evolutionary principle of “variation-selection-adaptation” and jointly drive the development and progression of HCC. The high-risk HBV mutation profile， circulating HBV integration fragments， and the TERT promoter mutations can be used to guide precision HCC prevention via antiviral prophylaxis and assist in early screening and monitoring of postoperative recurrence， which provides a scientific basis for refining stratified prevention and control strategies against HCC.
- Hepatitis B Virus /
- Carcinoma， Hepatocellular /
- Pathologic Processes /
- Disease Prevention

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注： HBV，乙型肝炎病毒；cccDNA，共价闭合环状DNA；IL-6，白细胞介素6；TNF-α，肿瘤坏死因子α；SCI，全身低强度慢性炎症；APOBEC3B，载脂蛋白B mRNA编辑酶催化多肽样3B；UNG，尿嘧啶-DNA糖基化酶；PreS，乙型肝炎病毒前S区；Ct-HBx，C端截短型乙型肝炎病毒X蛋白；TERT，端粒酶逆转录酶；KMT2B/MLL4，赖氨酸甲基转移酶2B/混合谱系白血病蛋白4；CCNE1，细胞周期蛋白E1；FN1，纤维连接蛋白1；CNV，拷贝数变异；CDKN2A/B，细胞周期蛋白依赖性激酶抑制因子2A/2B；TP53，肿瘤蛋白p53；Me，甲基化；Ac，乙酰化；LGDN，低度异型增生结节；HGDN，高度异型增生结节；HCC，肝细胞癌。

图 1 HBV致癌的关键机制

Figure 1. Key mechanisms of HBV-induced carcinogenesis

下载: 全尺寸图片幻灯片

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