Analysis of hepatitis B virus integration identifies KMT2B as a novel cancer-related gene in pancreatic cancer

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-07-31 DOI:10.1002/ctm2.70424

Mengge Li, Huimin Li, Dejun Liu, Shunan Liu, Hui Yuan, Yan Wu, Min Du, Yuan Fang, Jin Li, Hui Cong, Dan Zhao, Chunsun Fan, Qing Wang, Cenkai Shen, Yu Gan, Yongwei Sun, Hong Tu

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few well-established risk factors. Emerging epidemiological evidence suggests a link between hepatitis B virus (HBV) infection and PDAC. However, the underlying mechanisms remain unclear.

Methods

High-throughput sequencing-based approach was employed to identify HBV integrations in tumour and para-tumour tissues of PDAC. The biological functions of KMT2B were evaluated in PDAC cell lines as well as in subcutaneous and orthotopic mouse models of PDAC. Chromatin immunoprecipitation sequencing and RNA sequencing were used to identify the pathway involved in PDAC development.

Results

HBV integration was detected in approximately one-third of HBV DNA-positive PDAC and adjacent para-tumour tissues. A total of 425 viral‒host junctions were identified, with the majority located in intergenic regions (51.29%), followed by introns (43.29%) and exons (2.35%) of the human genome. Lysine methyltransferase 2B (KMT2B, also known as MLL4), a gene frequently targeted by HBV integration in hepatocellular carcinoma, was also found to be interrupted by HBV in PDAC. KMT2B was significantly upregulated in PDAC and promoted malignant behaviours both in vitro and in vivo. Mechanistically, KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN through histone H3K4 trimethylation, leading to the activation of the PI3K/Akt signalling pathway.

Conclusion

HBV integration is a common event in HBV-related PDAC and KMT2B has been identified as a novel PDAC-related gene.

Key points

Hepatitis B virus (HBV) integrates in both tumour and adjacent para-tumour tissues of pancreatic ductal adenocarcinoma (PDAC).
KMT2B, a target gene of HBV integration, promotes PDAC proliferation and metastasis in vivo and in vitro experiments.
KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN via histone H3K4 trimethylation, activating the PI3K/Akt signalling pathway.

Abstract Image

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乙型肝炎病毒整合分析发现KMT2B是胰腺癌中一种新的癌症相关基因

胰腺导管腺癌（PDAC）是一种高度侵袭性的恶性肿瘤，几乎没有确定的危险因素。新出现的流行病学证据表明乙型肝炎病毒（HBV）感染与PDAC之间存在联系。然而，潜在的机制仍不清楚。方法采用基于高通量测序的方法鉴定HBV在PDAC肿瘤和肿瘤旁组织中的整合。在PDAC细胞系以及PDAC皮下和原位小鼠模型中评价了KMT2B的生物学功能。染色质免疫沉淀测序和RNA测序用于鉴定参与PDAC发展的途径。结果在大约三分之一的HBV dna阳性PDAC和邻近肿瘤旁组织中检测到HBV整合。共鉴定出425个病毒-宿主连接，其中大部分位于基因间区（51.29%），其次是内含子（43.29%）和外显子（2.35%）。赖氨酸甲基转移酶2B （KMT2B，也称为MLL4）是肝细胞癌中HBV整合的一个经常靶向的基因，在PDAC中也被HBV打断。KMT2B在PDAC中显著上调，并在体外和体内促进恶性行为。机制上，KMT2B通过组蛋白H3K4三甲基化调控下游靶基因FYN，激活PI3K/Akt信号通路，发挥其致癌作用。结论HBV整合是HBV相关PDAC的常见事件，KMT2B已被确定为新的PDAC相关基因。乙型肝炎病毒（HBV）在胰腺导管腺癌（PDAC）的肿瘤和邻近肿瘤旁组织中均有整合。在体内和体外实验中，KMT2B是HBV整合的靶基因，促进PDAC的增殖和转移。KMT2B通过组蛋白H3K4三甲基化调控下游靶基因FYN，激活PI3K/Akt信号通路，发挥其致癌作用。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.