Li Mengge, Li Huimin, Liu Dejun, Liu Shunan, Yuan Hui, Wu Yan, Du Min, Fang Yuan, Li Jin, Cong Hui, Zhao Dan, Fan Chunsun, Wang Qing, Shen Cenkai, Gan Yu, Sun Yongwei, Tu Hong
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Clin Transl Med. 2025 Aug;15(8):e70424. doi: 10.1002/ctm2.70424.
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.
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.
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.
HBV integration is a common event in HBV-related PDAC and KMT2B has been identified as a novel PDAC-related gene.
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.
胰腺导管腺癌（PDAC）是一种侵袭性很强的恶性肿瘤，已知的风险因素很少。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，其潜在机制仍不清楚。
采用基于高通量测序的方法，在PDAC的肿瘤组织和癌旁组织中鉴定HBV整合情况。在PDAC细胞系以及PDAC的皮下和原位小鼠模型中评估KMT2B的生物学功能。采用染色质免疫沉淀测序和RNA测序来确定参与PDAC发生发展的途径。
在约三分之一的HBV DNA阳性的PDAC及其相邻癌旁组织中检测到HBV整合。共鉴定出425个病毒-宿主连接点，其中大部分位于人类基因组的基因间区域（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）是肝癌中经常被HBV整合靶向的基因，在PDAC中也被发现被HBV中断。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H3K4三甲基化调节下游靶基因FYN，从而激活PI3K/Akt信号通路，发挥其致癌作用。
HBV整合是HBV相关PDAC中的常见事件，KMT2B已被鉴定为一个新的PDAC相关基因。
乙型肝炎病毒（HBV）整合到胰腺导管腺癌（PDAC）的肿瘤组织和相邻癌旁组织中。HBV整合的靶基因KMT2B在体内和体外实验中促进PDAC增殖和转移。KMT2B通过组蛋白H3K4三甲基化调节下游靶基因FYN，激活PI3K/Akt信号通路，发挥其致癌作用。
