乙型肝炎病毒HBx分子在弥漫大B细胞淋巴瘤中的作用与机制研究

Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma. The cause of this disease is strongly correlated to the host immunity and infection status. Our long-term clinical work showed that the positive rate of serum hepatitis B virus (HBV) was significantly increased in DLBCL patients. HBV antigens and nucleic acid were also found in lymphoma tissues from these patients, characterized by tumor-related hepatitis B x (HBx) gene integration and high level expression of this protein. Meanwhile, our preliminary cellular experiment revealed that B lymphocyte was able to be infected by HBV. Therefore, we reasonably propose a hypothesis that HBV can infect and integrate B lymphocyte participating in the genesis and progression of DLBCL through HBx pathway. In order to verify the hypothesis, we plan to make a thorough analysis of the correlation between HBV and DLBCL by detecting HBV in various kind of clinical specimens. Furthermore, B lymphocytes stable infected and integrated by HBV will be screened by cell experiments in vitro. The key molecules causing HBx-related DLBCL will be further verified by using appropriate protein and nucleic acid technology so as to reveal the molecular pathway of tumor development induced by virus. This project will not only shed light on the novel etiology mechanism of DLBCL, but also provide a new strategy and foundation for the diagnosis and prevention of this disease.

弥漫大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤最常见的病理类型，其致病原因与宿主的感染免疫密不可分。我们在长期的临床工作中发现：血清乙型肝炎病毒（HBV）的阳性率在DLBCL患者中显著增高；DLBCL的肿瘤组织同样存在HBV抗原与核酸，并以肿瘤相关HBx分子的高表达与基因整合为特征。同时，细胞实验证实HBV可以直接感染B淋巴细胞。因此，我们提出假说：HBV通过感染整合途径介导HBx分子参与DLBCL的发生发展。为验证这一假说，本课题拟通过对多种临床标本的HBV检测，结合临床深入分析HBV与DLBCL之间的相关性；同时进行体外细胞实验，筛选HBV稳定感染并整合的B淋巴细胞；利用相应蛋白与核酸检测技术，进一步筛查和验证潜在引起HBx相关DLBCL的关键分子，揭示病毒参与肿瘤发生发展的分子途径。通过本课题的研究，不仅能为DLBCL阐明新的病因学机制，也对该类疾病的预防诊治提供新的策略与依据。

弥漫大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤最常见的病理类型，其致病原因与宿主的感染免疫密不可分。前期研究发现：血清乙型肝炎病毒（HBV）的阳性率在DLBCL患者中显著增高；DLBCL的肿瘤组织存在HBV抗原与核酸，并以肿瘤相关HBx分子的高表达与基因整合为特征；细胞实验证实HBV可以直接感染B淋巴细胞。因此，HBV可能通过感染整合途径介导HBx分子参与DLBCL的发生发展。本项目成功构建HBx稳转并整合的DLBCL细胞，分析了HBx的整合位点图谱；发现HBx整合能够引起淋巴瘤细胞凋亡水平降低等生物学效应；揭示DLBCL中的HBx-BCL2凋亡分子机制；此外，发现HBV的感染与整合，能够引起相关受体与耐药性的变化，提示更多地病毒参与肿瘤发生发展的分子途径。通过本项目的研究，不仅能为DLBCL阐明新的病因学机制，也对该类疾病的预防诊治提供新的策略与依据。