DLBCL患者易感HBV及其相互作用的分子机制研究

In clinic, it was found that the patients with DLBCL are easy to infect with hepatitis B virus (HBV), but there were few researches about the mechanisms. We have previously found in a group of 995 cases of lymphoma patients that the HBV infection was correlated with B cell non-hodgkin’s lymphoma, particularly DLBCL, and affected the outcome and prognosis of patients. The pre-experiments demonstrated that there is a possible regulatory pathway for HBV infection and replication in DLBCL patients, which may involve in p53, miR-34a, SHIP1, IFN-γ, HBV-X, miR-21. In this project, we will investigate the anti-virus replication effect of miR-34a, the protection effect of P53 for miR-34a, and the regulatory mechanism of miR-34a on the expression and secretion of SHIP1 and IFN-γ, and the effect of HBV infection on DLBCL biological characteristics. The DLBCL exnograft mouse model was used to investigate the regulatory pathway between DLBCL and HBV infection and their interaction, and finally to explain the mechanism of DLBCL patients with HBV infection, and the influence of HBV on the therapeutic outcome and prognosis of DLBCL patients. The findings will help to construct a novel target strategy of biotherapy by interrupting the middle link in the regulatory pathway between DLBCL and HBV.

临床发现DLBCL患者易感HBV，但研究较少，机制不明。我们前期对一组995例大样本量淋巴瘤患者研究发现，HBV感染与B细胞非霍奇金淋巴瘤特别是DLBCL相关，并影响患者疗效和预后。预实验已证实DLBCL患者存在一条HBV感染复制的可能调控通路，可能涉及P53、miR-34a、SHIP1、IFN-γ、HBV-X及miR-21等。本项目拟通过对DLBCL细胞学、临床样本和动物模型实验，验证miR-34a抗HBV复制的作用、P53对miR-34a的保护作用、miR-34a对免疫效应细胞SHIP1表达和IFN-γ分泌的调控、HBV感染对DLBCL细胞生物学特性的影响等，通过裸鼠DLBCL移植瘤模型验证阻断DLBCL感染HBV及相互影响的通路，最终阐明DLBCL患者易感HBV的机制，明确HBV对DLBCL疗效和预后的影响，并期望建立一种阻断DLBCL与HBV相互调控的中间环节的靶向生物治疗新策略。

临床发现DLBCL患者易感HBV，但研究较少，机制不明。本项研究我们通过对DLBCL细胞学、临床样本和动物模型实验，验证了miR-34a抗HBV复制的作用、P53对miR-34a的保护作用、miR-34a对免疫效应细胞SHIP1表达和IFN-γ分泌的调控、HBV感染对DLBCL细胞生物学特性的影响等，通过裸鼠DLBCL移植瘤模型验证阻断DLBCL感染HBV及相互影响的通路，最终阐明DLBCL患者易感HBV的机制，明确HBV对DLBCL疗效和预后的影响；通过对DLBCL相关的差异表达miRNAs的筛选以及DLBCL细胞内miR-34a的表达及其抗HBV活性的研究，对ART影响增殖相关周期蛋白表达的研究，HBV对DLBCL细胞增殖、周期和凋亡影响的研究，特别是HBV感染对DLBCL影响的机制研究，我们揭示了DLBCL易感HBV的机制以及HBV对DLBCL 临床疗效和患者预后的影响，DLBCL 患者存在着一种调控通路，控制HBV的感染和复制。这条调控通路涉及P53的功能状态、miR-34a的表达水平、效应T细胞SHIP1的表达和IFN-γ的分泌、HBV-X蛋白及miR-21的作用等，其中还有大量的疑难问题需要进一步解决。我们的研究结果，对指导临床DLBCL 的治疗、改善患者预后，有十分重要的现实意义，并由此期望建立一种阻断DLBCL与HBV相互调控的中间环节的靶向生物治疗新策略。