EB病毒编码的潜伏膜蛋白LMP2A促进霍奇金淋巴瘤复发及其机制研究

EBV-encoded LMP2A plays an important role in EBV-associated tumors. We found that LMP2A induced cancer stem cell characteristics in nasopharyngeal carcinoma (PLoS Pathog 2010). About 40% of Hodgkin's lymphoma (HL) is associatied with EBV infection, and LMP2A expresses in part of HL, but its function and the mechanism are still not clear. In our previous study, LMP2A and Bmi1 were highly expressed in the relapsed patient samples, and the expression of LMP2A was positively correlated with the expression of Bmi1 (r=0.782, p<0.001). Exogenous overexpression of LMP2A increased the number of side population (SP) cells, upregulated the expression of Bmi1, induced the promoter activity of both NF-κb and Bmi1 by luciferase assay. In this study, we aim to investigate the effects and possible mechanisms of LMP2A in HL. First, we will detect the number of SP cells, the cancer stem cell markers' expression, and the chemosensitivity in NOD-SCID mouse model after overexpressing LMP2A or knocking LMP2A in order to examine the ability of LMP2A inducing HL cells cancer stem cell characteristics. Meanwhile, we will check the expression of LMP2A and Bmi1 in clinical specimens by real-time PCR and immunohistochemistry assays to analyze the correlation between LMP2A and Bmi1, and to explore the relationship between LMP2A/Bmi1 expression, pathological features, and prognosis, providing important indicators of the prognosis of HL patients and the potential molecular targets of HL treatment.

EBV编码的LMP2A在EBV相关肿瘤中发挥重要作用，我们报道LMP2A可诱导鼻咽癌细胞肿瘤干细胞特性（PLoS Pathog 2010）。EBV感染与约40%霍奇金淋巴瘤（HL）的发病相关，部分HL表达LMP2A，但功能和机制尚不清。申请者前期发现复发患者标本中表达较高LMP2A、Bmi1（P<0.001），且二者表达呈正相关（r=0.782，P<0.001）；过表达LMP2A增加SP细胞数目、上调Bmi1表达，荧光素酶报告示LMP2A增加NF-kB和Bmi1活性。本项目拟通过检测SP细胞、肿瘤干细胞标志、化疗药物敏感性及建立移植瘤复发模型，研究LMP2A是否诱导HL细胞肿瘤干细胞特性而参与调控HL复发，并检测LMP2A、Bmi1 mRNA和蛋白水平表达及与病人病理特征、预后的关系，及NF-kB通路在LMP2A调控Bmi1中的作用和机制；为实现LMP2A作为HL复发的分子靶。

EBV 编码的LMP2A 在EBV 相关肿瘤中发挥重要作用，我们报道LMP2A 可诱导鼻咽癌细胞肿瘤干细胞特性（PLoS Pathog 2010）。EBV 感染与约40%霍奇金淋巴瘤（HL）的发病相关，部分HL 表达LMP2A，但功能和机制尚不清。申请者在本研究中发现霍奇金淋巴瘤中EBERs的表达与临床分期呈正相关。LMP2A、Bmi1高表达与霍奇金淋巴瘤复发密切相关，且LMP2A与Bmi1的表达呈正相关；LMP2A调控Bmi-1的表达，参与调控的信号通路可能是NF-kB。本研究期望通过对以上功能及机制的研究，初步阐明LMP2A 促进HL复发的分子机制，进而为寻找治疗HL 的潜在分子靶点、以及准确判断预后的指标提供重要依据。