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研究生: 黄雅琪
研究生(外文): Ya-Chi Huang
论文名称: EB病毒对EphA4的调控及其对EB病毒相关之淋巴增殖疾病的致病性之影响
论文名称(外文): Regulation of Eph receptor A4 (EphA4) expression by Epstein-Barr virus and its impact on the pathogenesis of EBV-associated lymphoproliferative disorders
指导教授: 蔡锦华
指导教授(外文): Ching-Hwa Tsai
口试委员: 李明学、吕春敏、董馨莲、林素珍
口试委员(外文): Ming-Shyue Lee、Chuen-Miin Leu、Shin-Lian Doong、Sue-Jane Lin
口试日期: 2016-08-19
学位类别: 博士
校院名称: 国立台湾大学
系所名称: 微生物学研究所
学门: 生命科学学门
学类: 微生物学类
论文种类: 学术论文
论文出版年: 2016
毕业学年度: 104
语文别: 英文
论文页数: 112
中文关键词: EphA4酪胺酸激、EB病毒、淋巴母细胞株、潜伏膜蛋白1、移植后淋巴增生疾病、瀰漫性大B细胞淋巴瘤
外文关键词: Erythropoietin-producing hepatocellular receptor A4 (EphA4)、Epstein-Barr virus (EBV)、lymphoblastoid cell lines (LCLs)、latent membrane protein 1 (LMP1)、post-transplantation lymphoproliferative disorder (PTLD)、diffuse large B-cell lymphoma (DLBCL)

EB病毒 (Epstein-Barr virus, EBV),为致癌性之疱疹病毒,与许多淋巴性细胞异常之疾病有高度相关性,包括柏金氏淋巴瘤 (Burkitt’s lymphoma)、霍金氏症 (Hodgkin disease)、瀰漫性大B细胞淋巴瘤 (diffuse large B-cell lymphoma,DLBCL)、移植后淋巴增生症 (post-transplant lymphoproliferative diseases,PTLD)、等疾病,在体外实验中具备使人类B细胞 (primary B cell) 转形成不朽化淋巴母细胞株 (lymphoblastoid cell line, LCL) 的能力。近年来,在EB病毒相关之肿瘤形成 (neoplasia) 中发现,受体酪胺酸激酶 (Receptor tyrosine kinase, RTK) 扮演了一个很重要的角色,然而EB病毒是如何藉由调控B细胞内受体酪胺酸激酶,进而导致B细胞恶性肿瘤形成的机制,目前并未十分清楚。本篇我们发现人类B细胞受到EB病毒感染会造成受体酪胺酸激酶中隶属于最大Eph家族的EphA4在转录以及转译的表现量下降,从外送 (overexpression) 与抑制 (knockdown) 的实验证明LMP1造成EphA4降低。在细胞调控机制方面,LMP1透过ERK路径去促进Sp1来达到抑制EphA4启动子之活性 (promoter activity);在功能上面,外送EphA4会抑制LCL的细胞生长;在病理上,我们发现EB病毒阴性的扁桃腺检体可侦测到EphA4之表现,而EB病毒阳性的PTLD检体则无EphA4表现,除此之外,利用免疫化学染色 (Immunochemical staining) 之方法,在有无感染EB病毒的DLBCL检体中发现,EphA4的表现与EB病毒的感染呈负相关;从资料库分析DLBCL病人的存活率,发现低度表现EphA4的病人,其存活率较差。我们的发现为B细胞中的EphA4如何被致癌蛋白LMP1调控,提供了一个崭新的机制,并发掘EphA4在B细胞中的功能,这些研究成果能提供EphA4在EB病毒阳性之PTLD及DLBCL所扮演的角色一些新的观点。

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt’s lymphoma, Hodgkin’s disease, diffuse large B-cell lymphoma (DLBCL) and post-transplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B cell neoplasia and malignancies remain largely unclear. Here, we found that EphA4, which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the ERK pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV-negative tonsils but not in EBV-positive PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV-positive and EBV-negative DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public dataset showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV-positive PTLD and DLBCL.

中文摘要………………………………………………………………. ……… i
英文摘要………………………………………………………………. ……… iii
Contents………………………………………………………………................ v
Introduction ………………………………………………………….................. 1
Materials and methods ………………………………………………………… 17
Results…………………………………………………………………………. 32
Discussion………………………………………………………………………. 40
References……………………………………………………………………… 47
Tables…………………………………………………………………………… 59
Figures…………………………………………………………………………. 63
Appendix ………………………………………………………………………. 101

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