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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

阅读量:02021-11-19作者:黄雅琪来源:微生物学研究所
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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


Aasheim, H. C., Delabie, J. & Finne, E. F. (2005). Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2. Blood 105, 2869-2876.
Allday, M. J. & Crawford, D. H. (1988). Role of epithelium in EBV persistence and pathogenesis of B-cell tumours. Lancet 1, 855-857.
Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. (1998). EBV persistence in memory B cells in vivo. Immunity 9, 395-404.
Barrios, A., Poole, R. J., Durbin, L., Brennan, C., Holder, N. & Wilson, S. W. (2003). Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis. Current biology : CB 13, 1571-1582.
Begum, S., Emami, N., Cheung, A., Wilkins, O., Der, S. & Hamel, P. A. (2005). Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR. Oncogene 24, 1860-1872.
Bonello, M. R. & Khachigian, L. M. (2004). Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter. The Journal of biological chemistry 279, 2377-2382.
Bowden, T. A., Aricescu, A. R., Nettleship, J. E., Siebold, C., Rahman-Huq, N., Owens, R. J., Stuart, D. I. & Jones, E. Y. (2009). Structural plasticity of eph receptor A4 facilitates cross-class ephrin signaling. Structure 17, 1386-1397.
Burkitt, D. (1962a). A children's cancer dependent on climatic factors. Nature 194, 232-234.
Burkitt, D. (1962b). A tumour syndrome affecting children in tropical Africa. Postgraduate medical journal 38, 71-79.
Cader, F. Z., Vockerodt, M., Bose, S., Nagy, E., Brundler, M. A., Kearns, P. & Murray, P. G. (2013). The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 122, 4237-4245.
Carmona, M. A., Murai, K. K., Wang, L., Roberts, A. J. & Pasquale, E. B. (2009). Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proceedings of the National Academy of Sciences of the United States of America 106, 12524-12529.
Chakraborty, S., Veettil, M. V., Bottero, V. & Chandran, B. (2012). Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proceedings of the National Academy of Sciences of the United States of America 109, E1163-1172.
Chan, A. C., Ho, J. W., Chiang, A. K. & Srivastava, G. (1999). Phenotypic and cytotoxic characteristics of peripheral T-cell and NK-cell lymphomas in relation to Epstein-Barr virus association. Histopathology 34, 16-24.
Chang, Y., Lee, H. H., Chang, S. S., Hsu, T. Y., Wang, P. W., Chang, Y. S., Takada, K. & Tsai, C. H. (2004). Induction of Epstein-Barr virus latent membrane protein 1 by a lytic transactivator Rta. Journal of virology 78, 13028-13036.
Chou, Y. C., Chen, C. L., Yeh, T. H., Lin, S. J., Chen, M. R., Doong, S. L., Lu, J. & Tsai, C. H. (2012). Involvement of recepteur d'origine nantais receptor tyrosine kinase in Epstein-Barr virus-associated nasopharyngeal carcinoma and its metastasis. The American journal of pathology 181, 1773-1781.
Chou, Y. C., Lin, S. J., Lu, J., Yeh, T. H., Chen, C. L., Weng, P. L., Lin, J. H., Yao, M. & Tsai, C. H. (2011). Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation. Blood 118, 1340-1349.
Chu, S. (2012). Transcriptional regulation by post-transcriptional modification--role of phosphorylation in Sp1 transcriptional activity. Gene 508, 1-8.
Chua, H. H., Yeh, T. H., Wang, Y. P., Huang, Y. T., Sheen, T. S., Lo, Y. C., Chou, Y. C. & Tsai, C. H. (2008). Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma. Head & neck 30, 427-436.
Cohen, J. I., Wang, F., Mannick, J. & Kieff, E. (1989). Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Proc Natl Acad Sci U S A 86, 9558-9562.
Countryman, J. & Miller, G. (1985). Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. Proc Natl Acad Sci U S A 82, 4085-4089.
Dawson, C. W., Port, R. J. & Young, L. S. (2012). The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Seminars in cancer biology 22, 144-153.
Dolcetti, R., Dal Col, J., Martorelli, D., Carbone, A. & Klein, E. (2013). Interplay among viral antigens, cellular pathways and tumor microenvironment in the pathogenesis of EBV-driven lymphomas. Seminars in cancer biology 23, 441-456.
Easty, D. J., Mitchell, P. J., Patel, K., Florenes, V. A., Spritz, R. A. & Bennett, D. C. (1997). Loss of expression of receptor tyrosine kinase family genes PTK7 and SEK in metastatic melanoma. International journal of cancer Journal international du cancer 71, 1061-1065.
Ellis, C., Kasmi, F., Ganju, P., Walls, E., Panayotou, G. & Reith, A. D. (1996). A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene 12, 1727-1736.
Epstein, M. A., Achong, B. G. & Barr, Y. M. (1964). VIRUS PARTICLES IN CULTURED LYMPHOBLASTS FROM BURKITT'S LYMPHOMA. Lancet (London, England) 1, 702-703.
Epstein, M. A., Achong, B. G., Barr, Y. M., Zajac, B., Henle, G. & Henle, W. (1966). Morphological and virological investigations on cultured Burkitt tumor lymphoblasts (strain Raji). Journal of the National Cancer Institute 37, 547-559.
ErnbergI, Masucci, G. & Klein, G. (1976). Persistence of Epstein-Barr viral nuclear antigen (EBNA) in cells entering the EB viral cycle. Int J Cancer 17, 197-203.
Farrell, P. J. (1998). Signal transduction from the Epstein-Barr virus LMP-1 transforming protein. Trends Microbiol 6, 175-177; discussion 177-178.
Feederle, R., Kost, M., Baumann, M., Janz, A., Drouet, E., Hammerschmidt, W. & Delecluse, H. J. (2000). The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19, 3080-3089.
Feugier, P., Van Hoof, A., Sebban, C., Solal-Celigny, P., Bouabdallah, R., Ferme, C., Christian, B., Lepage, E., Tilly, H., Morschhauser, F., Gaulard, P., Salles, G., Bosly, A., Gisselbrecht, C., Reyes, F. & Coiffier, B. (2005). Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23, 4117-4126.
Fox, C. P., Shannon-Lowe, C. & Rowe, M. (2011). Deciphering the role of Epstein-Barr virus in the pathogenesis of T and NK cell lymphoproliferations. Herpesviridae 2, 8.
Fukai, J., Yokote, H., Yamanaka, R., Arao, T., Nishio, K. & Itakura, T. (2008). EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. Molecular cancer therapeutics 7, 2768-2778.
Furne, C., Ricard, J., Cabrera, J. R., Pays, L., Bethea, J. R., Mehlen, P. & Liebl, D. J. (2009). EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis. Biochimica et biophysica acta 1793, 231-238.
Gires, O., Kohlhuber, F., Kilger, E., Baumann, M., Kieser, A., Kaiser, C., Zeidler, R., Scheffer, B., Ueffing, M. & Hammerschmidt, W. (1999). Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO J 18, 3064-3073.
Gires, O., Zimber-Strobl, U., Gonnella, R., Ueffing, M., Marschall, G., Zeidler, R., Pich, D. & Hammerschmidt, W. (1997). Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J 16, 6131-6140.
Graham, D. K., DeRyckere, D., Davies, K. D. & Earp, H. S. (2014). The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nature reviews Cancer 14, 769-785.
Graham, J. P., Arcipowski, K. M. & Bishop, G. A. (2010). Differential B-lymphocyte regulation by CD40 and its viral mimic, latent membrane protein 1. Immunological reviews 237, 226-248.
Greenspan, J. S., Greenspan, D., Lennette, E. T., Abrams, D. I., Conant, M. A., Petersen, V. & Freese, U. K. (1985). Replication of Epstein-Barr virus within the epithelial cells of oral 'hairy' leukoplakia, an AIDS-associated lesion. N Engl J Med 313, 1564-1571.
Grimminger, F., Schermuly, R. T. & Ghofrani, H. A. (2010). Targeting non-malignant disorders with tyrosine kinase inhibitors. Nature reviews Drug discovery 9, 956-970.
Gruffat, H., Manet, E., Rigolet, A. & Sergeant, A. (1990). The enhancer factor R of Epstein-Barr virus (EBV) is a sequence-specific DNA binding protein. Nucleic Acids Res 18, 6835-6843.
Guan, M., Romano, G. & Henderson, E. E. (1999). Epstein-Barr virus (EBV)-induced long-term proliferation of CD4+ lymphocytes leading to T lymphoblastoid cell lines carrying EBV. Anticancer research 19, 3007-3017.
Guan, M., Zhang, R. D., Wu, B. & Henderson, E. E. (1996). Infection of primary CD4+ and CD8+ T lymphocytes by Epstein-Barr virus enhances human immunodeficiency virus expression. Journal of virology 70, 7341-7346.
Haan, K. M., Kwok, W. W., Longnecker, R. & Speck, P. (2000). Epstein-Barr virus entry utilizing HLA-DP or HLA-DQ as a coreceptor. J Virol 74, 2451-2454.
Hahn, A. S. & Desrosiers, R. C. (2013). Rhesus monkey rhadinovirus uses eph family receptors for entry into B cells and endothelial cells but not fibroblasts. PLoS pathogens 9, e1003360.
Hahn, A. S., Kaufmann, J. K., Wies, E., Naschberger, E., Panteleev-Ivlev, J., Schmidt, K., Holzer, A., Schmidt, M., Chen, J., Konig, S., Ensser, A., Myoung, J., Brockmeyer, N. H., Sturzl, M., Fleckenstein, B. & Neipel, F. (2012). The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus. Nature medicine 18, 961-966.
Hammerschmidt, W. & Sugden, B. (1989). Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature 340, 393-397.
Hardwick, J. M., Lieberman, P. M. & Hayward, S. D. (1988). A new Epstein-Barr virus transactivator, R, induces expression of a cytoplasmic early antigen. J Virol 62, 2274-2284.
Henle, G. & Henle, W. (1966). Immunofluorescence in cells derived from Burkitt's lymphoma. J Bacteriol 91, 1248-1256.
Henle, W., Diehl, V., Kohn, G., Zur Hausen, H. & Henle, G. (1967). Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157, 1064-1065.
Holen, H. L., Nustad, K. & Aasheim, H. C. (2010). Activation of EphA receptors on CD4+CD45RO+ memory cells stimulates migration. Journal of leukocyte biology 87, 1059-1068.
Horikawa, T., Sheen, T. S., Takeshita, H., Sato, H., Furukawa, M. & Yoshizaki, T. (2001). Induction of c-Met proto-oncogene by Epstein-Barr virus latent membrane protein-1 and the correlation with cervical lymph node metastasis of nasopharyngeal carcinoma. The American journal of pathology 159, 27-33.
Hsu, M. C., Chang, H. C. & Hung, W. C. (2006). HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion. The Journal of biological chemistry 281, 4718-4725.
Inoue, E., Deguchi-Tawarada, M., Togawa, A., Matsui, C., Arita, K., Katahira-Tayama, S., Sato, T., Yamauchi, E., Oda, Y. & Takai, Y. (2009). Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. The Journal of cell biology 185, 551-564.
Iwasato, T., Katoh, H., Nishimaru, H., Ishikawa, Y., Inoue, H., Saito, Y. M., Ando, R., Iwama, M., Takahashi, R., Negishi, M. & Itohara, S. (2007). Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell 130, 742-753.
Johansson, B., Klein, G., Henle, W. & Henle, G. (1970). Epstein-Barr virus (EBV)-associated antibody patterns in malignant lymphoma and leukemia. I. Hodgkin's disease. Int J Cancer 6, 450-462.
Kaenel, P., Mosimann, M. & Andres, A. C. (2012). The multifaceted roles of Eph/ephrin signaling in breast cancer. Cell adhesion & migration 6, 138-147.
Kandouz, M. (2012). The Eph/Ephrin family in cancer metastasis: communication at the service of invasion. Cancer metastasis reviews 31, 353-373.
Kaye, K. M., Izumi, K. M. & Kieff, E. (1993). Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A 90, 9150-9154.
Kemp, H. A., Cooke, J. E. & Moens, C. B. (2009). EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel. Developmental biology 327, 313-326.
Kieff, E. & Rickinson, A. B. (2007). Epstein-Barr Virus and Its Replication. In Fields Virology, 5 edn, pp. 2603-2667. Edited by D. M. K. a. P. M. Howley: Lippincott Williams & Wilkins.
Kim, E. S. & Dhillon, S. (2015). Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. Drugs 75, 769-776.
Klein, E., Kis, L. L. & Klein, G. (2007). Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions. Oncogene 26, 1297-1305.
Klein, G., Clifford, P., Henle, G., Henle, W., Geering, G. & Old, L. J. (1969). EBV-associated serological patterns in a Burkitt lymphoma patient during regression and recurrence. Int J Cancer 4, 416-421.
Kuang, S. Q., Bai, H., Fang, Z. H., Lopez, G., Yang, H., Tong, W., Wang, Z. Z. & Garcia-Manero, G. (2010). Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia. Blood 115, 2412-2419.
Kung, C. P., Meckes, D. G., Jr. & Raab-Traub, N. (2011). Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta. Journal of virology 85, 4399-4408.
Kung, C. P. & Raab-Traub, N. (2010). Epstein-Barr virus latent membrane protein 1 modulates distinctive NF- kappaB pathways through C-terminus-activating region 1 to regulate epidermal growth factor receptor expression. Journal of virology 84, 6605-6614.
Kung, H. J., Chen, H. C. & Robinson, D. (1998). Molecular profiling of tyrosine kinases in normal and cancer cells. Journal of biomedical science 5, 74-78.
Lai, K. O., Chen, Y., Po, H. M., Lok, K. C., Gong, K. & Ip, N. Y. (2004). Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. The Journal of biological chemistry 279, 13383-13392.
Lai, K. Y., Chou, Y. C., Lin, J. H., Liu, Y., Lin, K. M., Doong, S. L., Chen, M. R., Yeh, T. H., Lin, S. J. & Tsai, C. H. (2015). Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cdelta Pathway. Journal of virology 89, 5968-5980.
Li, H. P. & Chang, Y. S. (2003). Epstein-Barr virus latent membrane protein 1: structure and functions. J Biomed Sci 10, 490-504.
Li, J. S., Zhou, B. S., Dutschman, G. E., Grill, S. P., Tan, R. S. & Cheng, Y. C. (1987). Association of Epstein-Barr virus early antigen diffuse component and virus-specified DNA polymerase activity. J Virol 61, 2947-2949.
Li, Q., Spriggs, M. K., Kovats, S., Turk, S. M., Comeau, M. R., Nepom, B. & Hutt-Fletcher, L. M. (1997). Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol 71, 4657-4662.
Li, Q., Turk, S. M. & Hutt-Fletcher, L. M. (1995). The Epstein-Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells. J Virol 69, 3987-3994.
Lin, C. S., Kuo, H. H., Chen, J. Y., Yang, C. S. & Wang, W. B. (2000). Epstein-barr virus nuclear antigen 2 retards cell growth, induces p21(WAF1) expression, and modulates p53 activity post-translationally. J Mol Biol 303, 7-23.
Lin, C. T., Chan, W. Y., Chen, W., Huang, H. M., Wu, H. C., Hsu, M. M., Chuang, S. M. & Wang, C. C. (1993). Characterization of seven newly established nasopharyngeal carcinoma cell lines. Laboratory investigation; a journal of technical methods and pathology 68, 716-727.
Lin, J. C., Sista, N. D., Besencon, F., Kamine, J. & Pagano, J. S. (1991). Identification and functional characterization of Epstein-Barr virus DNA polymerase by in vitro transcription-translation of a cloned gene. J Virol 65, 2728-2731.
Lin, J. H., Lin, J. Y., Chou, Y. C., Chen, M. R., Yeh, T. H., Lin, C. W., Lin, S. J. & Tsai, C. H. (2015a). Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1. Blood 125, 2228-2238.
Lin, J. H., Tsai, C. H., Chu, J. S., Chen, J. Y., Takada, K. & Shew, J. Y. (2007). Dysregulation of HER2/HER3 signaling axis in Epstein-Barr virus-infected breast carcinoma cells. Journal of virology 81, 5705-5713.
Lin, S. J., Wu, S. W., Chou, Y. C., Lin, J. H., Huang, Y. C., Chen, M. R., Ma, N. & Tsai, C. H. (2015b). Novel expression and regulation of TIMP-1 in Epstein Barr virus-infected cells and its impact on cell survival. Virology 481, 24-33.
Liu, P. & Speck, S. H. (2003). Synergistic autoactivation of the Epstein-Barr virus immediate-early BRLF1 promoter by Rta and Zta. Virology 310, 199-206.
Lo, A. K., Dawson, C. W., Young, L. S., Ko, C. W., Hau, P. M. & Lo, K. W. (2015). Activation of the FGFR1 signalling pathway by the Epstein-Barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells. The Journal of pathology.
Lu, J., Chen, S. Y., Chua, H. H., Liu, Y. S., Huang, Y. T., Chang, Y., Chen, J. Y., Sheen, T. S. & Tsai, C. H. (2000). Upregulation of tyrosine kinase TKT by the Epstein-Barr virus transactivator Zta. Journal of virology 74, 7391-7399.
Lu, T. X., Liang, J. H., Miao, Y., Fan, L., Wang, L., Qu, X. Y., Cao, L., Gong, Q. X., Wang, Z., Zhang, Z. H., Xu, W. & Li, J. Y. (2015). Epstein-Barr virus positive diffuse large B-cell lymphoma predict poor outcome, regardless of the age. Scientific reports 5, 12168.
Lupberger, J., Zeisel, M. B., Xiao, F., Thumann, C., Fofana, I., Zona, L., Davis, C., Mee, C. J., Turek, M., Gorke, S., Royer, C., Fischer, B., Zahid, M. N., Lavillette, D., Fresquet, J., Cosset, F. L., Rothenberg, S. M., Pietschmann, T., Patel, A. H., Pessaux, P., Doffoel, M., Raffelsberger, W., Poch, O., McKeating, J. A., Brino, L. & Baumert, T. F. (2011). EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nature medicine 17, 589-595.
Macsween, K. F. & Crawford, D. H. (2003). Epstein-Barr virus-recent advances. The Lancet infectious diseases 3, 131-140.
Mannick, J. B., Cohen, J. I., Birkenbach, M., Marchini, A. & Kieff, E. (1991). The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs is important in B-lymphocyte transformation. J Virol 65, 6826-6837.
Menezes, J., Leibold, W., Klein, G. & Clements, G. (1975). Establishment and characterization of an Epstein-Barr virus (EBC)-negative lymphoblastoid B cell line (BJA-B) from an exceptional, EBV-genome-negative African Burkitt's lymphoma. Biomedicine / [publiee pour l'AAICIG] 22, 276-284.
Miao, H., Li, D. Q., Mukherjee, A., Guo, H., Petty, A., Cutter, J., Basilion, J. P., Sedor, J., Wu, J., Danielpour, D., Sloan, A. E., Cohen, M. L. & Wang, B. (2009). EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer cell 16, 9-20.
Milanini-Mongiat, J., Pouyssegur, J. & Pages, G. (2002). Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. The Journal of biological chemistry 277, 20631-20639.
Miller, G., Shope, T., Lisco, H., Stitt, D. & Lipman, M. (1972). Epstein-Barr virus: transformation, cytopathic changes, and viral antigens in squirrel monkey and marmoset leukocytes. Proc Natl Acad Sci U S A 69, 383-387.
Miller, N. & Hutt-Fletcher, L. M. (1988). A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein-Barr virus. J Virol 62, 2366-2372.
Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y. & Pasquale, E. B. (2003). Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature neuroscience 6, 153-160.
Narayan, G., Pulido, H. A., Koul, S., Lu, X. Y., Harris, C. P., Yeh, Y. A., Vargas, H., Posso, H., Terry, M. B., Gissmann, L., Schneider, A., Mansukhani, M., Rao, P. H. & Murty, V. V. (2003). Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression. Oncogene 22, 3489-3499.
Nie, D., Di Nardo, A., Han, J. M., Baharanyi, H., Kramvis, I., Huynh, T., Dabora, S., Codeluppi, S., Pandolfi, P. P., Pasquale, E. B. & Sahin, M. (2010). Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature neuroscience 13, 163-172.
Nishikawa, J., Imai, S., Oda, T., Kojima, T., Okita, K. & Takada, K. (1999). Epstein-Barr virus promotes epithelial cell growth in the absence of EBNA2 and LMP1 expression. Journal of virology 73, 1286-1292.
Oertel, S. H., Verschuuren, E., Reinke, P., Zeidler, K., Papp-Vary, M., Babel, N., Trappe, R. U., Jonas, S., Hummel, M., Anagnostopoulos, I., Dorken, B. & Riess, H. B. (2005). Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 5, 2901-2906.
Oshima, T., Akaike, M., Yoshihara, K., Shiozawa, M., Yamamoto, N., Sato, T., Akihito, N., Nagano, Y., Fujii, S., Kunisaki, C., Wada, N., Rino, Y., Tanaka, K., Masuda, M. & Imada, T. (2008). Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. International journal of oncology 33, 573-577.
Oyama, T., Ichimura, K., Suzuki, R., Suzumiya, J., Ohshima, K., Yatabe, Y., Yokoi, T., Kojima, M., Kamiya, Y., Taji, H., Kagami, Y., Ogura, M., Saito, H., Morishima, Y. & Nakamura, S. (2003). Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. The American journal of surgical pathology 27, 16-26.
Pasquale, E. B. (2005). Eph receptor signalling casts a wide net on cell behaviour. Nature reviews Molecular cell biology 6, 462-475.
Pasquale, E. B. (2010). Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nature reviews Cancer 10, 165-180.
Pope, J. H., Achong, B. G. & Epstein, M. A. (1968). Cultivation and fine structure of virus-bearing lymphoblasts from a second New Guinea Burkitt lymphoma: establishment of sublines with unusual cultural properties. International journal of cancer Journal international du cancer 3, 171-182.
Prevost, N., Woulfe, D., Tanaka, T. & Brass, L. F. (2002). Interactions between Eph kinases and ephrins provide a mechanism to support platelet aggregation once cell-to-cell contact has occurred. Proceedings of the National Academy of Sciences of the United States of America 99, 9219-9224.
Prevost, N., Woulfe, D. S., Tognolini, M., Tanaka, T., Jian, W., Fortna, R. R., Jiang, H. & Brass, L. F. (2004). Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1. Blood 103, 1348-1355.
Ragoczy, T., Heston, L. & Miller, G. (1998). The Epstein-Barr virus Rta protein activates lytic cycle genes and can disrupt latency in B lymphocytes. J Virol 72, 7978-7984.
Richter, M., Murai, K. K., Bourgin, C., Pak, D. T. & Pasquale, E. B. (2007). The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 14205-14215.
Rickinson, A. B. & Kieff, E. (2007). Epstein-Barr virus. In Fields' virology 5 edn edn, pp. 2655-2700. Edited by D. M. Knipe & P. M. Howley: Lippincott Williams & Wilkins, Philadelphia, Pa
Roberts, M. L., Luxembourg, A. T. & Cooper, N. R. (1996). Epstein-Barr virus binding to CD21, the virus receptor, activates resting B cells via an intracellular pathway that is linked to B cell infection. J Gen Virol 77 ( Pt 12), 3077-3085.
Robinson, D. R., Wu, Y. M. & Lin, S. F. (2000). The protein tyrosine kinase family of the human genome. Oncogene 19, 5548-5557.
Saintigny, P., Peng, S., Zhang, L., Sen, B., Wistuba, II, Lippman, S. M., Girard, L., Minna, J. D., Heymach, J. V. & Johnson, F. M. (2012). Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion. Molecular cancer therapeutics 11, 2021-2032.
Savard, M., Belanger, C., Tardif, M., Gourde, P., Flamand, L. & Gosselin, J. (2000). Infection of primary human monocytes by Epstein-Barr virus. Journal of virology 74, 2612-2619.
Sinclair, A. J., Brimmell, M., Shanahan, F. & Farrell, P. J. (1991). Pathways of activation of the Epstein-Barr virus productive cycle. J Virol 65, 2237-2244.
Singh, A., Winterbottom, E. & Daar, I. O. (2012). Eph/ephrin signaling in cell-cell and cell-substrate adhesion. Frontiers in bioscience (Landmark edition) 17, 473-497.
Sixbey, J. W., Nedrud, J. G., Raab-Traub, N., Hanes, R. A. & Pagano, J. S. (1984). Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310, 1225-1230.
Soni, V., Cahir-McFarland, E. & Kieff, E. (2007). LMP1 TRAFficking activates growth and survival pathways. Advances in experimental medicine and biology 597, 173-187.
Spriggs, M. K., Armitage, R. J., Comeau, M. R., Strockbine, L., Farrah, T., Macduff, B., Ulrich, D., Alderson, M. R., Mullberg, J. & Cohen, J. I. (1996). The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation. J Virol 70, 5557-5563.
Straathof, K. C., Savoldo, B., Heslop, H. E. & Rooney, C. M. (2002). Immunotherapy for post-transplant lymphoproliferative disease. British journal of haematology 118, 728-740.
Swerdlow, S. H., Campo, E., Pileri, S. A., Harris, N. L., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G. A., Zelenetz, A. D. & Jaffe, E. S. (2016). The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood.
Takeuchi, S., Yamaki, N., Iwasato, T., Negishi, M. & Katoh, H. (2009). Beta2-chimaerin binds to EphA receptors and regulates cell migration. FEBS letters 583, 1237-1242.
Thompson, M. P. & Kurzrock, R. (2004). Epstein-Barr Virus and Cancer. Clinical Cancer Research 10, 803-821.
Thornburg, N. J. & Raab-Traub, N. (2007). Induction of epidermal growth factor receptor expression by Epstein-Barr virus latent membrane protein 1 C-terminal-activating region 1 is mediated by NF-kappaB p50 homodimer/Bcl-3 complexes. Journal of virology 81, 12954-12961.
Tomkinson, B., Robertson, E. & Kieff, E. (1993). Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol 67, 2014-2025.
Tsai, S. C., Lin, S. J., Chen, P. W., Luo, W. Y., Yeh, T. H., Wang, H. W., Chen, C. J. & Tsai, C. H. (2009). EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood 114, 109-118.
Tsai, S. C., Lin, S. J., Lin, C. J., Chou, Y. C., Lin, J. H., Yeh, T. H., Chen, M. R., Huang, L. M., Lu, M. Y., Huang, Y. C., Chen, H. Y. & Tsai, C. H. (2013). Autocrine CCL3 and CCL4 induced by the oncoprotein LMP1 promote Epstein-Barr virus-triggered B cell proliferation. Journal of virology 87, 9041-9052.
Tworkoski, K. & Raab-Traub, N. (2015). LMP1 promotes expression of insulin-like growth factor 1 (IGF1) to selectively activate IGF1 receptor and drive cell proliferation. Journal of virology 89, 2590-2602.
Urier, G., Buisson, M., Chambard, P. & Sergeant, A. (1989). The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J 8, 1447-1453.
Winter, J., Roepcke, S., Krause, S., Muller, E. C., Otto, A., Vingron, M. & Schweiger, S. (2008). Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines. PloS one 3, e2780.
Yan, Y., Luo, Y. C., Wan, H. Y., Wang, J., Zhang, P. P., Liu, M., Li, X., Li, S. & Tang, H. (2013). MicroRNA-10a is involved in the metastatic process by regulating Eph tyrosine kinase receptor A4-mediated epithelial-mesenchymal transition and adhesion in hepatoma cells. Hepatology 57, 667-677.
Yao, Q. Y., Rickinson, A. B. & Epstein, M. A. (1985). A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. International journal of cancer Journal international du cancer 35, 35-42.
Yaswen, L. R., Stephens, E. B., Davenport, L. C. & Hutt-Fletcher, L. M. (1993). Epstein-Barr virus glycoprotein gp85 associates with the BKRF2 gene product and is incompletely processed as a recombinant protein. Virology 195, 387-396.
Yates, J. L., Warren, N. & Sugden, B. (1985). Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313, 812-815.
Yokote, H., Fujita, K., Jing, X., Sawada, T., Liang, S., Yao, L., Yan, X., Zhang, Y., Schlessinger, J. & Sakaguchi, K. (2005). Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains. Proceedings of the National Academy of Sciences of the United States of America 102, 18866-18871.
Young, L. S. & Rickinson, A. B. (2004). Epstein-Barr virus: 40 years on. Nature reviews Cancer 4, 757-768.
Yumoto, N., Wakatsuki, S., Kurisaki, T., Hara, Y., Osumi, N., Frisen, J. & Sehara-Fujisawa, A. (2008). Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction. PloS one 3, e3322.

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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
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