title: Regulation of EBV LMP1-triggered EphA4 downregulation in EBV-associated B lymphoma and its impact on patients' survival.
abstract: Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant 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 erythropoietin-producing hepatocellular receptor A4 (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 extracellular signal-regulated kinase (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(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set 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(+) PTLD and DLBCL.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Research Center for Emerging Viral Infections and Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan;
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Kai-Min
authors.initials: KM
authors.lastname: Lin
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chou
authors.affiliation: Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Chung-Wu
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Shan-Chi
authors.initials: SC
authors.lastname: Yu
authors.affiliation: Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan;
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Plant Pathology and Microbiology, National Taiwan University, Taipei, Taiwan;
authors.forename: Tang-Long
authors.initials: TL
authors.lastname: Shen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Kuan
authors.initials: CK
authors.lastname: Chen
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan; and.
authors.forename: Jean
authors.initials: J
authors.lastname: Lu
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Mei-Ru
authors.initials: MR
authors.lastname: Chen
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Tsai
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000821:virology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D004854:Herpesvirus 4, Human; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000401:mortality* / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000378:metabolism / Q000401:mortality* / Q000821:virology; D011379:Prognosis; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015996:Survival Rate; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D036122:Receptor, EphA4; D048049:Extracellular Signal-Regulated MAP Kinases