title: Epstein-Barr virus protein can upregulate cyclo-oxygenase-2 expression through association with the suppressor of metastasis Nm23-H1.
abstract: Previous studies have demonstrated the interaction between the Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and the metastatic suppressor Nm23-H1 both in vitro and in vivo (C. Subramanian, M. A. Cotter II, and E. S. Robertson, Nat. Med. 7:350-355, 2001). EBNA3C can reverse the ability of Nm23-H1 to suppress migration of Burkitt's lymphoma and breast carcinoma cell lines in vitro. EBNA3C contributes to EBV-associated human cancers by regulating transcription of a number of cellular and viral promoters and by targeting and altering the transcription activities of the metastasis suppressor Nm23-H1. Cyclo-oxygenase-2 (COX-2), an inducible enzyme important in inflammation, is overexpressed in a variety of cancers and can influence cell migration. In this report we show that Nm23-H1 and EBNA3C can modulate expression of COX-2 in the context of EBV infection and transformation. The levels of COX-2 were consistently higher in EBV-positive cells than in EBV-negative cells. Additionally, we show that Nm23-H1 can upregulate the COX-2 promoter element in luciferase reporter assays, whereas EBNA3C alone did not affect the level of response but clearly contributed to an additive increase when coexpressed with Nm23-H1. The downstream effect of COX-2 expression was also evaluated and showed that prostaglandin E(2) levels increased with Nm23-H1 and that there was some level of cooperativity in the presence of EBNA3C. The majority of this response was mediated through the cyclic AMP response element and NF-kappaB sites. These studies suggest a potential role for COX-2 in EBV-associated human cancers.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Kaul
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Verma
authors.forename: Masanao
authors.initials: M
authors.lastname: Murakami
authors.forename: Ke
authors.initials: K
authors.lastname: Lan
authors.forename: Tathagata
authors.initials: T
authors.lastname: Choudhuri
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000956:Antigens, Viral / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000503:physiopathology / Q000821:virology; D019309:Epstein-Barr Virus Nuclear Antigens; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D054778:NM23 Nucleoside Diphosphate Kinases; D009362:Neoplasm Metastasis; D009701:Nucleoside-Diphosphate Kinase / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000956:Antigens, Viral; D018076:DNA, Complementary; C498774:EBNA-3C, epstein-barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D016328:NF-kappa B; D054778:NM23 Nucleoside Diphosphate Kinases; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase