Epstein-Barr virus induces invasion and metastasis factors.
The oncogenic properties of the principal EBV oncoprotein, Latent Membrane Protein 1 (LMP-1), include the ability to induce invasiveness and metastasis factors. We have shown that LMP-1 induces matrix metalloproteinase 9 (MMP-9), a type IV collagenase that disrupts basement membrane. Also, cyclooxygenase-2 (COX-2), which is overexpressed in diverse malignancies, is induced by LMP-1; the enzyme is functional, and co-expressed with LMP-1 in NPC. Inhibitors of the NF kappa B signaling pathway, which is activated by LMP-1, including I kappa B super-repressor and aspirin reduce or cancel induction of MMP-9, COX-2 and invasiveness of LMP-1-expressing cells. Production of VEGF, also induced by LMP-1, is decreased by a COX-2-specific inhibitor. We now show that LMP-1 induces expression of the angiogenic Fibroblast Growth Factor-2 (FGF-2). Furthermore, LMP-1 also causes secretion of the 18 kDa isoform of this protein--a newly identified function for LMP-1. Secretion of FGF-2 is independently signaled through the NF-kappa B pathway. Release of the protein is not dependent on the classical ER/Golgi secretory pathway, but secretion of FGF-2 is suppressed by ouabain, an inhibitor of the Na+/K(+)-ATPase alpha 1 subunit. Finally LMP-1 induces expression of Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha), which mediates adaptation of cells to O2-depleted states. Thus LMP-1 is not only directly oncogenic, it can induce a constellation of factors that reveal the additional role of EBV in invasive cancers such as NPC. Alteration of cellular phenotype independent of transforming effects may be a property of other tumor viruses.
Wakisaka
Naohiro
N
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA.
Pagano
Joseph S
JS
D000818:Animals; D051546:Cyclooxygenase 2; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004790:Enzyme Induction; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014763:Viral Matrix Proteins / Q000378:metabolism / Q000502:physiology
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014763:Viral Matrix Proteins; D016222:Fibroblast Growth Factor 2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9