title: KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS)-one of the most common tumors arising in the setting of immune suppression. Hallmarks of KS lesions include KSHV-infected cells of endothelial lineage and neoangiogenesis. Promigratory factors secreted in the tumor microenvironment by KSHV-infected cells promote endothelial cell (EC) migration and angiogenesis but existing therapies targeting these pathways are not widely utilized. This underscores the need for additional characterization of KSHV-host interactions relevant to EC pathogenesis to identify new therapeutic targets. We recently demonstrated that de novo infection by KSHV promotes EC invasion through upregulation of extracellular matrix metalloproteinase inducer (emmprin)-a multifunctional glycoprotein previously shown to induce tumor cell invasion and regional angiogenesis through upregulation of signal transduction and promotion of tumor-stroma interactions. This study was undertaken to determine whether EC invasion for KSHV-infected cells is induced through activation of specific signal transduction pathways and proangiogenic factors by emmprin. We found that KSHV activation of emmprin induces PI3K/Akt- and mitogen-activated protein kinase (MAPK)-dependent secretion of vascular endothelial growth factor (VEGF). Functionally, EC invasion following de novo infection is induced by emmprin-dependent PI3K/Akt and MAPK activation of VEGF. These findings support the potential utility of targeting emmprin for reducing VEGF secretion and EC migration in the KS microenvironment.
authors.affiliation: Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.forename: Momka
authors.initials: M
authors.lastname: Bratoeva
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Toole
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Qin
authors.forename: Chris
authors.initials: C
authors.lastname: Parsons
mesh_terms: D051926:Basigin / Q000502:physiology*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C497886:BSG protein, human; D042461:Vascular Endothelial Growth Factor A; D051926:Basigin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases