Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells.
Kaposi's sarcoma (KS) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and consists of proliferating spindle cells, which are related to lymphatic endothelial cells (LEC). Angiopoietin-2 (Ang2) is a secreted proangiogenic and lymphangiogenic molecule. Here, we show the expression of Ang2 protein in KS and confirm that KSHV infection up-regulates Ang2 in LEC. We show that a paracrine mechanism contributes to this up-regulation. A lentiviral library of individual KSHV-encoding genes, comprising the majority of known latent genes and a selection of lytic viral genes, was constructed to investigate the underlying mechanism of this up-regulation. Two lytic genes, viral interleukin-6 (vIL6) and viral G-protein-coupled receptor (vGPCR), up-regulated Ang2 expression in LEC. Both vIL6 and vGPCR are expressed in KSHV-infected LEC and caused up-regulation of Ang2 in a paracrine manner. KSHV, vIL6, and vGPCR up-regulated Ang2 through the mitogen-activated protein kinase (MAPK) pathway. Gene expression microarray analysis identified several other angiogenic molecules affected by KSHV, including the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis, which is also affected by vIL6 and vGPCR in LEC, and matrix metalloproteinases, which could act in concert with Ang2 to contribute to KS development. These findings support the paracrine and autocrine roles of the lytic KSHV-encoded proteins, vIL6 and vGPCR, in KS pathogenesis and identify Ang2 as a potential therapeutic target for this neoplasm.
Vart
Richard J
RJ
Cancer Research U.K. Viral Oncology Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
Nikitenko
Leonid L
LL
Lagos
Dimitrios
D
Trotter
Matthew W B
MW
Cannon
Mark
M
Bourboulia
Dimitra
D
Gratrix
Fiona
F
Takeuchi
Yasuhiro
Y
Boshoff
Chris
C
D042702:Angiopoietin-2 / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D015972:Gene Expression Regulation, Neoplastic; D015723:Gene Library; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000821:virology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D015854:Up-Regulation
D042702:Angiopoietin-2; D015850:Interleukin-6; D043562:Receptors, G-Protein-Coupled; D020928:Mitogen-Activated Protein Kinases