KSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi's sarcoma

Kaposi's sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi's sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a ke...

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Published in:	PLoS pathogens Vol. 16; no. 10; p. e1009006
Main Authors:	Medina, María Victoria, D Agostino, Agata, Ma, Qi, Eroles, Pilar, Cavallin, Lucas, Chiozzini, Chiara, Sapochnik, Daiana, Cymeryng, Cora, Hyjek, Elizabeth, Cesarman, Ethel, Naipauer, Julian, Mesri, Enrique A, Coso, Omar A
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 15-10-2020 Public Library of Science (PLoS)
Subjects:	3' Untranslated regions Acquired immune deficiency syndrome AIDS Angiogenesis Animal models Animals Biology Biology and life sciences Cancer Carcinogenesis Care and treatment Celecoxib Cell Transformation, Neoplastic - genetics Cellular signal transduction Consortia Control stability Cyclooxygenase-2 Cyclooxygenases Development and progression Endothelial Cells - metabolism Extracellular signal-regulated kinase G protein-coupled receptors Gene deletion Gene expression Genetic aspects Genomes GTP-Binding Proteins - genetics Health aspects Herpesvirus 8, Human - genetics Herpesvirus 8, Human - metabolism Immunology Inflammation Kaposi's sarcoma Kaposis sarcoma MAP kinase MAP Kinase Signaling System Matrix Metalloproteinase 2 - biosynthesis Matrix Metalloproteinase 2 - genetics Matrix Metalloproteinase 2 - metabolism Medicine Medicine and health sciences Mice Mice, Nude mRNA stability Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Neovascularization, Pathologic - virology NIH 3T3 Cells Nonsteroidal anti-inflammatory drugs Oncogenes Pathology Pathways Proteins Receptors Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Sarcoma Sarcoma, Kaposi - blood supply Sarcoma, Kaposi - metabolism Sarcoma, Kaposi - pathology Sarcoma, Kaposi - virology Signal Transduction Signaling Software Supervision Transcriptional Activation Transformed cells Tumorigenesis Tumors Argentina New York Florida United States > US
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Summary:	Kaposi's sarcoma-associated herpesvirus (KSHV) vGPCR is a constitutively active G protein-coupled receptor that subverts proliferative and inflammatory signaling pathways to induce cell transformation in Kaposi's sarcoma. Cyclooxygenase-2 (COX-2) is an inflammatory mediator that plays a key regulatory role in the activation of tumor angiogenesis. Using two different transformed mouse models and tumorigenic full KSHV genome-bearing cells, including KSHV-Bac16 based mutant system with a vGPCR deletion, we demostrate that vGPCR upregulates COX-2 expression and activity, signaling through selective MAPK cascades. We show that vGPCR expression triggers signaling pathways that upregulate COX-2 levels due to a dual effect upon both its gene promoter region and, in mature mRNA, the 3'UTR region that control mRNA stability. Both events are mediated by signaling through ERK1/2 MAPK pathway. Inhibition of COX-2 in vGPCR-transformed cells impairs vGPCR-driven angiogenesis and treatment with the COX-2-selective inhibitory drug Celecoxib produces a significant decrease in tumor growth, pointing to COX-2 activity as critical for vGPCR oncogenicity in vivo and indicating that COX-2-mediated angiogenesis could play a role in KS tumorigenesis. These results, along with the overexpression of COX-2 in KS lesions, define COX-2 as a potential target for the prevention and treatment of KSHV-oncogenesis.
Bibliography:	new_version The authors declare no competing financial interests.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1009006