Open AccessKSHV G-protein coupled receptor vGPCR oncogenic signaling upregulation of Cyclooxygenase-2 expression mediates angiogenesis and tumorigenesis in Kaposi’s sarcoma
Author(s) -
María Victoria Medina,
Agata D ́Agostino,
Qi Ma,
Pîlar Eroles,
Lucas E. Cavallin,
Chiara Chiozzini,
Daiana Sapochnik,
Cora Cymeryng,
Elizabeth Hyjek,
Ethel Cesarman,
Julián Naipauer,
Enrique A. Mesri,
Omar A. Coso
Publication year - 2020
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009006
Subject(s) - angiogenesis , carcinogenesis , downregulation and upregulation , mapk/erk pathway , signal transduction , cancer research , kaposi's sarcoma associated herpesvirus , biology , kaposi's sarcoma , g protein coupled receptor , gene silencing , microbiology and biotechnology , immunology , cancer , gene , genetics , virus , human herpesvirus , viral disease , herpesviridae
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.