An NF-kappaB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia.
Kaposi's sarcoma (KS) is the most frequent AIDS-associated malignancy, etiologically linked to the infection with the human herpesvirus 8 (HHV-8/KSHV). This member of the gamma-herpesviridae family encodes 81 open reading frames, several bearing oncogenic potential. A constitutively active virally encoded G protein-coupled receptor (vGPCR) readily induces KS-like lesions when expressed in endothelial cells in vivo, and unmasks the oncogenic potential of other HHV-8 genes in a paracrine fashion. How vGPCR causes endothelial cell transformation is still not fully understood. Using full-genome microarray analysis we show here that the expression of nuclear factor-kappaB (NF-kappaB)-regulated genes is a prominent feature triggered by vGPCR in cells expressing this viral oncogene and in cells exposed to vGPCR-induced secretions, thus mimicking its paracrine effect. Indeed, vGPCR activates the NF-kappaB pathway potently, and NF-kappaB activation is a hallmark of both human and experimental KS. Of interest, whereas constitutive NF-kappaB signaling is not sufficient to promote endothelial cells transformation, NF-kappaB function is strictly required for vGPCR-induced direct and paracrine neoplasia. Taken together, these results strongly support the role of NF-kappaB regulated genes in KS pathogenesis, thus providing the rationale for the development of novel mechanism-based therapies for this angioproliferative disease.
Martin
D
D
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4330, USA.
Galisteo
R
R
Ji
Y
Y
Montaner
S
S
Gutkind
J S
JS
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D019707:Receptors, Chemokine / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050863:Synaptotagmin I / Q000378:metabolism; D014183:Transplantation, Heterologous
C115448:G protein-coupled receptor, Human herpesvirus 8; D016328:NF-kappa B; D019707:Receptors, Chemokine; D050863:Synaptotagmin I