Abstract
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 γ-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-κB (NF-κB)-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-κB pathway potently, and NF-κB activation is a hallmark of both human and experimental KS. Of interest, whereas constitutive NF-κB signaling is not sufficient to promote endothelial cells transformation, NF-κB function is strictly required for vGPCR-induced direct and paracrine neoplasia. Taken together, these results strongly support the role of NF-κB regulated genes in KS pathogenesis, thus providing the rationale for the development of novel mechanism-based therapies for this angioproliferative disease.
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This research was supported by a National Institutes of Health Intramural AIDS Targeted Antiviral Program grant and the National Institute of Dental and Craniofacial Research.
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Martin, D., Galisteo, R., Ji, Y. et al. An NF-κB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene 27, 1844–1852 (2008). https://doi.org/10.1038/sj.onc.1210817
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DOI: https://doi.org/10.1038/sj.onc.1210817
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