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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References
Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E . (1997). Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385: 347–350.
Asou H, Said JW, Yang R, Munker R, Park DJ, Kamada N et al. (1998). Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. Blood 91: 2475–2481.
Bais C, Santomasso B, Coso O, Arvanitakis L, Raaka EG, Gutkind JS et al. (1998). G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391: 86–89.
Balkwill F . (2004). Cancer and the chemokine network. Nat Rev Cancer 4: 540–550.
Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS . (2004). Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64: 5212–5224.
Bower M, Palmieri C, Dhillon T . (2006). AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy. Curr Opin Infect Dis 19: 14–19.
Cesarman E, Mesri EA . (2007). Kaposi sarcoma-associated herpesvirus and other viruses in human lymphomagenesis. Curr Top Microbiol Immunol 312: 263–287.
Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.
Dorsam RT, Gutkind JS . (2007). G-protein-coupled receptors and cancer. Nat Rev Cancer 7: 79–94.
Ensoli B, Nakamura S, Salahuddin SZ, Biberfeld P, Larsson L, Beaver B et al. (1989). AIDS-Kaposi's sarcoma-derived cells express cytokines with autocrine and paracrine growth effects. Science 243: 223–226.
Guasparri I, Keller SA, Cesarman E . (2004). KSHV vFLIP is essential for the survival of infected lymphoma cells. J Exp Med 199: 993–1003.
Hamilton TA, Ohmori Y, Tebo J . (2002). Regulation of chemokine expression by antiinflammatory cytokines. Immunol Res 25: 229–245.
Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR et al. (2003). Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem 278: 8508–8515.
Hiscott J, Nguyen TL, Arguello M, Nakhaei P, Paz S . (2006). Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene 25: 6844–6867.
Kanegane H, Wakiguchi H, Kanegane C, Kurashige T, Tosato G . (1997). Viral interleukin-10 in chronic active Epstein–Barr virus infection. J Infect Dis 176: 254–257.
Karin M . (2006). Nuclear factor-kappaB in cancer development and progression. Nature 441: 431–436.
Montaner S, Sodhi A, Molinolo A, Bugge TH, Sawai ET, He Y et al. (2003). Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3: 23–36.
Montaner S, Sodhi A, Pece S, Mesri EA, Gutkind JS . (2001). The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res 61: 2641–2648.
Montaner S, Sodhi A, Ramsdell AK, Martin D, Hu J, Sawai ET et al. (2006). The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma. Cancer Res 66: 168–174.
Morris K . (2003). Cancer? In Africa? Lancet Oncol 4: 5.
Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Duran EM et al. (2007). In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced kaposi's sarcoma. Cancer Cell 11: 245–258.
Pelengaris S, Khan M, Evan G . (2002). c-MYC: more than just a matter of life and death. Nat Rev Cancer 2: 764–776.
Rezza G, Andreoni M, Dorrucci M, Pezzotti P, Monini P, Zerboni R et al. (1999). Human herpesvirus 8 seropositivity and risk of Kaposi's sarcoma and other acquired immunodeficiency syndrome-related diseases. J Natl Cancer Inst 91: 1468–1474.
Schwarz M, Murphy PM . (2001). Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-kappa B and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J Immunol 167: 505–513.
Sciacca FL, Sturzl M, Bussolino F, Sironi M, Brandstetter H, Zietz C et al. (1994). Expression of adhesion molecules, platelet-activating factor, and chemokines by Kaposi's sarcoma cells. J Immunol 153: 4816–4825.
Sodhi A, Montaner S, Gutkind JS . (2004). Viral hijacking of G-protein-coupled-receptor signalling networks. Nat Rev Mol Cell Biol 5: 998–1012.
Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M et al. (2000). Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J Exp Med 191: 445–454.
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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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