The Human Cytomegalovirus–Encoded Chemokine Receptor US28 Promotes Angiogenesis and Tumor Formation via Cyclooxygenase-2

¹Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam; ²Department of Otolaryngology/Head and Neck Surgery, Vrije Universiteit Medical Center, Amsterdam, the Netherlands; ³Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands; and ⁴Institute of Virology, University Clinic Ulm, Ulm, Germany

^* To whom correspondence should be addressed. E-mail: mj.smit{at}few.vu.nl.

	Abstract

The human cytomegalovirus (HCMV), potentially associated with the development of malignancies, encodes the constitutively active chemokine receptor US28. Previously, we have shown that US28 expression induces an oncogenic phenotype both in vitro and in vivo. Microarray analysis revealed differential expression of genes involved in oncogenic signaling in US28-expressing NIH-3T3 cells. In particular, the expression of cyclooxygenase-2 (COX-2), a key mediator of inflammatory diseases and major determinant in several forms of cancer, was highly up-regulated. US28 induced increases in COX-2 expression via activation of nuclear factor-B, driving the production of vascular endothelial growth factor. Also, in HCMV-infected cells, US28 contributed to the viral induction of COX-2. Finally, the involvement of COX-2 in US28-mediated tumor formation was evaluated using the COX-2 selective inhibitor Celecoxib. Targeting COX-2 in vivo with Celecoxib led to a marked delay in the onset of tumor formation in nude mice injected with US28-transfected NIH-3T3 cells and a reduction of subsequent growth by repressing the US28-induced angiogenic activity. Hence, the development of HCMV-related proliferative diseases may partially be ascribed to the ability of US28 to activate COX-2. [Cancer Res 2009;69(7):2861–9]

Key Words: viral chemokine receptor, cyclooxygenase-2 (COX-2), microarray, tumor formation, human cytomegalovirus

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