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J. Virol. doi:10.1128/JVI.00016-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Infection Promotes Invasion of Primary Human Umbilical Vein Endothelial Cells by Inducing Matrix Metalloproteinases

Tumor Virology Program, Greehey Children's Cancer Research Institute; Departments of Pediatrics, Microbiology and Immunology, and Molecular Medicine; and San Antonio Cancer Institute, The University of Texas Health Science Center, San Antonio, TX, USA; and Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

^* To whom correspondence should be addressed. Email: gaos{at}uthscsa.edu.

	Abstract

Matrix metalloproteinases (MMPs) play important roles in cancer invasion, angiogenesis and inflammatory infiltration. Kaposi's sarcoma is a highly disseminated angiogenic tumor of proliferative endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we showed that KSHV infection increased the invasiveness of primary human umbilical vein endothelial cells (HUVEC) in a Matrigel-based cell invasion assay. KSHV-induced cell invasion was abolished by an inhibitor of MMPs, BB94, and occurred in both autocrine and paracrine-dependent fashions. Analysis by zymography and Western-blotting showed that KSHV-infected HUVEC cultures had increased secretion of MMP-1, -2, and -9. KSHV increased the secretion of MMP-2 within 1 h following infection without upregulating its mRNA expression level. In contrast, the secretion of MMP-1 and -9 was not increased until 6 h following KSHV infection, and was correlated with the upregulation of their mRNA expression levels. Promoter analysis by reporter assays and electrophoretic mobility shift assays identified an AP-1 cis-element as the dominant KSHV-responsive site in the MMP-1 promoter. Together, these results suggest that KSHV infection modulates the production of multiple MMPs to increase cell invasiveness, and thus contributes to the pathogenesis of KSHV-induced malignancies.

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