title: Kaposi's sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases.
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, BB-94, 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 after 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.
authors: Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors: Li-Wu
authors: LW
authors: Qian
authors: Jianping
authors: J
authors: Xie
authors: Fengchun
authors: F
authors: Ye
authors: Shou-Jiang
authors: SJ
authors: Gao
mesh_terms: D019898:Autocrine Communication / Q000187:drug effects; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D019899:Paracrine Communication / Q000187:drug effects; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020218:Response Elements; D012514:Sarcoma, Kaposi / Q000201:enzymology* / Q000473:pathology; D013876:Thiophenes / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014471:Umbilical Veins / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D011480:Protease Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013876:Thiophenes; D018808:Transcription Factor AP-1; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases