Constitutive Release of Metalloproteinase-9 (92-kd Type IV Collagenase) by Kaposi's Sarcoma Cells

Blankaert, D.; Simonart, Th.; Vooren, J. P. Van; Parent, Dominique; Liesnard, Corinne; Farber, Claire-Michèle; Marique, Thierry; Wérenne, John

doi:10.1097/00042560-199807010-00002

Cited by 33 publications

(41 citation statements)

References 35 publications

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“…Western blots usually failed to resolve the three isoforms of the MMPs because of the diffusion of the proteins during transfer from gels to the membranes. 6 hpi, which peaked at 24 hpi and was sustained for up to 48 hpi (Fig. 4C).…”

Section: Kshv Infection Enhances Huvec Invasion Of the Extracellular mentioning

confidence: 92%

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

Qian

Xie

et al. 2007

J Virol

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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 Matrigelbased 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.

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Section: Kshv Infection Enhances Huvec Invasion Of the Extracellular mentioning

confidence: 92%

“…A number of MMPs, including MMP-1, -2, -3, -9, and -19, have been detected in KS tumor cells, implicating their roles in the pathogenesis of these tumors (6,23,29,42). Indeed, an inhibitor of MMPs, COL-3, had an overall 44% response rate in AIDS-KS patients.…”

mentioning

confidence: 99%

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

Qian

Xie

et al. 2007

J Virol

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“…Of these cytokines, IL-2, tumor necrosis factor alpha, and IFN-␥ are elevated in KD. Furthermore, pro-MMP-9 levels have been demonstrated to be elevated in certain viral infections, most notably those caused by retroviruses and herpesviruses (2,8,9,19,33). Recently, Takeshita and colleagues suggested that the acutephase response to lipopolysaccharide may be involved in the pathogenesis of KD, supporting the thesis that KD may have an infectious and/or postinfectious etiology (36).…”

Section: Vol 10 2003 Elevated Pro-mmp-9 and Timp-1 In Kd 311mentioning

confidence: 96%

Elevated Levels of Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 during the Acute Phase of Kawasaki Disease

Chua

Melish

et al. 2003

Clin Vaccine Immunol

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Kawasaki disease (KD) is an acute, self-limiting, multisystem vasculitis of unknown etiology affecting infants and young children. Unless treated promptly with high-dose intravenous gamma globulin and aspirin, patients frequently develop coronary aneurysms. Previously, matrix metalloproteinase 9 (MMP-9), which is secreted complexed to tissue inhibitor of metalloproteinase 1 (TIMP-1), has been implicated in abdominal aortic aneurysm formation. Since the clinical and pathological features of KD include inflammation and weakening of blood vessels, we analyzed acute-and convalescent-phase paired plasma or serum samples from 31 KD patients, 7 patients who did not completely meet the criteria for KD, and 26 non-KD controls (9 febrile and 17 afebrile patients) for pro-MMP-9 (92 kDa) enzyme activity by gelatin zymography and for active MMP-9 (83 kDa), pro-MMP-9, and TIMP-1 protein levels by enzyme-linked immunosorbent assay. Statistical analysis was performed by using Student t tests, linear regression, and the Wilcoxon rank-sum test. Markedly elevated pro-MMP-9 enzymatic activity, pro-MMP-9 protein levels, and TIMP-1 protein levels were found during the acute phase of illness in patients with clinically established KD and in patients who were suspected of having KD but did not meet all of the criteria. There was no significant difference in active MMP-9 levels. Furthermore, pro-MMP-9 and TIMP-1 protein levels were significantly elevated among KD patients, compared to those of febrile and afebrile non-KD controls. The significantly elevated pro-MMP-9 enzyme and protein levels during the acute phase of KD may reflect vascular remodeling or an inflammatory response to a microbial agent, suggesting a pathophysiological role for MMP-9 in coronary aneurysm formation.

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“…19,22 In addition, KS-derived cells constitutively release matrix metalloproteinase 9 (MMP-9). 23 KSHV encodes for many proteins, and some of these are involved in cell proliferation and the up-regulation of angiogenesis. The viral G protein-coupled receptor (vGPCR) is a homolog of the human IL-8 receptor that induces expression of mitogenic and angiogenic growth factors including VEGF.…”

Section: Introductionmentioning

confidence: 99%

Latent KSHV infection increases the vascular permeability of human endothelial cells

Guilluy¹,

Zhang

Bhende

et al. 2011

Blood

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Kaposi sarcoma-associated herpesvirus (KSHV) is associated with 3 different human malignancies: Kaposi sarcoma (KS), primary effusion lymphoma, and multicentric Castleman disease. The KS lesion is driven by KSHV-infected endothelial cells and is highly dependent on autocrine and paracrine factors for survival and growth. We report that latent KSHV infection increases the vascular permeability of endothelial cells. Endothelial cells with latent KSHV infection display increased Rac1 activation and activation of its downstream modulator, p21-activated kinase 1 (PAK1). The KSHV-infected cells also exhibit increases in tyrosine phosphorylation of vascular endothelial (VE)-cadherin and ␤-catenin, whereas total levels of these proteins remained unchanged, suggesting that latent infection disrupted endothelial cell junctions. Consistent with these findings, we found that KSHVinfected endothelial cells displayed increased permeability compared with uninfected endothelial cells. Knockdown of Rac1 and inhibition of reactive oxygen species (ROS) resulted in decreased permeability in the KSHV-infected endothelial cells. We further demonstrate that the KSHV K1 protein can activate Rac1. Rac1 was also highly activated in KSHVinfected endothelial cells and KS tumors. In conclusion, KSHV latent infection increases Rac1 and PAK1 activity in endothelial cells, resulting in the phosphorylation of VE-cadherin and ␤-catenin and leading to the disassembly of cell junctions and to increased vascular permeability of the infected endothelial cells. (Blood. 2011;118(19):5344-5354) IntroductionThe endothelial cell barrier function is regulated by vascular endothelial (VE)-cadherin-containing adherens junctions in addition to tight junctions. 1 VE-cadherin is involved in maintaining the integrity of endothelial cell junctions by preventing the disassembly of the endothelial barrier and regulating the movement of macromolecules through the endothelium. 1-3 However, upon VEGF stimulation, these normal endothelial cell junctions are reorganized to allow the extravasation of cellular factors. 4 This involves the disruption of VE-cadherin at the adherens junction 2,4,5 and internalization of VE-cadherin from the cell surface. 6 VEGF stimulation leads to the induction of Rac1 activity 7,8 and its downstream effector, p21-activated kinase 1 (PAK1). 8 In addition, Rac1 has also been shown to regulate VE-cadherin phosphorylation through the generation of reactive oxygen species (ROS). 9,10 Kaposi sarcoma (KS) is a multifocal vascular tumor of mixed cellular composition. KS lesions are composed of a mixed population of cells, including spindle-shaped endothelial cells and infiltrating leukocytes. 11,12 KS is the most common neoplasm in patients with AIDS. Areas that have the highest HIV burden, such as sub-Saharan Africa, also have the highest rate of KS. KSassociated herpesvirus (KSHV) is the etiological agent found in all epidemiologic forms of KS, 13 and viral genomic DNA is present in AIDS-associated KS, as well as in HIV-negative classic and tra...

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Constitutive Release of Metalloproteinase-9 (92-kd Type IV Collagenase) by Kaposi's Sarcoma Cells

Cited by 33 publications

References 35 publications

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

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

Elevated Levels of Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 1 during the Acute Phase of Kawasaki Disease

Latent KSHV infection increases the vascular permeability of human endothelial cells

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