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Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer.

ABSTRACT: Matrix metalloproteinase-2 (MMP-2) expression is often up-regulated in advanced cancers and known to play an important role in tumor angiogenesis. We previously showed that adenoviral-mediated delivery of siRNA for MMP-2 (Ad-MMP-2-Si) inhibited lung cancer growth, angiogenesis, and metastasis. In this study, we investigated the signaling mechanisms involved in Ad-MMP-2-Si-mediated inhibition of angiogenesis. Ad-MMP-2-Si treatment inhibited neovascularization in vivo as determined by mouse dorsal air sac model, and conditioned medium from Ad-MMP-2-Si-infected A549 lung cancer cells (Ad-MMP-2-Si-CM) inhibited endothelial tube formation in vitro. Ad-MMP-2-Si-CM decreased proliferation as determined by Ki-67 immunofluorescence and induced apoptosis in endothelial cells as determined by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) assay. Furthermore, Ad-MMP-2-Si-CM inhibited AKT phosphorylation and induced phosphorylation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase in endothelial cells. Overexpression of constitutively active AKT reversed the Ad-MMP-2-Si-CM-mediated inhibition of tube formation and induction of ERK phosphorylation. Conversely, Ad-MMP-2-Si-CM induced tissue inhibitor of metalloproteinase (TIMP) 3 expression, and the interaction of vascular endothelial growth factor 2 and TIMP-3 was determined by coimmunoprecipitation experiments. TIMP-3 induction was mediated by ERK activation. In addition, electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1 transcription factor mediated Ad-MMP-2-Si-CM-stimulated increase of TIMP-3. Vasculature destruction was confirmed with colocalization studies with TUNEL and an endothelial marker, CD31, in tumor sections of Ad-MMP-2-Si-treated mice. Our data collectively suggest that MMP-2 inhibition induces endothelial apoptosis in vivo and inhibits endothelial tube formation. These experiments provide the first evidence that inhibition of p-AKT and induction of p-ERK1/2 are crucial events in the induction of TIMP-3-mediated endothelial apoptosis in MMP-2 inhibited lung tumors.

SUBMITTER: Chetty C

PROVIDER: S-EPMC2586602 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer.

Chetty Chandramu C Lakka Sajani S SS Bhoopathi Praveen P Kunigal Sateesh S Geiss Roger R Rao Jasti S JS

Cancer research 20080601 12

Matrix metalloproteinase-2 (MMP-2) expression is often up-regulated in advanced cancers and known to play an important role in tumor angiogenesis. We previously showed that adenoviral-mediated delivery of siRNA for MMP-2 (Ad-MMP-2-Si) inhibited lung cancer growth, angiogenesis, and metastasis. In this study, we investigated the signaling mechanisms involved in Ad-MMP-2-Si-mediated inhibition of angiogenesis. Ad-MMP-2-Si treatment inhibited neovascularization in vivo as determined by mouse dorsal ...[more]

PMID: 18559520

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Project description:Myocardial ischemia/reperfusion (I/R) injury is a serious complication of reperfusion therapy for myocardial infarction. At present, there is not an effective treatment strategy available for myocardial I/R. The present study aimed to investigate the effects of human tissue kallikrein 1 (hTK1) and human tissue inhibitors of matrix metalloproteinase 1 (hTIMP1) gene co‑expression on myocardial I/R injury. A rat model of myocardial I/R injury and a cell model with hypoxia/reoxygenation (H/R) treatment in cardiac microvascular endothelial cells (CMVECs) were established, and treated with adenovirus (Ad)‑hTK1/hTIMP1. Following which, histological and triphenyl‑tetrazolium‑chloride staining assays were performed. Cardiac function was tested by echocardiographic measurement. The serum levels of oxidative stress biomarkers in rats and the intracellular reactive oxygen species (ROS) levels in CMVECs were measured. Additionally, experiments, including immunostaining, reverse transcription‑quantitative PCR, western blotting, and MTT, wound healing, Transwell and tube formation assays were also performed. The results of the present study demonstrated that Ad‑hTK1/hTIMP1 alleviated myocardial injury and improved cardiac function in myocardial I/R model rats. Ad‑hTK1/hTIMP1 also significantly enhanced microvessel formation, decreased matrix metalloproteinase (MMP)2 and MMP9 expression, and reduced oxidative stress in myocardial I/R model rats. Furthermore, Ad‑hTK1/hTIMP1 significantly enhanced proliferation, migration and tube formation in H/R‑treated CMVECs. Additionally, Ad‑hTK1/hTIMP1 significantly decreased intracellular ROS production and γ‑H2A.X variant histone expression levels in H/R‑treated CMVECs. In conclusion, the results of the present study demonstrated that co‑expression of hTK1 and hTIMP1 genes displayed significant protective effects on myocardial I/R injury by promoting angiogenesis and suppressing oxidative stress; therefore, co‑expression of hTK1 and hTIMP1 may serve as a potential therapeutic strategy for myocardial I/R injury.

Dataset Information

Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer.

Publications

Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer.

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