Endothelial progenitor cell–dependent angiogenesis requires localization of the full-length form of uPAR in caveolae

Margheri, Francesca; Chillà, Anastasia; Laurenzana, Anna; Serratì, Simona; Mazzanti, Benedetta; Saccardi, Riccardo; Santosuosso, Michela; Danza, Giovanna; Sturli, Niccolò; Rosati, Fabiana; Magnelli, Lucia; Papucci, Laura; Calorini, Lido; Bianchini, Francesca; Rosso, Mario Del; Fibbi, Gabriella

doi:10.1182/blood-2011-02-338681

Cited by 74 publications

(112 citation statements)

References 46 publications

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“…27 Overexpression of MMP12 controls uPAR-dependent activities required for tumor angiogenesis and malignant cells spreading. 28 In the present study, we found MMP12 knockdown downregulated the expression of PCNA and VEGF in LAC cells, suggesting that MMP12 might be involved in the development of LAC cells through the PCAN and VEGF expression.…”

Section: Discussionsupporting

confidence: 59%

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells

et al. 2015

Int J Immunopathol Pharmacol

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Matrix metalloproteinase-12 (MMP12) is involved in many pathological processes including cancer. The expression and function of MMP12 in lung adenocarcinoma (LAC) remain unclear. The present study aimed to investigate the correlation of MMP12 expression with LAC patients and clarify its role in growth and invasion of LAC cells. The expression of MMP12 in human LAC was examined by immunohistochemical assay using a tissue microarray procedure. A loss-offunction experiment was used for observing the effects of lentiviral vector-mediated MMP12 shRNA (shMMP12) on cell growth and invasion in LAC cell lines (A549), indicated by MTT and Transwell assays. We found that the expression of MMP12 protein was significantly increased in LAC tissues compared with that in adjacent non-cancerous tissues (ANCT) (57.69% vs. 32.69%, P = 0.019), and was closely correlated with the pathological stage and lymph node metastasis of LAC patients (P = 0.01; P = 0.003). Knockdown of MMP12 inhibited proliferation and invasion of LAC cells followed by the downregulation of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF).In conclusion, our findings show that high expression of MMP12 is correlated with the pathological stage and tumor metastasis of LAC patients, and knockdown of MMP12 suppresses the development of LAC cells, suggesting that MMP12 may be a promising therapeutic target for the treatment of LAC.

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Section: Discussionsupporting

confidence: 59%

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells

et al. 2015

Int J Immunopathol Pharmacol

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“…Cell Isolation, Culture Conditions, and VEGF Treatment-EPCs were isolated from Ͼ 50 ml human umbilical cord blood (UCB) of healthy newborns, essentially as described (3,5,13). The selected cord blood units had a total of Ͻ 1.3 ϫ 10 9 nucleated cells (threshold of suitability for the banking established by the Umbilical Cord Bank of Careggi, Firenze, Italy) Blood samples were taken after maternal informed consent and was in compliance with Italian legislation.…”

Section: Methodsmentioning

confidence: 99%

Proteomic Identification of VEGF-dependent Protein Enrichment to Membrane Caveolar-raft Microdomains in Endothelial Progenitor Cells

Chillà

Magherini

Margheri

et al. 2013

Molecular & Cellular Proteomics

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Endothelial cell caveolar-rafts are considered functional platforms that recruit several pro-angiogenic molecules to realize an efficient angiogenic program. Here we studied the differential caveolar-raft protein composition of endothelial colony-forming cells following stimulation with VEGF, which localizes in caveolae on interaction with its type-2 receptor. Endothelial colony-forming cells are a cell population identified in human umbilical blood that show all the properties of an endothelial progenitor cell and a high proliferative rate. Two-dimensional gel electrophoresis analysis was coupled with mass spectrometry to identify candidate proteins. The twenty-eight differentially expressed protein spots were grouped according to their function using Gene Ontology classification. In particular, functional categories relative to cell death inhibition and hydrogen peroxide metabolic processes resulted enriched. In these categories, Peroxiredoxin-2 and 6, that control hydrogen peroxide metabolic processes, are the main enriched molecules together with the anti-apoptotic 78 kDa glucose regulated protein. Some of the proteins we identified had never before identified as caveolar-raft components. Other identified proteins include calpain small subunit-1, known to mediates angiogenic response to VEGF, gelsolin, which regulates stress fiber assembly, and annexin A3, an angiogenic mediator that induces VEGF production. We validated the functional activity of the above proteins, showing that the siRNA silencing of these resulted in the inhibition of capillary morphogenesis. Overall, our data show that VEGF stimulation triggers the caveolar-raft recruitment of proteins that warrant a physiological amount of reactive oxygen species to maintain a proper angiogenic function of endothelial colony-forming cells and preserve the integrity of the actin cytoskeleton. Molecular & Cellular

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“…This system has classically been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of invading cancer cells (6). In addition to mediating proteolysis, several mechanistic studies demonstrated that uPAR also had a role in cancer cell survival, invasion, migration, and angiogenesis in vitro, and its knockdown showed reduced tumor burden in in vivo conditions (7)(8)(9)(10)(11)(12). Recent data provided new insights into the role of uPAR to facilitate epithelial-mesenchymal transition and to induce CSC-like properties in medulloblastoma and breast cancer cells (13,14).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Translocation of Hand-1 Acts as a Molecular Switch to Regulate Vascular Radiosensitivity in Medulloblastoma Tumors: The Protein uPAR Is a Cytoplasmic Sequestration Factor for Hand-1

Asuthkar

Gogineni

Rao

et al. 2014

Molecular Cancer Therapeutics

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Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in the tumor-stromal invasive microenvironment in many human cancers, including medulloblastoma. The role of uPAR in tumor progression and angiogenesis has been well characterized. Previously, in medulloblastoma cells, we showed that ionizing radiation (IR)-induced uPAR is a potent activator of cancer stem cell (CSC)-like properties and is associated with various transcription factors that are involved during embryonic development and cancer. In the present study, we show that uPAR protein acts as a cytoplasmic sequestration factor for a novel basic helixloop-helix transcription factor, Hand-1. The Hand-1 protein plays an essential role in the differentiation of trophoblast giant cells and cardiac morphogenesis, and yet its precise cellular function and its contribution to cancer remain mostly unknown. We also observed that the Hand-1 protein is upregulated in uPAR short hairpin RNA-treated medulloblastoma cells and accompanies sustained cell growth and angiogenesis. Furthermore, IR-induced uPAR overexpression negatively regulates Hand-1 activity and results in the stabilization of angiogenesis-promoting molecules, including hypoxia-inducible factor-1a. Finally, uPAR overexpression and its association with Hand-1 after IR treatment indicate that uPAR is capable of regulating Hand-1 and that uPAR has a role in the process of IR-induced tumor angiogenesis.

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Endothelial progenitor cell–dependent angiogenesis requires localization of the full-length form of uPAR in caveolae

Cited by 74 publications

References 46 publications

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells

Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells

Proteomic Identification of VEGF-dependent Protein Enrichment to Membrane Caveolar-raft Microdomains in Endothelial Progenitor Cells

Nuclear Translocation of Hand-1 Acts as a Molecular Switch to Regulate Vascular Radiosensitivity in Medulloblastoma Tumors: The Protein uPAR Is a Cytoplasmic Sequestration Factor for Hand-1

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