Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression

Stepanova, Victoria; Jayaraman, Padma-Sheela; Зайцев, С. В.; Lebedeva, Tatiana; Bdeir, Khalil; Kershaw, Rachael M.; Holman, Kelci R.; Parfyonova, Y.; Semina, Ekaterina V.; Белоглазова, И. Б.; Tkachuk, Vsevolod A.; Cines, Douglas B.

doi:10.1074/jbc.m115.678490

Cited by 63 publications

(57 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…7). Indeed, antibody array results obtained in conditioned medium of miR-34a-reconstituted cells (at 72 h following transfection) showed a reduced secretion of the urokinase-type plasminogen activator (uPA), which plays a major role in promoting angiogenesis [36], together with and increased release of maspin, a member of the serine protease inhibitor (serpin) superfamily, which exerts antiangiogenic effects through the inhibition of both the growth and migration of endothelial cells [37, 38] (Fig. 7a).…”

Section: Resultsmentioning

confidence: 99%

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

et al. 2017

View full text Add to dashboard Cite

BackgroundThe value of microRNAs (miRNAs) as novel targets for cancer therapy is now widely recognized. However, no information is currently available on the expression/functional role of miRNAs in diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional treatments, for which the development of new therapeutic strategies is urgently needed. Here, we evaluated the expression and biological effects of miR-34a—one of the most widely deregulated miRNAs in cancer and for which a lipid-formulated mimic is already clinically available—in a large cohort of DMPM clinical samples and a unique collection of in house-developed preclinical models, with the aim to assess the potential of a miR-34a-based approach for disease treatment.MethodsmiR-34a expression was determined by qRT-PCR in 45 DMPM and 7 normal peritoneum specimens as well as in 5 DMPM cell lines. Following transfection with miR-34a mimic, the effects on DMPM cell phenotype, in terms of proliferative potential, apoptotic rate, invasion ability, and cell cycle distribution, were assessed. In addition, three subcutaneous and orthotopic DMPM xenograft models were used to examine the effect of miR-34a on tumorigenicity. The expression of miRNA targets and the activation status of relevant pathways were investigated by western blot.ResultsmiR-34a was found to be down-regulated in DMPM clinical specimens and cell lines compared to normal peritoneal samples. miR-34a reconstitution in DMPM cells significantly inhibited proliferation and tumorigenicity, induced an apoptotic response, and declined invasion ability, mainly through the down-regulation of c-MET and AXL and the interference with the activation of downstream signaling. Interestingly, a persistent activation of ERK1/2 and AKT in miR-34a-reconstituted cells was found to counteract the antiproliferative and proapoptotic effects of miRNA, yet not affecting its anti-invasive activity.ConclusionsOur preclinical data showing impressive inhibitory effects induced by miR-34a on DMPM cell proliferation, invasion, and growth in immunodeficient mice strongly suggest the potential clinical utility of a miR-34a-replacement therapy for the treatment of such a still incurable disease. On the other hand, we provide the first evidence of a potential cytoprotective/resistance mechanism that may arise towards miRNA-based therapies through the persistent activation of RTK downstream signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0387-6) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Promotion of angiogenesis is regulated by binding of single chain urokinase-type plasminogen activator (scuPA) to its receptor on the endothelial cell surface, and subsequent transport of the protease to the nucleus [77]. scuPA de-represses transcription of the VEGF receptor 1 (VEGFR1) and 2 (VEGFR2) genes by interfering with the proline-rich homeodomain protein that represses the activity of vegfr1 and vegfr2 gene promoters.…”

Section: Regulation Of Physiological Processesmentioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

View full text Add to dashboard Cite

Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

show abstract

“…that create a gradient inside the vascular wall and promote EPC homing to the damaged area via the adhesion and transendothelial migration mechanisms. The urokinase system is known to be involved in the regulation of angioarteriogenesis in ischemia and inflammation [85][86][87], in particular via regulation of directed migration of EPCs [88,89] expressing high levels of uPA and uPAR [90]. In this case, in nonstimulated EPCs, the urokinase receptor is localized in lipid rafts and absent in caveolae; however, stimulation by VEGF causes increased expression of caveolin-1 and uPAR, assembly of caveolae, and uPAR internalization in EPCs [91].…”

Section: Urokinase System and Endothelial Progenitor Cellsmentioning

confidence: 99%

Multifaced Roles of the Urokinase System in the Regulation of Stem Cell Niches

Dergilev¹,

Štěpánová²,

Beloglazova³

et al. 2018

Acta Naturae

View full text Add to dashboard Cite

Proliferation, subsequent migration to the damaged area, differentiation into appropriate cell types, and/or secretion of biologically active molecules and extracellular vesicles are important processes that underlie the involvement of stem/progenitor cells in the repair and regeneration of tissues and organs. All these functions are regulated through the interaction between stem cells and the microenvironment in the tissue cell niches that control these processes through direct cell-cell interactions, production of the extracellular matrix, release of extracellular vesicles, and secretion of growth factors, cytokines, chemokines, and proteases. One of the most important proteolytic systems involved in the regulation of cell migration and proliferation is the urokinase system represented by the urokinase plasminogen activator (uPA, urokinase), its receptor (uPAR), and inhibitors. This review addresses the issues of urokinase system involvement in the regulation of stem cell niches in various tissues and analyzes the possible effects of this system on the signaling pathways responsible for the proliferation, programmed cell death, phenotype modulation, and migration properties of stem cells.

show abstract

Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression

Cited by 63 publications

References 72 publications

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

Proteases: Pivot Points in Functional Proteomics

Multifaced Roles of the Urokinase System in the Regulation of Stem Cell Niches

Contact Info

Product

Resources

About