Plasminogen activator inhibitor type-1: Its structure, biological activity and role in tumorigenesis (Review)

Department of Laboratory Diagnostics and Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
International Journal of Molecular Medicine (Impact Factor: 1.88). 07/2004; 13(6):759-66. DOI: 10.3892/ijmm.13.6.759
Source: PubMed

ABSTRACT Plasminogen activator inhibitor type-1 (PAI-1), is a unique member of serpin superfamily, the primary regulator of plasminogen activation and therefore essential factor regulating physiological thrombotic/fibrinolytic balance in vivo. Via interactions with integrins and extracellular matrix components it orchestrates also cell adhesion and migration. Therefore, PAI-1 is considered one of the key regulators of tumor invasion and metastasis, as well as cancer-related angiogenesis. This review summarizes recent findings on the structure and functional activity of the plasminogen activator inhibitor type-1, and current opinions on its role in tumorigenesis.

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    • "are the spesific point mutations that have been reported as a risk factors for the development of venous thrombosis for Factor V gene (Zaatari et al., 2006). The plasminogen activator inhibitor-1 gene (PAI-1) is an essential regulator of plasminogen activation and has been linked to the pathogenesis of lung carcinomas (Pavey et al., 1996; Chorostowska-Wynimko et al., 2004). The angiotensinconverting enzyme (ACE) is a zinc metallopeptidase that plays an important role in the blood pressure and inflammation. "
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    ABSTRACT: Background: A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas. Materials and Methods:A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared. Results: Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers. Conclusions: The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.
    Asian Pacific journal of cancer prevention: APJCP 09/2013; 14(9):5449-54. DOI:10.7314/APJCP.2013.14.9.5449 · 2.51 Impact Factor
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    • "The fibrinolytic system also plays an important role in tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is one of the key regulators of tumor invasion, metastasis and cancer related angiogenesis (Falanga and Rickles, 1999; Chorostowska-Wynimko et al., 2004). Whole blood thromboelastography (TEG Haemoscope) evaluates primary hemostasis, secondary hemostasis, the fibrinolytic system, and clot strength. "
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    ABSTRACT: Hemostatic abnormalities were investigated in 32 dogs with carcinoma and 19 age-matched healthy dogs. Thromboelastography, hemostasis profile (i.e. prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen concentration), platelet count (PLT), thrombin-antithrombin complexes (TAT), and plasminogen activator inhibitor-1 (PAI-1) activity were evaluated. Dogs with carcinomas had faster thrombus generation (TEG(TG), a mathematic value obtained from the first derivate of the thromboelastographic tracing; 834.8±91.1 vs. 707.8±75.8mm/min; mean±SD), increased fibrinogen concentration (276 vs. 151mg/dL), and PLT (425 vs. 324U×10(9)/L), but had decreased PAI-1 activity (15.7 vs. 26.2IU/mL).The most common hemostatic abnormalities found in carcinoma dogs were hypercoagulability (TEG(TG)>mean+2 SD of healthy dogs) and thrombocytosis (PLT>424×10(9)U/L) in 46% of cases, and hyperfibrinogenemia (fibrinogen >384mg/dL) in 32% of cases. Disseminated intravascular coagulation was uncommon and the extent of disease was not correlated with hypercoagulability. TEG(TG) showed good correlation with fibrinogen (r=0.80) and hyperfibrinogenemia seems to be a main factor of the hypercoagulable state in carcinoma dogs. In conclusion, TEG(TG) is a valid parameter to diagnose hypercoagulability.
    The Veterinary Journal 03/2011; 190(2):e78-83. DOI:10.1016/j.tvjl.2011.02.025 · 2.17 Impact Factor
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    ABSTRACT: Plasminogen activator inhibitor type-1 (PAI-1) is considered one of the key regulators of tumor invasion, metastasis, as well as cancer-related angiogenesis. The literature suggests that PAI-1 plays a dual role in these processes because it inhibits plasmin-originated proteolysis and binds to vitronectin or integrins. Stimulation or inhibition of angiogenesis largely depends on which of these elements PAI-1 interacts. Wild PAI-1 converts quickly into its latent, inactive form and loses its anti-proteolytic activity, but still binds to vitronectin and integrins. Thus we constructed PAI-1s with extended half-life to prolong their anti-proteolytic activity. We have analyzed the effects of sprout formation inhibition by PAI-1s on two functionally different endothelial cell (EC) systems, human umbilical vein endothelial cells (HUVEC), expressing moderate amounts of urokinase (uPA), and human lung microvascular endothelial cells (HLMVEC), expressing high amounts of this enzyme. We have used wild-type PAI-1 (wPAI-1) (t(1/2) = 1.6 h) and PAI-1 cysteine mutants (CysPAI-1) characterized by their prolonged half-life time (hDbetaT) (t(1/2) = 63.6 h and t(1/2) = 7,000 h). We have observed a significant inhibitory dose-dependent effect exerted by the CysPAI-1s on sprout formation by HUVEC and HLMVEC cells. The inhibition rate was considerably stronger in lung capillary cell cultures and significantly more pronounced for CysPAI-1 mutants with longer anti-uPA activity (betaT). wPAI-1 with a short anti-proteolytic half-life has induced sprout formation in HUVEC, but not in HLMVEC cultures. This difference in behavior was most likely related to the presence of excessive amounts of uPA in HLMVEC cells and the known mechanism of clearing PAI-1/uPA/uPAR complexes from the cell surface. A less efficient system of HUVEC cells might give wPAI-1 the chance to interact with non-proteolytic pathways of angiogenesis stimulation. We conclude that while the anti-proteolytic properties of PAI-1 constructs are preserved, these proteins inhibit angiogenesis and inhibitory activity dominates over any stimulatory effects of PAI-1.
    Oncology Reports 01/2005; 12(6):1155-62. DOI:10.3892/or.12.6.1155 · 2.19 Impact Factor
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