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Cancers Aug 2021Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen... (Review)
Review
Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma.
Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.
PubMed: 34439251
DOI: 10.3390/cancers13164097 -
JCI Insight Mar 2024Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis....
Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.
Topics: Animals; Mice; Humans; Fibrinolysin; Osteoarthritis; Fibrinolysis; Urokinase-Type Plasminogen Activator; Receptors, Urokinase Plasminogen Activator; Disease Models, Animal; Male; Female; Mice, Inbred C57BL; Plasminogen; Signal Transduction; Mice, Knockout
PubMed: 38502232
DOI: 10.1172/jci.insight.173603 -
Proceedings of the National Academy of... Jan 2023The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are...
The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are predominantly expressed by blood cells, including neutrophils, monocytes, and macrophages, and play important roles in cell activation, adhesion, migration, and extravasation. Here, we report that PLAUR, which is highly expressed in macrophages and dendritic cells (DCs) but hardly expressed in CD4 T cells, inhibits the release of HIV-1 progeny virions from the cell membrane. Silencing markedly enhanced the transmission of HIV-1 in macrophages and DCs. We further demonstrated that PLAUR is localized at the cell membrane to block the release of HIV-1 virions. Interestingly, we found that uPA compromises the PLAUR-mediated inhibition to slightly enhance HIV-1 production in primary macrophages and DCs. In the absence of PLAUR, this enhanced effect induced by uPA is abrogated. In conclusion, PLAUR is a new anti-HIV-1 protein produced in both macrophages and DCs where it inhibits HIV-1 transmission. This discovery may provide a novel therapeutic target for combating HIV.
Topics: Humans; Cell Membrane; HIV-1; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator; Virion; Virus Replication
PubMed: 36638209
DOI: 10.1073/pnas.2212991120 -
International Journal of Molecular... Jun 2023The development of infections caused by pathogenic bacteria is largely related to the specific properties of the bacterial cell surface and extracellular hydrolytic... (Review)
Review
The development of infections caused by pathogenic bacteria is largely related to the specific properties of the bacterial cell surface and extracellular hydrolytic activity. Furthermore, a significant role of hijacking of host proteolytic cascades by pathogens during invasion should not be disregarded during consideration of the mechanisms of bacterial virulence. This is the key factor for the pathogen evasion of the host immune response, tissue damage, and pathogen invasiveness at secondary infection sites after initial penetration through tissue barriers. In this review, the mechanisms of bacterial impact on host plasminogen-the precursor of the important plasma serine proteinase, plasmin-are characterized, principally focusing on cell surface exposition of various proteins, responsible for binding of this host (pro)enzyme and its activators or inhibitors, as well as the fibrinolytic system activation tactics exploited by different bacterial species, not only pathogenic, but also selected harmless residents of the human microbiome. Additionally, the involvement of bacterial factors that modulate the process of plasminogen activation and fibrinolysis during periodontitis is also described, providing a remarkable example of a dual use of this host system in the development of chronic diseases.
Topics: Humans; Plasminogen; Persistent Infection; Bacteria; Fibrinolysin; Fibrinolysis
PubMed: 37445613
DOI: 10.3390/ijms241310436 -
International Journal of Molecular... Feb 2023Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects,... (Review)
Review
Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.
Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions.
Topics: Humans; Tissue Plasminogen Activator; Plasminogen Activator Inhibitor 1; Glucocorticoids; Mental Disorders
PubMed: 36901924
DOI: 10.3390/ijms24054496 -
Cells Aug 2019Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence... (Review)
Review
Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.
Topics: Animals; Disease Models, Animal; Humans; Inflammation; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Receptors, Urokinase Plasminogen Activator; Retinal Diseases; Urokinase-Type Plasminogen Activator
PubMed: 31426601
DOI: 10.3390/cells8080925 -
Haemophilia : the Official Journal of... Nov 2019Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of...
INTRODUCTION
Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype.
METHODS
The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls.
RESULTS
Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect.
CONCLUSION
Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.
Topics: Adult; Child; Coagulation Protein Disorders; Female; Fibrinolysin; Genotype; Hemorrhagic Disorders; Humans; Male; Middle Aged; Phenotype; Plasminogen Activator Inhibitor 1; Thrombin
PubMed: 31469483
DOI: 10.1111/hae.13842 -
Journal of Cerebral Blood Flow and... Oct 2021Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of...
Plasminogen is involved in the process of angiogenesis; however, the underlying mechanism is unclear. Here, we investigated the potential contribution of plasmin/plasminogen in mediating angiogenesis and thereby contributing to functional recovery post-stroke. Wild-type plasminogen naive (Plg) mice and plasminogen knockout (Plg) mice were subjected to unilateral permanent middle cerebral artery occlusion (MCAo). Blood vessels were labeled with FITC-dextran. Functional outcomes, and cerebral vessel density were compared between Plg and Plg mice at different time points after stroke. We found that Plg mice exhibited significantly reduced functional recovery, associated with significantly decreased vessel density in the peri-infarct area in the ipsilesional cortex compared with Plg mice. In vitro, cerebral endothelial cells harvested from Plg mice exhibited significantly reduced angiogenesis assessed using tube formation assay, and migration, as evaluated using Scratch assays, compared to endothelial cells harvested from Plg mice. In addition, using Western blots, expression of thrombospondin (TSP)-1 and TSP-2 were increased after MCAo in the Plg group compared to Plg mice, especially in the ipsilesional side of brain. Taken together, our data suggest that plasmin/plasminogen down-regulates the expression level of TSP-1 and TSP-2, and thereby promotes angiogenesis in the peri-ischemic brain tissue, which contributes to functional recovery after ischemic stroke.
Topics: Animals; Male; Mice; Neovascularization, Pathologic; Plasminogen; Recovery of Function; Stroke
PubMed: 33853408
DOI: 10.1177/0271678X211007958 -
Frontiers in Endocrinology 2021Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to...
BACKGROUND
Early diagnosis and therapy of papillary thyroid carcinoma (PTC) is essential for reducing recurrence and improving the long-term survival. In this study, we aimed to investigate the proteome profile of plasma and screen unique proteins which could be used as a biomarker for predicting PTC.
METHODS
Serum samples were collected from 29 PTC patients and 29 nodular goiter (NG) patients. Five PTC serum samples and five NG serum samples were selected for proteome profiles by proteomics. Eight proteins in PTC and NG serum samples were selected for confirmation by enzyme-linked immunosorbent assay analysis. Receiver operating characteristic curves was used to evaluate the diagnostic value of potential biomarkers.
RESULTS
Complement C4-A (C4A) and plasminogen (PLG) were significantly lower in serum samples of PTC patients compared with NG patients. C4A was observed to have excellent diagnostic accuracy for PTC, with a sensitivity of 91.67% and specificity of 83.33%. The diagnostic value of PLG for PTC was demonstrated by a sensitivity at 87.50% and specificity at 75.00%. The AUC for C4A and PLG was 0.97 ± 0.02 and 0.89 ± 0.05.
CONCLUSION
C4A and PLG appeared to be excellent potential biomarkers for the prediction of PTC.
Topics: Adult; Biomarkers, Tumor; Complement C4a; Female; Humans; Male; Middle Aged; Plasminogen; Proteomics; Sensitivity and Specificity; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 34803909
DOI: 10.3389/fendo.2021.737638 -
International Journal of Molecular... Jan 2023Various species of non-coding RNAs (ncRNAs) may act as functional molecules regulating diverse biological processes. In cancer cell biology, ncRNAs include RNAs that... (Review)
Review
Various species of non-coding RNAs (ncRNAs) may act as functional molecules regulating diverse biological processes. In cancer cell biology, ncRNAs include RNAs that regulate the expression of oncogenes and tumor suppressor genes through various mechanisms. The urokinase (uPA)-mediated plasminogen activation system (PAS) includes uPA, its inhibitors PAI-1 and PAI-2 and its specific cellular receptor uPAR; their increased expression represents a negative prognostic factor in several cancers. Here, we will briefly describe the main uPA-mediated PAS components and ncRNA species; then, we will review more recent evidence of the roles that ncRNAs may play in regulating the expression and functions of uPA-mediated PAS components in cancer.
Topics: Humans; Neoplasms; Gene Expression Regulation; Plasminogen Activator Inhibitor 1; Urokinase-Type Plasminogen Activator; RNA, Untranslated; Plasminogen
PubMed: 36674481
DOI: 10.3390/ijms24020962