THE ROLE OF THE UROKINASE SYSTEM IN LYMPHOGENOUS METASTASIS OF COLORECTAL CANCER

The aim of this work was to study the role and relationship of the levels of the components of the urokinase system with lymphogenous metastasis in patients with colorectal cancer.Materials and methods: the study was carried out on the basis of the Medical Scientific and Educational Center of the Moscow State University named after M.V. Lomonosov from 2019 to 2021. The study included healthy donors (control group) and patients with a verified diagnosis of stage I-III colorectal cancer in accordance with the inclusion criteria; all patients underwent surgical resection of the primary tumor with lymphadenectomy of the appropriate level. All patients underwent determination of the level of uPA and uPAR in blood serum before surgery. We also analyzed the clinical and demographic data of the patients, as well as the pathomorphological characteristics of the tumor.Results. The study included 7 healthy donors and 49 patients with stage I-III colorectal cancer. The average level of serum urokinase in the control group was 2.7±1.04 ng / ml, in the study group – 4, 15±1.9 ng / ml (p = 0.071), the level of the urokinase receptor in the control and study groups was 1.36 ±0.8 ng / ml vs 3.22±2.06 ng / ml (p = 0.05). The average level of serum urokinase in patients without and with lesions of lymph nodes was 3.4±1.4 ng / ml and 4.4±2.3 ng / ml (p = 0.068).Conclusion. There is a tendency to an increase in the level of components of the urokinase system in the peripheral blood in patients with colon neoplasms in the preoperative period, depending on the presence of metastatic lesions of regional lymph nodes, which indicates the need for further research in this area.

Associations between SNPS in the genes encoding urokinase system proteins and the risk of placental insufficiency

Placental insufficiency (PI) and its complications are multifactorial conditions that cause perinatal morbidity and mortality. Since the urokinase system is involved in placentation, it should have a role in PI pathogenesis. The aim of this work was to study the associations between single nucleotide polymorphisms (SNPs) of genes coding for protein components of the urokinase system and PI, as well as investigate their effect on the expression of these proteins in the placenta and placental structure. We examined 114 women with uncomplicated pregnancy and delivery, 48 female patients with pre-eclampsia and/or intrauterine growth restriction (IUGR), and 95 newborns, (pre-eclampsia and/or IUGR: n = 60; uncomplicated pregnancy and delivery: n = 35). Maternal and fetal DNAs were genotyped using real-time PCR. Placenta fragments were subjected to morphometry and immunohistochemistry. We discovered the associations between PI and the maternal C allele of rs4065 (PI group: СС-СТ 64.1%, TT 35.9%; controls: СС-СТ 25.6%, TT 74.49%; OR (95%CI): 6.83 (2.63–17.79)), the maternal A allele of rs2302524 (GG-GA 20.5%, AA 79.5% vs. GG-GA 48.1%, AA 51.9%, OR (95%CI): 0.27 (0.1–0.71)), the fetal C allele of rs4065 (СС-СТ 76.4 %, TT 23.6% vs. СС-СТ 69.6%, TT 30.4%, OR (95%CI): 1.37 (0.45–4.17)), and the fetal C allele of rs344781 (TT-TC 69.1%, СС 30.9% vs. TT-TC 95.7%, СС 4.3%, OR (95% CI): 5.02 (1.07–23.6)). The multivariate analysis confirmed the significance of the fetal rs4065 genotype. In patients with PI, uPA expression was lower (ME (95%CI): 116.45 (100.5; 128.74) vs. 126.09 (113.76; 139.19); р < 0.05). No associations were established between SNPs and protein expression. The degree of vascularization depended on the maternal rs4065 genotype (the stroma-to-vessel ratio for the CC genotype was 0.17 (0.15; 0.19); for the CT genotype, 0.18 (0.15; 0.21) and for the TT genotype, 0.23 (0.2; 0.27); p < 0.05). We conclude that high placental uPA and the presence of the fetal TT rs4065 genotype are protective against the risk of PI.

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

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.

ASSOCIATION OF MOLECULAR GENETIC FACTORS WITH THE SIGNS OF ATEROSCLEROTIC PLAQUES INSTABILITY

Aim. Analysis of possible associations of polymorphisms of the urokinase system and matrix metalloproteases genes with criteria of atherosclerotic plaques instability.Material and methods. Totally, 50 patients were investigated, with carotid atherosclerosis (32 males and 18 females). Inclusion criteria were carotid stenosis ≥70% and carotid endarterectomy. Patients were selected to groups according to macroscopic signs of instability of the lesions and thickness of fibrous cap. The groups were compared by the rates of mononucleotide polymorphisms С(-1306)Т (rs243865) gene MMP2, С(-1562)T (rs3918242) and A855G (Gln279Arg, rs17576) gene MMP9, Pro141Leu (C7240T, rs2227564) and С/T 3′-UTR (rs4065) gene PLAU, Lys220Arg (A659G, rs2302524) and T(-516)C (rs344781) gene PLAUR, (-675)4G/5G (rs1799768)gene SERPINE1.Results. Monofactorial analysis showed the association of the variants 279Gln/Gln of gene MMP9 and 141Leu/Leu gene PLAU with development of macroscopically stable plaques. By multifactorial analysis, only the carriage of genotype 141Leu/Leugene PLAU was associated with development of stable plaques. For the group of genotype carriers 141Pro/Leu and 141Leu/Leu odds ratio is 0,22 (95% confidence interval 0,05-0,93). With the development of plaques with capsule less than 65 mcm, by monofactorial analysis, the associated variants are 3′-UTR C/T gene PLAU and (-516)T/C gene PLAUR, and normal body mass. Presence of obesity and the carriage of allele (-516) C gene PLAUR are protective against the thin cap plaques development. In patients with absent obesity and genotype (-516)T/T gene PLAUR odds ratio for the thin cap plaque occurrence is 10,16 (95% confidence interval 2,5740,16).Conclusion. In the work, an association is shown of the polymorphism of urokinase system gene (urokinase plasminogen activator and receptor) with criteria of atherosclerotic lesion instability. Also, an association demonstrated of obesity with more stable plaques.