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首页> 外文期刊>Ukrainian Biochemical Journal >Aggregation of platelets, proliferation of endothelial cells and motility of cancer cells are mediated by the Bβ1(15)-42 residue of fibrin(ogen)
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Aggregation of platelets, proliferation of endothelial cells and motility of cancer cells are mediated by the Bβ1(15)-42 residue of fibrin(ogen)

机译：血小板聚集，内皮细胞的增殖和癌细胞的运动性由Bβ1（15）-42纤维蛋白（ELOGEN）的残基介导

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The fibrinogen molecule contains multiple binding motifs for different types of cellular receptors, acting as a molecular link between coagulation and cell adhesion. In this study we generated a truncated form of the fibrinogen molecule lacking the Bβ1-42 sequence by site-specific proteolysis and evaluated the role of the fragment in adhesive capabilities of platelets, endothelial and cancer cells. Fibrinogen with the removed Bβ1-42 sequence and fibrin without the Bβ15-42 fragment (desβ1-42 fibrinogen and desABβ15-42 fibrin) were obtained by proteolysis using the specific protease from the venom of Echis multisquamatis. The cleaved fragment was purified by HPLC and was identified using MALDI-TOF. ADP- and collagen-induced aggregation of washed platelets in the presence of fibrinogen desBβ1-42 was studied using an aggregometer. Proliferation of mice aortic endothelial cells (MAEC) and human umbilical vein endothelial cells (HUVEC) was studied using the fibrin desABβ15-42 as the scaffold. Cell viability was quantified by the MTT test (MAEC). Generation time was calculated for the estimation of proliferative activity of HUVEC. Lung cancer cell line Н1299 was used to evaluate cancer cell motility in vitro using the scratch assay. Direct comparison of cellular behavior in the presence of truncated vs native forms demonstrated attenuated cell adhesion in the presence of fibrinogen desBβ1-42 and fibrin desBβ15-42. The platelet aggregation rate was only slightly decreased in the presence of fibrinogen desBβ1-42 but resulted in 15-20% disaggregation of adhered platelets. We also observed the substantial decrease of generation time of HUVEC and inhibition of viability of MAEC cells grown on scaffolds of a desABβ15-42 matrix. Finally, desBβ1-42 modulated the motility of H1299 cells in vitro and suppressed the wound healing by 20% compared to the full-length fibrinogen. We postulate that fragment 1-42 of the BβN-domain of fibrinogen is not sufficient for platelet aggregation, however it may contribute to platelet clot formation in later stages. At the same time, this fragment may be important for establishing proper cell-to-cell contacts and cell viability of endothelial cells. Also, 1-42 amino acid fragment of the BβN-domain supported the migration of cancer cells suggesting that interactions of fibrinogen with cancer cells could be a target for anticancer therapy. The Bβ1-42 fragment of fibrinogen contributes to efficient intracellular interactions of different types of cells, including platelets, endothelial cells and cancer cells.
机译：纤维蛋白原分子含有用于不同类型的细胞受体的多个结合基序，作用为凝血和细胞粘附之间的分子链。在该研究中，我们通过特异性蛋白水解产生缺乏Bβ1-42序列的纤维蛋白原分子的截短形式，并评估片段在血小板，内皮和癌细胞的粘合能力中的作用。通过使用来自Echis MultiSquamtis的毒液的毒液，通过蛋白水解获得除去Bβ1-42序列和没有Bβ15-42片段的序列和纤维蛋白的纤维蛋白（DESβ1-42纤维蛋白原和DESABβ15-42纤维蛋白）。通过HPLC纯化切割的片段，并使用MALDI-TOF鉴定。使用聚集计研究了在纤维蛋白原DSBβ1-42存在下洗涤的血小板的ADP和胶原蛋白诱导的聚集。使用纤维蛋白Desabβ15-42作为支架，研究了小鼠主动脉内皮细胞（MAEC）和人脐静脉内皮细胞（HUVEC）的增殖。通过MTT试验（MAEC）量化细胞活力。计算出现时间以估计Huvec的增殖活性。使用划痕测定，使用肺癌细胞系Н1299评估体外癌细胞运动。在截短的VS本地形式存在下的细胞行为的直接比较在纤维蛋白原DSBβ1-42和纤维蛋白DESBβ15-42存在下证明了减毒的细胞粘附。在纤维蛋白原DSBβ1-42存在下，血小板聚集速率仅略微降低，但导致粘附血小板的15-20％的分解。我们还观察到Huvec发电时间的显着降低，并抑制在Desabβ15-42基质支架上生长的Maec细胞的活力。最后，DESBβ1-42与全长纤维蛋白原相比，在体外调节H1299细胞的动力并抑制伤口愈合20％。我们假设纤维蛋白原的Bβ-结构域的片段1-42不足以足以用于血小板聚集，然而它可能有助于在后续阶段中的血小板凝块形成。同时，该片段对于建立适当的细胞对细胞接触和内皮细胞的细胞活力可能是重要的。此外，BβN结构域的1-42个氨基酸片段支持癌细胞的迁移，表明纤维蛋白原与癌细胞的相互作用可能是抗癌治疗的靶标。纤维蛋白原的Bβ1-42片段有助于有效的不同类型细胞的细胞内相互作用，包括血小板，内皮细胞和癌细胞。

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