The mechanism of cancer progression regulated by protease-activated receptors (PARs)
| Autor: | Li-Hsun Chang, 張儷薰 |
|---|---|
| Rok vydání: | 2013 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 101 Cancer is the top one leading cause of death over ten years and cancer-related complications are also the reasons of death. Venous thromboembolism (VTE) is a common complication in cancer patients. Since 1865, Armand Trousseau has discovered the clinical phenomena in patients with recurrent VTE. These patients were subsequently diagnosed with advanced cancer. Therefore, deep vein thrombosis associated with advanced cancer is known as Trousseau’s syndrome. Until now, many researchers have been interested in exploring the association between cancer and thrombosis. In the first part of study, we hypothesized that thrombin has an effect on tumor metastasis through activation of PARs. We demonstrated that thrombin and the PAR-1 activating peptide (AP) SFLLRN, but not the PAR-4 AP GYPGKF, induced HIF-1α activities, protein expression, upregulation of Twist and cell motility in colorectal cancer cells, and these actions were significantly inhibited by the PAR-1 antagonist SCH79797, translation pathway inhibitors, including the ERK, PI3K, and mTOR inhibitors. Moreover, thrombin-mediated Twist regulated epithelial–mesenchymal transition (EMT) by increase of N-cadherin to promote cell motility. The aim of the second study was to investigate the activation of PAR-2-increased HIFs-α, transforming growth factor-α (TGF-α) and angiogenesis in pancreatic cancer with overexpression of tissue factor (TF). PAR-2 signaling activated by FVIIa or PAR-2 AP induced accumulation of HIF-1α as well as HIF-2α. Furthermore, PAR-2 signaling increased transcription and translation of TGF-α as well as VEGF. Using small interfering RNA (siRNA) assay, depletion of integrin-linked kinase (ILK), HIF-1α or HIF-2α abolished the activated PAR-2-mediated TGF-α but not VEGF-A. According to microarray analysis, PAR-2 signaling enhanced MEK-ERK pathway, transcriptional factor ETS-1 and VEGF-A. Therefore, PAR-2-induced VEGF-A enhanced endothelial cell proliferation and tube formation, which were blocked by the MEK inhibitor. In summary, our thesis demonstrates that aberrant coagulant factors, such as thrombin or TF, may promote cancer progression, angiogenesis and metastasis through a PARs signaling-mediated HIFs activity. PARs play an important role in the crosstalk with cancer-related thrombosis and cancer progression. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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