Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells
Journal
Journal of Cellular Physiology
Journal Volume
226
Journal Issue
4
Pages
1060-1068
Date Issued
2011
Author(s)
Abstract
Deep vein thrombosis associated with advanced cancer is known as Trousseau's syndrome. We hypothesized that thrombin, an activator of protease-activated receptor (PAR)-1 and PAR-4 contributes to tumor metastasis. In this study, 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, and cell motility in colorectal cancer cells, and these actions were significantly inhibited by the PAR-1 antagonist SCH79797. Moreover, thrombin-induced HIF-1α activity and cell motility were blocked by inhibiting important mediators of signaling transduction, including the ERK, PI3K, and mTOR pathways. These results showed that thrombin induced HIF-1α protein expression through PAR-1 and HIF-1α translational de novo protein synthesis. Twist can regulate epithelial-mesenchymal transition (EMT) and increase tumor metastasis. However, we observed that thrombin-induced HIF-1α increased Twist mRNA and its protein level was mediated by the modulation of PAR-1 activation and the HIF-1α translational pathway. In addition, Twist could increase N-cadherin but not E-cadherin to promote tumor metastasis. Overexpression of dominant-negative HIF-1α reversed thrombin-mediated Twist and Twist-induced N-cadherin expression. Moreover, siTwist inhibited Twist-induced N-cadherin and Thrombin-induced cell motility. In conclusion, our study showed that thrombin-induced HIF-1α upregulated Twist at the transcriptional level to enhance cell motility. These findings show that thrombin upregulates Twist via HIF-1α to make tumor cells malignant and also establish a link between the coagulation disorder and cancer metastasis. ? 2010 Wiley-Liss, Inc.
SDGs
Other Subjects
hypoxia inducible factor 1alpha; nerve cell adhesion molecule; proteinase activated receptor 1; thrombin; transcription factor Twist; article; cancer cell; cell motility; colorectal cancer; controlled study; enzyme activity; epithelial mesenchymal transition; gene overexpression; human; human cell; Jacobsen syndrome; metastasis; priority journal; protein expression; protein synthesis; signal transduction; Cadherins; Cell Movement; Colorectal Neoplasms; Down-Regulation; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mitogen-Activated Protein Kinases; Nuclear Proteins; Phosphatidylinositol 3-Kinases; Protein Binding; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Receptor, PAR-1; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Thrombin; TOR Serine-Threonine Kinases; Transcription, Genetic; Twist Transcription Factor
Type
journal article