Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells.

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.

• Authors: Li-Hsun Chang, Chun-Han Chen, Der-Yi Huang, Hui-Chen Pai, Shiow-Lin Pan, Che-Ming Teng
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 226 Issue 4 Pg. 1060-8 (Apr 2011) ISSN: 1097-4652 [Electronic] United States
• PMID: 20857420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Cadherins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Nuclear Proteins
• RNA, Messenger
• RNA, Small Interfering
• Receptor, PAR-1
• TWIST1 protein, human
• Twist-Related Protein 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• Thrombin

Topics

• Cadherins (metabolism)
• Cell Movement (drug effects)
• Colorectal Neoplasms (enzymology, genetics, pathology)
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HCT116 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Nuclear Proteins (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Binding (drug effects)
• Protein Biosynthesis (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Receptor, PAR-1 (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Thrombin (pharmacology)
• Transcription, Genetic (drug effects)
• Twist-Related Protein 1 (genetics, metabolism)