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

Li Hsun Chang, Chun-Han Chen, Der Yi Huang, Hui Chen Pai, Shiow Lin Pan, Che Ming Teng

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1060-1068
Number of pages9
JournalJournal of Cellular Physiology
Volume226
Issue number4
DOIs
Publication statusPublished - Apr 2011

Fingerprint

Hypoxia-Inducible Factor 1
Thrombin
Cell Movement
Colorectal Neoplasms
PAR-1 Receptor
Cells
Cadherins
Tumors
Neoplasm Metastasis
Neoplasms
Proteins
Peptides
Epithelial-Mesenchymal Transition
Coagulation
Phosphatidylinositol 3-Kinases
Venous Thrombosis
Up-Regulation
Chemical activation
Modulation
Messenger RNA

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1α translational pathway in colorectal cancer cells. / Chang, Li Hsun; Chen, Chun-Han; Huang, Der Yi; Pai, Hui Chen; Pan, Shiow Lin; Teng, Che Ming.

In: Journal of Cellular Physiology, Vol. 226, No. 4, 04.2011, p. 1060-1068.

Research output: Contribution to journalArticle

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