Thrombin-mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase-activated receptors 1 and 4

• Published in: Journal of cellular physiology Vol. 211; no. 3; pp. 699 - 707
• Main Authors: Kaufmann, Roland, Rahn, Stephanie, Pollrich, Kristin, Hertel, Julia, Dittmar, Yves, Hommann, Merten, Henklein, Peter, Biskup, Christoph, Westermann, Martin, Hollenberg, Morley D., Settmacher, Utz
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2007
• Subjects: Calcium - metabolism; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - physiology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Enzyme Inhibitors - pharmacology; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; Hemostatics - pharmacology; Humans; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Matrix Metalloproteinases - metabolism; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Phosphorylation; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptor, PAR-1 - genetics; Receptor, PAR-1 - metabolism; Receptors, Thrombin - genetics; Receptors, Thrombin - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Thrombin - pharmacology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.21027

Proteinase‐activated receptor‐1 (PAR1), a thrombin receptor and the prototype of a newly discovered G‐protein‐coupled receptor subfamily, plays an important role in tumor development and progression. In this study, we documented the expression of the thrombin receptors PAR1, PAR3, and PAR4 in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR1‐selective activating peptide, TFLLRN‐NH2, increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR1 antagonist SCH 79797, confirming that the PAR1 thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR4‐selective agonist, AYPGKF‐NH2, also stimulated HCC cell migration whilst the PAR4 antagonist, trans‐cinnamoyl‐YPGKF‐NH2, attenuated the effect of thrombin on HCC cell migration. PAR1‐ and PAR4‐triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the Gi/Go family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP‐dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR1/PAR4 signaling network that contributes to thrombin‐mediated tumor cell migration. We suggest that a combined inhibition of coagulation cascade serine proteinases, the two PARs and their complex signaling pathways may provide a new strategy for treating hepatocellular carcinoma. J. Cell. Physiol. 211: 699–707, 2007. © 2007 Wiley‐Liss, Inc.