Thrombin-mediated hepatocellular carcinoma cell migration: Cooperative action via proteinase-activated receptors 1 and 4
✍ Scribed by Roland Kaufmann; Stephanie Rahn; Kristin Pollrich; Julia Hertel; Yves Dittmar; Merten Hommann; Peter Henklein; Christoph Biskup; Martin Westermann; Morley D. Hollenberg; Utz Settmacher
- Book ID
- 102312355
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 356 KB
- Volume
- 211
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Proteinase‐activated receptor‐1 (PAR~1~), 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 PAR~1~, PAR~3~, and PAR~4~ in permanent hepatocellular carcinoma (HCC) cell lines and primary HCC cell cultures. Stimulation of HCC cells with thrombin and the PAR~1~‐selective activating peptide, TFLLRN‐NH~2~, increased transmembrane migration across a collagen barrier. This effect was blocked by the PAR~1~ antagonist SCH 79797, confirming that the PAR~1~ thrombin receptor subtype is involved in regulating hepatoma cell migration. In addition, the PAR~4~‐selective agonist, AYPGKF‐NH~2~, also stimulated HCC cell migration whilst the PAR~4~ antagonist, trans‐cinnamoyl‐YPGKF‐NH~2~, attenuated the effect of thrombin on HCC cell migration. PAR~1~‐ and PAR~4~‐triggered HCC cell migration was blocked by inhibiting a number of key mediators of signal transduction, including G proteins of the G~i~/G~o~ family, matrix metalloproteinases, ERK/MAPKinase, cyclic AMP‐dependent protein kinase, Src tyrosine kinase, and the EGF receptor kinase. Our data point to a cooperative PAR~1~/PAR~4~ 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.