In order to understand the biological significance of the hepatoma tumor marker DCP or PIVKA-II, we previously found that the K-vitamin dependent coagulation protein prothrombin was a potent inhibitor of EGF-mediated rat hepatocyte DNA synthesis. We report here that prothrombin is converted to α-thrombin by primary cultures of normal adult rat hepatocytes and α-thrombin had similar inhibitory effects on hepatocytes. In contrast to primary hepatocytes, rat hepatoma cells cultured under similar conditions were relatively resistant to α-thrombin mediated growth inhibition. The inhibitory effect on hepatocyte DNA synthesis was antagonized by hirudin and antithrombin III, two specific α-thrombin inhibitors. Both the protease and receptor binding activities of α-thrombin were necessary for its growth-inhibitory actions, whereas G-protein coupled signal transduction via thrombin receptor was not necessary. Matrix fibronectin was degraded by α-thrombin. These results suggest a role for α-thrombin as a potent growth inhibitor of normal hepatocytes, possibly through control of matrix fibronectin.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA