Growth inhibitory actions of prothrombin on normal hepatocytes: influence of matrix.
Most hepatomas have a defect in prothrombin carboxylation, and can secrete under-carboxylated prothrombin or des-gamma-carboxy-prothrombin (DCP), the function of which is unknown. We considered that the prothrombin-DCP axis might also be involved in growth control. Hepatocytes and hepatoma cells were treated with prothrombin and DNA synthesis and cytoskeletal changes were studied. Prothrombin inhibited DNA synthesis in hepatocytes on fibronectin, but not collagen matrix. Hepatoma cell lines were not inhibited. We found that hepatoma cell matrix conferred resistance to hepatocytes. Prothrombin decreased fibronectin but not collagen amounts, but only in the presence of hepatocytes and not hepatoma cells, indicating that it has a differential action on matrix proteins. It also caused changes in cell shape and actin depolymerization. In vivo, there was a decrease in plasma prothrombin activity after a partial hepatectomy (PH), concomitant with the peak of DNA synthesis in the hepatocytes at 24h after PH. Injection of warfarin at the time of PH, further inhibited PT activity and enhanced this 24h peak of DNA synthesis. Furthermore, repeated injection of prothrombin lowered the peak DNA synthesis after PH. The data support the hypothesis that prothrombin can act as a hepatocyte growth inhibitor, likely at the level of fibronectin loss and result in cytoskeletal changes. Hepatomas resist this action, possibly due to their different matrix proteins. This represents a novel mechanism for growth regulation and provides a possible biological significance for the tumor marker DCP.
Carr
Brian I
BI
Liver Cancer Center, Starzl Transplantation Institute, University of Pittsburgh, E1552 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15260, USA. brian.carr@mail.jci.tju.edu
Kar
Siddhartha
S
Wang
Meifang
M
Wang
Ziqiu
Z
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D011516:Prothrombin / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D014812:Vitamin K / Q000494:pharmacology
D014812:Vitamin K; D004815:Epidermal Growth Factor; D011516:Prothrombin; D004247:DNA