Des-gamma-carboxy prothrombin is a potential autologous growth factor for hepatocellular carcinoma.
Des-gamma-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma (HCC). In the present study, we demonstrate that DCP has a mitogenic effect on HCC cell lines. Purified DCP stimulated DNA synthesis of Hep3B and SK-Hep-1 cells in a dose-dependent manner. DCP was found to bind with cell surface receptor Met causing Met autophosphorylation and also to activate STAT3 signaling pathway through Janus kinase 1. Luciferase gene reporter analysis showed that DCP induced STAT3-related transcription. Small interfering RNAs against both STAT3 and Met abrogated DCP-induced cell proliferation. DCP did not affect the mitogen-activated protein kinase pathway, Myc signaling pathway, or phosphoinositide 3-kinase/Akt pathway. Based on these results, we believe that DCP acts as an autologous mitogen for HCC cell lines. The Met-Janus kinase 1-STAT3 signaling pathway may be a major signaling pathway for DCP-induced cell proliferation.
Suzuki
Mayumi
M
Department of Medicine and Medical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Shiraha
Hidenori
H
Fujikawa
Tatsuya
T
Takaoka
Nobuyuki
N
Ueda
Naoki
N
Nakanishi
Yutaka
Y
Koike
Kazuko
K
Takaki
Akinobu
A
Shiratori
Yasushi
Y
D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000209:etiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006133:Growth Substances; D006801:Humans; D053613:Janus Kinase 1; D010766:Phosphorylation; D011498:Protein Precursors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011516:Prothrombin / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D015415:Biomarkers; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D006133:Growth Substances; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C008208:acarboxyprothrombin; D011516:Prothrombin; D004247:DNA; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C507904:JAK1 protein, human; D053613:Janus Kinase 1