caa a22 4500 445888490 CHVBK 20180317145607.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s00535-011-0432-8 doi (NATIONALLICENCE)springer-10.1007/s00535-011-0432-8 Phenotype-dependent production of des-γ-carboxy prothrombin in hepatocellular carcinoma [Elektronische Daten] [Hideto Suzuki, Kazumoto Murata, Takaya Gotoh, Masao Kusano, Hiroshi Okano, Takashi Oyamada, Yoshikazu Yasuda, Masatoshi Imamura, Masatoshi Kudo, Masashi Mizokami, Atsushi Sakamoto] Background: Des-γ-carboxy prothrombin (DCP) is an established tumor marker for hepatocellular carcinoma (HCC), but the precise mechanism of its production remains unknown. We have recently demonstrated that cytoskeletal rearrangement during the phenotypic changes involved in epithelial mesenchymal transition (EMT) plays a crucial role in DCP production through the impairment of vitamin K uptake. However, DCP production in long-lasting severe hypoxic conditions with nutrient deprivation-such as transarterial embolization-remains unknown. Methods: We examined the effects of long-lasting hypoxia with nutrient deprivation, as well as the constitutive expression of hypoxia-inducible factor (HIF)-1α, on EMT status, DCP production, and protein synthesis in human hepatoma cell lines by enzyme-linked immunosorbent assay, immunofluorescent studies, and western blotting. Immunohistochemistry findings for DCP, anti-hepatocyte paraffin 1 (Hep Par 1), and vimentin were examined using human resected HCC samples. Results: Both severe hypoxia with nutrient deprivation and HIF-1α transfection led to the cessation of DCP production, by attenuating protein synthesis through the hypophosphorylation of mammalian target of rapamycin and its effector proteins, indicative of a further phenotypic shift involving impaired liver-specific protein synthesis. In immunohistochemistry, the distribution of DCP- and Hep Par 1-positive HCC cells was mostly similar and vimentin-positive HCC cells were frequently observed in the areas that were negative for Hep Par 1 and/or DCP. Conclusions: HCC cells produce DCP when they undergo mild phenotypic changes. However, when HCC cells adopt mesenchymal properties they lose their capacity for protein synthesis, and the production of DCP is attenuated. Building upon our previous works, it appears that DCP could be a unique tumor marker that reflects the stepwise phenotypic changes of HCC. Springer, 2011 Tumor marker nationallicence Epithelial mesenchymal transition nationallicence O2 conformance nationallicence Mammalian target of rapamycin pathway nationallicence Suzuki Hideto Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut Murata Kazumoto Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut Gotoh Takaya Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut Kusano Masao Department of Gastroenterology, Iwaki Kyoritsu General Hospital, Iwaki, Japan aut Okano Hiroshi Internal Medicine, Suzuka General Hospital, Suzuka, Japan aut Oyamada Takashi Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut Yasuda Yoshikazu Department of Surgery, Jichi Medical University, Shimotsuke, Japan aut Imamura Masatoshi The Research Center for Hepatitis and Immunology, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, 272-8516, Ichikawa, Japan aut Kudo Masatoshi Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-sayama, Japan aut Mizokami Masashi The Research Center for Hepatitis and Immunology, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, 272-8516, Ichikawa, Japan aut Sakamoto Atsushi Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut Journal of Gastroenterology Springer Japan 46/10(2011-10-01), 1219-1229 0944-1174 46:10<1219 2011 46 535 https://doi.org/10.1007/s00535-011-0432-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00535-011-0432-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Suzuki Hideto Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 700 1- Murata Kazumoto Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 700 1- Gotoh Takaya Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 700 1- Kusano Masao Department of Gastroenterology, Iwaki Kyoritsu General Hospital, Iwaki, Japan aut NATIONALLICENCE 700 1- Okano Hiroshi Internal Medicine, Suzuka General Hospital, Suzuka, Japan aut NATIONALLICENCE 700 1- Oyamada Takashi Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 700 1- Yasuda Yoshikazu Department of Surgery, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 700 1- Imamura Masatoshi The Research Center for Hepatitis and Immunology, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, 272-8516, Ichikawa, Japan aut NATIONALLICENCE 700 1- Kudo Masatoshi Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-sayama, Japan aut NATIONALLICENCE 700 1- Mizokami Masashi The Research Center for Hepatitis and Immunology, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, 272-8516, Ichikawa, Japan aut NATIONALLICENCE 700 1- Sakamoto Atsushi Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan aut NATIONALLICENCE 773 0- Journal of Gastroenterology Springer Japan 46/10(2011-10-01), 1219-1229 0944-1174 46:10<1219 2011 46 535 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer