title: Phenotype-dependent production of des-γ-carboxy prothrombin in hepatocellular carcinoma.
abstract: 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.
authors: Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan.
authors: Hideto
authors: H
authors: Suzuki
authors: Kazumoto
authors: K
authors: Murata
authors: Takaya
authors: T
authors: Gotoh
authors: Masao
authors: M
authors: Kusano
authors: Hiroshi
authors: H
authors: Okano
authors: Takashi
authors: T
authors: Oyamada
authors: Yoshikazu
authors: Y
authors: Yasuda
authors: Masatoshi
authors: M
authors: Imamura
authors: Masatoshi
authors: M
authors: Kudo
authors: Masashi
authors: M
authors: Mizokami
authors: Atsushi
authors: A
authors: Sakamoto
mesh_terms: D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008113:Liver Neoplasms / Q000473:pathology*; D010641:Phenotype; D011498:Protein Precursors / Q000096:biosynthesis*; D011516:Prothrombin / Q000096:biosynthesis*; D014162:Transfection; D014746:Vimentin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011498:Protein Precursors; D014746:Vimentin; C008208:acarboxyprothrombin; D011516:Prothrombin