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Phenotype-dependent production of des-γ-carboxy prothrombin in hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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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.

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Acknowledgments

This work was partially supported by a Grant-in-Aid for Scientific Research from the Japan Society.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan

    Hideto Suzuki, Kazumoto Murata, Takaya Gotoh, Takashi Oyamada & Atsushi Sakamoto

  2. Department of Gastroenterology, Iwaki Kyoritsu General Hospital, Iwaki, Japan

    Masao Kusano

  3. Internal Medicine, Suzuka General Hospital, Suzuka, Japan

    Hiroshi Okano

  4. Department of Surgery, Jichi Medical University, Shimotsuke, Japan

    Yoshikazu Yasuda

  5. The Research Center for Hepatitis and Immunology, Kohnodai Hospital, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, 272-8516, Japan

    Kazumoto Murata, Masatoshi Imamura & Masashi Mizokami

  6. Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-sayama, Japan

    Masatoshi Kudo

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  1. Hideto Suzuki
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Correspondence to Kazumoto Murata.

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Suzuki, H., Murata, K., Gotoh, T. et al. Phenotype-dependent production of des-γ-carboxy prothrombin in hepatocellular carcinoma. J Gastroenterol 46, 1219–1229 (2011). https://doi.org/10.1007/s00535-011-0432-8

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  • DOI: https://doi.org/10.1007/s00535-011-0432-8

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