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Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K2

  • Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Vitamin K2 has been reported to suppress the growth of human hepatocellular carcinoma (HCC) in vitro and hepatocarcinogenesis in hepatitis C virus (HCV)-related cirrhosis in vivo. Hepatoma-derived growth factor (HDGF) is a unique nuclear targeting growth factor that is highly expressed in HCC cells and is a possible prognostic factor for patients with HCC. We investigated the regulation of HDGF expression by vitamin K2.

Methods

Three HCC-derived cell lines, HepG2, HuH-7, and SK-Hep-1, were used. Cell number was determined with the MTT assay. The expression levels of HDGF mRNA and protein were measured by the real-time reverse transcriptase-polymerase chain reaction (PCR) method and ELISA and Western blot analysis, respectively. The HDGF promoter activity was measured by a dual luciferase-reporter assay.

Results

Vitamin K2 suppressed the growth of the three HCC cell lines in a dose-dependent manner. Vitamin K2 significantly suppressed the expression of the HDGF protein and mRNA in three cell lines. By a luciferase assay, vitamin K2 significantly suppressed the promoter activity of the HDGF protein. Based on some luciferase-reporter plasmids containing truncated promoter regions, the possible responsive site of vitamin K2 seems to reside in the region −1 to −150 bp of the HDGF gene.

Conclusions

These findings suggested that regulation of the HDGF gene expression is one of the crucial mechanisms of vitamin K2-induced cell growth suppression for HCC.

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Authors and Affiliations

  1. Division of Hepatobiliary and Pancreatic Medicine, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Teruhisa Yamamoto, Hideji Nakamura, Weidong Liu, Ke Cao, Shohei Yoshikawa, Hirayuki Enomoto, Yoshinori Iwata, Noritoshi Koh, Masaki Saito, Hiroyasu Imanishi, Soji Shimomura, Hiroko Iijima, Toshikazu Hada & Shuhei Nishiguchi

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  1. Teruhisa Yamamoto
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  2. Hideji Nakamura
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  3. Weidong Liu
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  4. Ke Cao
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Yamamoto, T., Nakamura, H., Liu, W. et al. Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K2 . J Gastroenterol 44, 228–235 (2009). https://doi.org/10.1007/s00535-008-2304-4

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  • DOI: https://doi.org/10.1007/s00535-008-2304-4

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