Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2)

J Gastroenterol. 2009;44(3):228-35. doi: 10.1007/s00535-008-2304-4. Epub 2009 Feb 13.


Background: Vitamin K(2) 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 K(2).

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 K(2) suppressed the growth of the three HCC cell lines in a dose-dependent manner. Vitamin K(2) significantly suppressed the expression of the HDGF protein and mRNA in three cell lines. By a luciferase assay, vitamin K(2) 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 K(2) 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 K(2)-induced cell growth suppression for HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, Reporter
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vitamin K 2 / administration & dosage
  • Vitamin K 2 / pharmacology*


  • Antineoplastic Agents
  • Intercellular Signaling Peptides and Proteins
  • RNA, Messenger
  • hepatoma-derived growth factor
  • Vitamin K 2
  • Luciferases