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Ephrin-A1 expression contributes to the malignant characteristics of α-fetoprotein producing hepatocellular carcinoma
  1. H Iida1,
  2. M Honda1,
  3. H F Kawai1,
  4. T Yamashita1,
  5. Y Shirota1,
  6. B-C Wang2,
  7. H Miao2,
  8. S Kaneko1
  1. 1Department of Cancer Gene Regulation, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
  2. 2Rammelkamp Center for Research, MetroHealth Campus, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
  1. Correspondence to:
    Dr S Kaneko
    Department of Cancer Gene Regulation, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, 920-8641, Japan; skaneko{at}


Background and aims: α-Fetoprotein (AFP), a tumour marker for hepatocellular carcinoma (HCC), is associated with poor prognosis. Using cDNA microarray analysis, we previously found that ephrin-A1, an angiogenic factor, is the most differentially overexpressed gene in AFP producing hepatoma cell lines. In the present study, we investigated the significance of ephrin-A1 expression in HCC.

Methods: We examined ephrin-A1 expression and its effect on cell proliferation and gene expression in five AFP producing hepatoma cell lines, three AFP negative hepatoma cell lines, and 20 human HCC specimens.

Results: Ephrin-A1 expression levels were lowest in normal liver tissue, elevated in cirrhotic tissue, and further elevated in HCC specimens. Ephrin-A1 expression was strongly correlated with AFP expression (r = 0.866). We showed that ephrin-A1 induced expression of AFP. This finding implicates ephrin-A1 in the mechanism of AFP induction in HCC. Ephrin-A1 promoted the proliferation of ephrin-A1 underexpressing HLE cells, and an ephrin-A1 antisense oligonucleotide inhibited the proliferation of ephrin-A1 overexpressing Huh7 cells. Thus ephrin-A1 affects hepatoma cell growth. cDNA microarray analysis showed that ephrin-A1 induced expression of genes related to the cell cycle (p21), angiogenesis (angiopoietin 1 and thrombospondin 1), and cell-cell interactions (Rho, integrin, and matrix metalloproteinases) in cultured hepatoma cells. These ephrin-A1 induced genes are also activated in HCC tissues that overexpress AFP.

Conclusion: These findings suggest that the poor prognosis of patients with AFP producing HCC is partially caused by ephrin-A1 expression, which induces expression of genes related to tumour cell growth, angiogenesis, invasion, and metastasis.

  • AFP, α-fetoprotein
  • HCC, hepatocellular carcinoma
  • RIA, radioimmunoassay
  • IGF-II, insulin-like growth factor II
  • TGF-β, transforming growth factor β
  • BMP, bone morphogenetic protein
  • TSP-1, thrombospondin 1
  • MMP-2, matrix metalloproteinase 2
  • SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis
  • cDNA microarray
  • EphA1
  • p21
  • thrombospondin 1
  • matrix metalloproteinase 2

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  • Conflict of interest: None declared.

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