Ephrin-A1 expression contributes to the malignant characteristics of α-fetoprotein producing hepatocellular carcinoma. Issue 6 (11th May 2005)

• Record Type: Journal Article
• Authors: Iida, H; Honda, M; Kawai, H F; Yamashita, T; Shirota, Y; Wang, B-C; Miao, H; Kaneko, S
• Is Part Of: Gut. Volume 54:Issue 6(2005)
• Page Start: 843
• Page End: 851
• Publication Date: 2005-05-11
• Subjects: 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; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2004.049486
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.