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Ephrin-A1 Expression Contributes to the Malignant Characteristics of A 843 HEPATOBILIARY DISEASE Ephrin-A1 expression contributes to the malignant Gut: first published as 10.1136/gut.2004.049486 on 11 May 2005. Downloaded from characteristics of a-fetoprotein producing hepatocellular carcinoma H Iida, M Honda, H F Kawai, T Yamashita, Y Shirota, B-C Wang, H Miao, S Kaneko ............................................................................................................................... Gut 2005;54:843–851. doi: 10.1136/gut.2004.049486 Background and aims: a-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. See end of article for Methods: We examined ephrin-A1 expression and its effect on cell proliferation and gene expression in authors’ affiliations five AFP producing hepatoma cell lines, three AFP negative hepatoma cell lines, and 20 human HCC ....................... specimens. Correspondence to: Results: Ephrin-A1 expression levels were lowest in normal liver tissue, elevated in cirrhotic tissue, and Dr S Kaneko, Department further elevated in HCC specimens. Ephrin-A1 expression was strongly correlated with AFP expression of Cancer Gene (r = 0.866). We showed that ephrin-A1 induced expression of AFP. This finding implicates ephrin-A1 in Regulation, Kanazawa University Graduate the mechanism of AFP induction in HCC. Ephrin-A1 promoted the proliferation of ephrin-A1 School of Medical Science, underexpressing HLE cells, and an ephrin-A1 antisense oligonucleotide inhibited the proliferation of 13-1 Takara-Machi, ephrin-A1 overexpressing Huh7 cells. Thus ephrin-A1 affects hepatoma cell growth. cDNA microarray Kanazawa, 920-8641, Japan; skaneko@ analysis showed that ephrin-A1 induced expression of genes related to the cell cycle (p21), angiogenesis medf.m.kanazawa-u.ac.jp (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 Revised version received HCC tissues that overexpress AFP. 26 December 2004 Accepted for publication Conclusion: These findings suggest that the poor prognosis of patients with AFP producing HCC is partially 11 January 2005 caused by ephrin-A1 expression, which induces expression of genes related to tumour cell growth, ....................... angiogenesis, invasion, and metastasis. http://gut.bmj.com/ lpha-fetoprotein (AFP), a tumour marker for hepato- participates in tumorigenesis, the biological significance and cellular carcinoma (HCC), is expressed in fetal liver but expression pattern of ephrin-A1 in HCC are unknown. Ais not expressed in normal adult liver. Approximately In the present study, we investigated ephrin-A1 expression 70% of HCCs are positive for AFP, and levels of AFP increase in HCC specimens and hepatoma cell lines, and we examined with tumour progression.1 HCCs with high levels of AFP have the effect of ephrin-A1 on cell proliferation and gene a poor prognosis and exhibit multicentric growth more expression. We also discuss the significance of ephrin-A1 frequently than AFP negative HCCs.2–4 In a previous study, expression in AFP producing HCC. on October 2, 2021 by guest. Protected copyright. we identified a gene cluster that was characteristically expressed in AFP producing hepatoma cell lines but not in MATERIALS AND METHODS non-AFP producing hepatoma cell lines.5 In this cluster, Cell lines ephrin-A1 was the most differentially overexpressed gene in Huh7, Hep3B, HepG2, Huh6, PLC/PRF/5, SK-Hep1, and HLE AFP producing hepatoma cell lines. cells were maintained in Dulbecco’s modified Eagle’s Ephrin-A1, a ligand for the Eph receptor tyrosine kinase, is medium supplemented with 10% fetal bovine serum. The involved in vascular development, tissue border formation, simian virus 40 large-T antigen-immortalised normal cell migration, axon guidance, synaptic plasticity, and adult human hepatocyte cell line (THLE-5b) was maintained in neovascularisation.6 Several lines of evidence suggest that PMFR-4.13 14 ephrin-A1 plays roles in multiple aspects of tumorigenesis, including abnormal cell growth, angiogenesis, invasion, and Tissue specimens metastasis.7–12 Overexpression of ephrin-A1 in melanoma Cancerous and non-cancerous tissues were obtained from cells correlates with an increase in tumour cell growth, patients who underwent partial hepatectomy for HCC. indicating that ephrin-A1 acts as a cell survival factor or a Normal controls were histologically normal tissues and were promoter of abnormal cell growth in tumour cells.9–11 Ephrin- obtained from patients who underwent partial hepatectomy A1 and its receptor are consistently expressed in endothelial for metastatic liver tumours. These patients had no obvious cells of tumour associated vessels in a variety of human underlying disease, tested negative for all hepatitis virus tumours, including lung, stomach, and colorectal cancers,7 markers, and had normal levels of serum transaminase. and blocking the EphA receptor inhibits tumour angiogenesis and tumour progression in vivo.8 Inappropriate expression Abbreviations: AFP, a-fetoprotein; HCC, hepatocellular carcinoma; and regulation of ephrin ligands and Eph receptors affects RIA, radioimmunoassay; IGF-II, insulin-like growth factor II; TGF-b, 12 transforming growth factor b; BMP, bone morphogenetic protein; TSP-1, cell-matrix interaction by modulating integrin activity. thrombospondin 1; MMP-2, matrix metalloproteinase 2; SDS-PAGE, Although these findings suggest that ephrin-A1 expression sodium dodecyl sulphate-polyacrylamide gel electrophoresis www.gutjnl.com 844 Iida, Honda, Kawai, et al incubated overnight at 4˚C with anti-ephrin-A1 (Santa Cruz AFP Biotechnology, Santa Cruz, California, USA), anti-EphA1 (R&D Systems, Minneapolis, Minnesota, USA), or anti-AFP 2.01 0.98 1.23 1.01 0.88 0.06 0.08 0.06 antibodies (DakoCytomation, Glostrup, Denmark), and were Gut: first published as 10.1136/gut.2004.049486 on 11 May 2005. Downloaded from subjected to the ABC immunostaining procedure using a Ephrin-A1 Vectorstain ABC kit (Vector, Burlingame, California, USA), followed by DAB (Sigma-Aldrich Co., S. Louis, Missouri, 1.39 1.41 0.98 1.47 1.39 0.10 0.09 0.08 USA). Negative controls were normal liver tissues in which northern blotting and western blotting confirmed the β-actin absence of ephrin-A1, AFP, and EphA1 expression. HLE Antisense-oligodeoxynucleotide and cell proliferation Huh7 Huh6 Hep3B HepG2 SK-Hep1 THLE-5b assay PLC/PRF/5 We designed an antisense phosphorothioate oligodeoxy- nucleotide (59-CCA GAG GAA CTC CAT AGC GC-39) Figure 1 Expression of a-fetoprotein (AFP) and ephrin-A1 mRNA in complementary to the ephrin-A1 gene nucleotide sequence eight human hepatoma cell lines determined by northern blotting (20 mg RNA/lane). Expression levels of AFP and ephrin-A1 mRNA were that spans from five nucleotides upstream of the predicted quantified. The ratio of AFP or ephrin-A1 to b-actin is shown below each translational initiation site to 15 nucleotides downstream northern blot. from this site. We also used a sense oligodeoxynucleotide (59- GCG CTA TGG AGT TCC TCT GG-39) as a negative control. Cancerous and non-cancerous tissues were separately enu- For positive controls, we used an antisense oligodeoxy- cleated from resected tissues and were then immediately nucleotide for the potent HCC growth factor, insulin-like frozen in liquid nitrogen. Histological characterisation of HCC growth factor II (IGF-II; 59-TCT GCC TCG CAG TTG G-39), and normal liver tissue was performed as described pre- and its control sense oligodeoxynucleotide (59-TGT CTC CCA 17 3 viously.15 16 Informed consent was obtained from all patients GGC GGT T-39). For the proliferation assay, 3610 cells and ethics approval for the study was obtained from the were cultured in 96 well plates for 24 hours. Various ethics committee for human genome/gene analysis research concentrations of oligodeoxynucleotides were then added to at Kanazawa University Graduate School of Medical Science. the medium using the FuGENE6 transfection reagent (Boehringer Mannheim, Mannheim, Germany), and cultures were incubated for 72 hours. Cell growth was measured Northern blotting using the MTS assay kit (Promega, Madison, Wisconsin, Total RNA was isolated from cultured cells and frozen tissues USA). using a ToTally-RNA kit (Ambion, Austin, Texas, USA). Northern blotting was performed using a NorthernMax kit (Ambion). cDNA probes containing unique sequences from Clonal growth assay human AFP, ephrin-A1, EphA1, EphA2, p21WAF1/CIP1, thrombo- For studies using soluble ephrin-A1-Fc, 250 cells were plated spondin 1 (TSP-1), matrix metalloproteinase 2 (MMP-2), and in triplicate directly onto 12 well cell culture dishes in the b-actin were labelled with [a32P] dCTP by random presence of 0.3 mg/ml ephrin-A1-Fc. The medium was http://gut.bmj.com/ priming. mRNA expression levels were quantified with a changed every two days. After 8–10 days of culture, cell Fujix-MacBas1000 Bio-imaging analyser (Fujix, Tokyo, Japan). growth was measured using the MTS assay kit (Promega). Immunohistochemistry Ligand stimulation and cDNA microarray analysis Tissue specimens were fixed in 10% formalin, embedded in Subconfluent HLE cells were cultured with or without 1 mg/ paraffin blocks, and cut
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