title: Peritumoral small ephrinA5 isoform level predicts the postoperative survival in hepatocellular carcinoma.
abstract: BACKGROUND
  EphrinA5, a member of Eph/Ephrin family, possesses two alternative isoforms, large ephrinA5 isoform (ephrinA5L) and small ephrinA5 isoform (ephrinA5S). EphrinA5L is a putative tumor suppressor in several types of human cancers. However, the role of ephrinA5S in hepato-carcinogenesis remains unclear. In this study, we evaluate the role of ephrinA5 isoforms in human hepatocellular carcinomas (HCC).
  
  
  RESULTS
  A total of 142 paired HCCs and peritumoral liver tissue was examined for relative expression of ephrinA5L and ephrinA5S by using quantitative real-time polymerase chain reaction. We analyzed their expression in relation to clinical parameters, disease-free survival and overall survival. Functional assays were performed to dissect the possible underlying mechanisms. Both ephrinA5L and ephrinA5S were significantly downregulated in HCCs, as compared to those in peritumoral tissue (p = 0.013 and 0.001). Univariate analysis demonstrated that ephrinA5S was positively correlated with old age and histological grade. In multivariate analysis, high ephrinA5S expression in peritumoral tissue had better disease-free survival (p = 0.002) and overall survival (p = 0.045) in patients with HCC after surgical resection. Functional analysis in HCC cell lines revealed that ephrinA5S had a more potent suppressive effect than ephrinA5L on cell proliferation (p<0.05) and migration (p<0.01). Furthermore, forced expression of both ephrinA5 isoforms in HCC cell lines significantly down-regulated epidermal growth factor receptor (EGFR) expression by promoting c-Cbl-mediated EGFR degradation.
  
  
  CONCLUSIONS
  EphrinA5S might be a useful prognostic biomarker for HCCs after surgical resection. EphrinA5, especially ephrinA5S, acts as a tumor suppressor in hepatocarcinogenesis. Peritumoral small ephrinA5 isoform level could determine the postoperative survival in hepatocellular carcinoma.
authors.affiliation: Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.
authors.forename: Tong-Hong
authors.initials: TH
authors.lastname: Wang
authors.forename: Kwai-Fong
authors.initials: KF
authors.lastname: Ng
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Wang
authors.forename: Kung-Hao
authors.initials: KH
authors.lastname: Liang
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018572:Disease-Free Survival; D015536:Down-Regulation; D036386:Ephrin-A5 / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000378:metabolism; D059748:Proteolysis; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D036386:Ephrin-A5; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D036081:Receptors, Eph Family; C067419:CBL protein, human