title: Granulin-epithelin precursor interacts with heparan sulfate on liver cancer cells.
abstract: Granulin-epithelin precursor (GEP) is a pluripotent secretory growth factor which promotes cancer progression in a number of human cancers. However, how cancer cells interact with GEP remains unknown. In this study, we aimed to identify the cell surface-binding partner of GEP on liver cancer cells. Human recombinant GEP (rGEP) was expressed and purified to homogeneity. The rGEP was shown to trigger phosphorylation of AKT and ERK1/2 in liver cancer cells. We demonstrated cell surface attachment of rGEP, which was blocked by prebinding of platelet-derived growth factor-AA, platelet-derived growth factor-BB and fibroblast growth factor-2. Therefore, heparan sulfate (HS) had been reasoned as the binding partner of rGEP. Heparinase digestion validated the role of HS on supporting the attachment. The heparin-binding domain of GEP was mapped to RRH(555-557) in the C-terminal region. Suppression of the HS polymerase exostosin-1 reduced the rGEP binding and rGEP-mediated signaling transduction. Suppression of a specific HS proteoglycan, glypican-3, also showed a partial reduction of rGEP binding and an inhibition on rGEP-mediated activation of AKT. Furthermore, glypican-3 was shown to correlate with the expressions of GEP in clinical samples (Spearman's ρ = 0.363, P = 0.001). This study identified HS, partly through glypican-3, as a novel binding partner of GEP on the surface of liver cancer cells.
authors.affiliation: Department of Surgery, Centre for Cancer Research and.
authors.forename: Chi Wai
authors.initials: CW
authors.lastname: Yip
authors.affiliation: Department of Surgery, Centre for Cancer Research and.
authors.forename: Phyllis F Y
authors.initials: PF
authors.lastname: Cheung
authors.affiliation: Department of Surgery.
authors.forename: Idy C Y
authors.initials: IC
authors.lastname: Leung
authors.affiliation: Department of Surgery.
authors.forename: Nicholas C L
authors.initials: NC
authors.lastname: Wong
authors.affiliation: Department of Surgery.
authors.forename: Christine K C
authors.initials: CK
authors.lastname: Cheng
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.affiliation: stcheung@hku.hk.
authors.forename: Siu Tim
authors.initials: ST
authors.lastname: Cheung
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053673:Glypicans / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056945:Hep G2 Cells; D006497:Heparan Sulfate / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D000077153:Progranulins; D011485:Protein Binding
chemical_list: D016222:Fibroblast Growth Factor 2; D053673:Glypicans; D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D051058:Oncogene Protein v-akt; D000077153:Progranulins; C492314:GRN protein, human