Stable transfection of a glypican-1 antisense construct decreases tumorigenicity in PANC-1 pancreatic carcinoma cells.
Glypican-1 belongs to a family of glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycans (HSPGs) that affect cell growth, invasion, and adhesion. Cell-surface HSPGs are believed to act as co-receptors for heparin-binding mitogenic growth factors. It was reported that glypican-1 is strongly expressed in human pancreatic cancer, and that it may play an essential role in regulating growth-factor responsiveness in pancreatic carcinoma cells. In this study we investigated the effects of decreased glypican-1 expression in PANC-1 pancreatic cancer cells. To this end, PANC-1 cells were stable transfected with a full-length glypican-1 antisense construct. The glypican- antisense transfected clones displayed markedly reduced glypican- protein levels and a marked attenuation of the mitogenic responses to heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor-2 (FGF2), heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and hepatocyte growth factor (HGF). In addition, glypican-1 antisense-expressing PANC-1 cells exhibited a significantly reduced ability to form tumors in nude mice in comparison with parental and sham-transfected PANC-1 cells. These data suggest that glypican-1 plays an important role in the responses of pancreatic cancer cells to heparin-binding growth factors, and documents for the first time that its expression may enhance tumorigenic potential in vivo.
Kleeff
J
J
Department of Medicine, University of California, Irvine 92697, USA.
Wildi
S
S
Kumbasar
A
A
Friess
H
H
Lander
A D
AD
Korc
M
M
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016373:DNA, Antisense / Q000096:biosynthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011133:Polysaccharide-Lyases / Q000378:metabolism; D016372:RNA, Antisense / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016373:DNA, Antisense; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D016372:RNA, Antisense; D012333:RNA, Messenger; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase