The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer
The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer
复制标题
DOI：
10.1172/jci4105
复制
发表时间：
1998-11-01
影响因子：
15.9
通讯作者：
Korc, M
中科院分区：
文献类型：
--
作者：
Kleeff, J;Ishiwata, T;Korc, M
硫酸乙酰肝素蛋白聚糖（HSPG）在细胞识别、生长和粘附中发挥着不同的作用。体外研究表明，细胞表面HSPG作为肝素结合促有丝分裂生长因子的共受体，在这里，我们表明，糖基磷脂酰肌醇-（GPI-）锚定的HSPG磷脂酰肌醇蛋白聚糖-1在人胰腺癌中强烈表达，无论是癌细胞和相邻的成纤维细胞，而磷脂酰肌醇蛋白聚糖-1的表达是低的正常胰腺和慢性胰腺炎。用磷酸肌醇特异性磷脂酶C（PI-PLC）处理表达磷脂酰肌醇蛋白聚糖-1的两种胰腺癌细胞系，可消除其对两种肝素结合生长因子（通常在胰腺癌中过表达）的促有丝分裂反应：成纤维细胞生长因子2（FGF 2）和肝素结合EGF样生长因子（HB-EGF）。PI-PLC不改变对非肝素结合生长因子EGF和IGF-1的反应。磷脂酰肌醇蛋白聚糖-1的一种形式的稳定表达被工程化以具有跨膜结构域而不是GPI锚，赋予对PI-PLC对生长因子反应性的抑制作用的抗性。此外，磷脂酰肌醇蛋白聚糖-1反义构建体的转染减弱了磷脂酰肌醇蛋白聚糖-1蛋白水平和对FGF 2和HB-ECF的促有丝分裂反应。我们建议磷脂酰肌醇蛋白聚糖-1在胰腺癌细胞对某些促有丝分裂刺激的反应中起重要作用，它相对于其他HSPGs是独特的，并且胰腺癌细胞表达它可能在这种疾病的病理生物学中具有重要意义。
Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recognition, growth, and adhesion. In vitro studies suggest that cell-surface HSPGs act as coreceptors for heparin-binding mitogenic growth factors, Here we show that the glycosylphosphatidylinositol- (GPI-) anchored HSPG glypican-1 is strongly expressed in human pancreatic cancer, both by the cancer cells and the adjacent fibroblasts, whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1, Stable expression of a form of glypican-1 engineered to possess a transmembrane domain instead of a GPI anchor conferred resistance to the inhibitory effects of PI-PLC on growth factor responsiveness. Furthermore, transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-ECF. We propose that glypican-1 plays an essential role in the responses of pancreatic cancer cells to certain mitogenic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder.