Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder
Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder
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DOI：
10.1172/jci119230
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发表时间：
1997-03-01
影响因子：
15.9
通讯作者：
Atala, A
中科院分区：
文献类型：
--
作者：
Freeman, MR;Yoo, JJ;Atala, A
表皮生长因子受体（HER 1）与人膀胱上皮的再生生长和增殖性疾病有关（尿路上皮细胞），然而，尚未鉴定出可作为正常人尿路上皮细胞（HUC）的生长因子的同源HER 1配体。在此，我们表明肝素结合EGF样生长因子（HB-EGF），一种活化HER 1配体，是HUC生长的自分泌调节剂，这一结论是基于原代培养HUC合成和分泌HB-EGF的证明，HUC表面可活化的HB-EGF受体HER 1的鉴定，HB-EGF对HUC克隆生长的刺激，肝素对HB-EGF刺激的生长的抑制和HB-EGF/HER 1相互作用的特异性抑制剂CRM 197对对数期生长的抑制，和鉴定人尿路上皮作为HB-EGF前体的位点在体内的ProHB-EGF合成中，在人膀胱的血管和逼尿肌平滑肌中也检测到ProHB-EGF表达，这些数据表明HB-EGF在调节粘膜损伤后的尿路上皮增殖和再生中的生理作用，proHB-EGF的表达也是膀胱中分化的血管和逼尿肌平滑肌的特征，因为已知proHB-EGF是人细胞中的高亲和力白喉毒素（DT）受体，人尿路上皮细胞合成HB-EGF前体也提示了使用proHB-EGF的DT结合位点作为尿路上皮疾病腔内治疗的体内靶点的可能性。
The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified, Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth, This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo, ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder, These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury, Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder, Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.