Freeman M R, Paul S, Kaefer M, Ishikawa M, Adam R M, Renshaw A A, Elenius K, Klagsbrun M
Department of Urology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Cell Biochem. 1998 Mar 1;68(3):328-38. doi: 10.1002/(sici)1097-4644(19980301)68:3<328::aid-jcb4>3.0.co;2-w.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an activating ligand for the EGF receptor (HER1/ErbB1) and the high-affinity receptor for diphtheria toxin (DT) in its transmembrane form (proHB-EGF). HB-EGF was immunolocalized within human benign and malignant prostatic tissues, using monospecific antibodies directed against the mature protein and against the cytoplasmic domain of proHB-EGF. Prostate carcinoma cells, normal glandular epithelial cells, undifferentiated fibroblasts, and inflammatory cells were not decorated by the anti-HB-EGF antibodies; however, interstitial and vascular smooth muscle cells were highly reactive, indicating that the smooth muscle compartments are the major sites of synthesis and localization of HB-EGF within the prostate. In marked contrast to prostatic epithelium, proHB-EGF was immunolocalized to seminal vesicle epithelium, indicating differential regulation of HB-EGF synthesis within various epithelia of the reproductive tract. HB-EGF was not overexpressed in this series of cancer tissues, in comparison to the benign tissues. In experiments with LNCaP human prostate carcinoma cells, HB-EGF was similar in potency to epidermal growth factor (EGF) in stimulating cell growth. Exogenous HB-EGF and EGF each activated HER1 and HER3 receptor tyrosine kinases and induced tyrosine phosphorylation of cellular proteins to a similar extent. LNCaP cells expressed detectable but low levels of HB-EGF mRNA; however, proHB-EGF was detected at the cell surface indirectly by demonstration of specific sensitivity to DT. HB-EGF is the first HER1 ligand to be identified predominantly as a smooth muscle cell product in the human prostate. Further, the observation that HB-EGF is similar to EGF in mitogenic potency for human prostate carcinoma cells suggests that it may be one of the hypothesized stromal mediators of prostate cancer growth.
肝素结合表皮生长因子样生长因子（HB-EGF）是表皮生长因子受体（HER1/ErbB1）的激活配体，其跨膜形式（proHB-EGF）是白喉毒素（DT）的高亲和力受体。使用针对成熟蛋白和proHB-EGF胞质结构域的单特异性抗体，将HB-EGF免疫定位在人良性和恶性前列腺组织内。抗HB-EGF抗体未标记前列腺癌细胞、正常腺上皮细胞、未分化的成纤维细胞和炎性细胞；然而，间质和平滑肌细胞具有高反应性，表明平滑肌区室是前列腺内HB-EGF合成和定位的主要部位。与前列腺上皮形成鲜明对比的是，proHB-EGF免疫定位在精囊上皮，表明生殖道各上皮内HB-EGF合成的调节存在差异。与良性组织相比，在这一系列癌组织中HB-EGF未过度表达。在LNCaP人前列腺癌细胞实验中，HB-EGF在刺激细胞生长方面的效力与表皮生长因子（EGF）相似。外源性HB-EGF和EGF均激活HER1和HER3受体酪氨酸激酶，并在相似程度上诱导细胞蛋白的酪氨酸磷酸化。LNCaP细胞表达可检测但低水平的HB-EGF mRNA；然而，通过对DT的特异性敏感性间接检测到细胞表面存在proHB-EGF。HB-EGF是在人前列腺中主要被鉴定为平滑肌细胞产物的首个HER1配体。此外，HB-EGF在对人前列腺癌细胞的促有丝分裂效力方面与EGF相似这一观察结果表明，它可能是前列腺癌生长的假定基质介质之一。
