Adam R M, Borer J G, Williams J, Eastham J A, Loughlin K R, Freeman M R
Department of Urology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Endocrinology. 1999 Dec;140(12):5866-75. doi: 10.1210/endo.140.12.7221.
Peptide growth factors have been proposed as mediators of smooth muscle-epithelial cell interactions in the human prostate; however, the identity of these molecules has not been established. In this study, we compared expression levels of messenger RNAs (mRNAs) encoding the epidermal growth factor (EGF) receptor-related receptor tyrosine kinases (ErbB1 through 4), the six EGF receptor ligands, EGF, transforming growth factor (TGF)-alpha, amphiregulin (ARG), HB-EGF, betacellulin, and epiregulin, and the related molecule heregulin-alpha, in a series of 10 prostate tissue specimens. Only EGF showed a disease-specific association, with increased mRNA levels in four of five PCa specimens in comparison to matched normal tissue from the same subject. In contrast, ARG and HB-EGF mRNAs showed a coordinate pattern of expression in 7/10 specimens that was distinct from all other growth factor or receptor genes examined and from mRNAs for prostate specific antigen, the androgen receptor and GAPDH, a house-keeping enzyme. Analysis of an additional series of benign prostatic hyperplasia and prostate cancer specimens from 60 individuals confirmed that ARG and HB-EGF mRNA levels varied in a highly coordinate manner (r = 0.93; P < 0.0001) but showed no association with disease. ARG was immunolocalized largely to interstitial smooth muscle cells (SMC), previously identified as the site of synthesis of HB-EGF in the prostate, while the cognate ARG and HB-EGF receptor, ErbB1, was localized exclusively to ductal epithelial cells and carcinoma cells. Although ARG was a relatively poor mitogen for Balb/c3T3 cells in comparison to HB-EGF, it was similar in potency to HB-EGF in stimulating human prostate epithelial cell growth, suggesting that prostate epithelia may be a physiologic target for ARG in vivo. Expression of both ARG and HB-EGF mRNAs was induced in cultured prostate SMC by fibroblast growth factor-2, a human prostate SMC mitogen linked to prostate disease. These findings indicate that ARG and HB-EGF are likely to be key mediators of directional signaling between SMC and epithelial cells in the human prostate and appear to be coordinately regulated.
肽生长因子被认为是人类前列腺中平滑肌-上皮细胞相互作用的介质；然而，这些分子的身份尚未确定。在本研究中，我们比较了编码表皮生长因子（EGF）受体相关受体酪氨酸激酶（ErbB1至4）、六种EGF受体配体（EGF、转化生长因子（TGF）-α、双调蛋白（ARG）、肝素结合表皮生长因子（HB-EGF）、β-细胞素和表皮调节素）以及相关分子神经调节蛋白-α的信使核糖核酸（mRNA）在一系列10个前列腺组织标本中的表达水平。只有EGF显示出疾病特异性关联，与来自同一受试者的匹配正常组织相比，五个前列腺癌（PCa）标本中有四个的mRNA水平升高。相比之下，ARG和HB-EGF的mRNA在7/10的标本中呈现出一种协同表达模式，这与所有其他检测的生长因子或受体基因以及前列腺特异性抗原、雄激素受体和管家酶甘油醛-3-磷酸脱氢酶（GAPDH）的mRNA不同。对另外一系列来自60名个体的良性前列腺增生和前列腺癌标本的分析证实，ARG和HB-EGF的mRNA水平以高度协同的方式变化（r = 0.93；P < 0.0001），但与疾病无关。ARG主要免疫定位在间质平滑肌细胞（SMC），先前已确定其为前列腺中HB-EGF的合成部位，而同源的ARG和HB-EGF受体ErbB1仅定位在导管上皮细胞和癌细胞中。尽管与HB-EGF相比，ARG对Balb/c3T3细胞是一种相对较弱的促有丝分裂原，但它在刺激人前列腺上皮细胞生长方面的效力与HB-EGF相似，这表明前列腺上皮细胞可能是ARG在体内的生理靶点。成纤维细胞生长因子-2（一种与前列腺疾病相关的人前列腺SMC有丝分裂原）可诱导培养的前列腺SMC中ARG和HB-EGF的mRNA表达。这些发现表明，ARG和HB-EGF可能是人类前列腺中SMC与上皮细胞之间定向信号传导的关键介质，并且似乎受到协同调节。
