Cohen P, Peehl D M, Baker B, Liu F, Hintz R L, Rosenfeld R G
Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania.
J Clin Endocrinol Metab. 1994 Nov;79(5):1410-5. doi: 10.1210/jcem.79.5.7525636.
Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. To assess whether patients with BPH have alterations in their prostatic IGF axis, we measured the expression (by Northern blotting) and the production (by Western ligand blotting and RIA) of insulin-like growth factor-II (IGF-II) and IGF-binding proteins (IGFBPs) in prostatic epithelial and stromal cell strains grown from normal (n = 7), hyperplastic (n = 7), and malignant (n = 5) surgical specimens. Levels of IGF-II messenger ribonucleic acid (mRNA; normalized for actin expression) were 10-fold higher in BPH stromal cell strains compared to those in normal stromal cell strains (P < 0.0001). Western ligand blotting of conditioned medium (CM) from normal stromal cells demonstrated the presence of IGFBP-2, -3, and -4. In the CM of BPH stromal cells, IGFBP-2 levels were dramatically reduced to less than 20% of normal (P < 0.001). Additionally, IGFBP-5, which was not observed in significant amounts in normal stromal cell-CM, was found in large quantities in BPH stromal cell-CM. Northern blot analysis of mRNA from normal and BPH stromal cells demonstrated a 5-fold decrease in IGFBP-2 mRNA (P < 0.001) and a 4-fold increase in IGFBP-5 mRNA (P < 0.01) in BPH compared to normal cells. In prostate stromal cells from cancer specimens, no abnormalities were found. No abnormalities were observed in the IGF axis parameters evaluated in prostate epithelial cells from BPH or cancer strains. We conclude that prostatic stromal cell strains isolated from patients with BPH hyperexpress the mRNA for IGF-II and IGFBP-5 while expressing reduced amounts of IGFBP-2 mRNA. IGFBP, but not IGF-II, peptide levels in CM correspond to the mRNA differences. This is the first documentation of altered gene and protein expression in this common disease. We speculate that these abnormalities in the IGF axis may be important in the pathogenesis of BPH.
良性前列腺增生（BPH）是一种病因不明的常见增殖性疾病。为了评估BPH患者的前列腺胰岛素样生长因子（IGF）轴是否存在改变，我们检测了从正常（n = 7）、增生（n = 7）和恶性（n = 5）手术标本中培养的前列腺上皮和基质细胞系中胰岛素样生长因子-II（IGF-II）和IGF结合蛋白（IGFBPs）的表达（通过Northern印迹法）和产生（通过Western配体印迹法和放射免疫分析法）。与正常基质细胞系相比，BPH基质细胞系中IGF-II信使核糖核酸（mRNA；经肌动蛋白表达标准化）水平高10倍（P < 0.0001）。对正常基质细胞条件培养基（CM）进行Western配体印迹分析显示存在IGFBP-2、-3和-4。在BPH基质细胞的CM中，IGFBP-2水平显著降低至正常水平的不到20%（P < 0.001）。此外，在正常基质细胞-CM中未大量观察到的IGFBP-5在BPH基质细胞-CM中大量存在。对正常和BPH基质细胞mRNA进行Northern印迹分析显示，与正常细胞相比，BPH中IGFBP-2 mRNA减少5倍（P < 0.001），IGFBP-5 mRNA增加4倍（P < 0.01）。在癌标本的前列腺基质细胞中未发现异常。在BPH或癌性细胞系的前列腺上皮细胞中评估的IGF轴参数未观察到异常。我们得出结论，从BPH患者分离的前列腺基质细胞系过度表达IGF-II和IGFBP-5的mRNA，同时IGFBP-2 mRNA表达量减少。CM中的IGFBP（而非IGF-II）肽水平与mRNA差异相对应。这是这种常见疾病中基因和蛋白质表达改变的首次记录。我们推测IGF轴的这些异常可能在BPH的发病机制中起重要作用。
