Cohen P, Nunn S E, Peehl D M
Pediatric Endocrinology, UCLA, Los Angeles, California 90095, USA.
J Endocrinol. 2000 Feb;164(2):215-23. doi: 10.1677/joe.0.1640215.
The IGF axis has been implicated in the pathogenesis of benign prostatic hyperplasia (BPH) via the paracrine action of IGFs and IGF-binding proteins (IGFBPs). In this study, we examined the regulation of cell growth and IGFBP-3 secretion by transforming growth factor-beta (TGF-beta) in prostatic stromal cell (PC-S) cultures from histologically normal tissues and tissues from BPH. PC-S cultures were treated with varying doses of TGF-beta1. Forty-eight hour conditioned media (CM) from these cultures were subjected to Western immunoblotting and ligand blotting for detection and quantification of IGFBPs. IGFBPs-2, -3 and -4 were detected in the CM from normal PC-S cultures. In CM from BPH PC-S, IGFBP-3 levels were 2-fold lower at baseline than in the normal PC-S CM, in addition to the differences in IGFBPs-2 and -5 which we have previously reported. In response to TGF-beta1, a 15-fold increase in the levels of IGFBP-3 was observed in normal PC-S CM, while a mere 2-fold increase was observed in BPH PC-S CM (P<0.001). These findings were confirmed by specific immunoblotting and immunocytochemistry. IGFBP-3 mRNA levels detected by Northern blotting of total RNA extracted from similar cultures showed the induction of IGFBP-3 expression by TGF-beta1 in normal PC-S and its lack of induction in BPH PC-S. Cell growth inhibition in response to TGF-beta1 correlated with the IGFBP-3 concentrations found in CM. Normal PC-S showed a 60% decrease in cell number after 10 days in media with 1 ng/ml TGF-beta1, compared with the untreated control. The decrease in proliferation observed in comparably treated BPH cells was only 20% (P<0.001). In conclusion, BPH PC-S had a reduced IGFBP-3 response to TGF-beta1 and demonstrated decreased TGF-beta1-induced growth inhibition relative to normal PC-S. We hypothesize that in normal PC-S, TGF-beta exerts its anti-proliferative effects by stimulating the production of IGFBP-3, which acts as an inhibitory factor, either by inhibiting IGFs or directly by interacting with cells, and that this process is altered in BPH PC-S.
胰岛素样生长因子（IGF）轴通过IGF和IGF结合蛋白（IGFBPs）的旁分泌作用参与了良性前列腺增生（BPH）的发病机制。在本研究中，我们检测了转化生长因子-β（TGF-β）对来自组织学正常组织和BPH组织的前列腺基质细胞（PC-S）培养物中细胞生长和IGFBP-3分泌的调节作用。用不同剂量的TGF-β1处理PC-S培养物。对这些培养物48小时的条件培养基（CM）进行Western免疫印迹和配体印迹，以检测和定量IGFBPs。在正常PC-S培养物的CM中检测到IGFBP-2、-3和-4。在BPH PC-S的CM中，IGFBP-3水平在基线时比正常PC-S CM低2倍，此外还有我们之前报道的IGFBP-2和-5的差异。对TGF-β1的反应中，正常PC-S CM中IGFBP-3水平增加了15倍，而BPH PC-S CM中仅增加了2倍（P<0.001）。这些发现通过特异性免疫印迹和免疫细胞化学得到证实。通过对从相似培养物中提取的总RNA进行Northern印迹检测到的IGFBP-3 mRNA水平显示，TGF-β1在正常PC-S中诱导IGFBP-3表达，而在BPH PC-S中未诱导。对TGF-β1的细胞生长抑制与CM中发现的IGFBP-3浓度相关。与未处理的对照相比，在含有1 ng/ml TGF-β1的培养基中培养10天后，正常PC-S的细胞数量减少了60%。在相同处理的BPH细胞中观察到的增殖减少仅为20%（P<0.001）。总之，BPH PC-S对TGF-β1的IGFBP-3反应降低，并且相对于正常PC-S，TGF-β1诱导的生长抑制作用减弱。我们推测，在正常PC-S中，TGF-β通过刺激IGFBP-3的产生发挥其抗增殖作用，IGFBP-3作为一种抑制因子，要么通过抑制IGF，要么直接与细胞相互作用，而在BPH PC-S中这个过程发生了改变。
