Lin V K, Wang D, Lee I L, Vasquez D, Fagelson J E, McConnell J D
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Prostate. 2000 Aug 1;44(3):193-203. doi: 10.1002/1097-0045(20000801)44:3<193::aid-pros3>3.0.co;2-a.
Benign prostatic hyperplasia (BPH) is common among aging men. Over 80% of males 50-60 years and older have various degrees of bladder outlet obstruction secondary to BPH. Despite the tremendous medical impact of BPH, its molecular pathophysiology remains unclear. Current BPH research focuses on steroid hormonal effects, stromal-epithelial cell interaction, and oncogenes and growth factors. But little is known about the potential prostatic smooth muscle (SM) alterations that may occur during stromal hyperplasia.
To study SM phenotypic modulation in hyperplastic prostatic growth, we isolated and characterized the 3' end of human SM myosin heavy chain (SMMHC) cDNA as a molecular probe. Expression of SMMHC and nonmuscle myosin heavy chain (NMMHC) in human prostates was analyzed using Western blot, Northern blot, and in situ hybridization to determine if BPH tissue expresses significantly less SMMHC and more NMMHC than a normal prostate. In addition, a competitive, reverse transcription (RT) polymerase chain reaction (PCR) method was adapted to quantify SMMHC and NMMHC mRNA expression at the sensitivity level of 10(-21) mole per mg of wet tissue.
Western blot, Northern blot, and in situ hybridization results reveal that both SMMHC and NMMHC are expressed in the human prostate, while SMMHC is the predominant form found in normal prostate stroma. Results from competitive RT-PCR analysis indicate that NMMHC mRNA expression is approximately 10(-20) mole/mg of tissue. The SMMHC mRNA expressed is approximately 10(-18) mole/mg. No significant difference was found when NMMHC mRNA expression was compared between normal and BPH periurethral tissues. However, SMMHC expression was reduced almost fivefold in BPH compared to normal prostate, despite an increase in prostatic stromal mass.
Our results suggest the pathogenesis of BPH is associated with a unique type of SM proliferation. Such proliferation is characterized by downregulation of SMMHC mRNA expression but without upregulation of NMMHC mRNA expression, the pattern seen in proliferating SM cells in culture and in other pathologic forms of SM hyperplasia (e.g., atherosclerosis). These findings support a model of BPH typified by active smooth muscle proliferation early in the disease process, and supports clinical observations that suggest ongoing prostate growth of the prostate is minimal in older men. Therapeutic strategies to prevent disease progression should therefore focus on early phases of prostatic growth.
良性前列腺增生（BPH）在老年男性中很常见。80%以上的50 - 60岁及以上男性因BPH继发不同程度的膀胱出口梗阻。尽管BPH对医学有巨大影响，但其分子病理生理学仍不清楚。目前BPH研究集中在类固醇激素作用、基质 - 上皮细胞相互作用以及癌基因和生长因子方面。但对于基质增生过程中可能发生的前列腺平滑肌（SM）潜在改变知之甚少。
为研究增生性前列腺生长过程中SM表型调节，我们分离并鉴定了人SM肌球蛋白重链（SMMHC）cDNA的3'端作为分子探针。使用蛋白质免疫印迹法、Northern印迹法和原位杂交法分析人前列腺中SMMHC和非肌肉肌球蛋白重链（NMMHC）的表达，以确定BPH组织中SMMHC表达是否明显低于正常前列腺，而NMMHC表达是否高于正常前列腺。此外，采用竞争性逆转录（RT）聚合酶链反应（PCR）方法，以每毫克湿组织10（-21）摩尔的灵敏度水平定量SMMHC和NMMHC mRNA表达。
蛋白质免疫印迹法、Northern印迹法和原位杂交结果显示，SMMHC和NMMHC均在人前列腺中表达，而SMMHC是正常前列腺基质中的主要形式。竞争性RT - PCR分析结果表明，NMMHC mRNA表达约为每毫克组织10（-20）摩尔。所表达的SMMHC mRNA约为每毫克组织10（-18）摩尔。比较正常和BPH尿道周围组织的NMMHC mRNA表达时未发现显著差异。然而，尽管前列腺基质质量增加，但与正常前列腺相比，BPH中SMMHC表达降低了近五倍。
我们的结果表明BPH的发病机制与一种独特类型的SM增殖有关。这种增殖的特征是SMMHC mRNA表达下调，但NMMHC mRNA表达未上调，这是培养的增殖SM细胞和其他SM增生病理形式（如动脉粥样硬化）中所见的模式。这些发现支持了一种BPH模型，其典型特征是在疾病早期平滑肌活跃增殖，并支持临床观察结果，即老年男性前列腺的持续生长极小。因此，预防疾病进展的治疗策略应侧重于前列腺生长的早期阶段。
