EMT在雌激素效应增强诱导良性前列腺增生发生中作用机制的研究

Benign prostatic hyperplasia (BPH) is one of the most common diseases in aging men. The causes of BPH are not fully understood. Testosterone decline with advancing age aroses the ratio of estrogen to testosterone in the body, and the relatively enhanced estrogenic effect is believed to be critical for the development of BPH. The applicants have long been engaged in studying the role of estrogen actions in the etiology of BPH. Recently, we noticed that there are some cellular clusters budding towards the stroma from the basal layer in human BPH tissues, and there are also a few cellular clusters cresting towards the inner side of acinis from the luminal layer. Interestingly, the cells in these clusters lost the expression of their epithelial specific marker, E-cadherin, but express the mesenchymal cell marker, Vimentin. We have successfully established testosterone/estradiol induced rat BPH model before. We find in the early stage of the development of hyperplasia, the expression of SMemb, a well known de-differential marker, is dramatically increased, and the basal layer cells are reactive to Vimentin antibody staining. Laser Capture Microdissection (LCM)/Microarray techniques was used to analyze the gene expression profiles in prostate epithelial and stromal cells during the progression of BPH. The results show that in the early development of BPH, the progenitor cell marker, CD133, and the embryonic stem cell specific transcriptional factor, SOX2, are apparently up-regulated in epithelial cells; the expression of MMP2 and SDF1, which are extremely important factors generally secreted from the reactive stroma, are also increased in epithelial cells. These data suggest that existence of cell de-differentiation and epithelial-mensenchymal transition (EMT) in the pathogenesis of BPH. Based on our previous study, herein we make the hypothesis that "The relatively enhanced estrogenic effects result in the de-differentiation of plastic cells and activate the progression of EMT which plays a critical role in prostate development, thus are essentially involved in the pathogenesis of BPH". These ideas have never been reported yet. The achievements of this study will provide novel annotation of the pathogenesis of BPH, and generate an enormous improvement in the management of such a benign disorder which seriously affects an elder man's quality of life.

良性前列腺增生症（BPH）是高龄男性常见疾病，在2008年度体检异常排行榜居首位。雌激素效应增强是BPH发生的重要诱因。申请人长期从事雌激素效应在BPH中作用机制研究。近期发现人前列腺增生组织基底细胞出芽和分泌型上皮细胞向腺泡腔内生长出脊的细胞表达间质细胞标记分子Vimentin，失去上皮细胞特异的E-Cadherin。在雌雄激素诱导大鼠增生早期前列腺组织中去分化标记分子SMemb表达增加，基底细胞呈Vimentin阳性染色；大鼠上皮细胞中干/祖细胞标志分子CD133和胚胎干细胞特异转录因子Sox2以及间质细胞表达基因MMP2和SDF1的表达明显上调；初步证明在BPH发生中发生了可塑性细胞去分化和EMT。提出"雌激素效应增强使可塑性细胞去分化和前列腺发育中EMT程序激活是前列腺增生发生重要机制"的研究假说。这些理念在国内外尚无研究报道，其研究成果将对BPH发生机制和转归提供新的诠释和途径。

良性前列腺增生症（benign prostatic hyperplasia，BPH）是高龄男性常见的疾病。前列腺是一个性激素依赖的器官，其中因雌/雄激素比例升高引起的雌激素效应增加在BPH的病理过程中发挥了重要的作用。在国家自然科学基金主任基金的资助下，课题组探讨了抗雌药物雷洛昔芬防治雌激素比例增加诱导大鼠良性前列腺增生的作用及其可能的作用机制。在研究中，我们将70只雄性SD大鼠随机分为9组，其中一组大鼠行假去势手术作为正常对照组，其余各组大鼠行去势手术，随机分为雌/雄激素造模组和雷洛昔芬治疗组，并分别在给药第3、10、17、28天取前列腺组织，计算前列腺指数，并对其进行HE染色、免疫组化染色和Western blot方法检测。研究发现，用抗雌药物雷洛昔芬处理后，大鼠前列腺指数降低；前列腺组织中腺泡腔体积变小，周围平滑肌层厚度降低；PCNA、SMemb和ERɑ表达减少；上皮细胞中-SMA的表达减少和E-cadherin的表达增加。结果表明，抗雌药物雷洛昔芬能够防治高比例雌/雄激素诱导的大鼠良性前列腺增生；抗雌药物雷洛昔芬通过抑制前列腺增生过程中的EMT抑制前列腺增生的发生和发展。这一成果为研究BPH发生机制和治疗靶标提供了新思路。