Increased CK5/CK8-Positive Intermediate Cells with Stromal Smooth Muscle Cell Atrophy in the Mice Lacking Prostate Epithelial Androgen Receptor

Results from tissue recombination experiments documented well that stromal androgen receptor (AR) plays essential roles in prostate development, but epithelial AR has little roles in prostate development. Using cell specific knockout AR strategy, we generated pes-ARKO mouse with knock out of AR only in the prostate epithelial cells and demonstrated that epithelial AR might also play important roles in the development of prostate gland. We found mice lacking the prostate epithelial AR have increased apoptosis in epithelial CK8-positive luminal cells and increased proliferation in epithelial CK5-positive basal cells. The consequences of these two contrasting results could then lead to the expansion of CK5/CK8-positive intermediate cells, accompanied by stromal atrophy and impaired ductal morphogenesis. Molecular mechanism dissection found AR target gene, TGF-β1, might play important roles in this epithelial AR-to-stromal morphogenesis modulation. Collectively, these results provided novel information relevant to epithelial AR functions in epithelial-stromal interactions during the development of normal prostate, and suggested AR could also function as suppressor in selective cells within prostate.

组织重组实验（tissue recombination experiments）的结果已充分证实，基质雄激素受体（stromal androgen receptor, AR）在前列腺发育过程中发挥关键作用，而上皮雄激素受体（epithelial AR）在前列腺发育中的作用则甚微。本研究采用细胞特异性AR敲除策略（cell specific knockout AR strategy），构建了仅在前列腺上皮细胞中敲除AR的pes-ARKO小鼠模型，并证实上皮雄激素受体同样在前列腺腺体发育中具有重要功能。研究发现，缺失前列腺上皮AR的小鼠，其上皮CK8阳性腔上皮细胞的凋亡水平显著升高，而上皮CK5阳性基底上皮细胞的增殖活性则增强。这两种相反的生物学效应最终可导致CK5/CK8阳性中间态细胞的扩增，同时伴随基质萎缩与导管形态发生受损。分子机制解析显示，AR靶基因转化生长因子β1（transforming growth factor-β1, TGF-β1）可能在该上皮AR调控间质形态发生的过程中发挥重要作用。综上，本研究为正常前列腺发育过程中上皮-间质互作的上皮AR功能提供了全新认知，并提示AR在前列腺内的特定细胞类型中亦可发挥抑制因子的作用。