Dicer ablation impairs prostate stem cell activity and causes prostate atrophy.
Dicer ablation impairs prostate stem cell activity and causes prostate atrophy.
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作者：
Zhang, Li;Zhang, Boyu;Valdez, Joseph M.;Wang, Fen;Ittmann, Michael;Xin, Li
Dicer 是一种对 microRNA 成熟至关重要的 RNase III 酶。不同组织中的 Dicer 消融已被证明可以阻止组织分化、诱导细胞凋亡、损害专门的细胞功能并扰乱器官结构。为了深入了解 microRNA 在前列腺组织功能和稳态中的作用，我们使用 ARR2PB-Cre 有条件地破坏小鼠前列腺中的 Dicer 活性。我们证明，前列腺基底细胞/干细胞和分化的管腔细胞中的 Dicer 活性均被破坏。 Dicer 敲除小鼠前列腺的尺寸和质量较小，并在 4 个月时出现腹侧前列腺上皮营养不良。 Dicer 消融诱导前列腺细胞凋亡增加，主要是在分化的管腔细胞中。矛盾的是，在基底细胞/干细胞和管腔细胞中观察到增殖同时增加，这可能是由于细胞的补偿性生长缺乏响应细胞凋亡增加的同源重组。我们之前已经证明 Lin(CD31CD45Ter119)−Sca-1+CD49fhigh (LSC) 细胞富含前列腺干细胞活性。通过增殖和分化，一些LSC细胞能够形成由处于不同分化阶段的细胞组成的前列腺球。尽管在 Dicer 敲除小鼠中，LSC 细胞扩增了三倍，但与野生型细胞相比，Dicer 敲除的前列腺细胞的球体形成单位减少了一半以上。此外，Dicer 敲除培养物中的大多数前列腺球源自未经历同源重组的细胞。我们的结果证明了 microRNA 对于前列腺干细胞的增殖能力和维持前列腺稳态的关键作用。
Dicer is an RNase III enzyme essential for microRNA maturation. Dicer ablation in diverse tissues has been shown to block tissue differentiation, induce cell apoptosis, impair specialized cellular function, and perturb organ structures. To gain insight into the role of microRNAs in prostate tissue function and homeostasis, we conditionally disrupted Dicer activity in the mouse prostate using an ARR2PB-Cre. We demonstrated that Dicer activity is disrupted in both prostatic basal/stem cells and differentiated luminal cells. Dicer knockout murine prostates are smaller in size and mass and develop epithelial hypotrophy in ventral prostates by 4 months. Dicer ablation induces increased apoptosis in the prostate, predominantly in the differentiated luminal cells. Paradoxically, a concurrent increase in proliferation is observed in both basal/stem cells and luminal cells, presumably due to compensatory growth of the cells devoid of homologous recombination in response to the elevated cellular apoptosis. We have previously shown that Lin(CD31CD45Ter119)−Sca-1+CD49fhigh (LSC) cells enrich for prostate stem cell activity. Through proliferation and differentiation, some LSC cells are capable of forming prostate spheres composed of cells at various stages of differentiation. Although LSC cells were expanded by threefold in Dicer knockout mice, the sphere-forming units of Dicer knockout prostate cells decreased by more than half compared with wild-type cells. In addition, most prostate spheres in the Dicer knockout culture were derived from cells that did not undergo homologous recombination. Our results demonstrate a critical role of microRNAs for the proliferative capacity of prostate stem cells and the maintenance of prostate homeostasis.
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