Abnormal intraglandular stromal-epithelial interactions have been known as a main key contributing factor for development of Benign Prostatic Hyperplasia (BPH). However, the underlying mechanism for the dysregulated intercellular communication remains unclear. In this study we compared the proteomic profiles of hyperplastic tissue with adjacent normal tissue of BPH and identified Rab27B small GTPase, a key regulator of exocytosis, as a protein that was overexpressed in the epithelium of BPH tissue. Overexpression of Rab27B in prostatic epithelial cells strongly increased the signaling activities of the PI3K/AKT and ERK1/2 pathways, whereas, downregulation of Rab27B expression in the epithelial cells of BPH reduced the signaling activities and decreased cell proliferation. The elevated Rab27B expression caused an overall increase in cell surface presentation of growth factor receptors without affecting their expression. However, the small GTPase also possesses an inhibitory activity against mTORC1 independent of its role in cell surface presentation of growth factor receptors. Our findings demonstrate a pivotal role of the small GTPase in autocrine and paracrine signaling and suggest that its abnormal expression underlies the dysregulated stromal-epithelial interactions in BPH.

已知异常的腺内基质-上皮相互作用是良性前列腺增生 (BPH) 发展的主要关键因素。然而，细胞间通讯失调的潜在机制仍不清楚。在这项研究中，我们比较了增生组织与 BPH 的邻近正常组织的蛋白质组学特征，并确定了 Rab27B 小 GTPase，一种胞吐作用的关键调节因子，是一种在 BPH 组织上皮中过度表达的蛋白质。Rab27B 在前列腺上皮细胞中的过表达强烈增加了 PI3K/AKT 和 ERK1/2 通路的信号活性，而 BPH 上皮细胞中 Rab27B 表达的下调降低了信号活性并降低了细胞增殖。Rab27B 表达升高导致生长因子受体的细胞表面呈递总体增加，但不影响其表达。然而，小 GTPase 也对 mTORC1 具有抑制活性，而与其在生长因子受体的细胞表面呈递中的作用无关。我们的研究结果证明了小 GTPase 在自分泌和旁分泌信号传导中的关键作用，并表明其异常表达是 BPH 中基质 - 上皮相互作用失调的基础。