Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men worldwide that may result in lower urinary tract symptoms (LUTS). At present, the specific pathophysiological mechanism for BPH/LUTS LUTS remains unclear. S100 calcium binding protein A4 (S100A4), a member of the calcium binding protein family, regulates a variety of biological processes including cell proliferation, apoptosis and fibrosis. The aim of the current study was to explore and clarify the possible role of S100A4 in BPH/LUTS. The human prostate stromal cell line (WPMY-1), rat prostate epithelial cells, human prostate tissues and two BPH rat models were employed in this study. The expression and localization of S100A4 were detected by quantitative real time PCR (qRT-PCR), immunofluorescence microscopy, Western blotting and immunohistochemistry analysis. Also, S100A4 knockdown or overexpression cell models were constructed and a BPH rat model was induced with testosterone (T) or phenylephrine (PE). The BPH animals were treated with Niclosamide, a S100A4 transcription inhibitor. Results demonstrated that S100A4 was mainly localized in human prostatic stroma and rat prostatic epithelium, and showed a higher expression in BPH. Knockdown of S100A4 induced cell apoptosis, cell proliferation arrest and a reduction of tissue fibrosis markers. Overexpression of S100A4 reversed the aforementioned changes. We also demonstrated that S100A4 regulated proliferation and apoptosis mainly through the ERK pathway and modulated fibrosis Wnt/β-catenin signaling. In conclusion, our novel data demonstrate that S100A4 could play a crucial role in BPH development and may be explored as a new therapeutic target of BPH.

中文翻译：

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S100A4 调节增生性前列腺中的细胞增殖、凋亡和纤维化

良性前列腺增生（BPH）是全球老年男性最常见的疾病之一，可能导致下尿路症状（LUTS）。目前，BPH/LUTS LUTS的具体病理生理机制尚不清楚。S100 钙结合蛋白 A4 (S100A4) 是钙结合蛋白家族的成员，调节多种生物过程，包括细胞增殖、细胞凋亡和纤维化。本研究的目的是探索和阐明 S100A4 在 BPH/LUTS 中的可能作用。本研究采用人前列腺基质细胞系 (WPMY-1)、大鼠前列腺上皮细胞、人前列腺组织和两种 BPH 大鼠模型。通过实时定量PCR（qRT-PCR）、免疫荧光显微镜、Western blotting和免疫组化分析检测S100A4的表达和定位。此外，构建了S100A4敲低或过表达细胞模型，并用睾酮（T）或去氧肾上腺素（PE）诱导BPH大鼠模型。BPH 动物接受氯硝柳胺（一种 S100A4 转录抑制剂）治疗。结果表明，S100A4主要定位于人前列腺间质和大鼠前列腺上皮，并且在BPH中表达较高。S100A4 的敲低诱导细胞凋亡、细胞增殖停滞和组织纤维化标志物减少。S100A4的过度表达逆转了上述变化。我们还证明，S100A4 主要通过 ERK 通路调节增殖和凋亡，并调节纤维化 Wnt/β-catenin 信号传导。总之，我们的新数据表明 S100A4 在 BPH 的发展中发挥着至关重要的作用，并可能被探索作为 BPH 的新治疗靶点。