Fu Xun, Zhang Hao, Liu Jiang, Li Yan, Wang Zhen, Yang Shu, Liu Daoquan, Zhou Yongying, Chen Ping, DiSanto Michael E, Li Hongjun, Zhang Xinhua
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Urology, Peking Union Medical Collage Hospital, Beijing, China.
Front Endocrinol (Lausanne). 2025 Mar 26;16:1543295. doi: 10.3389/fendo.2025.1543295. eCollection 2025.
Benign prostatic hyperplasia (BPH) is a common disease that impairs the life quality of elderly men. The close relationship of BPH and diabetes has been generally established, however, the exact molecular mechanism remains unclear. Midline-1 (MID1) is an E3 ubiquitin ligase belonging to Tripartite Motif family and its involvement in the initiation and progression of many diseases, such as diabetic kidney disease has been well accepted. This study aims to illuminate the potential impact of high glucose (HG) on prostatic cells and elucidate the molecular role of MID1 in the development of BPH.
In this work, human prostate specimens and cultured human prostate cell lines (BPH-1 and WPMY-1) were employed. The impact of HG treatment on these two lines was assessed and the expression and localization of MID1, along with its potential downstream target protein phosphatase 2A (PP2A), were determined using multiple experimental methods. MID1-overexpressing cell models were further used to investigate the function of MID1 in regulating inflammation, fibrosis and epithelial-mesenchymal transition (EMT).
Herein we demonstrate diabetic individuals with BPH had lower expression of MID1 and higher expression of the catalytic subunit of PP2A (PP2Ac), larger prostate volume, higher international prostate symptom score (IPSS) and lower Qmax than non-diabetic groups. On a cellular level, HG treatment inhibited the expression of MID1, thus stimulating cellular proliferation and triggering EMT, fibrosis and inflammation of two prostatic cells via enhanced WNT/β-catenin signaling.
In general, our novel data demonstrate targeting MID1 might be a promising area of medical treatment for patients with both BPH and diabetes.
良性前列腺增生（BPH）是一种常见疾病，会损害老年男性的生活质量。BPH与糖尿病之间的密切关系已得到普遍证实，然而，确切的分子机制仍不清楚。中线蛋白-1（MID1）是一种属于三联基序家族的E3泛素连接酶，其参与多种疾病（如糖尿病肾病）的发生和发展已得到广泛认可。本研究旨在阐明高糖（HG）对前列腺细胞的潜在影响，并阐明MID1在BPH发生发展中的分子作用。
在本研究中，使用了人类前列腺标本和培养的人类前列腺细胞系（BPH-1和WPMY-1）。评估了HG处理对这两种细胞系的影响，并使用多种实验方法确定了MID1及其潜在下游靶蛋白磷酸酶2A（PP2A）的表达和定位。进一步使用过表达MID1的细胞模型来研究MID1在调节炎症、纤维化和上皮-间质转化（EMT）中的作用。
我们在此证明，与非糖尿病组相比，患有BPH的糖尿病个体MID1表达较低，PP2A催化亚基（PP2Ac）表达较高，前列腺体积较大，国际前列腺症状评分（IPSS）较高，最大尿流率（Qmax）较低。在细胞水平上，HG处理抑制了MID1的表达，从而通过增强WNT/β-连环蛋白信号通路刺激细胞增殖并引发两种前列腺细胞的EMT、纤维化和炎症。
总体而言，我们的新数据表明，靶向MID1可能是BPH和糖尿病患者一个有前景的治疗领域。
