Table1_miR-145-5p Inhibits Neuroendocrine Differentiation and Tumor Growth by Regulating the SOX11/MYCN Axis in Prostate cancer.XLSX

Recent studies have shown that the downregulation of miR-145-5p in prostate cancer (PCa) is significantly associated with poor differentiation and prognosis. We aimed to investigate the biological role of miR-145-5p in the neuroendocrine differentiation (NED) of PCa. In this study, TheCancer Genome Atlas was used to identify the association of miR-145-5p with PCa. The functions of miR-145-5p were evaluated using the Cell Counting Kit-8 (CCK-8) assay and cell cycle analysis. We validated changes in cell cycle control by testing the expression of cyclin-related genes by western blot. The luciferase reporter assay was performed to test miR-145-5p-targeting genes and direct transcriptional targets of SOX11. The expression of miR-145-5p was found to be significantly downregulated in castration-resistant PCa, and this was correlated with higher Gleason score and prostate-specific antigen. We confirmed these results using PC3 and LNCaP cell lines depicted a gradual decline of miR-145-5p while the cells were cultured under androgen depletion conditions. Moreover, the knockdown of miR-145-5p significantly promoted NED and proliferation of LNCaP cells, whereas overexpression of miR-145-5p significantly inhibited NED and proliferation of LNCaP cells. Mechanistically, we found that SOX11 was a direct target of miR-145-5p, which regulates MYCN might mediate induction of NED and proliferation of LNCaP cells. Furthermore, knockdown of miR-145-5p promoted tumor growth in vivo. Our findings suggest that miR-145-5p can inhibit NED and tumor growth by targeting SOX11, which regulates the expression of MYCN, and that this could be a novel therapeutic strategy for preventing the progression of PCa.

近期研究揭示，前列腺癌（PCa）中miR-145-5p的下调与肿瘤分化不良及预后不良显著相关。本研究旨在探究miR-145-5p在PCa神经内分泌分化（NED）中的生物学作用。本研究采用TheCancer Genome Atlas，以识别miR-145-5p与PCa的关联。通过细胞计数试剂盒-8（CCK-8）检测及细胞周期分析评估了miR-145-5p的功能。通过蛋白质印迹法检测细胞周期调控相关基因的表达，以验证细胞周期变化。利用荧光素酶报告基因实验检测miR-145-5p靶向基因及SOX11的直接转录靶点。研究发现，miR-145-5p在去势抵抗性PCa中的表达显著下调，且与更高的Gleason评分和前列腺特异性抗原相关。使用PC3和LNCaP细胞系验证了这些结果，在雄激素剥夺条件下培养细胞时，miR-145-5p的表达呈现逐渐下降的趋势。此外，miR-145-5p的敲低显著促进了LNCaP细胞的NED和增殖，而miR-145-5p的过表达则显著抑制了LNCaP细胞的NED和增殖。机制研究表明，SOX11是miR-145-5p的直接靶点，MYCN的表达调控可能介导了NED和LNCaP细胞的增殖。此外，miR-145-5p的敲低在体内促进了肿瘤生长。本研究结果表明，miR-145-5p通过靶向SOX11抑制MYCN的表达，从而抑制NED和肿瘤生长，这可能是预防PCa进展的一种新的治疗策略。