Li Dingchao, Jian Jingang, Shi Manhong, Chen Zihao, Zhao Anguo, Wei Xuedong, Huang Yuhua, Chen Yalan, Hou Jianquan, Lin Yuxin
Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
Department of Urology, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215000, China.
BMC Cancer. 2025 Jan 8;25(1):34. doi: 10.1186/s12885-025-13444-1.
Prostate cancer (PCa) is commonly occurred among males worldwide and its prognosis could be influenced by biochemical recurrence (BCR). MicroRNAs (miRNAs) are functional regulators in carcinogenesis, and miR-221-3p was reported as one of the significant candidates deregulated in PCa. However, its regulatory pattern in PCa BCR across literature reports was not consistent, and the targets and mechanisms in PCa malignant transition and BCR are less explored.
In this study, an evidence-based and knowledge-guided approach was proposed to decipher the role and mechanism of miR-221-3p in PCa development. First, the literature-reported inconsistency between miR-221-3p and PCa BCR was quantitatively measured by meta-analysis. Then a knowledge-guided network strategy was applied to prioritize key targets of miR-221-3p in PCa progression based both on topological and functional characterization of genes in multi-omics miRNA-mRNA and protein-protein interaction networks. Finally, a key gene was computationally identified and experimentally validated using cell line and clinical samples through EdU assay, scratch assay, transwell assay, dual-luciferase reporter assay and the epithelial-to-mesenchymal transition (EMT)-related analysis.
Down-regulation of miR-221-3p was correlated with a lower biochemical recurrence-free survival (BRFS) in PCa (HR: 0.72, 95%, CI: 0.64-0.81, P < 0.00001). A significant down-regulation of miR-221-3p was observed in most of the PCa cells compared with the normal control. KPNA2 was identified as a key target of miR-221-3p and it was over-expressed in all the PCa cells and human PCa tissues. Moreover, elevated miR-221-3p inhibited the proliferation, migration, invasion, and EMT of PCa cells in vitro via directly and negatively mediating KPNA2 expression.
miR-221-3p down-regulation was a risk factor for PCa BRFS, and its over-expression could inhibit the malignant phenotype and EMT of PCa cells by directly targeting KPNA2. Translational and personalized applications of the findings will be conducted in the future.
前列腺癌（PCa）在全球男性中普遍发生，其预后可能受生化复发（BCR）影响。微小RNA（miRNA）是致癌过程中的功能调节因子，据报道miR-221-3p是前列腺癌中失调的重要候选者之一。然而，在整个文献报道中，其在前列腺癌BCR中的调控模式并不一致，对前列腺癌恶性转化和BCR中的靶点及机制的探索较少。
在本研究中，提出了一种基于证据和知识引导的方法来解读miR-221-3p在前列腺癌发生发展中的作用及机制。首先，通过荟萃分析定量评估文献报道的miR-221-3p与前列腺癌BCR之间的不一致性。然后，基于多组学miRNA-mRNA和蛋白质-蛋白质相互作用网络中基因的拓扑和功能特征，应用知识引导的网络策略对miR-221-3p在前列腺癌进展中的关键靶点进行优先级排序。最后，通过EdU检测、划痕试验、Transwell试验、双荧光素酶报告基因检测以及上皮-间质转化（EMT）相关分析，利用细胞系和临床样本对一个关键基因进行计算鉴定和实验验证。
miR-221-3p的下调与前列腺癌较低的无生化复发生存率（BRFS）相关（风险比：0.72，95%置信区间：0.64 - 0.81，P < 0.00001）。与正常对照相比，在大多数前列腺癌细胞中观察到miR-221-3p显著下调。核转运蛋白α2（KPNA2）被鉴定为miR-221-3p的关键靶点，并且在所有前列腺癌细胞和人前列腺癌组织中均过表达。此外，miR-221-3p的上调通过直接负向调节KPNA2的表达抑制前列腺癌细胞在体外的增殖、迁移、侵袭和EMT。
miR-221-3p下调是前列腺癌BRFS的一个危险因素，其过表达可通过直接靶向KPNA2抑制前列腺癌细胞的恶性表型和EMT。未来将开展这些研究结果的转化和个性化应用。
