2. Academic Validation
  3. Elevated miR-221-3p inhibits epithelial-mesenchymal transition and biochemical recurrence of prostate cancer via targeting KPNA2: an evidence-based and knowledge-guided strategy

Elevated miR-221-3p inhibits epithelial-mesenchymal transition and biochemical recurrence of prostate cancer via targeting KPNA2: an evidence-based and knowledge-guided strategy

  • BMC Cancer. 2025 Jan 8;25(1):34. doi: 10.1186/s12885-025-13444-1.
Dingchao Li # 1 2,  Jingang Jian # 1 2,  Manhong Shi # 3,  Zihao Chen 1 2,  Anguo Zhao 2,  Xuedong Wei 1,  Yuhua Huang 1,  Yalan Chen 4,  Jianquan Hou 5 6,  Yuxin Lin 7 8
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
  • 2 Department of Urology, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215000, China.
  • 3 College of Information and Network Engineering, Anhui Science and Technology University, Bengbu, 233000, China.
  • 4 Department of Medical Informatics, School of Medicine, Nantong University, Nantong, 226001, China. ylchen@ntu.edu.cn.
  • 5 Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China. xf192@163.com.
  • 6 Department of Urology, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215000, China. xf192@163.com.
  • 7 Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China. linyuxin@suda.edu.cn.
  • 8 Center for Systems Biology, Soochow University, Suzhou, 215123, China. linyuxin@suda.edu.cn.
  • # Contributed equally.
PMID: 39780096 DOI: 10.1186/s12885-025-13444-1
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Biochemical recurrence; Epithelial-to-mesenchymal transition; Prostate cancer; Systems biology modelling; miR-221-3p/KPNA2 regulation.

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