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Objective(s): MicroRNAs, which are micro-coordinators of gene expression, have been recently investigated as a potential treatment for cancer. The study used computational techniques to identify microRNAs that could target a set of genes simultaneously. Due to their multi-target-directed nature, microRNAs have the potential to impact multiple key pathways and their pathogenic cross-talk. Materials and Methods: We identified microRNAs that target a prostate cancer-associated gene set using integrated bioinformatics analyses and experimental validation. The candidate gene set included genes targeted by clinically approved prostate cancer medications. We used STRING, GO, and KEGG web tools to confirm gene-gene interactions and their clinical significance. Then, we employed integrated predicted and validated bioinformatics approaches to retrieve hsa-miR-124-3p, 16-5p, and 27a-3p as the top three relevant microRNAs. KEGG and DIANA-miRPath showed the related pathways for the candidate genes and microRNAs Results: The Real-time PCR results showed that miR-16-5p simultaneously down-regulated all genes significantly except for PIK3CA/CB in LNCaP; miR-27a-3p simultaneously down-regulated all genes significantly, excluding MET in LNCaP and PIK3CA in PC-3; and miR-124-3p could not downregulate significantly PIK3CB, MET, and FGFR4 in LNCaP and FGFR4 in PC-3. Finally, we used a cell cycle assay to show significant G0/G1 arrest by transfecting miR-124-3p in LNCaP and miR-16-5p in both cell lines. Conclusion: Our findings suggest that this novel approach may have therapeutic benefits and these predicted microRNAs could effectively target the candidate genes. [ABSTRACT FROM AUTHOR]