Abstract Introduction: Tumor microRNAs (miRNAs) play a critical role in prostate cancer (PCa) biology and may serve as biomarkers for disease aggressiveness. However, robust identification and validation of tumor miRNA expressions across independent datasets remain challenging. This study aimed to discover and validate miRNAs associated with PCa aggressiveness using three independent cohorts. Methods: We analyzed tumor miRNA expression profiles from three datasets: our cohort (discovery set, 268 Whites), TCGA-PRAD (406 Whites), and GSE135535 (GSE, 320 men). In our cohort, we identified the top 25 miRNAs significantly associated with PCa aggressiveness (p 0.01) using univariate logistic models. Using these 25 miRNAs, stepwise selection was performed in the 1,000 bootstrap samples based on our cohort. Among the 9 miRNAs selected in 20% of 1000 bootstrap runs, many miRNA expressions are highly correlated. Therefore, we further performed stepwise selection to identify the most informative miRNAs associated with PCa aggressiveness. Then, the selected miRNAs were tested in the other two validation sets. Results: Two tumor miRNA expressions were significantly associated with PCa aggressiveness in our cohort (hsa-miR-145-5p, p0.001, and hsa-miR-182-5p, p = 0.001, AUC=0.74). In the GSE135535 cohort, the p-values were 0.003 and 0.099 for hsa-miR-145-5p and hsa-miR-182-5p, respectively (AUC=0.621). In the TCGA set, the p-values were 0.024 and 0.059 for hsa-miR-145-5p and hsa-miR-182-5p, respectively (AUC=0.591). Thus, these two miRNAs represent distinct biological clusters, suggesting complementary roles in PCa aggressiveness. Conclusion: Our multi-cohort analysis identified and validated two miRNAs associated with PCa aggressiveness. Other previous studies have supported the biological function of these two miRNAs. It has been shown that hsa-miR-145-5p significantly inhibits PCa cell growth and metastasis by negatively regulating metadherin (MTDH) expression and acts as a tumor suppressor. hsa-miR-182-5p acts as an oncogenic miRNA to contribute to poor prognosis for PCa patients. Up-regulation of miR-182 is significantly associated with PCa risk, progression, and treatment response. Functional enrichment analysis in previous studies revealed a significant association between miR-182 and its target genes, MITF (melanocyte inducing transcription factor) with epithelial-to-mesenchymal transition (EMT). Our findings support their potential utility as prognostic biomarkers and warrant further functional studies to elucidate underlying biological mechanisms. Citation Format: Huiyi Lin, Jong Y. Park, Masuma Mannan. Tumor microRNA expressions associated with prostate cancer aggressiveness across independent cohorts abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7584.
Lin et al. (Fri,) studied this question.