Coordinated miRNA regulation of AR-PI3K/MAPK crosstalk and EMT in prostate cancer

Prostate cancer (PCa) progression and therapeutic resistance are critically dependent on the Androgen Receptor (AR) axis and major survival networks, including PI3K/AKT, MAPK, and epithelial-mesenchymal transition (EMT) programs. While individual microRNAs (miRNAs) have been implicated in these pathways, the broader miRNA-driven regulatory systems controlling these interconnected oncogenic axes remain poorly understood. We performed miRNA expression profiling in a clinically well-annotated PCa cohort and conducted an integrative analysis, identifying functional miRNA clusters through network correlation, pathway enrichment, and mapping to established oncogenic and EMT-related signature scores. Literature-based functional annotation was then combined with our miRNA findings to investigate correlations against key EMT transcription factors and tumour suppressors such as PTEN. We identified distinct miRNA clusters whose targets collectively converge on common oncogenic hubs, including AR-PI3K/MAPK-WNT/NOTCH signalling. With a role in EMT modulation, several miRNAs displayed strong negative correlations with EMT transcription factors, including miR-221-5p and miR-542-3p with SNAI2 (r ~ -0.5), and miR-378d and miR-449b-5p with ZEB2 (r ~ -0.7 and -0.4), supporting their functional involvement in suppressing EMT programs. Additionally, miR-542-3p, miR-449b-5p, and miR-302d-3p correlated inversely with PTEN (-0.7, -0.5, -0.5), suggesting their participation in PI3K/AKT pathway modulation. These findings align with the established tumour-suppressive roles of miR-206, miR-302d-3p, and miR-2110-previously linked to MAPK/ERK, AKT/mTOR, and FGFR/RTK-PTEN regulatory axes (Cancers 2024). Pathway enrichment analyses revealed that targeted pathways, including WNT, NOTCH1, PI3K/AKT, MAPK, ERBB2, and FGFR signalling, form an interconnected oncogenic network. Within this framework, miR-378d and miR-449b-5p exhibited strong negative correlations with ERBB2 (-0.7 and -0.5, respectively). Consistent with these molecular interactions, Correlation with Scote-derived oncogenic signatures, including ERBB2 activation and BRCAness, demonstrated that miRNA clusters strongly associate with genomic instability, proliferation, and therapy resistance phenotypes. Collectively, these findings suggest that the identified miRNA clusters function as integrated regulatory modules that simultaneously coordinate the suppression of AR signalling crosstalk with PI3K/MAPK activation and modulation of EMT. Their strong associations with Scote oncogenic signatures and EMT transcription factors underscore their potential as prognostic biomarkers and as targets for rational combination strategies aimed at disrupting AR-survival network crosstalk and overcoming therapeutic resistance.