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Circulating microRNAs (miRNAs) are promising prostate cancer biomarkers, but their cellular origin and regulatory mechanisms remain unclear. Prostate samples from 70 men (30 prostate cancer, 40 benign) were analyzed by in situ hybridization for nine miRNAs identified via serum next-generation sequencing (NGS). Digital image analysis was used to quantify miRNAs in benign and malignant epithelial compartments and stromal cells. Five of the nine miRNAs were detected in prostate tissue. miR-550a, miR-4754, and miR-4326 exhibited an "epithelial down, stromal up" pattern accompanied by elevated serum levels; serum miR-550a correlated with high-grade tumor cells. miR-1246 progressively decreased from benign epithelium through Gleason grade 3 to grade 4 tumor cells, suggesting increased secretion by advanced tumor cells. However, extraprostatic contributions and assay cross-reactivity likely influenced its serum profile. miR-4632 exhibited distinct compartmental alterations, but methodological or extraprostatic factors appeared to affect serum detection. Overall, this integrative profiling reveals that not all miRNAs altered in serum from prostate cancer patients originate from prostate tissue, underscoring the value of comparative tissue/serum analyses. miR-550a, miR-1246, miR-4754, and miR-4326 emerge as promising biomarkers warranting further longitudinal evaluation.