Identification of Cancer-associated Fibroblasts-specific ncRNA–mRNA/Protein Regulatory Axes in Prostate Cancer

Background/Aim: Cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment and secrete factors that promote tumor growth, progression, and treatment resistance. Non-coding RNAs (ncRNAs) may regulate CAF-derived signals, but coordinated ncRNA-mRNA/protein networks in prostate cancer remain poorly characterized. This study aimed to identify CAF-specific ncRNA-mRNA/protein regulatory axes by comparing prostate cancer-derived CAFs with fibroblasts from benign prostatic hyperplasia (BPH). Materials and Methods: We integrated previously generated RNA sequencing data with label-free quantitative mass spectrometry of conditioned media from primary CAFs (n=3) and BPH-derived control fibroblasts (n=3). LINCRNA-interacting miRNAs and their putative mRNA targets were predicted using NPInter v5.0 and miRDB, respectively, and cross-referenced with differentially expressed secreted proteins. Prognostic associations were evaluated using progression-free interval data from the TCGA prostate adenocarcinoma cohort. Results: Secretome profiling identified 1,007 proteins, including 133 differentially expressed proteins and 90 proteins unique to either CAFs or control fibroblasts. Integration of transcriptomic, target-prediction, and proteomic data revealed 28 CAF-associated ncRNA-mRNA/protein regulatory axes. MYH11, SERPINF2, ANGPT1, and CRISPLD2 were significantly associated with progression-free interval. The identified axes are linked to extracellular matrix remodeling, angiogenesis, and immune modulation, processes that contribute to tumor maintenance, progression, metastasis, and therapeutic resistance. Conclusion: CAF-specific ncRNA-mRNA/protein networks provide mechanistic insight into prostate cancer progression and may serve as candidate biomarkers for disease monitoring and prognosis.