Abstract
African American (AA) men exhibit 1.6-fold higher prostate cancer (PCa) incidence and 2.4-fold higher mortality rates compared to European American (EA) men. In addition to socioeconomic factors, emerging evidence suggests that intrinsic biological differences may explain part of PCa disparities. In this study, we applied microRNA (miRNA)-driven bioinformatics to evaluate whether differential miRNA-mRNA regulatory networks play a role in promoting the AA PCa disparities. 10 differentially expressed miRNAs were imported to mirPath V.3 algorithm, leading to identification of 58 signaling pathways differentially regulated in AA PCa versus EA PCa. Among these pathways, we particularly focused on mTOR and VEGF signaling, where we identified 5 reciprocal miRNA-mRNA pairings: miR-34a-5p/HIF1A, miR-34a-5p/PIK3CB, miR-34a-5p/IGFBP2, miR-99b-5p/MTOR and miR-96-5p/MAPKAPK2 in AA PCa versus EA PCa. RT-qPCR validation confirmed that miR-34a-5p, miR-99b-5p and MAPKAPK2 were downregulated, while miR-96-5p, IGFBP2, HIF1A, PIK3CB and MTOR were upregulated in AA PCa versus EA PCa cells. Transfection of miRNA mimics/antagomir followed by RT-qPCR and Western blot analysis further verified that IGFBP2, HIF1A and PIK3CB are negatively regulated by miR-34a-5p, whereas MTOR and MAPKAPK2 are negatively regulated by miR-99b-5p and miR-96-5p, respectively, at mRNA and protein levels. Targeting reciprocal pairings by miR-34a-5p mimic, miR-99b-5p mimic or miR-96-5p antagomir downregulates HIF1α, PI3Kβ, mTOR, IGFBP2 but upregulates MAPKAPK2, subsequently reducing cell proliferation and sensitizing docetaxel-induced cytotoxicity in PCa cells. These results suggest that miRNA-mRNA regulatory network plays a critical role in AA PCa disparities, and targeting these core miRNA-mRNA pairings may reduce PCa aggressiveness and overcome the chemoresistance in AA patients.
Highlights
Analysis Reveals 68 Signaling Pathways Differentially Regulated by miRNA-mRNA Networks in AA prostate cancer (PCa) and European American (EA) PCa
Total RNA samples isolated from 20 AA and 15 EA PCa specimens were subjected to miRNA profiling [26] and mRNA profiling [26,27] analysis
Depleted/enriched miRNAs and mRNAs (Table 1). These results suggest that ErbB (EGFR)mTOR-HIF1A-VEGF axis as a critical signaling cascade mediated by miRNA-mRNA regulatory network in AA PCa
Summary
MiRNAs play critical roles in biological processes such as cell proliferation, cell growth, intracellular signaling, cell differentiation, cell apoptosis, cellular metabolism and carcinogenesis [3,4] They usually bind to the 30 -untranslated region (30 -UTR) of the target mRNAs, destabilizing the mRNA and control protein production through translational silencing [5]. Exportin-5 and Ran-GTP transports pre-miRNAs from the nucleus to cytoplasm, where Dicer further processes pre-miRNAs into 20–25 nucleotide long mature miRNA-miRNA duplexes. These mature miRNAs are loaded onto Argonaute 2 protein (AGO2) and RNA-induced silencing complex (RISC) to achieve site-specific cleavage/degradation or translational inhibition of the target mRNAs [7,8]
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