Identification of distinct mRNA & microRNA signatures and mRNA-miRNA pairs associated with inter-ethnic differences in prostate cancer aggressiveness

Introduction: The incidence of aggressive prostate cancer (PCa) and mortality is disproportionately higher in men of African-American (AA) ancestry. Treatment options for these patients are docetaxel or cabazitaxel alone or in combination with bevacizumab, thalidomide, and prednisone or immunotherapy. However, these chemotherapeutics typically only improve survival slightly (3-4 months). Further, majority of patients develop metastatic PCa over time, resistant to conventional chemotherapy (metastatic castration resistance PCa or mCRPC). Therefore, an understanding of the molecular mechanisms underlying the ethnic differences in disease aggressiveness and progression in PCa is needed.Methods: In this study, we performed mRNA and miRNA expression (RNAseq) analysis on PCa cell lines representing different tumor types (aggressive androgen receptor (AR) nonresponsive AR- vs. non-aggressive AR+) and derived from patients with European American/EA (PC3, PC3M, DU145, DUTXR, 22RV1, LNCaP, VCaP, LaPC4, C4, C4-2B) and AA (MDA-Pca-2b, RC77, RC165, RC43) ancestry to identify differentially expressed genes (DEG) associated with tumor aggressiveness and ethnicity. Next, we validated the top DEG signatures using an AA vs EA patient cohort dataset as well as in silico validation using The Cancer Genome Atlas (TCGA) database. For each miRNA, functional analysis was performed using miRBase datasets and mRNA-miRNA pairs and binding sites were predicted by TargetScan. Finally, IPA (Ingenuity Pathway Analysis) was performed to identify key regulators and downstream effects on biological and disease processes based on the expression patterns of DEGs. Results: We identified distinct mRNA and miRNA expression signatures associated with aggressive vs. non-aggressive PCa of EA vs. AA origin. The top DEGs that were associated with patient survival (p< 0.0001), stratified by Gleason scores, were PLAU, TGFB1, SERPINE1, MET, TIPM1, ITGA3, SERPINB5, PLAUR, MMPs, CDKN1A, and IGF1. The transporter genes SLC25A, SLC16A, and ABCB6 were also identified as important markers of aggressiveness. Notably, PLAU, MCAM, MET, TIMP1 were top DEGs in AA vs EA cell lines while SERPINE1 and MCAM were DEGs in AA vs EA patient cohort. IPA identified the activation of the angiogenesis pathway as a crucial factor for cancer aggressiveness. Top predicted miRNA-mRNA pairs included SERPINE1-let7, PLAU- mir181 which potentially influence differential gene expression in late-stage cancers. Finally, our immunoblotting results confirmed the protein expression changes of top DEGs. Next, we plan to perform CRISPR-based gene editing to functionally validate the molecular (mRNA/miRNA) signatures. Conclusion: An -omics-based approach was used to identify genetic signatures that provide insights into the molecular basis of PCa aggressiveness between men of EA vs AA ancestry. We believe this strategy will aid in developing effective targeted ethnicity-specific personalized treatment schedules for aggressive forms of PCa. This promises to address the known health disparity that is observed in AA men. Citation Format: Taraswi Mitra Ghosh, Jason White, Suman Mazumder, Joshua Davis, Grace Hurley, Brian Cummings, Gary Piazza, Amit K Mitra, Clayton Yates, Robert Arnold. Identification of distinct mRNA & microRNA signatures and mRNA-miRNA pairs associated with inter-ethnic differences in prostate cancer aggressiveness [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-126.