Abstract C058: Deregulated microRNA-mRNA reciprocal pairs as novel precision biomarkers and therapeutic targets for African American prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer death among American men. Notably, African American (AA) men exhibit 1.6-fold higher incidence rate and 2.4-fold higher mortality rate when compared to European American (EA) men. Besides socioeconomic factors, accumulating genomic data suggest that intrinsic genetic risk elements also play critical roles in promoting PCa disparities. MicroRNAs (miRNAs) are involved in epigenetic mechanisms regulating mRNA expression in various human diseases, including cancers. In this study, we have applied a systems biology approach (by integrating mRNA and miRNA profiling data, target prediction, and pathway analysis) to identify critical signaling networks differentially regulated between AA and EA PCa. Using miRNA-drive algorithm mirPath V.3 coupled with mRNA mapping, and global test algorithm coupled with miRNA mapping, we identified several cancer pathways, such as ERBB, mTOR, HIF, and VEGF signaling, that are significantly regulated by AA-depleted/enriched miRNAs and mRNAs. Specifically, reciprocal miRNA-mRNA pairs miR-34a-5p/HIF1A, miR-34a-5p/PIK3CB, miR-34a-5p/IGFBP2, and miR-99b-5p/MTOR (downregulated/upregulated in AA vs. EA PCa), and miR-96-5p/MAPKAPK2 (upregulated/downregulated in AA vs. EA PCa) were identified as core miRNA/mRNA regulators in activation of mTOR and VEGF signaling in AA PCa. RT-qPCR, Western blotting, and immunohistochemistry assays in AA and EA PCa cell lines and patient samples have confirmed that these miRNAs and mRNAs are differentially expressed in AA and EA PCa. Furthermore, molecular targeting miRNA/mRNA pairings using miR-34a-5p, miR-99b-5p mimics and/or miR-96-5p antagomir consequently reduced cell proliferation and enhanced docetaxel-induced cytotoxicity in AA PCa cells. In summary, these results suggest that deregulated miRNA/mRNA reciprocal pairs play critical roles in promoting cancer aggressiveness and chemoresistance in AA PCa. Further development of these miRNA/mRNA pairings as precision diagnostic/prognostic biomarkers and novel therapeutic targets may pave a new path for PCa diagnosis and treatment. Citation Format: Himali Gujrati, Siyoung Ha, Bi-Dar Wang. Deregulated microRNA-mRNA reciprocal pairs as novel precision biomarkers and therapeutic targets for African American prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C058.