Data from Identification and Functional Validation of Reciprocal microRNA–mRNA Pairings in African American Prostate Cancer Disparities

Abstract

<div>Abstract<p><b>Purpose:</b> African Americans (AA) exhibit higher rates of prostate cancer incidence and mortality compared with European American (EA) men. In addition to socioeconomic influences, biologic factors are believed to play a critical role in prostate cancer disparities. We investigated whether population-specific and -enriched miRNA–mRNA interactions might contribute to prostate cancer disparities.</p><p><b>Experimental Design:</b> Integrative genomics was used, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis, and functional validation, to map miRNA–mRNA interactions associated with prostate cancer disparities.</p><p><b>Results:</b> We identified 22 AA-specific and 18 EA-specific miRNAs in prostate cancer versus patient-matched normal prostate, and 10 “AA-enriched/-depleted” miRNAs in AA prostate cancer versus EA prostate cancer comparisons. Many of these population-specific/-enriched miRNAs could be paired with target mRNAs that exhibited an inverse pattern of differential expression. Pathway analysis revealed EGFR (or ERBB) signaling as a critical pathway significantly regulated by AA-specific/-enriched mRNAs and miRNA–mRNA pairings. Novel miRNA–mRNA pairings were validated by qRT-PCR, Western blot, and/or IHC analyses in prostate cancer specimens. Loss/gain of function assays performed in population-specific prostate cancer cell lines confirmed miR-133a<i>/MCL1</i>, miR-513c<i>/STAT1</i>, miR-96<i>/FOXO3A</i>, miR-145<i>/ITPR2</i>, and miR-34a<i>/PPP2R2A</i> as critical miRNA–mRNA pairings driving oncogenesis. Manipulating the balance of these pairings resulted in decreased proliferation and invasion, and enhanced sensitization to docetaxel-induced cytotoxicity in AA prostate cancer cells.</p><p><b>Conclusions:</b> Our data suggest that AA-specific/-enriched miRNA–mRNA pairings may play a critical role in the activation of oncogenic pathways in AA prostate cancer. Our findings also suggest that miR-133a/<i>MCL1</i>, miR-513c/<i>STAT1</i>, and miR-96/<i>FOXO3A</i> may have clinical significance in the development of novel strategies for treating aggressive prostate cancer. <i>Clin Cancer Res; 21(21); 4970–84. ©2015 AACR</i>.</p></div>