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Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.

ABSTRACT: 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.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.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/MCL1, miR-513c/STAT1, miR-96/FOXO3A, miR-145/ITPR2, and miR-34a/PPP2R2A 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.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/MCL1, miR-513c/STAT1, and miR-96/FOXO3A may have clinical significance in the development of novel strategies for treating aggressive prostate cancer.

SUBMITTER: Wang BD

PROVIDER: S-EPMC4631799 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Project description:Prostate cancer (PCa) disproportionately affects African American (AA) men, yet present biomarkers do not address the observed racial disparity. The objective of this study was to identify biomarkers with potential benefits to AA PCa patients. Differentially expressed genes (DEG) analysis coupled with gene set enrichment analysis (GSEA) and leading-edge genes analysis showed that the keratin family of genes, including KRT8, KRT15, KRT19, KRT34, and KRT80, constituted the single most prominent family of genes enriched in AA compared to European American (EA) PCa cell lines. In PCa patients (TCGA and MSKCC patient cohorts), KRT8, KRT15, and KRT19 expression were relatively higher in AA than in EA patients. The differences in the expression of KRT15 and KRT19, but not KRT8, were enhanced by Gleason score and ERG fusion status; in low Gleason (Gleason ≤ 6 [TCGA cohort] and Gleason ≤ 7 [MSKCC cohort]), the expression of KRT15 and KRT19 was significantly (p ≤ 0.05) higher in AA than in EA patients. Survival analysis revealed that high expression of KRT15 and KRT19 was associated with increased risk of biochemical recurrence in low Gleason category patients in the TCGA patient cohort. Interestingly, KRT15 and KRT19 expression were also associated with an increased risk of death in the metastatic prostate adenocarcinoma cohort, suggesting the potential to predict the risks of disease recurrence and death in the low Gleason category and advanced disease conditions respectively. Gene set enrichment analysis revealed known oncogenic gene signatures, including KRAS and ERBB2, to be enriched in patients expressing high KRT15 and KRT19. Furthermore, high KRT15 and KRT19 were linked to the basal and LumA PCa subtypes, which are associated with poor postoperative androgen deprivation therapy (ADT) response compared to the LumB subtype. Taken together, the present study identifies genes with high expression in AA than in EA PCa. The identified genes are linked to oncogenic gene signatures, including KRAS and ERBB2, and to basal and LumA PCa subtypes that are associated with poor postoperative ADT response. This study, therefore, reveals biomarkers with the potential to address biomarker bias in PCa risk stratification and/or prognosis.

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Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.

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