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  • miR Expression in Benign Prostate Epithelium Associated with


    miR-182 Expression in Benign Prostate Epithelium Associated with Gleason Grade of the Tumor and with Patient Ancestry
    The clinical data for the LCM cohort used for the miR-182 target discovery was limited but did contain single-nucleotide polymorphism quantified West African ancestry27 and Gleason grade (Supplemental Table S4). Notably, this cohort lacked outcome data and PCa samples. Benign epithelial levels of miR-182 trended toward being higher in patients with lower Gleason grade tumors but did not reach signifi-cance (Figure 4A). In this cohort, the 263717-53-9 of miR-182 was significantly twofold lower in benign epithelium from African American patients compared with white men of Eu-ropean ancestry (Figure 4B). Because African American pa-tients with PCa have an elevated risk of developing aggressive PCa and recurrence,43 whether the predicted miR-182 targets overlap with genes highly expressed in primary PCa tumors from African American patients was examined. The genes up-regulated in PCa tumors from African American men compared with PCa tumors from European men from the gene sets in the studies by Wallace et al38 and Powell et al44 were enriched in the predicted miR-182 targets, consistent with lower miR-182 associating with aggressive PCa (Figure 4, C and D). Neither gene set was significantly enriched in benign epithelium from African American patients in the microarray data set, suggesting these findings are not an artifact of the
    The American Journal of Pathology - 917
    Baumann et al
    Figure 3 miR-182eregulated genes identified by correlation with expression profiling are enriched for genes up-regulated in prostate cancer (PCa) metastasis. A: Analysis scheme to identify miR-182eregulated genes in prostate epithelial tissue. Gene expression profiling and miR-182 levels were examined in laser-capture microdissected (LCM) benign epithelium from 21 patients. Gene expression by Affymetrix GeneChip 1.0 Human Gene ST arrays and miR-182 by quantitative RT-PCR (RT-qPCR) normalized to RNU60, RNU44, and RNU48. Genes negatively correlated with miR-182 by Spearman analysis contain our predicted miR-182 targets. B: The predicted miR-182 targets are enriched for computationally predicted targets of miR-182 by gene-set enrichment analysis: TargetScan version 7.1 cumulative-weighted context score < 0.50, miRDB target score >85, and TarBase v8 prediction score >85. C: Kyoto Encyclopedia of Genes and Genomes version 6.1 pathways enriched in genes negatively correlated with miR-182 in prostate epithelium. The -log10 family-wise error rate corrected P value is shown. D: Predicted targets of miR-182 are enriched for the most strongly up-regulated genes in metastatic PCa compared with primary PCa from the gene set in the study 263717-53-9 by Chandran et al.37 E: PRKAR1A (left) and NR3C1 (right) correlation with miR-182 in The Cancer Genome Atlas (TCGA) prostate adenocar-cinoma tumor samples and RT-qPCR in two prostate epithelial (PrE) cell lines transfected with miR-182 pre-miRNA (PrE1: 50 mmol/L, PrE2: 25 mmol/L) or mock transfected. Data are expressed as means SD. ****P < 0.0001. CPM, counts per million; NES, normalized enrichment score; RQ, relative quantity; TCGA PRAD, TCGA prostate adenocarcinoma.
    lower miR-182 levels in African American patients in our cohort (Supplemental Figure S6). In summary, our findings support that both lower miR-182 expression in benign epithelium and a smaller increase in miR-182 expression in PCa are associated with more aggressive PCa (Figure 4E).
    Dysregulated miRs in PCa have been proposed to contribute to disease progression, as well as act as po-
    tential biomarkers for the presence of PCa or to predict PCa outcomes.11,13,45e47 We examined the association of 
    miR-182 expression with clinical markers of PCa aggres-siveness in a TMA cohort and proposed gene and pathway targets of miR-182 in prostate epithelium using LCM-collected tissue. This study yielded expected and unex-pected expression patterns for miR-182 in PCa, which prompted us to examine its mRNA targets, ultimately determining that PCa with high levels of miR-182 behave less aggressively than tumors with less overexpression of this oncomiR.
    In line with previous reports by our group and others, miR-182 expression was higher in PCa epithelium than benign epithelium.14e18,39 However, the negative
    918 - The American Journal of Pathology
    High miR-182 in Low-Risk Prostate Cancer
    Table 4 Top Predicted Targets of miR-182 in Prostate Epithelium
    TarBase TargetScan miRDB
    Genes that are strongly negatively correlated with miR-182 expression in benign prostate epithelium and are predicted targets by either TargetScan version 7.1 cumulative-weighted context score < 0.50, miRDB target score >85, or TarBase v8 prediction score >85.
    association detected between miR-182 expression and recurrence has not been reported before in PCa and was unexpected. The results in PCa are supported by studies in breast, lung, and bone cancers in which low expression of miR-182 has been associated with metastasis.48e50 Conversely, studies in PCa cell lines have found high miR-182 as increasing in vitro and in vivo phenotypes of