Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
Identification and Functional Validation of Reciprocal microRNA-mRNA Pairings in African American Prostate Cancer Disparities.
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DOI：
10.1158/1078-0432.ccr-14-1566
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发表时间：
2015-11-01
期刊：
影响因子：
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通讯作者：
Lee NH
中科院分区：
文献类型：
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作者：
Wang BD;Ceniccola K;Yang Q;Andrawis R;Patel V;Ji Y;Rhim J;Olender J;Popratiloff A;Latham P;Lai Y;Patierno SR;Lee NH
非裔美国人（AA）与欧洲裔美国人（EA）相比，前列腺癌（PCa）的发病率和死亡率更高。除了社会经济影响外，生物因素被认为在PCa差异中起着关键作用。我们研究了群体特异性和富集的miRNA-mRNA相互作用是否可能导致PCa差异。采用整合基因组学，结合miRNA和mRNA分析、miRNA靶点预测、通路分析和功能验证，绘制与PCa差异相关的miRNA-mRNA相互作用图谱。我们在PCa与患者匹配的正常前列腺中鉴定了22个AA特异性mirna和18个EA特异性mirna，在AA型PCa与EA型PCa比较中鉴定了10个“AA富集/缺失”mirna。许多这些群体特异性/富集的mirna可以与表现出相反差异表达模式的靶mrna配对。通路分析显示表皮生长因子受体（EGFR或ERBB）信号通路是受aa特异性/富集mrna和miRNA-mRNA配对显著调控的关键通路。新的miRNA-mRNA配对通过qRT-PCR、western blot和/或免疫组化分析在PCa标本中进行验证。在群体特异性PCa细胞系中进行的功能丧失/获得分析证实，miR-133a/MCL1、miR-513c/STAT1、miR-96/FOXO3A、miR-145/ITPR2和miR-34a/PPP2R2A是驱动肿瘤发生的关键miRNA-mRNA配对。操纵这些配对的平衡导致AA PCa细胞的增殖和侵袭减少，并增强对多西他赛诱导的细胞毒性的敏感性。我们的数据表明，AA特异性/富集的miRNA-mRNA配对可能在AA PCa的致癌途径激活中发挥关键作用。我们的研究结果还表明，miR-133a/MCL1、miR-513c/STAT1和miR-96/FOXO3A可能在开发治疗侵袭性PCa的新策略方面具有临床意义。
African Americans (AA) exhibit higher rates of prostate cancer (PCa) incidence and mortality compared to European American (EA) men. In addition to socioeconomic influences, biological factors are believed to play a critical role in PCa disparities. We investigated whether population-specific and -enriched miRNA-mRNA interactions might contribute to PCa disparities. Integrative genomics was employed, combining miRNA and mRNA profiling, miRNA target prediction, pathway analysis and functional validation, to map miRNA-mRNA interactions associated with PCa disparities. We identified 22 AA-specific and 18 EA-specific miRNAs in PCa versus patient-matched normal prostate, and 10 ‘AA-enriched/-depleted’ miRNAs in AA PCa versus EA PCa 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 epidermal growth factor receptor (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 PCa specimens. Loss/gain of function assays performed in population-specific PCa 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 PCa cells. Our data suggest that AA-specific/-enriched miRNA-mRNA pairings may play a critical role in the activation of oncogenic pathways in AA PCa. 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 PCa.