The role of miR-24 as a race related genetic factor in prostate cancer.
The role of miR-24 as a race related genetic factor in prostate cancer.
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DOI：
10.18632/oncotarget.15016
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发表时间：
2017-03-07
期刊：
影响因子：
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通讯作者：
Dahiya R
中科院分区：
文献类型：
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作者：
Hashimoto Y;Shiina M;Kato T;Yamamura S;Tanaka Y;Majid S;Saini S;Shahryari V;Kulkarni P;Dasgupta P;Mitsui Y;Sumida M;Deng G;Tabatabai L;Kumar D;Dahiya R
非洲裔美国人（AfA）的前列腺癌（PCa）发病率明显高于高加索裔美国人（CaA），但这种差异的遗传基础尚不清楚。为了解决这个问题，我们分析了AfA（n = 81）和CaA（n = 51）PCa患者中的miRNA表达。在此，我们发现miR-24在AfA和CaA PCa患者中差异表达，并试图阐明其在AfA患者中的作用。此外，miR-24启动子的公开测序数据证实，它在PCa患者中高度甲基化并下调。利用VAMCSF和NDRI患者队列，我们发现miR-24表达与AfA/CaA PCa患者之间的种族差异有关。有趣的是，在AfA细胞系（MDA-PCa-2b）中用5Aza-CdR处理PCa细胞后，miR-24恢复，而在CaA细胞DU-145中未观察到miR-24的恢复。miR-24的异位表达显示生长降低并诱导凋亡，尽管与AfA细胞系相比，CaA细胞系中的作用较小。最后，我们通过基于定量PCR的基因表达阵列发现了与miR-24转染的AfA细胞相关的生物学途径和过程的独特变化。对改变的途径的评估表明，与CaA细胞相比，AfA衍生细胞系中AR、IGF 1、IGFBP 5和ETV 1显着减少，并且前列腺癌患者中miR-24/靶点表达存在相互调节关系。这些结果表明，miR-24可能是促进种族相关肿瘤发生的关键事件的中心调节因子，并有可能成为PCa治疗的治疗剂。
The incidence of prostate cancer (PCa) among African-Americans (AfA) is significantly higher than Caucasian-Americans (CaA) but the genetic basis for this disparity is not known. To address this problem, we analyzed miRNA expression in AfA (n = 81) and CaA (n = 51) PCa patients. Here, we found that miR-24 is differentially expressed in AfA and CaA PCa patients and attempt to clarify its role in AfA patients. Also, the public sequencing data of the miR-24 promoter confirmed that it was highly methylated and down-regulated in PCa patients. Utilizing a VAMCSF and NDRI patient cohorts, we discovered that miR-24 expression was linked to a racial difference between AfA/CaA PCa patients. Interestingly, miR-24 was restored after treatment of PCa cells with 5Aza-CdR in an AfA cell line (MDA-PCa-2b), while restoration of miR-24 was not observed in CaA cells, DU-145. Ectopic expression of miR-24 showed decreased growth and induced apoptosis, though the effect was less in the CaA cell line compared to the AfA cell line. Finally, we found unique changes in biological pathways and processes associated with miR-24 transfected AfA cells by quantitative PCR-based gene expression array. Evaluation of the altered pathways showed that AR, IGF1, IGFBP5 and ETV1 were markedly decreased in the AfA derived cell line compared with CaA cells, and there was a reciprocal regulatory relationship of miR-24/target expression in prostate cancer patients. These results demonstrate that miR-24 may be a central regulator of key events that contribute to race-related tumorigenesis and has potential to be a therapeutic agent for PCa treatment.