MicroRNA-200a suppresses prostate cancer progression through BRD4/AR signaling pathway
MicroRNA-200a suppresses prostate cancer progression through BRD4/AR signaling pathway
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MicroRNA-200a 通过 BRD4/AR 信号通路抑制前列腺癌进展
DOI：
10.1002/cam4.2029
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发表时间：
2019-04-01
期刊：
影响因子：
4
通讯作者：
Chen, Ming
中科院分区：
文献类型：
--
作者：
Guan, Han;You, Zonghao;Chen, Ming
前列腺癌仍然被认为是世界范围内的重大卫生保健挑战，部分原因是雄激素依赖型前列腺癌(ADPC)向治疗难治性去势抵抗前列腺癌(CRPC)的转变。因此，迫切需要探索ADPC耐药的新的分子机制。尽管许多研究已经暗示miR-200A在几种癌症中的作用，但miR-200A在前列腺癌中的生物学意义仍不清楚。基因芯片分析和公开可用的纪念斯隆-凯特琳癌症中心数据集的再分析后，发现miR-200a在ADPC组织中的表达较高，且其表达与CRPC患者的生存呈正相关。体外研究表明，在CRPC细胞中过表达miR-200A可显著抑制细胞增殖，促进细胞凋亡。体内研究表明，miR-200A过表达抑制了前列腺癌的生长和转移。荧光素酶报告基因分析表明，BRD4是miR-200A的直接靶基因，可以逆转miR-200A介导的前列腺癌生物学效应。最重要的是，我们的发现表明miR-200A通过抑制BRD4介导的AR信号的激活来抑制CRPC的进展。这一发现为CRPC患者开发更个性化的治疗方法提供了基础。
Prostate cancer is still considered a significant health care challenge worldwide due in part to the distinct transformation of androgen-dependent prostate cancer (ADPC) into treatment-refractory castration-resistant prostate cancer (CRPC). Consequently, there is an urgent need to explore novel molecular mechanisms underlying treatment resistance in ADPC. Although numerous studies have alluded to the role of miR-200a in several cancers, the biological significance of miR-200a in prostate cancer remains unknown. After performing microarray analysis and reanalysis of the publicly available Memorial Sloan Kettering Cancer Center dataset, miR-200a expression was found higher in ADPC tissues and its expression was positively associated with survival of CRPC patients. In vitro studies showed that miR-200a overexpression in CRPC cells markedly suppressed cellular proliferation and facilitated apoptosis. In vivo studies indicated that overexpression of miR-200a inhibited growth and metastasis of prostate cancer. The luciferase reporter assay demonstrated that BRD4 is a direct target gene of miR-200a and it could reverse miR-200a-mediated biological effects in prostate cancer cells. Most importantly, our findings indicated that miR-200a suppresses the progression of CRPC by inhibiting the activation of BRD4-mediated AR signaling. This finding provides the foundation for the development of more personalized therapeutic approaches for CRPC patients.