Meng Delong, Yang Shu, Wan Xuechao, Zhang Yalong, Huang Wenhua, Zhao Peiqing, Li Tao, Wang Lianqing, Huang Yan, Li Tao, Li Yao
State Key Laboratory of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
Center of Translational Medicine, Central Hospital of Zibo, Zibo, Shangdong Province, China.
Int J Biochem Cell Biol. 2016 Apr;73:30-40. doi: 10.1016/j.biocel.2016.01.018. Epub 2016 Jan 28.
Prostate cancer is one of the most common malignancies, and microRNAs have been recognized to be involved in tumorigenesis of various kinds of cancer including prostate cancer (PCa). Androgen receptor (AR) plays a core role in prostate cancer progression and is responsible for regulation of numerous downstream targets including microRNAs. This study identified an AR-repressed microRNA, miR-421, in prostate cancer. Expression of miR-421 was significantly suppressed by androgen treatment, and correlated to AR expression in different prostate cancer cell lines. Furthermore, androgen-activated AR could directly bind to androgen responsive element (ARE) of miR-421, as predicted by bioinformatics resources and demonstrated by ChIP and luciferase reporter assays. In addition, over-expression of miR-421 markedly supressed cell viability, delayed cell cycle, reduced glycolysis and inhibited migration in prostate cancer cells. According to the result of miR-421 target genes searching, we focused on 4 genes NRAS, PRAME, CUL4B and PFKFB2 based on their involvement in cell proliferation, cell cycle progression and metabolism. The expression of these 4 downstream targets were significantly repressed by miR-421, and the binding sites were verified by luciferase assay. Additionally, we explored the expression of miR-421 and its target genes in human prostate cancer tissues, both in shared microarray data and in our own cohort. Significant differential expression and inverse correlation were found in PCa patients.
前列腺癌是最常见的恶性肿瘤之一，且已认识到微小RNA参与包括前列腺癌（PCa）在内的各种癌症的肿瘤发生过程。雄激素受体（AR）在前列腺癌进展中起核心作用，并负责调控包括微小RNA在内的众多下游靶点。本研究在前列腺癌中鉴定出一种AR抑制的微小RNA，即miR-421。雄激素处理显著抑制了miR-421的表达，且其表达与不同前列腺癌细胞系中的AR表达相关。此外，如生物信息学资源预测并经染色质免疫沉淀（ChIP）和荧光素酶报告基因检测所证实，雄激素激活的AR可直接结合至miR-421的雄激素反应元件（ARE）。另外，miR-421的过表达显著抑制了前列腺癌细胞的细胞活力，延迟了细胞周期，降低了糖酵解并抑制了细胞迁移。根据miR-421靶基因搜索结果，基于NRAS、PRAME、CUL4B和PFKFB2这4个基因参与细胞增殖、细胞周期进程和代谢，我们将研究重点聚焦于它们。miR-421显著抑制了这4个下游靶点的表达，且荧光素酶检测验证了其结合位点。此外，我们在共享的微阵列数据以及我们自己的数据集中，探索了miR-421及其靶基因在人前列腺癌组织中的表达。在前列腺癌患者中发现了显著的差异表达和负相关。
