Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Department of Urology & Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
Cell Death Dis. 2018 Feb 21;9(3):301. doi: 10.1038/s41419-018-0293-7.
Our recent study identified a list of differentially expressed microRNAs (miRNAs) in human prostate cancer (PCa) tissues compared to adjacent benign prostate tissues. In the current study, to identify the crucial miRNA-mRNA regulatory biomodule involved into prostate carcinogenesis based on the previous miRNA expression profile in PCa, we proposed an integrated systematic approach which combined miRNA-mediated gene expression regulatory network analysis, experimental validations in vitro and in vivo, as well as clinical significance evaluation. As a result, the CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I axis was identified as a bottleneck in the miRNA-mediated gene expression regulatory network of PCa according to network topological analysis. The direct binding relationship between TP73 and PCa downregulated miR-193a-5p, and the direct binding relationship between UBE2I and PCa upregulated miR-188-5p were both experimentally validated. In addition, miR-193a-5p had a more significant regulatory effect on the tumor promoter isoform of TP73-deltaNp73 than on the tumor suppressive isoform of TP73-TAp73. Importantly, the deregulation of either the miR-193a-5p-TP73 or miR-188-5p-UBE2I axes was significantly associated with aggressive progression and poor prognosis in PCa patients. Gain- and loss-of-function experiments showed that miR-193a-5p efficiently inhibited in vitro PCa cell proliferation, migration, and invasion, and in vivo tumor growth, and markedly induced PCa cell apoptosis via regulating TP73 with a corresponding suppression of the CCND1-RNASEL-CDKN1A-MDM2 axis. In contrast, miR-188-5p exerted its tumor promoter roles through targeting UBE2I with a subsequent activation of the CCND1-RNASEL-CDKN1A-MDM2 axis. Taken together, this integrated analysis revealed the potential roles of the miR-193a-5p/TP73 and miR-188-5p/UBE2i negative regulation pairs in PCa. In addition to the significant clinical relevance, miR-193a-5p- and miR-188-5p-regulated CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I signaling may be a novel regulatory biomodule in prostate carcinogenesis.
我们最近的研究确定了一组在人类前列腺癌 (PCa) 组织与相邻良性前列腺组织相比差异表达的 microRNAs (miRNAs)。在本研究中，为了根据之前在 PCa 中的 miRNA 表达谱鉴定涉及前列腺癌发生的关键 miRNA-mRNA 调节生物模块，我们提出了一种综合系统方法，该方法结合了 miRNA 介导的基因表达调控网络分析、体外和体内实验验证以及临床意义评估。结果表明，根据网络拓扑分析，CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I 轴被鉴定为 PCa 中 miRNA 介导的基因表达调控网络的瓶颈。TP73 与 PCa 下调的 miR-193a-5p 之间存在直接结合关系，UBE2I 与 PCa 上调的 miR-188-5p 之间也存在直接结合关系，这两种关系均通过实验得到验证。此外，miR-193a-5p 对肿瘤促进型异构体 TP73-deltaNp73 的调节作用比对肿瘤抑制型异构体 TP73-TAp73 更为显著。重要的是，miR-193a-5p-TP73 或 miR-188-5p-UBE2I 轴的失调与 PCa 患者的侵袭性进展和不良预后显著相关。增益和缺失功能实验表明，miR-193a-5p 通过调节 TP73 有效地抑制体外 PCa 细胞的增殖、迁移和侵袭以及体内肿瘤生长，并通过相应抑制 CCND1-RNASEL-CDKN1A-MDM2 轴显著诱导 PCa 细胞凋亡。相比之下，miR-188-5p 通过靶向 UBE2I 发挥其肿瘤促进作用，随后激活 CCND1-RNASEL-CDKN1A-MDM2 轴。综上所述，这种综合分析揭示了 miR-193a-5p/TP73 和 miR-188-5p/UBE2i 负调控对 PCa 的潜在作用。除了具有重要的临床相关性外，miR-193a-5p 和 miR-188-5p 调节的 CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I 信号可能是前列腺癌发生的新调节生物模块。
