Identification of a novel microRNA-mRNA regulatory biomodule in human prostate cancer.
Identification of a novel microRNA-mRNA regulatory biomodule in human prostate cancer.
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人类前列腺癌中新型 microRNA-mRNA 调节生物模块的鉴定
DOI：
10.1038/s41419-018-0293-7
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发表时间：
2018-02-21
影响因子：
9
通讯作者：
Lin N
中科院分区：
文献类型：
--
作者：
Zhang Y;Jiang F;He H;Ye J;Mao X;Guo Q;Wu SL;Zhong W;Wu CL;Lin N
我们最近的研究确定了人类前列腺癌 (PCa) 组织中与邻近良性前列腺组织相比差异表达的 microRNA (miRNA) 列表。在本研究中，为了根据先前PCa中的miRNA表达谱来识别参与前列腺癌发生的关键miRNA-mRNA调控生物模块，我们提出了一种综合系统方法，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，根据网络拓扑分析，CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I轴被确定为miRNA介导的PCa基因表达调控网络中的瓶颈。 TP73和PCa之间的直接结合关系下调miR-193a-5p，以及UBE2I和PCa之间的直接结合关系上调miR-188-5p均经过实验验证。此外，miR-193a-5p对TP73-deltaNp73的肿瘤启动子异构体比TP73-TAp73的肿瘤抑制异构体具有更显着的调节作用。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着相关。功能获得和丧失实验表明，miR-193a-5p 可有效抑制体外 PCa 细胞增殖、迁移和侵袭，以及体内肿瘤生长，并通过调节 TP73 并相应抑制 CCND1-RNASEL-CDKN1A-MDM2 轴，显着诱导 PCa 细胞凋亡。相比之下，miR-188-5p 通过靶向 UBE2I 并随后激活 CCND1-RNASEL-CDKN1A-MDM2 轴来发挥其肿瘤促进作用。综上所述，这一综合分析揭示了 miR-193a-5p/TP73 和 miR-188-5p/UBE2i 负调控对在 PCa 中的潜在作用。除了显着的临床相关性外，miR-193a-5p 和 miR-188-5p 调节的 CCND1-RNASEL-CDKN1A-TP73-MDM2-UBE2I 信号传导可能是前列腺癌发生中的新型调节生物模块。
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.
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影响因子：
4.6
作者：
Cheng J;Yang K;Zhang Q;Yu Y;Meng Q;Mo N;Zhou Y;Yi X;Ma C;Lei A;Liu Y
通讯作者：
Liu Y
影响因子：
--
作者：
Lin CH;Tsai CH;Yeh CT;Liang JL;Hung WC;Lin FC;Chang WL;Li HY;Yao YC;Hsu TI;Lee YC;Wang YC;Sheu BS;Lai WW;Calkins MJ;Hsiao M;Lu PJ
通讯作者：
Lu PJ
影响因子：
--
作者：
Jacques C;Calleja LR;Baud'huin M;Quillard T;Heymann D;Lamoureux F;Ory B
通讯作者：
Ory B
影响因子：
14.9
作者：
Al-Haj L;Blackshear PJ;Khabar KS
通讯作者：
Khabar KS
影响因子：
4.3
作者：
Yu, Haiyuan;Kim, Philip M.;Sprecher, Emmett;Trifonov, Valery;Gerstein, Mark
通讯作者：
Gerstein, Mark