Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer
Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer
复制标题
CCNA2 在调节 CDK6 和 MET 介导的细胞周期途径中的双重调节作用以及膀胱癌中 miR-381-3p 阻断 EMT 进展
DOI：
10.1096/fj.201800667r
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发表时间：
2019-01-01
期刊：
影响因子：
4.8
通讯作者：
Xie, Liping
中科院分区：
文献类型：
--
作者：
Li, Jiangfeng;Ying, Yufan;Xie, Liping
新的证据表明，从DLK-Dio3印迹结构域的miRNA簇转录的microRNAs(MiRNAs)参与了多种癌症的发生。然而，作为该簇的一员，miR-381-3p在膀胱癌(BCA)中的作用机制仍不清楚。在这里，我们通过亚硫酸氢盐测序聚合酶链式反应证明，上游母体表达的基因3分歧甲基化区域的高甲基化状态降低了BCA中miR-381-3p的表达。体外和体内实验表明，miR-381-3p的过表达通过下调MET和CcNA2诱导的EMT进程，诱导细胞G(1)期停滞和迁移，从而显著抑制细胞增殖。生物信息学分析和双荧光素酶报告基因分析表明，CDK6/CcNA2/MET均为miR-381-3p的直接靶点。此外，miR-381-3p介导的Ccna2抑制不仅参与了CDK6对细胞周期的增殖调控，而且还通过ROCK/AKT/-catenin/Snail途径调控EMT的进展，从而建立了与miR-381-3p/Met/AKT/GSK-3/Snail通路相结合的EMT通路，而Snail是诱导EMT进展的最后一个共聚焦靶点。综上所述，我们提出了两个由miR-381-3p介导的新的BCA调控通路，它们可能有助于未来开发更有效的治疗BCA的方法：Li，J.，Ying，Y.，Xie，H.，jin，Kim，K.，Yen，H.，Wang，S.，Xu，M.，Xu，X.，Wang，X.，Yang，K.，郑，X.，Xie，L.，Ccna2在调控CDK6和MET介导的细胞周期途径和EMT进展中的双重调节作用被miR-381-3p阻断。
Emerging evidence has elucidated that microRNAs (miRNAs) transcribed from miRNA cluster at DLK-DIO3 imprinted domain are involved in various cancers. However, as one member of this cluster, the underlying mechanisms and functions of miR-381-3p in bladder cancer (BCa) still remains elusive. Here we demonstrate that the hypermethylated status of upstream maternally expressed gene 3 divergent methylation region reduces the expression of miR-381-3p in BCa by bisulfite-sequencing PCR. In vitro and in vivo experiments indicate that overexpression of miR-381-3p significantly inhibits cell proliferation via inducing G(1) phase arrest and migration via down-regulating MET and CCNA2 induced EMT progression. CDK6/CCNA2/MET are all identified as the direct targets of miR-381-3p by bioinformatics analysis and dual-luciferase reporter assay. Furthermore, inhibition of CCNA2 mediated by miR-381-3p as the crucial biregulator not only participates in the proliferation regulation with CDK6 in cell cycle but also modulates the EMT progression via ROCK/AKT/-catenin/SNAIL pathway, which establishes an EMT circuit combined with miR-381-3p/MET/AKT/GSK-3/SNAIL pathway, and SNAIL is the last confocal target to induce EMT progression. To conclude, we propose 2 novel regulatory circuits mediated by miR-381-3p in BCa, which may assist in the development of more effective therapies against BCa in the future.Li, J., Ying, Y., Xie, H., Jin, K., Yan, H., Wang, S., Xu, M., Xu, X., Wang, X., Yang, K., Zheng, X., Xie, L. Dual regulatory role of CCNA2 in modulating CDK6 and MET-mediated cell-cycle pathway and EMT progression is blocked by miR-381-3p in bladder cancer.