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

Wiley - Tập 33 Số 1 - Trang 1374-1388 - 2019
Jiangfeng Li1,2, Yufan Ying1,2, Haiyun Xie1,2, Ke Jin1, Huaqing Yan1, Song Wang1, Mingjie Xu1, Xin Xu1, Xiao Wang1, Kai Yang1, Xiangyi Zheng1, Liping Xie1
1Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
2these authors contributed equally to this work

Tóm tắt

ABSTRACTEmerging 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 G1 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/β‐catenin/SNAIL pathway, which establishes an EMT circuit combined with miR‐381‐3p/MET/AKT/GSK‐3β/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. FASEB J. 33, 1374–1388 (2019). www.fasebj.org

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Wiley

Tập 33 Số 1

1374-1388

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