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

• Published in: The FASEB journal Vol. 33; no. 1; pp. 1374 - 1388
• Main Authors: Li, Jiangfeng, Ying, Yufan, Xie, Haiyun, Jin, Ke, Yan, Huaqing, Wang, Song, Xu, Mingjie, Xu, Xin, Wang, Xiao, Yang, Kai, Zheng, Xiangyi, Xie, Liping
• Format: Journal Article
• Language: English
• Published: United States 01-01-2019
• Subjects: DLK-DIO3 imprinted domain; MEG3-DMR; metastasis; miRNA; urologic cancer; miRNA; MEG3-DMR; metastasis; urologic cancer; DLK-DIO3 imprinted domain
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201800667R

ABSTRACT
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 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