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.

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.