MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27Kip1 Pathway In Vitro

Uterine leiomyoma is found in ~50–80% of women of a reproductive age and is the most common reason for hysterectomy. Recently, posttranscriptional gene silencing by microRNAs (miRs) has been reported as a mechanism for regulating gene expression stability in the pathogenesis of uterine leiomyomas. In this study, miR microarray analysis of leiomyomas and paired myometrial tissue revealed numerous aberrantly expressed miRs, including miR-150. In functional assays, transfection with miR-150 mimic resulted in decreased migration and fibrosis, implying an inhibition of leiomyoma growth. To identify the target genes of miR-150 in leiomyoma, gene set analysis and network analysis were performed. To overcome the limitations of in silico analysis, changes in expression levels of hallmark genes in leiomyoma after transfection with a miR-150 mimic were also evaluated using qRT-PCR. As a result, the Akt/p27Kip1 pathway was presumed to be one of the target pathways of miR-150. After transfecting cultured leiomyoma cells with the miR-150 mimic, expression levels of its target gene Akt decreased, whereas those of p27Kip1 increased significantly. Our results suggest that miR-150 affects the cell cycle regulation in uterine leiomyoma through the Akt/p27Kip1 pathway.

Stable maintenance of a hidden switch as a way to increase the gene expression stability

In response to severe stress, wild-type organisms can release alternative phenotypes that are hidden under normal conditions and are associated with underlying genetic variations. A number of such stress-induced phenotypic switchings have been reported to be based on reactivation of hidden thresholds; under the normal condition, a high barrier separating alternative phenotypes ensures the expression of single discrete phenotype, but a severe perturbation can lower the barrier to a level at which to expose cryptic alternatives. While the importance of such threshold-based switches as the mechanism to generate adaptive novelties under variable environments has been appreciated, it still remains elusive how naturally selected organisms can maintain the phenotypic switching capability when such switching has been disused for a long period of time. Here, through the use of computer simulation, we analyzed adaptive evolution of gene circuits under stabilizing selection. We found that different strategies evolved to acquire reduced levels of gene expression noise around the optimum expression level. To incrementally improve the gene expression stability from a founding population with bistable individuals, the evolution consistently took the direction to raise the height of the potential barrier of bistable systems. Our results demonstrate that hidden phenotypic switches can be stably maintained during environmental stasis, facilitating the release of potentially adaptive phenotypic alternatives in the event of substantial perturbations.