Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma

Uterine leiomyomas (ulm) grow under high oxidative stress due to a hypoxic microenvironment and defects in redox metabolism. akt is one major pathway activated by reactive oxygen species (ros) that maintains ulm growth and survival. we previously reported that akt inactivated by akt inhibitors can significantly induce cellular senescence in ulm cells. since some mirnas are induced by akt inhibitors in an ros-dependent manner, we proposed that these mirnas modulate akt function and cellular senescence in ulm. we therefore established ex vivo models of a three-dimensional ulm spheroid culture system to study the role of mirnas in cellular senescence. four mirnas, mir-29b, mir-181a, mir-182, and mir-200c, were found to induce cellular senescence in primary ulm and myometrium spheroid cultures when stably overexpressed. mir-181a and mir-182 were found to repress akt3 and ccnd2, respectively. correspondingly, rnai of akt3 or ccnd2 also induced cellular senescence and g0/g1 arrest. thus, mir-181a and mir-182 drive cellular senescence in ulm by repressing akt3 and ccnd2 activity, respectively. we further demonstrated that senescent ulm cells can be effectively removed by bh3 mimetic abt263, which provides a new therapeutic venue for the treatment of ulm. our findings suggest that mirnas are potent modulators in regulating the ros-akt-cell cycle axis in uterine leiomyoma.