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

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Abstract

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 may 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 may 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.

Key messages

  • A subset of oxidative stress-induced miRNAs is involved in AKT signaling in uterine leiomyoma.

  • Overexpression of miR-181a and miR-182 resulted in cellular senescence in leiomyoma through repression of AKT3 and CCND2, respectively.

  • Silencing of AKT3 and CCND2 drives leiomyoma cell into senescence and cycle arrest.

  • Application of our newly developed 3D leiomyoma spheroids can provide a quick and reliable ex vivo model for cytopathologic and functional analysis.

  • BH3 mimetics can effectively reduce the viability of miRNA-mediated senescent cells in leiomyoma.

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Acknowledgements

We thank Drs. Serdar Bulun, Debabrata Chakravarti, and Ping Yin for their valuable scientific comments and technical supports, as well as Mrs. Stacy Ann Kujawa for consenting patients and providing all fresh samples for the study. All immunostains and histology were performed in the Pathology Core Facility.

Funding

This study was supported by NIH P01HD57877, NSFC grant 81572785, and China Scholarship Council.

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Author notes

  1. Xiuhua Xu

    Present address: Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China

Authors and Affiliations

  1. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Xiuhua Xu, Yinuo Li, Jia Xie & Jian-Jun Wei

  2. Key Laboratory of Experimental Teratology Ministry of Education, Department of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China

    Xiuhua Xu

  3. Department of Obstetrics and Gynecology-Division of Reproductive Science in Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    J. Julie Kim & Jian-Jun Wei

  4. The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine and State Key Laboratory of Radiation Medicine and Radioprotection, Soochow University, Suzhou, Jiangsu, China

    Changshun Shao

  5. Department of Pathology, Feinberg School of Medicine, Northwestern University, 251 East Huron Street, Feinberg 7-334, Chicago, IL, 60611, USA

    Jian-Jun Wei

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  1. Xiuhua Xu
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Correspondence to Jian-Jun Wei.

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Xu, X., Kim, J.J., Li, Y. et al. Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma. J Mol Med 96, 1095–1106 (2018). https://doi.org/10.1007/s00109-018-1682-1

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