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hsa-miR-199a-3p Inhibits Motility, Invasiveness, and Contractility of Ovarian Endometriotic Stromal Cells

  • Endometriosis: Original Article
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Abstract

It is suggested that aberrantly expressed microRNAs are involved in the pathogenesis of endometriosis. Our previous study demonstrated that expression of the microRNA hsa-miR-199a-3p is attenuated in human endometriotic cyst stromal cells (ECSCs). The current study aimed to define the roles of hsa-miR-199a-3p in the development of endometriosis. ECSCs and normal endometrial stromal cells (NESCs) were isolated from ovarian endometrioma and normal endometrial tissues, respectively. We evaluated the effect of transfected hsa-miR-199a-3p on the migration, invasion, and contractility of ECSCs using Transwell migration assays, in vitro wound healing assays, Transwell invasion assays, and collagen gel contraction assays. We also examined the downstream target of hsa-miR-199a-3p with an online public database search and luciferase reporter assay. Expression of hsa-miR-199a-3p in ECSCs was significantly lower than that in NESCs, whereas the expression of p21-activated kinase 4 (PAK4) mRNA was significantly higher. Transfection of hsa-miR-199a-3p inhibited the migration, invasion, and contractility of ECSCs via inhibition of PAK4 mRNA expression. PAK4 was confirmed to be the direct target of hsa-miR-199a-3p. Transfection of PAK4 small interfering RNA and the PAK4 inhibitor PF-3758309 also inhibited ECSC migration, invasion, and contractility. These findings suggest that hsa-miR-199a-3p may act as a tumor suppressor in endometriosis development. Attenuation of hsa-miR-199a-3p expression was favorable for ECSCs to acquire the highly invasive, motile, and contractile characteristics of endometriotic cells and is involved in the development of endometriosis. Accordingly, PAK4 inhibitors may be promising for the treatment of endometriosis.

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Acknowledgements

We would like to thank Ms. Sawako Adachi, Ms. Tomoko Ohkuma, and Ms. Nozomi Kai for their excellent technical assistance and Editage (www.editage.jp) for English language editing.

Funding

This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 20K09622 and no. 16K11093 to K.N., no. 18K16774 to T.H., and no. 15K10679 to H.N.) and the Study Fund of Oita Society of Obstetrics and Gynecology (to T.H. and Y.A.).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-shi, Oita, 879-5593, Japan

    Ruofei Zhu, Kaei Nasu, Masato Yoshihashi, Tomoko Hirakawa, Yoko Aoyagi & Hisashi Narahara

  2. Division of Obstetrics and Gynecology, Support System for Community Medicine, Faculty of Medicine, Oita University, Oita, Yufu-shi, Japan

    Kaei Nasu

  3. Department of Molecular Pathology, Faculty of Medicine, Oita University, Oita, Yufu-shi, Japan

    Naoki Hijiya

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  1. Ruofei Zhu
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  4. Masato Yoshihashi
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Contributions

R.Z. and K.N. participated in the study design, data analysis and interpretation, literature search, generation of figures, and writing and editing of the manuscript. N.H., M.Y., T.H., Y.A., and H.N. performed the data/case collection, experiments, data analysis, and interpretation. All authors read and approved the final manuscript.

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Correspondence to Kaei Nasu.

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Zhu, R., Nasu, K., Hijiya, N. et al. hsa-miR-199a-3p Inhibits Motility, Invasiveness, and Contractility of Ovarian Endometriotic Stromal Cells. Reprod. Sci. 28, 3498–3507 (2021). https://doi.org/10.1007/s43032-021-00604-4

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