MiRNA-99a can regulate proliferation and apoptosis of human granulosa cells via targeting IGF-1R in polycystic ovary syndrome
- 336 Downloads
We aimed to evaluate the regulation of miR-99a to the biological functions of granulosa cells in polycystic ovary syndrome (PCOS) via targeting IGF-1R.
We collected aspirated follicular fluid in both patients with and without PCOS. Granulosa cells (GCs) were isolated through Percoll differential centrifugation to detect both miR-99a and IGF-1R expressions. We further transfected COV434 cells with miR-99a mimics to establish a miRNA-99a (miR-99a) overexpression model. We explored the regulation of miR-99a to the proliferation and apoptosis of human GCs via IGF-1R in COV434. The effect of different insulin concentrations on miR-99a expression was also evaluated.
MiR-99a was significantly downregulated while IGF-1R was upregulated in patients with PCOS. MiR-99a can regulate IGF-1R on a post-transcriptional level. After transfection of miR-99a mimics, the proliferation rate was decreased and apoptosis rate was increased significantly in COV434. Exogenous insulin-like growth factor 1 (IGF-1) treatment could reverse the effect of miR-99a. MiR-99a was negatively and dose-dependently regulated by insulin in vitro.
MiR-99a expression was downregulated in patients with PCOS, the degree of which may be closely related to insulin resistance and hyperinsulinemia. MiR-99a could attenuate proliferation and promote apoptosis of human GCs through targeting IGF-1R, which could partly explain the abnormal folliculogenesis in PCOS.
KeywordsmiR-99a Granulosa cell IGF-1R Proliferation Apoptosis Polycystic ovary syndrome
This work was supported by the National Natural Science Foundation of China (Grant No. 81401268).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 3.McKenna LB, Schug J, Vourekas A, McKenna JB, Bramswig NC, Friedman JR, et al. MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology. 2010;139(5):1654–64, 64 e1. https://doi.org/10.1053/j.gastro.2010.07.040.CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Ge X, Liu X, Lin F, Li P, Liu K, Geng R, et al. MicroRNA-421 regulated by HIF-1alpha promotes metastasis, inhibits apoptosis, and induces cisplatin resistance by targeting E-cadherin and caspase-3 in gastric cancer. Oncotarget. 2016;7(17):24466–82. https://doi.org/10.18632/oncotarget.8228.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Artimani T, Saidijam M, Aflatoonian R, Amiri I, Ashrafi M, Shabab N, et al. Estrogen and progesterone receptor subtype expression in granulosa cells from women with polycystic ovary syndrome. Gynecol Endocrinol. 2015;31(5):379–83. https://doi.org/10.3109/09513590.2014.1001733.CrossRefPubMedGoogle Scholar
- 23.Roth LW, McCallie B, Alvero R, Schoolcraft WB, Minjarez D, Katz-Jaffe MG. Altered microRNA and gene expression in the follicular fluid of women with polycystic ovary syndrome. J Assist Reprod Genet. 2014;31(3):355–62. https://doi.org/10.1007/s10815-013-0161-4.CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Zhang ZW, Guo RW, Lv JL, Wang XM, Ye JS, Lu NH, et al. MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin. Biochem Biophys Res Commun. 2017;486(2):414–22. https://doi.org/10.1016/j.bbrc.2017.03.056.CrossRefPubMedGoogle Scholar
- 26.Tao J, Yang X, Han Z, Lu P, Wang J, Liu X, et al. Serum MicroRNA-99a helps detect acute rejection in renal transplantation. Transplant Proc. 2015;47(6):1683–7. https://doi.org/10.1016/j.transproceed.2015.04.094.CrossRefPubMedGoogle Scholar
- 29.Yao G, Yin M, Lian J, Tian H, Liu L, Li X, et al. MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4. Mol Endocrinol. 2010;24(3):540–51. https://doi.org/10.1210/me.2009-0432.CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Premoli AC, Santana LF, Ferriani RA, Moura MD, De Sa MF, Reis RM. Growth hormone secretion and insulin-like growth factor-1 are related to hyperandrogenism in nonobese patients with polycystic ovary syndrome. Fertil Steril. 2005;83(6):1852–5. https://doi.org/10.1016/j.fertnstert.2004.10.057.CrossRefPubMedGoogle Scholar
- 41.Luo L, Wang Q, Chen M, Yuan G, Wang Z, Zhou C. IGF-1 and IGFBP-1 in peripheral blood and decidua of early miscarriages with euploid embryos: comparison between women with and without PCOS. Gynecol Endocrinol. 2016;32(7):538–42. https://doi.org/10.3109/09513590.2016.1138459.CrossRefPubMedGoogle Scholar
- 45.Cai G, Ma X, Chen B, Huang Y, Liu S, Yang H, et al. MicroRNA-145 negatively regulates cell proliferation through targeting IRS1 in isolated ovarian granulosa cells from patients with polycystic ovary syndrome. Reprod Sci. 2016;24(6):902–10. https://doi.org/10.1177/1933719116673197.CrossRefPubMedGoogle Scholar