Decidualization Differentially Regulates microRNA Expression in Eutopic and Ectopic Endometrial Stromal Cells

Decidualization of the endometrium and endometriosis involves the morphological and biochemical reprogramming of the estrogen-primed proliferative stromal compartment under the continuing influence of progesterone. Here, we evaluated the involvement of microRNA in the decidualization processes of normal endometrial stromal cells (NESCs) and endometriotic cyst stromal cells (ECSCs). In vitro decidualization of NESCs and ECSCs was induced by long-term culture with a combination of 0.5 mmol/L of dibutyryl cyclic adenosine monophosphate and 100 nmol/L of dienogest. We investigated the effect of in vitro decidualization on the microRNA and messenger RNA (mRNA) expression profiles of the NESCs and ECSCs using global microarray techniques and an Ingenuity Pathways Analysis. Decidualization differentially enhanced the miR-30a-5p expression in the NESCs and the miR-210 expression in the ECSCs. The enhanced miR-30a-5p expression in the NESCs correlated with the increased mRNA expression of Krüppel-like factor 9 and period circadian clock 3 as well as the decreased mRNA expression of tolloid-like 1, tolloid-like 2, and paired-like homeodomain 1. The enhanced expression of miR-210 in the ECSCs correlated with the decreased mRNA expression of growth hormone receptor and thymidine kinase 1. Although there is no direct evidence, we speculate that the loss of miR-30a-5p-mediated mechanisms of decidualization and the acquisition of miR-210-mediated mechanisms of decidualization may be involved in the progesterone resistance in endometriosis. Further investigations are necessary to test this speculation. Similar content being viewed by others

Kim JJ, Taylor HS, Lu Z, et al. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13(5):323–332. Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol. 2003;178(3):357–372. Hess AP, Hamilton AE, Talbi S, et al. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod. 2007;76(1):102–117. Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445–453. Irwin JC, Utian WH, Eckert RL. Sex steroids and growth factors differentially regulate the growth and differentiation of cultured human endometrial stromal cells. Endocrinology. 1991;129(5):2385–2392. Tsuno A, Nasu K, Yuge A, Matsumoto H, Nishida M, Narahara H. Decidualization attenuates the contractility of eutopic and ectopic endometrial stromal cells: implications for hormone therapy of endometriosis. J Clin Endocrinol Metab. 2009;94(7):2516–2523. McDonnell DP, Shahbaz MM, Vegeto E, Goldman ME. The human progesterone receptor A-form functions as a transcriptional modulator of mineral corticoid receptor transcriptional activity. J Steroid Biochem Mol Biol. 1994;48(5-6):425–432. Matsui N, Kawano Y, Nakamura S, Miyakawa I. Changes in vascular endothelial growth factor production associated with decidualization by human endometrial stromal cells in vitro. Acta Obstet Gynecol Scand. 2004;83(2):138–143. Schatz F, Aigner S, Papp C, Toth-Pal E, Hausknecht V, Lockwood CJ. Plasminogen activator activity during decidualization of human endometrial stromal cells is regulated by plasminogen activator inhibitor 1. J Clin Endocrinol Metab. 1995;80(8):2504–2510. Lockwood CJ, Nemerson Y, Guller S, et al. Progestational regulation of human endometrial stromal cell tissue factor expression during decidualization. J Clin Endocrinol Metab. 1993;76(1):231–236. Osteen KG, Rodgers WH, Gaire M, Hargrove JT, Gorstein F, Matrisian LM. Stromal-epithelial interaction mediates steroidal regulation of metalloproteinase expression in human endometrium. Proc Natl Acad Sci U S A. 1994;91(21):10129–10133. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297. Abe W, Nasu K, Nakada C, Kawano Y, Moriyama M, Narahara H. miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod. 2013;28(3):750–761. Pillai RS. MicroRNA function: multiple mechanisms for a tiny RNA? RNA. 2005;11(12):1753–1761. Engels BM, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene. 2006;25(46):6163–6169. Qian K, Hu L, Chen H, et al. Hsa-miR-222 is involved in differentiation of endometrial stromal cells in vitro. Endocrinology. 2009;150(10):4734–4743. Estella C, Herrer I, Moreno-Moya JM, et al. MiRNA signature and dicer requirement during human endometrial stromal decidualization in vitro. PLoS One. 2012;7(7):e41080. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447):1789–1799. Burney RO, Hamilton AE, Aghajanova L, et al. MicroRNA expression profiling of eutopic secretory endometrium in women with versus without endometriosis. Mol Hum Reprod. 2009;15(10):625–631. Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, et al. MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol. 2009;23(2):265–275. Filigheddu N, Gregnanin I, Porporato PE, et al. Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J Biomed Biotech. 2010;2010:369-549. Kuokkanen S, Chen B, Ojalvo L, Benard L, Santoro N, Pollard JW. Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium. Biol Reprod. 2010;82(4):791–801. Ohlsson Teague EMC, Print CG, Hull ML. The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update. 2010;16(2):142–165. Hawkins SM, Creighton CJ, Han DY, et al. Functional microRNA involved in endometriosis. Mol Endocrinol. 2011;25(5):821–832. Braza-Boïls A, Marí-Alexandre J, Gilabert J, et al. MicroRNA expression profile in endometriosis: its relation to angiogenesis and fibrinolytic factors. Hum Reprod. 2014;29(5):978–988. Nishida M, Nasu K, Fukuda J, Kawano Y, Narahara H, Miyakawa I. Down-regulation of interleukin-1 receptor type 1 expression causes the dysregulated expression of CXC chemokines in endometriotic stromal cells: a possible mechanism for the altered immunological functions in endometriosis. J Clin Endocrinol Metab. 2004;89(10):5094–5100. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis - a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91(3):675–681. Okamoto M, Nasu K, Abe W, et al. Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3. Hum Reprod. 2015;30(3):632–641. Zhang Q, Zhang H, Jiang Y, et al. MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Krüppel-like factor 12. Reprod Biol Endocrinol. 2015;13:23. Jiang Q, Lagos-Quintana M, Liu D, et al. miR-30a regulates endothelial tip cell formation and arteriolar branching. Hypertension. 2013;62(3):592–598. Liu M, Huang F, Zhang D, et al. Heterochromatin protein HP1γ promotes colorectal cancer progression and is regulated by miR-30a. Cancer Res. 2015;75(21):4593–4604. Wang Z, Dai X, Chen Y, et al. miR-30a-5p is induced by Wnt/β-catenin pathway and promotes glioma cell invasion by repressing NCAM. Biochem Biophys Res Commun. 2015;465(3):374–380. Zheng B, Zhu H, Gu D, et al. MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib. Biochem Biophys Res Commun. 2015;459(2):234–239. Zhou Q, Yang M, Lan H, Yu X. miR-30a negatively regulates TGF-β1-induced epithelial-mesenchymal transition and peritoneal fibrosis by targeting Snai1. Am J Pathol. 2013;183(3):808–819. Pabona JM, Zeng Z, Simmen FA, Simmen RC. Functional differentiation of uterine stromal cells involves cross-regulation between bone morphogenetic protein 2 and Kruppel-like factor (KLF) family members KLF9 and KLF13. Endocrinology. 2010;151(7):3396–3406. Quentien MH, Manfroid I, Moncet D, et al. Pitx factors are involved in basal and hormone-regulated activity of the human prolactin promoter. J Biol Chem. 2002;277(46):44408–44416. Ge G, Fernández CA, Moses MA, Greenspan DS. Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor. Proc Natl Acad Sci U S A. 2007;104(24):10010–10015. Crosby ME, Kulshreshtha R, Ivan M, Glazer PM. MicroRNA regulation of DNA repair gene expression in hypoxic stress. Cancer Res. 2009;69(3):1221–1229. Giannakakis A, Sandaltzopoulos R, Greshock J, et al. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther. 2008;7(2):255–264. Noman MZ, Buart S, Romero P, et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res. 2012;72(18):4629–4641. Maruyama T, Yoshimura Y. Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium. Endocr J. 2008;55(5):795–810. Tang B, Guller S, Gurpide E. Cyclic adenosine 3′,5′-monophosphate induces prolactin expression in stromal cells isolated from human proliferative endometrium. Endocrinology. 1993;133(5):2197–2203. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Aoyagi, Y., Nasu, K., Kai, K. et al. Decidualization Differentially Regulates microRNA Expression in Eutopic and Ectopic Endometrial Stromal Cells. Reprod. Sci. 24, 445–455 (2017). https://doi.org/10.1177/1933719116657894 Published: Issue date: DOI: https://doi.org/10.1177/1933719116657894