{"paper_id":"ad97899c-9358-4118-9d16-0b3592ff0e1d","body_text":"Abstract\nEndometriosis, as a prevalent gynecological disease, is characterized by the presence of endometrial-like tissue outside the uterus, causing infertility and considerable pain and affecting the quality of life of women. The pathogenic mechanism has not been fully elucidated, and there are no effective biomarkers for endometriosis. In our study, microRNA (miRNA) expression profiling of 10 ectopic endometrial plasma from patients with ovarian endometriosis and 10 normal plasma from healthy controls was analyzed using a microarray. As a result, 114 differentially expressed miRNAs were identified. Among them, 14 miRNAs were significantly downregulated in patients with ovarian endometriosis, which matched the microarray results. The diagnostic value of the 14 downregulated miRNAs in ovarian endometriosis was evaluated by receiver operating characteristic (ROC) curve analysis, and hsa-let-7i-5p showed the highest area under the ROC curve (AUC) with a value of 0.900. The target genes of the 14 miRNAs were predicted by miRWalk2.0, and the genes that were targeted by at least 2 of the 14 miRNAs were analyzed by function enrichment. The target genes were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, such as microRNAs in cancer, bladder cancer, and endocrine resistance pathways, and the Gene Ontology (GO) terms such as nucleobase-containing compound metabolic process, cellular nitrogen compound biosynthetic process, and heterocycle metabolic process. The identified 14 differentially expressed miRNAs could be potential biomarkers and therapeutic targets for the diagnosis and treatment of endometriosis.\nSimilar content being viewed by others\nReferences\nLeyland N, Casper R, Laberge P, Singh SS, SOGC. Endometriosis: diagnosis and management. J Obstet Gynaecol Can. 2010;32:S1–32.\nMcLeod BS, Retzloff MG. Epidemiology of endometriosis: an assessment of risk factors. Clin Obstet Gynecol. 2010;53:389–96.\nBasta A, Brucka A, Górski J, et al. The statement of Polish Society’s Experts Group concerning diagnostics and methods of endometriosis treatment. Ginekol Pol. 2012;83:871–6.\nGiudice LC. Endometriosis. N Engl J Med. 2010;362:2389–98.\nCarvalho LF, Rossener R, Azeem A, Malvezzi H, Simões Abrão M, Agarwal A. From conception to birth - how endometriosis affects the development of each stage of reproductive life. Minerva Ginecol. 2013;65:181–98.\nKennedy S, Bergqvist A, Chapron C, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698–704.\nDe Graaff AA, D'Hooghe TM, Dunselman GA, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28:2677–85.\nHsu AL, Khachikyan I, Stratton P. Invasive and noninvasive methods for the diagnosis of endometriosis. Clin Obstet Gynecol. 2010;53:413–9.\nValle RF, Sciarra JJ. Endometriosis: treatment strategies. Ann N Y Acad Sci. 2003;997:229–39.\nKennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698–704.\nVercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75.\nDu T, Zamore PD. Micro Primer: the biogenesis and function of microRNA. Development. 2005;132:4645–52.\nHawkins SM, Creighton CJ, Han DY, Zariff A, Anderson ML, Gunaratne PH, et al. Functional microRNA involved in endometriosis. Mol Endocrinol. 2011;25:821–32.\nBraicu OL, Budisan L, Buiga R, et al. miRNA expression profiling in formalin-fixed paraffin-embedded endometriosis and ovarian cancer samples. Onco Targets Ther. 2017;10:4225–38.\nPetracco R, Grechukhina O, Popkhadze S, Massasa E, Zhou Y, Taylor HS. MicroRNA 135 regulates HOXA10 expression in endometriosis. J Clin Endocrinol Metab. 2011;96:E1925–33.\nOkamoto M, Nasu K, Abe W, Aoyagi Y, Kawano Y, Kai K, et al. Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3. Hum Reprod. 2015;30:632–41.\nLiu S, Gao S, Wang XY, Wang DB. Expression of miR-126 and Crk in endometriosis: miR-126 may affect the progression of endometriosis by regulating Crk expression. Arch Gynecol Obstet. 2012;285(4):1065–72.\nTian X, Xu L, Wang P. MiR-191 inhibits TNF-α induced apoptosis of ovarian endometriosis and endometrioid carcinoma cells by targeting DAPK1. Int J Clin Exp Pathol. 2015;8(5):4933–42.\nBulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.\nSeifer BJ, Su D, Taylor HS. Circulating miRNAs in murine experimental endometriosis. Reprod Sci. 2017;24(3):376–81.\nCho S, Mutlu L, Grechukhina O, Taylor HS. Circulating microRNAs as potential biomarkers for endometriosis. Fertil Steril. 2015;103(5):1252–60.\nRoush S, Slack FJ. The let-7 family of microRNAs. Trends Cell Biol. 2008;18(10):505–16.\nGrechukhina O, Petracco R, Popkhadze S, Massasa E, Paranjape T, Chan E, et al. A polymorphism in a let-7 microRNA binding site of KRAS in women with endometriosis. EMBO Mol Med. 2012;4(3):206–17.\nLv Y, Gao S, Zhang Y, Wang L, Chen X, Wang Y. miRNA and target gene expression in menstrual endometria and early pregnancy decidua. Eur J Obstet Gynecol Reprod Biol. 2016;197:27–30.\nGiroud M, Karbiener M, Pisani DF, et al. Let-7i-5p represses brite adipocyte function in mice and humans. Sci Rep. 2016;6:28613.\nChhabra R. let-7i-5p, miR-181a-2-3p and EGF/PI3K/SOX2 axis coordinate to maintain cancer stem cell population in cervical cancer. Sci Rep. 2018;8(1):7840.\nSong J, Wang L, Ma Q, Yang Y, Yang Z, Wang B, et al. Let-7i-5p inhibits the proliferation and metastasis of colon cancer cells by targeting kallikrein-related peptidase 6. Oncol Rep. 2018;40(3):1459–66.\nMorotti M, Vincent K, Becker CM. Mechanisms of pain in endometriosis. Eur J Obstet Gynecol Reprod Biol. 2017;209:8–13.\nNematian SE, Mamillapalli R, Kadakia TS, Majidi Zolbin M, Moustafa S, Taylor HS. Systemic inflammation induced by microRNAs: endometriosis-derived alterations in circulating microRNA 125b-5p and Let-7b-5p regulate macrophage cytokine production. J Clin Endocrinol Metab. 2018;103(1):64–74.\nCho S, Mutlu L, Zhou Y, Taylor HS. Aromatase inhibitor regulates let-7 expression and let-7f-induced cell migration in endometrial cells from women with endometriosis. Fertil Steril. 2016;106(3):673–80.\nCheng Z, Qiu S, Jiang L, Zhang A, Bao W, Liu P, et al. MiR-320a is downregulated in patients with myasthenia gravis and modulates inflammatory cytokines production by targeting mitogen-activated protein kinase 1. J Clin Immunol. 2013;33(3):567–76.\nStronati L, Pierdomenico M, Cesi V, et al. MIR320 family regulates NOD2/CARD15: a new mechanism for controlling inflammation? Dig Liver Dis. 2014;46:e82.\nKanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.\nShi S, Hu X, Xu J, et al. MiR-320d suppresses the progression of breast cancer via LncRNA HNF1A-AS1 regulation and SOX4 inhibition. RSC Adv. 2018;8(34):19196–207.\nGokul S, Sivachitra M, Vijayachitra S. Parkinson’s disease prediction using machine learning approaches. Fifth International Conference on Advanced Computing (ICoAC). IEEE. 2013; 246–252.\nShen H, Lu S, Dong L, Xue Y, Yao C, Tong C, et al. hsa-miR-320d and hsa-miR-582, miRNA biomarkers of aortic dissection, regulate apoptosis of vascular smooth muscle cells. J Cardiovasc Pharmacol. 2018;71(5):275–82.\nFunding\nGrants from National Natural Science Foundation of China: High-throughput sequencing identifying pathogenic genes of endometriosis (Grant No. 81571411).\nAuthor information\nAuthors and Affiliations\nContributions\nChenglei Gu and Zhe Zhang contributed to the conception of the study; Wensheng Fan and Li Lian performed the experiments; Mingxia Ye, Qian Zhang, and Nina Zhang helped for acquisition of data and analysis and interpretation of data; Yuanguang Meng has been involved in drafting the manuscript or revising it critically for important intellectual content; Zhen Li provided valuable instructions and suggestions for this paper and helped for revising the manuscript; all authors have read and approved the final version of the manuscript for publication.\nCorresponding author\nEthics declarations\nWritten informed consent forms were obtained from all participants prior to surgery, and our study was approved by the Ethics Committee of the Chinese PLA General Hospital.\nConflict of Interest\nThe authors declare that they have no competing interests.\nAdditional information\nHighlights\n•Microarray analysis identified 114 DEmiRNAs in endometriosis patients.\n•Fourteen miRNAs were validated to be downregulated by RT-qPCR.\n•The 14 DEmiRNAs may be potential biomarkers for endometriosis.\nRights and permissions\nAbout this article\nCite this article\nGu, Cl., Zhang, Z., Fan, Ws. et al. Identification of MicroRNAs as Potential Biomarkers in Ovarian Endometriosis. Reprod. Sci. 27, 1715–1723 (2020). https://doi.org/10.1007/s43032-020-00148-z\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-020-00148-z","source_license":"CC0","license_restricted":false}