Systematic enrichment analysis of microRNA expression profiling studies in endometriosis

Document Type : Review Article


Department of Gynecology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, Province, China


Objective(s): The purpose of this study was to conduct a meta-analysis on human microRNAs (miRNAs) expression data of endometriosis tissue profiles versus those of normal controls and to identify novel putative diagnostic markers.
Materials andMethods: PubMed, Embase, Web of Science, Ovid Medline were used to search for endometriosis miRNA expression profiling studies of endometriosis. The miRNAs expression data were extracted, and study quality of each article was assessed. The frequently reported miRNAs with consistent regulation were screened out by a meta-profiling algorithm. The putative targets of consistently expressed miRNAs were predicted by using four target prediction tools (TargetScan, PicTar, miRanda, miRDB), and gene ontology pathway enrichment analysis (KEGG and Panther pathways) of the miRNA targets were carried out with GeneCodis web tool.
Results: A total of 194 related literatures were retrieved in four databases. One hundred and thirty four differentially expressed miRNAs were found in the 12 microRNA expression profiling studies that compared endometriosis tissues with normal tissues, with 28 miRNAs reported in at least two studies, and 9882 candidate genes retrieved for 13 consistently expressed miRNAs. Kyoto encyclopedia of genes and genomes (KEGG) and Panther pathways enrichment analysis showed that endometriosis related differently expressed miRNA targets were mainly enriched in cancer, endocytosis, Wnt signalling pathway, and angiogenesis. It showed that these differently expressed miRNAs and gene are potential biomarkers of endometriosis.
Conclusion: miRNAs appear to be potent regulators of gene expression in endometriosis and its associated reproductive disorders, raising the prospect of using miRNAs as biomarkers and therapeutic agent in endometriosis.


1.   Majid S, Saini S, Dar AA, Hirata H, Shahryari V, Tanaka Y, et al. MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer. Cancer Res 2011; 71:2611-2621.
2. Pan Q, Luo X, Toloubeydokhti T, Chegini N. The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol Hum Rep 2007; 13:797-806.
3. Jiang QY, Wu RJ. Growth mechanisms of endometriotic cells in implanted places: a review. Gynecol Endocrinol 2012; 28:562-567.
4. Vlahos NF, Economopoulos KP, Fotiou S. Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer. Best Pract Res Clin Obstet Gynaecol 2010; 24:39-50.
5. Suryawanshi S, Vlad AM, Lin HM, Mantia-Smaldone G, Laskey R, Lee M, et al. Plasma microRNAs as novel biomarkers for endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 2013; 19:1213-1224.
6. Verit FF, Cetin O. Biomarkers of endometriosis. Fertil Steril 2013; 100:e19.
7. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005; 435:839-843.
8. Chang SH, Hla T. Gene regulation by RNA binding proteins and microRNAs in angiogenesis. Trends Mol Med 2011; 17: 650-658.
9.   Tabas-Madrid D, Nogales-Cadenas R, Pascual-Montano A. GeneCodis3: a non-redundant and modular enrichment analysis tool for functional genomics. Nucl Acids Res 2012; 40:W478-483.
10. Nogales-Cadenas R, Carmona-Saez P, Vazquez M, Vicente C, Yang X, Tirado F, et al. GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res 2009;37:W317-322.
11. Toloubeydokhti T, Pan Q, Luo X, Bukulmez O, Chegini N. The expression and ovarian steroid regulation of endometrial micro-RNAs. Reprod Sci 2008; 15:993-1001.
12. Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, Perry N, Wagaarachchi P, Robertson SA, et al. MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol 2009; 23:265-275.
13. Ramon LA, Braza-Boils A, Gilabert-Estelles J, Gilabert J, Espana F, Chirivella M, et al. MicroRNAs expression in endometriosis and their relation to angiogenic factors. Hum Reprod 2011; 26:1082-1090.
14. Hawkins SM, Creighton CJ, Han DY, Zariff A, Anderson ML, Gunaratne PH, et al. Functional microRNA involved in endometriosis. Mol Endocrinol 2011; 25:821-832.
15. Petracco R, Grechukhina O, Popkhadze S, Massasa E, Zhou Y, Taylor HS. MicroRNA 135 regulates HOXA10 expression in endometriosis. J Clin Endocrinol Metab 2011; 96:E1925-1933.
16. Dai L, Gu L, Di W. MiR-199a attenuates endometrial stromal cell invasiveness through suppression of the IKKbeta/NF-kappaB pathway and reduced interleukin-8 expression. Mol Hum Reprod 2012; 18:136-145.
17. Liu 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; 285:1065-1072.
18. Lin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab 2012; 97:E1515-1523.
19. Shen L, Yang S, Huang W, Xu W, Wang Q, Song Y, et al. MicroRNA23a and microRNA23b deregulation derepresses SF-1 and upregulates estrogen signaling in ovarian endometriosis. J Clin Endocrinol Metab 2013; 98:1575-1582.
20. Laudanski P, Charkiewicz R, Kuzmicki M, Szamatowicz J, Charkiewicz A, Niklinski J. MicroRNAs expression profiling of eutopic proliferative endometrium in women with ovarian endometriosis. Reprod Biol Endocrinol 2013; 11:78.
21. Vosa U, Vooder T, Kolde R, Vilo J, Metspalu A, Annilo T. Meta-analysis of microRNA expression in lung cancer. Int J Cancer J Int du Cancer 2013; 132:2884-2893.
22. Teague EM, Print CG, Hull ML. The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update 2010; 16:142-165.
23. Jia SZ, Yang Y, Lang J, Sun P, Leng J. Plasma miR-17-5p, miR-20a and miR-22 are down-regulated in women with endometriosis. Hum Reprod 2013; 28:322-330.
24. Pacurari M, Addison JB, Bondalapati N, Wan YW, Luo D, Qian Y, et al. The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol 2013; 43:548-560.
25. Yoshino H, Enokida H, Itesako T, Tatarano S, Kinoshita T, Fuse M, et al. Epithelial-mesenchymal transition-related microRNA-200s regulate molecular targets and pathways in renal cell carcinoma. J Hum Gen 2013; 58:508-516.
26. He M, Liu Y, Deng X, Qi S, Sun X, Liu G, et al. Down-regulation of miR-200b-3p by low p73 contributes to the androgen-independence of prostate cancer cells. Prostate 2013; 73:1048-1056.
27. Castilla MA, Diaz-Martin J, Sarrio D, Romero-Perez L, Lopez-Garcia MA, Vieites B, et al. MicroRNA-200 family modulation in distinct breast cancer phenotypes. PloS One 2012; 7:e47709.
28. Duns G, van den Berg A, van Dijk MC, van Duivenbode I, Giezen C, Kluiver J, et al. The entire miR-200 seed family is strongly deregulated in clear cell renal cell cancer compared to the proximal tubular epithelial cells of the kidney. Genes Chromosomes Cancer 2013; 52:165-173.
29. Perez-Iratxeta C, Bork P, Andrade MA. Association of genes to genetically inherited diseases using data mining. Nat Genet 2002; 31:316-319.
30. Mohammadi A, Saraee MH, Salehi M. Identification of disease-causing genes using microarray data mining and Gene Ontology. BMC Med Genom 2011; 4:12.