Investigating the expressions of miRNA-125b and TP53 in endometriosis. Does it underlie cancer-like features of endometriosis? A case-control study
Background: Endometriosis is generally considered as a benign condition; however, there is a possibility for it to become cancerous. miR-125b is upregulated in both endometriotic tissues and serum samples of women with endometriosis but its potential targets in endometriosis are still not fully understood.
Objective: The role of miR-125b in the regulation of TP53 expression in endometriosis was tested with a bioinformatics approach. In addition, the expression of miR-125b and TP53 in both eutopic (Eu-p) and ectopic endometrium (Ec-p) in the endometrium tissues of women with endometriosis was compared to those in the normal endometrium tissues of controls (Normal).
Materials and Methods: In this case-control study, the Eu-p and Ec-p samples were collected from 20 women who underwent laparoscopic surgery, and the normal endometrium tissues were collected from 20 controls with no evidence of endometriosis. For bioinformatics approach, a protein-protein interaction network was constructed based on co-expressed potential targets of miR-125b. Quantitative polymerase chain reaction technique was used for the measurement of miR125b and TP53 expression.
Results: Our results showed that miR-125b was significantly overexpressed in Ec-p (p-value: 0.021). In addition, there was a significant TP53 under expression in both the Ec-p and Eu-p samples compared with the Normal tissues (p-value: 0.003).
Conclusion: The negative correlation between miR-125b and TP53 as well as a noticeable decreased expression of TP53 in both Ec-p and Eu-p samples may be interpreted as the roles of miR-125b/TP53 axis in the pathogenesis of endometriosis. In addition, these findings and bioinformatic analyses imply a possible role of miR-125b in cancer-like features of endometriosis.
Key words: Endometriosis, TP53, miR-125b, Ectopic endometrium, Eutopic endometrium.
 Halis G, Arici A. Endometriosis and inflammation in infertility. Ann N Y Acad Sci 2004; 1034: 300–315.
 Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422–469.
 Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. Gynecol Oncol 2012; 124: 164–169.
 Mogensen JB, Kjær SK, Mellemkjær L, Jensen A. Endometriosis and risks for ovarian, endometrial and breast cancers: a nationwide cohort study. Gynecol Oncol 2016; 143: 87–92.
 Yang HP, Meeker A, Guido R, Gunter MJ, Huang GS, Luhn P, et al. PTEN expression in benign human endometrial tissue and cancer in relation to endometrial cancer risk factors. Cancer Causes Control 2015; 26: 1729–1736.
 Ishii M, Yamamoto M, Tanaka K, Asakuma M, Masubuchi S, Hamamoto H, et al. Intestinal endometriosis combined with colorectal cancer: a case series. J Med Case Rep 2018; 12: 21–24.
 Mann S, Patel P, Matthews CM, Pinto K, O’Connor J. Malignant transformation of endometriosis within the urinary bladder. Proc Bayl Univ Med Cent 2012; 25: 293–295.
 Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003; 144: 2870–2881.
 Wu Y, Kajdacsy-Balla A, Strawn E, Basir Z, Halverson G, Jailwala P, et al. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology 2006; 147: 232–246.
 Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, et al. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Nati Acad Sci U S A 2007; 104: 12451–12456.
 Arimoto T, Katagiri T, Oda K, Tsunoda T, Yasugi T, Osuga Y, et al. Genome-wide cDNA microarray analysis of gene-expression profiles involved in ovarian endometriosis. Int J Oncol 2003; 22: 551– 560.
 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.
 Tang W, Jiang Y, Mu X, Xu L, Cheng W, Wang X. MiR- 135a functions as a tumor suppressor in epithelial ovarian cancer and regulates HOXA10 expression. Cell Signal 2014; 26: 1420–1426.
 Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet 2004; 20: 617–624.
 Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res 2005; 33: 1290–1297.
 Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: A new source of biomarkers. Mutat Res 2011; 717: 85–90.
 Ghasemi N, Karimi-Zarchi M, Mortazavi-Zadeh MR, Atash-Afza A. Evaluation of the frequency of TP53 gene codon 72 polymorphisms in Iranian patients with endometrial cancer. Cancer Genet Cytogenet 2010; 196: 167–170.
 Sun YM, Lin KY, Chen YQ. Diverse functions of miR- 125 family in different cell contexts. J Hematol Oncol 2013; 6: 6–13.
 Ohlsson Teague EMC, 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.
 Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B, Taylor HS. Serum microRNAs as diagnostic markers of endometriosis: A comprehensive array-based analysis. Fertil Steril 2016; 106: 402–409.
 Chang CYY, Chen Y, Lai MT, Chang HW, Cheng J, Chan C, et al. BMPR1B up-regulation via a miRNA binding site variation defines endometriosis susceptibility and CA125 levels. PloS One 2013; 8: e80630–e80639.
 Ohlsson Teague EMC, Print CG, Hull ML. The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update 2009; 16: 142–165.
 Le MTN, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev 2009; 23: 862–876.
 Yang H, Kang K, Cheng C, Mamillapalli R, Taylor HS. Integrative analysis reveals regulatory programs in endometriosis. Reprod Sci 2015; 22: 1060–1072.
 Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F, Maellaro E. Autophagy is upregulated in ovarian endometriosis: a possible interplay with p53 and heme oxygenase-1. Fertil Steril 2015; 103: 1244–1251. e1.
 Gloria-Bottini F, Ammendola M, Saccucci P, Neri A, Magrini A, Bottini E. The effect of ACP 1, ADA 6 and PTPN22 genetic polymorphisms on the association between p53 codon 72 polymorphism and endometriosis. Arch Gynecol Obstet 2016; 293: 399–402.
 Lao X, Chen Z, Qin A. p53 Arg72Pro polymorphism confers the susceptibility to endometriosis among Asian and Caucasian populations. Arch Gynecol Obstet 2016; 293: 1023–1031.
 Mirabutalebi SH, Karami N, Montazeri F, Fesahat F, Sheikhha MH, Hajimaqsoodi E, et al. The relationship between the expression levels of miR- 135a and HOXA10 gene in the eutopic and ectopic endometrium. Int J Reprod Biomed 2018; 16: 501– 506.
 Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: proteinprotein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43: D447–D452.
 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498–2504.
 Morris JH, Apeltsin L, Newman AM, Baumbach J, Wittkop T, Su G, et al. clusterMaker: A multi-algorithm clustering plugin for cytoscape. BMC Bioinformatics 2011; 12: 436–449.
 Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016; 44: W90–W97.
 Vlachos IS, Zagganas K, Paraskevopoulou MD, Georgakilas G, Karagkouni D, Vergoulis T, et al. DIANA-miRPath v3. 0: deciphering microRNA function with experimental support. Nucleic Acids Res 2015; 43: W460–W466.
 Gemmill JAL, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Cancers, infections, and endocrine diseases in women with endometriosis. Fertil Steril 2010; 94: 1627–1631.
 Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.
 Razi MH, Eftekhar M, Ghasemi N, Sheikhha MH, Dehghani Firoozabadi A. Expression levels of circulatory mir-185-5p, vascular endothelial growth factor, and platelet-derived growth factor target genes in endometriosis. Int J Reprod BioMed 2020; 18: 347–358.
 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.
 Zhou M, Liu Z, Zhao Y, Ding Y, Liu H, Xi Y, et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of proapoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J Biol Chem 2010; 285: 21496–21507.
 Bousquet M, Harris MH, Zhou B, Lodish HF. MicroRNA miR-125b causes leukemia. Proc Natl Acad Sci U S A 2010; 107: 21558–21563.
 Xia HF, He TZ, Liu CM, Cui Y, Song PP, Jin XH, et al. MiR-125b expression affects the proliferation and apoptosis of human glioma cells by targeting Bmf. Cell Physiol Biochem 2009; 23: 347–358.
 Bousquet M, Nguyen D, Chen C, Shields L, Lodish HF. MicroRNA-125b transforms myeloid cell lines by repressing multiple mRNA. Haematologica 2012; 97: 1713–1721.
 Nagpal V, Rai R, Place AT, Murphy SB, Verma SK, Ghosh AK, et al. MiR-125b is critical for fibroblastto- myofibroblast transition and cardiac fibrosis. Circulation 2016; 133: 291–301.
 Jiang L, Huang Q, Chang J, Wang E, Qiu X. MicroRNA HSA-miR-125a-5p induces apoptosis by activating p53 in lung cancer cells. Exp Lung Res 2011; 37: 387– 398.
 Wang Y, Zhang Y, Kong C, Zhang Z, Zhu Y. Loss of P53 facilitates invasion and metastasis of prostate cancer cells. Mol Cell Biochem 2013; 384: 121–127.
 Neilsen PM, Noll JE, Mattiske S, Bracken CP, Gregory PA, Schulz RB, et al. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene 2013; 32: 2992–3000.
 Kao AP, Wang KH, Chang CC, Lee JN, Long CY, Chen HS, et al. Comparative study of human eutopic and ectopic endometrial mesenchymal stem cells and the development of an in vivo endometriotic invasion model. Fertil Steril 2011; 95: 1308–1315. E1.