Endometrial Expression of Homeobox Genes and Cell Adhesion Molecules in Infertile Women With Intramural Fibroids During Window of Implantation

This study was designed to examine the expression and cellular distribution of homeobox (HOX) genes (HOXA10 and HOXA11) and cell adhesion molecules (E-cadherin, N-cadherin, and β-catenin) during the window of implantation in infertile women with noncavity-distorting intramural (IM) fibroids (n = 18) and in fertile controls (n = 12). Quantitative real-time polymerase chain reaction and immunohistochemistry were used to evaluate the messenger RNA (mRNA) levels and protein expression, respectively. When compared to fertile controls, reduced HOXA10 and HOXA11 transcript and protein levels were observed in infertile women. However, changes only in the expression of HOXA10 mRNA (-1.72-fold; P =.03) and stromal protein (P =.001) were statistically significant. Significantly lower E-cadherin mRNA (-10.97-fold; P =.02) and protein levels were seen in infertile patients. E-cadherin immunostaining was significantly reduced both in the luminal (P =.048) and in the glandular (P =.014) epithelium of endometrium from infertile patients when compared to controls. No significant change was observed either in the mRNA levels or in the immunoexpression of N-cadherin and β-catenin. However, a trend toward lower N-cadherin expression in the luminal epithelium (P =.054) and decreased β-catenin expression in the glandular epithelium (P =.070) was observed in infertile patients. The present findings suggest that altered endometrial HOXA10 and E-cadherin mRNA and protein expression observed in infertile women with IM fibroids during the mid-secretory phase might impair endometrial receptivity leading to infertility in these patients. Similar content being viewed by others

Eldar-Geva T, Meagher S, Healy DL, McLachlan V, Breheny S, Wood C. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil Steril. 1998;70(4):687–691. Surrey ES, Lietz AK, Schoolcraft WB. Impact of intramural leiomyomata in patients with a normal endometrial cavity on in vitro fertilization-embryo transfer cycle outcome. Fertil Steril. 2001;75(2):405–410. Hart R, Khalaf Y, Yeong CT, Seed P, Taylor A, Braude P. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Hum Reprod. 2001;16(11):2411–2417. Surrey ES, Minjarez D, Stevens J, Schoolcraft WB. Effects of myomectomy on the outcome of assisted reproductive technologies. Fertil Steril. 2005;83(5):1473–1479. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum Reprod. 2010;25(2):418–429. Guven S, Kart C, Unsal MA, Odaci E. Intramural leiomyoma without endometrial cavity distortion may negatively affect the ICSI-ET outcome. Reprod Biol Endocrinol. 2013;11:102. Pier BD, Bates GW. Potential causes of subfertility in patients with intramural fibroids. Fertil Res Pract. 2015;1:12–19. Yan L, Ding L, Li C, Wang Y, Tang R, Chen ZJ. Effect of fibroids not distorting the endometrial cavity on the outcome of in vitro fertilization treatment: a retrospective cohort study. Fertil Steril. 2014;101(3):716–721. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–2034. Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: Clinical manifestations and contemporary management. Reprod Sci. 2014;21(9):1067–1092. Makker A, Goel MM. Uterine leiomyomas: Effects on architectural, cellular, and molecular determinants of endometrial receptivity. Reprod Sci. 2013;20(6):631–638. Szczepanska M, Wirstlein P, Luczak M, Jagodzinski PP, Skrzypczak J. Expression of HOXA-10 and HOXA-11 in the endometria of women with idiopathic infertility. Folia Histochem Cytobiol. 2011;49(1):111–118. Du H, Taylor HS. The role of Hox genes in female reproductive tract development, adult function, and fertility. Cold Spring Harb Perspect Med. 2015;6(1):a023002. Benson GV, Lim H, Paria BC. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeostasis and loss of maternal Hoxa-10 expression. Development. 1996;122(9):2687–2696. Bagot CN, Troy HS, Taylor HS. Alteration of maternal HOXA10 mRNA expression by in vivo gene transfection affects implantation. Gene Ther. 2000;7(16):1378–1384. Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo EW. Aberrant metylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometrioisis. Am J Obstet Gynecol. 2005;193(2):371–380. Matsuzaki S, Canis M, Darcha C, Pouly JL, Mage G. HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility. Hum Reprod. 2009;24(12):3180–3187. SoaresLopes IMR, Baracat MCP, JesusSimoes M, SantosSimoes R, Baracat EC, Soares JM, Jr. Endometrium in women with polycystic ovary syndrome during the window of implantation. Rev Assoc Med Bras. 2011;57(6):688–695. Daftary GS, Kayisli U, Seli E, Bukulmez O, Arici A, Taylor HS. Salpingectomy increases peri-implantation endometrial HOXA10 expression in women with hydrosalpinx. Fertil Steril. 2007;87(2):367–372. Szczepanska M, Wirstlein P, Skrzypczak J, Jagodzinski PP. Expression of HOXA11 in the midluteal endometrium from women with endometriosis associated infertility. Reprod Biol Endocrinol. 2012;10:1–8. Rosales C, O’Brien V, Kornberg L, Juliano R. Signal transduction by cell adhesion receptors. Biochim Biophys Acta. 1995;1242(1):77–98. Riethmacher D, Brinkmann V, Birchmeier C. A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci U S A. 1995;92(3):855–859. Rahnama F, Thompson B, Steiner M, Shafiei F, Lobie PE, Mitchell MD. Epigenetic regulation of E-cadherin controls endometrial receptivity. Endocrinology. 2009;150(3):1466–1472. Uchida H, Maruyama T, Uchida SN, et al. Studies using an in vitro model show evidence of involvement of epithelial-mesenchymal transition of human endometrial epithelial cells in human embryo implantation. J Biol Chem. 2012;287(7):4441–4450. Tulac S, Nayak NR, Kao LC, et al. Identification, characterization and regulation of the canonical Wnt signaling pathway in human endometrium. J Clin Endocrinol Metab. 2003;88(8):3860–3866. Matsuzaki S, Darcha C, Maleysson E, Canis M, Mage G. Impaired down-regulation of E-cadherin and beta-catenin protein expression in endometrial epithelial cells in the midsecretory endometrium of infertile patients with endometriosis. J Clin Endocrinol Metab. 2010;95(7):3437–3445. Tsuchiya B, Sato Y, Kameya T, Okayasu I, Mukai K. Differential expression of N-cadherin and E-cadherin in normal human tissues. Arch Histol Cytol. 2006;69(2):135–145. Poncelet C, Cornelis F, Tepper M, et al. Expression of E- and N-cadherin and CD44 in endometrium and hydrosalpinges from infertile women. Fertil Steril. 2010;94(7):2909–2912. Makker A, Tandon I, Goel MM, Singh M, Singh MM. Effect of ormeloxifene, a selective estrogen receptor modulator, on biomarkers of endometrial receptivity and pinopode development and its relation to fertility and infertility in Indian subjects. Fertil Steril. 2009;91(6):2298–2307. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263. Somigliana E, Vercellini P, Daguati R, Pasin R, De Giorgi O, Crosigniani PG. Fibroids and female reproduction: a critical analysis of the evidence. Hum Reprod Update. 2007;13(5):465–476. Taylor HS, Bagot C, Olive D, Arici A. HOX gene expression is altered in endometrium of women with endometriosis. Hum Reprod. 1999;14(5):1328–1331. Shokrzadeh N, Alizadeh Z. Semi-quantitative analysis of endometrial receptivity marker mRNA expression in the mid-secretory endometrium of patients with uterine fibromas. Afr J Biotech. 2012;11(23):6220–6225. Unlu C, Celik O, Celik N, Otlu B. Expression of endometrial receptivity genes increase after myomectomy of intramural leiomyomas not distorting the endometrial cavity. Reprod Sci. 2016;23(1):31–41. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2 mediated decidualization and anticoagulant expression through secretion of TGF-β3. J Clin Endocrinol Metab. 2011;96(2):412–421. Doherty LF, Taylor HS. Leiomyoma-derived TGF-β impairs BMP-2 mediated endometrial receptivity. Fertil Steril. 2015;103(3):845–852. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–746. Fujimoto J, Ichigo S, Hori M, Tamaya T. Alteration of E-cadherin, alpha- and beta-catenin mRNA expression in human uterine endometrium during the menstrual cycle. Gynecol Endocrinol. 1996;1010(3):187–91. Li Y, Ran R, Guan Y, Zhu X, Kang S. Aberrant methylation of the E-cadherin gene promoter region in the endometrium of women with uterine fibroids. Reprod Sci. 2016;23(8):1096–102. Marinakis G, Nikolaou D. What is role of assisted reproduction technology in the management of age-related infertility? Hum Fertil. 2011;14(1):8–15. Singh H, Aplin JD. Adhesion molecules in endometrial epithelium: tissue integrity and embryo implantation. J Anat. 2009;215(1):3–13. Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002;2(6):442–454. Li Z, Gou J, Jia J, Zhao X. MicroRNA-429 functions as a regulator of epithelial-mesenchymal transition by targeting Pcdh8 during murine embryo implantation. Hum Reprod. 2015;30(3):507–518. doi:10.1093/humrep/dev001. Chen Q, Zhang Y, Lu JE. Embryo-uterine cross-talk during implantation: the role of Wnt signaling. Mol Hum Reprod. 2009;15(4):215–221. Herington JL, Bi J, Martin JD, Bany BM. B-catenin (CTNNB1) in the mouse uterus during decidualization and the potential role of two pathways in regulating its degradation. J Histochem Cytochem. 2007;55(9):963–974. Taniguchi Y., Hox transcription factors: Modulators of cell-cell and cell-extracellular matrix adhesion. BioMed Res Int. 2014;2014:591374. doi:10.1155/2014/591374. Yoshida H, Broaddus R, Cheng W, Xie S, Naora H. Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: Role in epithelial-mesenchymal transition. Cancer Res. 2006;66(2):889–897. Khalaf Y, Ross C, EI-Toukhy T, Hart R, Seed P, Braude P. The effect of small intramural uterine fibroids on the cumulative outcome of assisted conception. Hum Reprod. 2006;21(10):2640–2644. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Makker, A., Goel, M.M., Nigam, D. et al. Endometrial Expression of Homeobox Genes and Cell Adhesion Molecules in Infertile Women With Intramural Fibroids During Window of Implantation. Reprod. Sci. 24, 435–444 (2017). https://doi.org/10.1177/1933719116657196 Published: Issue date: DOI: https://doi.org/10.1177/1933719116657196