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

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Abstract

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.

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References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pier BD, Bates GW. Potential causes of subfertility in patients with intramural fibroids. Fertil Res Pract. 2015;1:12–19.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–2034.

    Article  CAS  PubMed  Google Scholar 

  10. Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: Clinical manifestations and contemporary management. Reprod Sci. 2014;21(9):1067–1092.

    Article  PubMed  Google Scholar 

  11. Makker A, Goel MM. Uterine leiomyomas: Effects on architectural, cellular, and molecular determinants of endometrial receptivity. Reprod Sci. 2013;20(6):631–638.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosales C, O’Brien V, Kornberg L, Juliano R. Signal transduction by cell adhesion receptors. Biochim Biophys Acta. 1995;1242(1):77–98.

    PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. 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.

    CAS  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

  36. Doherty LF, Taylor HS. Leiomyoma-derived TGF-β impairs BMP-2 mediated endometrial receptivity. Fertil Steril. 2015;103(3):845–852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–746.

    Article  PubMed  Google Scholar 

  38. 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.

    Article  Google Scholar 

  39. 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  Google Scholar 

  41. Singh H, Aplin JD. Adhesion molecules in endometrial epithelium: tissue integrity and embryo implantation. J Anat. 2009;215(1):3–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2002;2(6):442–454.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

  46. 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.

    Google Scholar 

  47. 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.

    Article  CAS  PubMed  Google Scholar 

  48. 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.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Post-Graduate Department of Pathology, King George’s Medical University-UP, Lucknow, 226003, Uttar Pradesh, India

    Annu Makker PhD, Madhu Mati Goel MD, Dipti Nigam MSc & Vikram Bhatia PhD

  2. Department of Biochemistry, King George’s Medical University-UP, Lucknow, Uttar Pradesh, India

    Abbas Ali Mahdi PhD

  3. Department of Obstetrics and Gynecology, King George’s Medical University-UP, Lucknow, Uttar Pradesh, India

    Vinita Das MD & Amita Pandey

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  1. Annu Makker PhD
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  4. Vikram Bhatia PhD
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Correspondence to Annu Makker PhD.

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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

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