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HOXB4 Immunoreactivity in Endometrial Tissues From Women With or Without Endometriosis

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Abstract

Endometriosis is a common disease characterized by the presence of ectopic endometrial tissue. Although the pathogenesis of endometriosis remains unclear, several factors have been implicated, including the dysregulation of homeobox (HOX) genes. Our objective was to investigate the localization and immunoreactivity of HOXB4 in endometrial tissues from women with or without endometriosis. We studied samples of eutopic endometrium (EE), endometriomas (Eoma), superficial endometriosis (SE), and deep infiltrating endometriosis (DIE) from 34 women with endometriosis, as well as eutopic endometrium from 38 women without endometriosis (EC). HOXB4 localization and immunoreactivity was assessed using immunohistochemistry and histoscore analysis. Data were analyzed with and without stratification by menstrual cycle phase. HOXB4 protein was present in the nuclei of endometrial glandular epithelial cells but not in stromal cells. HOXB4 immunoreactivity was reduced in DIE samples compared to all other groups. A smaller reduction in HOXB4 immunoreactivity was observed in SE samples compared to EC samples. HOXB4 immunoreactivity was significantly greater in proliferative compared to secretory phase samples in the EC group but not in EE, Eoma, or DIE groups. Among only proliferative phase samples, HOXB4 immunoreactivity was reduced in EE, Eoma, and DIE groups compared to EC. Based on these data, we suggest that an impaired capacity of eutopic and ectopic endometrial tissue to upregulate levels of HOXB4 during the proliferative phase may play a role in the pathogenesis of endometriosis and that further downregulation of HOXB4 may enhance ectopic implant invasiveness.

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References

  1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):235–258.

    Article  CAS  PubMed  Google Scholar 

  2. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. doi:10.1056/NEJMra0804690.

    Article  CAS  PubMed  Google Scholar 

  3. Sinaii N, Plumb K, Cotton L, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril. 2008;89(3):538–545. doi:10.1016/j.fertnstert. 2007.03.069.

    Article  PubMed  Google Scholar 

  4. Sampson J. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–469.

    Article  Google Scholar 

  5. Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and immune dysfunction in endometriosis. BioMed Res Int. 2015;2015:795976. doi:10.1155/2015/795976.

  6. Hornung D, Ryan IP, ChaoVA, Vigne JL, Schriock ED, Taylor RN. Immunolocalization and regulation of the chemokine RANTES in human endometrial and endometriosis tissues and cells. J Clin Endocrinol Metab. 1997;82(5):1621–1628. doi:10.1210/jcem.82.5.3919.

    CAS  PubMed  Google Scholar 

  7. Tseng JF, Ryan IP, Milam TD, et al. Interleukin-6 secretion in vitro is up-regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab. 1996;81(3):1118–1122. doi:10.1210/jcem.81.3.8772585.

    CAS  PubMed  Google Scholar 

  8. Osteen KG, Bruner KL, Sharpe-Timms KL. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol. 1996;14(3):247–255. doi:10.1055/s-2007-1016334.

    Article  CAS  PubMed  Google Scholar 

  9. Kao LC, Germeyer A, Tulac S, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144(7):2870–2881. doi:10.1210/en.2003-0043.

    Article  CAS  PubMed  Google Scholar 

  10. Wu Y, Kajdacsy-Balla A, Strawn E, et al. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology. 2006;147(1):232–246. doi:10.1210/en.2005-0426.

    Article  CAS  PubMed  Google Scholar 

  11. Machado DE, Abrao MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril. 2008;90(1):148–155. doi:10.1016/j.fertnstert. 2007.05.076.

    Article  CAS  PubMed  Google Scholar 

  12. Abrao MS, Podgaec S, Dias JA Jr, et al. Deeply infiltrating endometriosis affecting the rectum and lymph nodes. Fertil Steril. 2006;86(3):543–547. doi:10.1016/j.fertnstert.2006.02.102.

    Article  PubMed  Google Scholar 

  13. Hufnagel D, Li F, Cosar E, Krikun G, Taylor HS. The role of stem cells in the etiology and pathophysiology of endometriosis. Semin Reprod Med. 2015;33(5):333–340. doi:10.1055/s-0035-1564609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ferguson BR, Bennington JL, Haber SL. Histochemistry of mucosubstances and histology of mixed mu¨llerian pelvic lymph node glandular inclusions. Evidence for histogenesis by mu¨llerian metaplasia of coelomic epithelium.ObstetGynecol. 1969;33(5):617–625.

    CAS  Google Scholar 

  15. Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22(9):1053–1059. doi:10.1177/1933719115592713.

    Article  CAS  PubMed  Google Scholar 

  16. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55(4):759–765.

    Article  CAS  PubMed  Google Scholar 

  17. Van Langendonckt A, Luyckx M, Gonzalez MD, Defrère S, Donnez J, Squifflet J. Differential expression of genes from the homeoboxA cluster in deep endometriotic nodules and peritoneal lesions. Fertil Steril. 2010;94(6):1995–2000. doi:10.1016/j.fertnstert.2010.01.003.

    Article  PubMed  CAS  Google Scholar 

  18. Samartzis N, Samartzis EP, Noske A, et al. Expression of the G protein-coupled estrogen receptor (GPER) in endometriosis: a tissue microarray study. Reprod Biol Endocrinol RBE. 2012;10:30. doi:10.1186/1477-7827.10-30.

    Article  CAS  Google Scholar 

  19. Santulli P, Chouzenoux S, Fiorese M, et al. Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Hum Reprod Oxf Engl. 2015;30(1): 49–60. doi:10.1093/humrep/deu290.

    Article  CAS  Google Scholar 

  20. Sanchez AM, Vigano` P, Somigliana E, Panina-Bordignon P, Vercellini P, Candiani M. The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary. Hum Reprod Update. 2014;20(2):217–230. doi:10.1093/ humupd/dmt053.

    Article  CAS  PubMed  Google Scholar 

  21. McGinnis W, Krumlauf R. Homeobox genes and axial patterning. Cell. 1992;68(2):283–302.

    Article  CAS  PubMed  Google Scholar 

  22. 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. doi:10.1101/cshperspect.a023002.

    Google Scholar 

  23. Akbas GE, Taylor HS. HOX C and HOXD gene expression in human endometrium: lack of redundancy with HOXA paralogs. Biol Reprod. 2004;70(1):39–45. doi:10.1095/biolreprod.102.014969.

    Article  CAS  PubMed  Google Scholar 

  24. Taylor HS, Igarashi P, Olive DL, Arici A. Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium. J Clin Endocrinol Metab. 1999;84(3):1129–1135. doi:10.1210/jcem.84.3.5573.

    CAS  PubMed  Google Scholar 

  25. Taylor HS, Arici A, Olive D, Igarashi P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J Clin Invest. 1998;101(7):1379–1384. doi:10.1172/JCI1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dyson MT, Roqueiro D, Monsivais D, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3): e1004158. doi:10.1371/journal.pgen.1004158.

    Google Scholar 

  27. Szczepańska M, Wirstlein P, Skrzypczak J, Jagodziński PP. Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis-associated infertility. Reprod Biol Endocrinol RBE. 2012;10:1. doi:10.1186/1477-7827.10-1.

    Article  CAS  Google Scholar 

  28. Borghese B, Mondon F, Noe¨l JC, et al. Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential. Mol Endocrinol Baltim Md. 2008;22(11):2557–2562. doi:10.1210/me.2008-0322.

    Article  CAS  Google Scholar 

  29. Gao J, Mazella J, Tseng L. Hox proteins activate the IGFBP-1 promoter and suppress the function of hPR in human endometrial cells. DNA Cell Biol. 2002;21(11):819–825. doi:10.1089/104454902320908469.

    Article  CAS  PubMed  Google Scholar 

  30. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 2013;41(Database issue): D991–D995. doi:10.1093/nar/gks1193.

    CAS  PubMed  Google Scholar 

  31. Hever A, Roth RB, Hevezi P, et al. Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. Proc Natl Acad Sci U S A. 2007;104(30): 12451–12456. doi:10.1073/pnas.0703451104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bedaiwy MA, Pope R, Henry D, et al. Standardization of laparoscopic pelvic examination: a proposal of a novel system. Minim Invasive Surg. 2013;2013:153235. doi:10.1155/2013/153235.

    PubMed  PubMed Central  Google Scholar 

  33. Zhang X. The Expression and Invasion-Suppressive Function of HOXB4 in Epithelial Ovarian Cancer [Dissertation]. Vancouver, British Columbia: University of British Columbia; 2014.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Sharpe-Timms KL, Ricke EA, Piva M, Horowitz GM. Differential expression and localization of de-novo synthesized endometriotic haptoglobin in endometrium and endometriotic lesions. Hum Reprod Oxf Engl. 2000;15(10):2180–2185.

    Article  CAS  Google Scholar 

  36. Browne H, Taylor H. HOXA10 expression in ectopic endometrial tissue. Fertil Steril. 2006;85(5):1386–1390. doi:10.1016/j.fertnstert.2005.10.072.

    Article  CAS  PubMed  Google Scholar 

  37. Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G, Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis. Mol Hum Reprod. 2014;20(7):591–598. doi:10.1093/molehr/gau025.

    Article  CAS  PubMed  Google Scholar 

  38. Struble J, Reid S, Bedaiwy MA. Adenomyosis: a clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23(2):164–185. doi:10.1016/j.jmig.2015.09.018.

    Article  PubMed  Google Scholar 

  39. Benagiano G, Brosens I, Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum Reprod Update. 2014;20(3):386–402. doi:10.1093/ humupd/dmt052.

    Article  CAS  PubMed  Google Scholar 

  40. Scurry J, Whitehead J, Healey M. Classification of ovarian endometriotic cysts. Int J Gynecol Pathol. 2001;20(2):147–154.

    Article  CAS  PubMed  Google Scholar 

  41. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril. 1994;61(6):1034–1038.

    Article  CAS  PubMed  Google Scholar 

  42. 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. doi:10.1158/0008-5472.CAN-05-2828.

    Article  CAS  PubMed  Google Scholar 

  43. Xiong Y, Liu Y, Xiong W, et al. Hypoxia-inducible factor 1ainduced epithelial-mesenchymal transition of endometrial epithelial cells may contribute to the development of endometriosis. Hum Reprod. 2016;31(6):1327–1338. doi:10.1093/humrep/dew081.

    Article  CAS  PubMed  Google Scholar 

  44. Proestling K, Birner P, Gamperl S, et al. Enhanced epithelial to mesenchymal transition (EMT) and upregulated MYC in ectopic lesions contribute independently to endometriosis. Reprod Biol Endocrinol. 2015;13:75. doi:10.1186/s12958- 015–0063.7.

    Google Scholar 

  45. Bartley J, Ju¨licher A, Hotz B, Mechsner S, Hotz H. Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium. Arch Gynecol Obstet. 2014;289(4):871–881. doi:10.1007/s00404-013.3040-4.

    Article  CAS  PubMed  Google Scholar 

  46. Matsuzaki S, Darcha C. Epithelial to mesenchymal transition-like and mesenchymal to epithelial transition-like processes might be involved in the pathogenesis of pelvic endometriosis. Hum Reprod Oxf Engl. 2012;27(3):712–721. doi:10.1093/humrep/der442.

    Article  CAS  Google Scholar 

  47. Zanatta A, Pereira RM, Rocha AM, et al. The relationship among HOXA10, estrogen receptor a, progesterone receptor, and progesterone receptor B proteins in rectosigmoid endometriosis: a tissue microarray study. Reprod Sci Thousand Oaks Calif. 2015;22(1): 31–37. doi:10.1177/1933719114549846.

    Article  CAS  Google Scholar 

  48. Block K, Kardana A, Igarashi P, Taylor HS. In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mu¨llerian system. FASEB J Off Publ Fed Am Soc Exp Biol. 2000;14(9):1101–1108.

    CAS  Google Scholar 

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Correspondence to Mohamed A. Bedaiwy MD, PhD.

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AlKusayer, G.M., Pon, J.R., Peng, B. et al. HOXB4 Immunoreactivity in Endometrial Tissues From Women With or Without Endometriosis. Reprod. Sci. 25, 950–957 (2018). https://doi.org/10.1177/1933719117732164

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