Comparative evaluation of NOTCH signaling molecules in the endometrium of women with various gynecological diseases during the window of implantation

Document Type: Original Article

Authors

1 Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Cellular and Molecular Research Center, Faculty of Advanced Technologies, Department of Anatomical Sciences, Iran University of Medical Sciences, Tehran, Iran

3 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), IVF Center, Iran University of Medical Sciences, Tehran, Iran

5 Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

6 Research and Clinical Center of Gynecology and Fertility, Shahid Akbarabadi Hospital, Iran University of Medical Sciences, Tehran, Iran

7 Department of Endocrinology and Female Infertility at Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

Abstract

Objective(s): NOTCH signaling pathway is well known for its role in cell fate, cell survival, cell differentiation, and apoptosis. Some of the NOTCH signaling genes are critical for endometrial function and implantation in animals and appear to play a similar role in humans. The purpose of the current study was to investigate the potential roles of some main components of the NOTCH family in human endometrium during implantation period in common gynecological diseases.
Materials and Methods: Endometrial NOTCH receptors NOTCH1, 3, 4 and ligand JAG1, 2 and survivin mRNA expression were investigated using the Q-PCR technique and the amount of the JAG1, 2 proteins was also determined by Western blot. Samples were obtained from 12 patients with endometriosis, 12 patients with repeated implantation failure (RIF), 12 patients with Polycystic Ovary Syndrome (PCOS) and 10 healthy fertile women as a control group. Data were analyzed using SPSS version 18. Group comparisons were performed by one-way ANOVA or Kruskal-Wallis.
Results: All patient groups failed to show the expected mid-luteal increase in NOTCH1, JAG 1, 2, and survivin expression as documented in the control group. Moreover, a significant rise in NOTCH3 expression levels was found only in PCOS women. There was a direct correlation between gene expression and protein level for JAG 1, 2.
Conclusion: Aberrant NOTCH signaling molecules expression suggests that altered development of the endometrium at the molecular level may be associated with the impaired decidualization and implantation failure in gynecological disorders such as endometriosis, PCOS, and RIF.

Keywords

Main Subjects


1. Boeddeker SJ, Hess AP. The role of apoptosis in human embryo implantation. J Reprod Immunol 2015;108:114-22.
2. Cobellis L, Caprio F, Trabucco E, Mastrogiacomo A, Coppola G, Manente L, et al. The pattern of expression of notch protein members in normal and pathological endometrium. J ANAT 2008;213:464-72.
3. Ohishi K, Katayama N, Shiku H, Varnum-Finney B, Bernstein I, editors. Notch signalling in hematopoiesis. Semin Cell Dev Biol 2003;14: 111-158.
4. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, et al. Activation of notch-1 signaling maintains the neoplastic phenotype in human ras-transformed cells. NAT MED 2002;8:979-86.
5. Zhang C-P, Yang J-L, Zhang J, Li L, Huang L, Ji S-Y, et al. Notch signaling is involved in ovarian follicle development by regulating granulosa cell proliferation. Endocrinology 2011;152:2437-47.
6. Sasnauskienė A, Jonušienė V, Krikštaponienė A, Butkytė S, Dabkevičienė D, Kanopienė D, et al. NOTCH1, NOTCH3, NOTCH4, and JAG2 protein levels in human endometrial cancer. Medicina 2014;50:14-8.
7. Maillard I, Pear WS. Notch and cancer: best to avoid the ups and downs. Cancer cell 2003;3:203-5.
8. Altieri DC. New wirings in the survivin networks. Oncogene 2008;27:6276-84.
9. Mitsuhashi Y, Horiuchi A, Miyamoto T, Kashima H, Suzuki A, Shiozawa T. Prognostic significance of notch signalling molecules and their involvement in the invasiveness of endometrial carcinoma cells. Histopathology 2012;60:826-37.
10. Afshar Y, Jeong J-W, Roqueiro D, DeMayo F, Lydon J, Radtke F, et al. Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J 2012;26:282-94.
11. Dunselman G, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, et al. Eshre guideline: management of women with endometriosis. Hum. Reprod 2014;29:400-12.
12. Baqai Z, Khanam M, Parveen S. Prevalence of pcos in infertile patients. Med Channel 2010;16:609.
13. Somigliana E, Vigano P, Busnelli A, Paffoni A, Vegetti W, Vercellini P. Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis. Reprod Biomed Online 2017;36:32-38.
14. Shi C, Han HJ, Fan LJ, Guan J, Zheng XB, Chen X, et al. Diverse endometrial mRNA signatures during the window of implantation in patients with repeated implantation failure. HUM FERTIL 2017; 21:183-194.
15. Amjadi F, Aflatoonian R, Javanmard SH, Saifi B, Ashrafi M, Mehdizadeh M. Apolipoprotein A1 as a novel anti-implantation biomarker in polycystic ovary syndrome: a case-control study. J RES MED SCI 2015;20:1039–1045.
16. Dimitriadis E, Stoikos C, Stafford-Bell M, Clark I, Paiva P, Kovacs G, et al. Interleukin-11, IL-11 receptorα and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J REPROD IMMUNOL 2006;69:53-64.
17. Amjadi F, Mehdizadeh M, Ashrafi M, Nasrabadi D, Taleahmad S, Mirzaei M, et al. Distinct changes in the proteome profile of endometrial tissues in polycystic ovary syndrome compared with healthy fertile women. Reprod Biomed Online 2018;37:184-200.
18. Taghavi SA, Ashrafi M, Mehdizadeh M, Karimian L, Joghataie MT, Aflatoonian R. Toll-like receptors expression in follicular cells of patients with poor ovarian response. Int J Fertil Steril 2014;8:183-92.
19. Giudice LC. Endometrium in pcos: implantation and predisposition to endocrine CA. BEST PRACT RES CL EN Journal 2006;20:235-44.
20. Timeva T, Shterev A, Kyurkchiev S. Recurrent implantation failure: the role of the endometrium. J Reprod Infertil 2014;15:173-183.
21. Selam B, Arici A. Implantation defect in endometriosis: endometrium or peritoneal fluid. J Reprod Fertil Suppl 2000;55:121-8.
22. Matteo M, Cicinelli E, Neri M, Carrubba R, Carpagnano F, Romeo F, et al. Pro-inflammatory M1/Th1 type immune network and increased expression of TSG-6 in the eutopic endometrium from women with endometriosis. EUR J OBSTET GYN R B 2017;218:99-105.
23. Cavagna M, Mantese J. Biomarkers of endometrial receptivity—a review. Placenta 2003;24:S39-S47.
24. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-89.
25. Leong KG, Karsan A. Recent insights into the role of notch signaling in tumorigenesis. Blood 2006;107:2223-33.
26. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, et al. Notch signaling is essential for vascular morphogenesis in mice. GENE DEV Journal 2000;14:1343-52.
27. Torry DS, Leavenworth J, Chang M, Maheshwari V, Groesch K, Ball ER, et al. Angiogenesis in implantation. J ASSIST REPROD GEN 2007;24:303-15.
28. Su R-W, Strug MR, Joshi NR, Jeong J-W, Miele L, Lessey BA, et al. Decreased notch pathway signaling in the endometrium of women with endometriosis impairs decidualization. J CLIN ENDOCR METAB 2015;100:E433-E42.
29. Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, et al. Notch3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer research 2008;68:1881-8.
30. Van Sinderen M, Cuman C, Gamage T, Rainczuk K, Osianlis T, Rombauts L, et al. Localisation of the notch family in the human endometrium of fertile and infertile women. J MOL HISTOL  2014;45:697-706.
31. Estrach S, Cordes R, Hozumi K, Gossler A, Watt FM. Role of the notch ligand Delta1 in embryonic and adult mouse epidermis. J INVEST DERMATOL 2008;128:825-32.
32. Liu N, Zhang J, Ji C. The emerging roles of notch signaling in leukemia and stem cells. Biomarker research 2013;1:23.