Skip to main content

Advertisement

SpringerLink
Log in

Expression of Proliferative and Preapoptotic Molecules in Human Myometrium and Leiomyoma Throughout the Menstrual Cycle

  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The pathogenesis of leiomyoma may be related to an imbalance in the interaction of sex steroids with paracrine growth factors that may control the modulation of mitogenesis and local immunity. The authors investigate the temporal and spatial expression of proliferative and preapoptotic molecules that may participate in the modulation of myometrial function and leiomyoma pathogenesis. Immunohistochemistry and Western blot analysis are used to investigate Fas ligand (FasL), phosphatase and tensin homolog deletion on chromosome 10 (PTEN), and proliferating cell nuclear antigen (PCNA) expression in myometrium and leiomyoma. Western blot results show that in the secretory phase, FasL expression is 1.8-fold and 2.3-fold higher compared with the proliferative phase in the myometrium and leiomyoma, respectively (P =.022 and.047, respectively). A paired comparison between myometrium and leiomyoma reveals higher FasL expression in the leiomyoma (P =.003). On the contrary, when compared with the secretory phase, PCNA expression during the proliferative phase is 4.6-fold and 3.7-fold higher in the myometrium and leiomyoma, respectively (P =.041 and.034, respectively). A paired comparison between myometrium and leiomyoma reveals higher PCNA expression in the leiomyoma. Furthermore, lower PTEN expression is detected in the leiomyoma compared with the myometrium (P <.032). Immunohistochemistry results reveal that FasL, PTEN, and PCNA are expressed in the myometrium and leiomyoma, consistent with the results from the Western blot analysis. The results suggest that FasL, PTEN, and PCNA may be involved in the pathophysiology of leiomyoma. A higher FasL level in the leiomyoma is likely to correspond to suppression of local immunity by inducing apoptosis of immune cells, while a higher level of PCNA and a lower level of PTEN may be related to increased mitogenesis and decreased apoptosis in leiomyoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kierszenbaum A. Follicle development and menstrual cycle: uterus. In: Histology and Cell Biology: An Introduction to Pathology. St Louis, MO:Mosby; 2002:565–585.

    Google Scholar 

  2. Flake GP, Andersen J., Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. 2003;111:1037–1054.

    Article  CAS  Google Scholar 

  3. Sozen I., Arici A. Cellular biology of myomas: interaction of sex steroids with cytokines and growth factors. Obstet Gynecol Clin North Am. 2006;33:41–58.

    Article  Google Scholar 

  4. Palomba S., Orio F. Jr, Russo T., et al. Antiproliferative and proapoptotic effects of raloxifene on uterine leiomyomas in postmenopausal women. Fertil Steril. 2005;84:154–161.

    Article  CAS  Google Scholar 

  5. Wei JJ, Zhang XM, Chiriboga L., Yee H., Perle MA, Mittal K. Spatial differences in biologic activity of large uterine leiomyomata. Fertil Steril. 2006;85:179–187.

    Article  CAS  Google Scholar 

  6. Sozen I., Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil Steril. 2002;78:1–12.

    Article  Google Scholar 

  7. Liang M., Wang H., Zhang Y., Lu S., Wang Z. Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata. Cancer Biol Ther. 2006;5:28–33.

    Article  CAS  Google Scholar 

  8. Cramer SF, Horiszny JA, Leppert P. Epidemiology of uterine leiomyomas: with an etiologic hypothesis. J Reprod Med. 1995;40:595–600.

    CAS  PubMed  Google Scholar 

  9. Nagata S., Golstein P. The Fas death factor. Science. 1995;267:1449–1456.

    Article  CAS  Google Scholar 

  10. Leslie NR, Downes CP PTEN: the down side of PI 3-kinase signalling. Cell Signal. 2002;14:285–295.

    Article  CAS  Google Scholar 

  11. Han SY, Kato H., Kato S., et al. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000;60:3147–3151.

    CAS  PubMed  Google Scholar 

  12. Myers MP, Pass I., Batty IH, et al.The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A. 1998;95:13513–13518.

    Article  CAS  Google Scholar 

  13. Majka J., Burgers PM The PCNA-RFC families of DNA clamps and clamp loaders. Prog Nucleic Acid Res Mol Biol. 2004;78:227–260.

    Article  CAS  Google Scholar 

  14. Maga G., Hubscher U. Proliferating cell nuclear antigen (PCNA): a dancer with many partners. J Cell Sci. 2003;116:3051–3060.

    Article  CAS  Google Scholar 

  15. Goumenou A., Panayiotides I., Mahutte NG, Matalliotakis I., Fragouli Y., Arici A. Immunohistochemical expression of p53, MDM2, and p21Waf1 oncoproteins in endometriomas but not adenomyosis. J Soc Gynecol Investig. 2005;12:263–266.

    Article  CAS  Google Scholar 

  16. Goumenou AG, Matalliotakis IM, Tzardi M., Fragouli YG, Mahutte NG, Arici A. Apoptosis and differential expression of apoptosis-related proteins in endometriotic glandular and stromal cells. J Soc Gynecol Investig. 2004;11:318–322.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Kayisli UA, Selam B., Demir R., Arici A. Expression of vasodilator-stimulated phosphoprotein in human placenta: possible implications in trophoblast invasion. Mol Hum Reprod. 2002;8:88–94.

    Article  CAS  Google Scholar 

  19. Cook JD, Walker CL. Treatment strategies for uterine leiomyoma: the role of hormonal modulation. Semin Reprod Med. 2004;22:105–111.

    Article  CAS  Google Scholar 

  20. Burroughs KD, Kiguchi K., Howe SR, et al. Regulation of apoptosis in uterine leiomyomata. Endocrinology. 1997;138:3056–3064.

    Article  CAS  Google Scholar 

  21. Shynlova O., Oldenhof A., Dorogin A., et al. Myometrial apoptosis: activation of the caspase cascade in the pregnant rat myometrium at midgestation. Biol Reprod. 2006;74:839–849.

    Article  CAS  Google Scholar 

  22. Huang SC, Tang MJ, Hsu KF, Cheng YM, Chou CY Fas and its ligand, caspases, and bcl-2 expression in gonadotropin-releasing hormone agonist-treated uterine leiomyoma. J Clin Endocrinol Metab. 2002;87:4580–4586.

    Article  CAS  Google Scholar 

  23. Wang Y., Matsuo H., Kurachi O., Maruo T. Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells. Eur J Endocrinol. 2002;146:447–456.

    Article  CAS  Google Scholar 

  24. Maruo T., Ohara N., Wang J., Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update. 2004;10:207–220.

    Article  CAS  Google Scholar 

  25. Selam B., Kayisli UA, Mulayim N., Arici A. Regulation of Fas ligand expression by estradiol and progesterone in human endometrium. Biol Reprod. 2001;65:979–985.

    Article  CAS  Google Scholar 

  26. Bourlev V., Pavlovitch S., Stygar D., Volkov N., Lindblom B., Olovsson M. Different proliferative and apoptotic activity in peripheral versus central parts of human uterine leiomyomas. Gynecol Obstet Invest. 2003;55:199–204.

    Article  Google Scholar 

  27. Kawaguchi K., Fujii S., Konishi I., Nanbu Y., Nonogaki H., Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol. 1989;160:637–641.

    Article  CAS  Google Scholar 

  28. Shimomura Y., Matsuo H., Samoto T., Maruo T. Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma. J Clin Endocrinol Metab. 1998;83:2192–2198.

    CAS  PubMed  Google Scholar 

  29. Lamminen S., Rantala I., Helin H., Rorarius M., Tuimala R. Proliferative activity of human uterine leiomyoma cells as measured by automatic image analysis. Gynecol Obstet Invest. 1992;34:111–114.

    Article  CAS  Google Scholar 

  30. Zaslawski R., Surowiak P., Dziegiel P., Pretnik L., Zabel M. Analysis of the expression of estrogen and progesterone receptors, and of PCNA and Ki67 proliferation antigens, in uterine myomata cells in relation to the phase of the menstrual cycle. Med Sci Monit. 2001;7:908–913.

    CAS  PubMed  Google Scholar 

  31. Chegini N., Verala J., Luo X., Xu J., Williams RS Gene expression profile of leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy. J Soc Gynecol Investig. 2003;10:161–171.

    Article  CAS  Google Scholar 

  32. Dixon D., Flake GP, Moore AB, et al. Cell proliferation and apoptosis in human uterine leiomyomas and myometria. Virchows Arch. 2002;441:53–62.

    Article  CAS  Google Scholar 

  33. Buttram VC Jr, Reiter RC Uterine leiomyomata: etiology, symptomatology, and management. Fertil Steril. 1981;36:433–445.

    Article  Google Scholar 

  34. Mutter GL, Ince TA, Baak JP, Kust GA, Zhou XP, Eng C. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res. 2001;61:4311–4314.

    CAS  PubMed  Google Scholar 

  35. Guzeloglu-Kayisli O., Kayisli UA, Al-Rejjal R., Zheng W., Luleci G., Arici A. Regulation of PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression by estradiol and progesterone in human endometrium. J Clin Endocrinol Metab. 2003;88:5017–5026.

    Article  CAS  Google Scholar 

  36. Kovacs KA, Lengyel F., Kornyei JL, et al. Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium. J Steroid Biochem Mol Biol. 2003;87:233–240.

    Article  CAS  Google Scholar 

  37. Wei J., Chiriboga L., Mizuguchi M., Yee H., Mittal K. Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata. Mod Pathol. 2005;18:179–188.

    Article  CAS  Google Scholar 

  38. Hussein-Fikret S., Fuller PJ, Gargett CE Expression of steroid receptor coactivators in cultured cells from paired myometrial and fibroid tissues. J Soc Gynecol Investig. 2005;12:445–451.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520-8063, USA

    Aydin Arici MD

Authors
  1. Umit A. Kayisli PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murat Berkkanoglu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gulnur Kizilay PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Levent Senturk MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aydin Arici MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aydin Arici MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kayisli, U.A., Berkkanoglu, M., Kizilay, G. et al. Expression of Proliferative and Preapoptotic Molecules in Human Myometrium and Leiomyoma Throughout the Menstrual Cycle. Reprod. Sci. 14, 678–686 (2007). https://doi.org/10.1177/1933719107305866

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719107305866

Key words

Search

Navigation