Molecular mechanisms of regulation of uterine leiomyoma growth

Cover Page

Abstract


Background: to elucidate the molecular mechanisms, regulating growth and proliferation of leiomyoma cells, the estimation of the activity of PR-A and PR-B isoforms of progesterone receptor and PI3K/Akt and MAPК kinases, participating in signal transduction from sex steroids and growth factors, has the special interest.

Aim of the work: to investigate the character of the expression of mRNAs of PR-A and PR-B isoforms of progesterone receptor in leiomyomas of different size and different intensity of cellular proliferation, and to elucidate the relationship between the PR-A and PR-B synthesis and activation of PI3K/Akt and MAPК signaling pathways in tumour tissue.

Materials and Methods. The examination of the PR-A, PR-B, Akt, PTEN, ERK and Ki67 mRNAs expression in normal myometrium and leiomyoma tissues of 29 women with uterine leiomyoma was performed using RP-PCR.

Results. It was found that in general the leiomyoma tissue was characterized by the high level of PR-A, PTEN and ERK mRNAs expression comparing to the miometrium. Distinctive characteristic of the small leiomyomas and leiomyomas with low proliferative activity was the highest synthesis of PR-A isoform of progesterone receptor. In large leiomyomas and in proliferating Ki67+ leiomymas the significant increase of ERK mRNA expression was seen.

Conclusion. Activation of the PR-A isoform of progesterone receptor and MAPK/ERK signaling pathway associated with the inhibition of PI3K/Akt signaling due to high synthesis of PTEN plays the important role in mechanisms, regulating leiomyoma growth.


Yulia S. Antsiferova

Author for correspondence.
niimid.immune@mail.ru
Ivanovo Research Institute of Maternity and Childhood named V.N. Gorodkov
Russian Federation, 20, Pobedy street, Ivanovo, 153045

BD, senior scientific worker of the laboratory of clinical immunology

Dmitry N. Voronin

niimid.immune@mail.ru
Ivanovo Research Institute of Maternity and Childhood named V.N. Gorodkov
Russian Federation, 20, Pobedy street, Ivanovo, 153045

PhD, scientific worker of the laboratory of clinical immunology

Natalya Yu. Sotnikova

niimid.immune@mail.ru
Ivanovo Research Institute of Maternity and Childhood named V.N. Gorodkov
Russian Federation, 20, Pobedy street, Ivanovo, 153045

MD, professor, head of the laboratory of clinical immunology

Anna I. Malyshkina

niimid.immune@mail.ru
Ivanovo Research Institute of Maternity and Childhood named V.N. Gorodkov
Russian Federation, 20, Pobedy street, Ivanovo, 153045

MD, associate professor, the director

  • Ciarmela P, Islam MS, Reis FM, et al. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update. 2011;17(6):772-90. doi: 10.1093/humupd/dmr031.
  • Ishikawa H, Ishi K, Serna VA, Kakazu R, et al. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 2010;151(6):2433-42. doi: 10.1210/en.2009-1225.
  • Chegini N. Proinflammatory and Profibrotic Mediators: Principal effectors of leiomyoma development as a fibrotic disorder. Semin Reprod Med. 2010;28(3): 180-203. doi: 10.1055/s-0030-1251476.
  • Kim JJ, Sefton EC. The role of progesterone sig naling in the pathogenesis of uterine leiomyoma. Mol Cell Endocrinol. 2012;358(2):223-31. doi: 10.1016/ j.mce.2011.05.044.
  • Kawaguchi K, Fujii S, Konishi I, Iwai T, et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy. Virchows Arch A Pathol Anat Histopathol. 1991;419(4):309-315.
  • Tsigkou A, Reis FM, Lee MH, Jiang B, et al. Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms. Fertil Steril. 2015;104(1):170-5. doi: 10.1016/j.fertnstert.2015.04.024.
  • Islam MS, Protic O, Stortoni P, Grechi G, et al. Complex networks of multiple factors in the pathogenesis of uterine leiomyoma. Fertil Steril. 2013;100(1):178-193. doi: 10.1016/j.fertnstert.2013.03.007.
  • Makker A, Goel MM, Das V, Agarwal A. PI3K-Akt-mTOR and MAPK signaling pathways in polycystic ovarian syndrome, uterine leiomyomas and endometriosis: an update. Gynecol Endocrinol. 2012;28(3):175-181. doi: 10.3109/09513590.2011.583955.
  • Stivala F, Mazzarino MC, Donia V, Fagone P, et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. AGING. 2011;3(3):192-222. doi: 10.18632/aging.100296.
  • Nierth-Simpson EN, Martin MM, Chiang TC, Melnik LI, et al. Human uterine smooth muscle and leiomyoma cells differ in their rapid 17beta-estradiol signaling: implications for proliferation. Endocrinology. 2009;150(5):2436-345. doi: 10.1210/en.2008-0224.
  • Kim JJ, Sefton EC, Bulun SE. Progesterone receptor action in leiomyoma and endometrial cancer. Prog Mol Biol Transl Sci. 2009;87:53-85. doi: 10.1016/S1877-1173(09)87002-6.
  • Giangrande PH, Kimbrel EA, Edwards DP, McDonnell DP. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol. 2000;20(9):3102-3115. doi: 10.1128/MCB.20.9.3102-3115.2000.
  • Borahay MA, Al-Hendy A, Kilic GS, Boehning D. Signaling pathways in leiomyoma: understanding pathobiology and implications for therapy. Mol Med. 2015;21:242-56. doi: 10.2119/molmed.2014.00053.
  • Bononi A, Agnoletto C, De Marchi E, Marchi S. Protein kinases and phosphatases in the control of cell fate. Enzyme Res. 2011;2011:329098. doi: 10.4061/ 2011/329098.
  • Keniry M, Parsons R. The role of PTEN signaling per turbations in cancer and in targeted therapy. Oncogene. 2008;27(41):5477-85. doi: 10.1038/onc. 2008.248.
  • Monje P, Hernández-Losa J, Lyons RJ, et al. Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J Biol Chem. 2005;280(42):35081-4. doi: 10.1074/jbc.C500353200.

Views

Abstract - 47

PDF (Russian) - 30


Copyright (c) 2017 ECO-vector LLC

Creative Commons License
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.