https://doi.org/10.4081/ejh.2023.3580

Growth hormone inhibits the JAK/STAT3 pathway by regulating SOCS1 in endometrial cells in vitro: a clue to enhance endometrial receptivity in recurrent implantation failure

Vol. 67 No. 1 (2023)
Submitted: 17 October 2022
Accepted: 24 November 2022
Published: 22 December 2022
Recurrent implantation failure, JAK/STAT pathway, leukemia inhibitory factor, growth hormone, SOCS1
Abstract Views: 891
PDF: 670
HTML: 25
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Haixia Li
Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Ning Sun
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Yaqiao Zhu
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Wei Wang
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Meihong Cai
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Xiaohuan Luo
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Wei Xia
rose-xw@163.com
https://orcid.org/0000-0002-5708-4650
Department of Reproductive Medicine Centre, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
Song Quan
Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Recurrent implantation failure (RIF) is defined as failure to achieve clinical pregnancy after at least 3 transfers of good-quality embryos by natural or artificial means. RIF is often a complex problem with a wide variety of etiologies and mechanisms as well as treatment options. In this study, using immunohistochemistry and Western blot, we demonstrated that the expression of leukemia inhibitory factor (LIF), Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) was increased, while that of suppressor of cytokine signaling 1 (SOCS1) was decreased in RIF patients. Growth hormone (GH) administration proved to have positive effects on embryo implantation in RIF patients, but the action mechanism of GH has not been elucidated yet. To this aim, we studied the effects of GH on the proliferation in vitro of endometrial adenocarcinoma Ishikawa cells. GH stimulated the expression of LIF and SOCS1, and through SOCS1 inhibits the expression of phosphorylated STAT3, and finally inhibits the occurrence of RIF. Excessive phosphorylation of STAT can lead to decreased endometrial receptivity and abnormal embryo implantation. We also examined the effects of LIF overexpression and an LIF inhibitor (EC330) on the JAK/STAT pathway. LIF promoted cell proliferation, and the up-regulation of LIF increased the expression of SOCS1 and JAK1/STAT3 pathway-related genes in Ishikawa cells. As GH can inhibit the JAK1/STAT3 pathway through LIF, we hypothesize that upregulating SOCS1 may be a potential approach to treat RIF at the molecular level. GH can inhibit the JAK1/STAT3 pathway through LIF, up-regulating SOCS1 to treat RIF at the molecular level.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Crossref
Scopus
Google Scholar
Europe PMC
Günther V, Otte SV, Freytag D, Maass N, Alkatout I. Recurrent implantation failure - an overview of current research. Gynecol Endocrinol 2021;37:584-590. DOI: https://doi.org/10.1080/09513590.2021.1878136
Santamaria X, Simón C. Endometrial factor in unexplained infertility and recurrent implantation failure. Semin Reprod Med 2021;39:227-32. DOI: https://doi.org/10.1055/s-0041-1735199
Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014;28:14-38. DOI: https://doi.org/10.1016/j.rbmo.2013.08.011
Mrozikiewicz A E, Ożarowski M, Jędrzejczak P. Biomolecular markers of recurrent implantation failure-A review. Int J Mol Sci 2021;22:10082. DOI: https://doi.org/10.3390/ijms221810082
Franasiak JM, Alecsandru D, Forman EJ, Gemmell LC, Goldberg JM, Llarena N, et al. A review of the pathophysiology of recurrent implantation failure. Fertil Steril 2021;116:1436-48. DOI: https://doi.org/10.1016/j.fertnstert.2021.09.014
Hill MJ. Recurrent implantation failure: Sapereaude. Fertil Steril 2021;116:1430-1. DOI: https://doi.org/10.1016/j.fertnstert.2021.09.030
Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021;6:402. DOI: https://doi.org/10.1038/s41392-021-00791-1
Demir M, Ince O, Ozkan B, Kelekci S, Sutcu R, Yilmaz B. Endometrial flushing αVβ3 integrin, glycodelin and PGF2α levels for evaluating endometrial receptivity in women with polycystic ovary syndrome, myoma uteri and endometrioma. Gynecol Endocrinol 2017;33:716-20. DOI: https://doi.org/10.1080/09513590.2017.1318276
Quenby S, Anim-Somuah M, Kalumbi C, Farquharson R, Aplin JD. Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometrium. Reprod Biomed Online 2007;14:224-34. DOI: https://doi.org/10.1016/S1472-6483(10)60791-2
Pastuschek J, Poetzsch J, Morales-Prieto DM, Schleußner E, Markert UR, Georgiev G. Stimulation of the JAK/STAT pathway by LIF and OSM in the human granulosa cell line COV434. J Reprod Immunol 2015;108:48-55. DOI: https://doi.org/10.1016/j.jri.2015.03.002
Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 2004;103:4630-5. DOI: https://doi.org/10.1182/blood-2003-06-2007
Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A. Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 2011;31:980-5. DOI: https://doi.org/10.1161/ATVBAHA.110.207464
Yang Y, Lei Y, Liang Y, Fu S, Yang C, Liu K, et al. Vitamin D protects glomerular mesangial cells from high glucose-induced injury by repressing JAK/STAT signaling. Int Urol Nephrol 2021;53:1247-54. DOI: https://doi.org/10.1007/s11255-020-02728-z
Gao J, Zhao BR, Zhang H, You YL, Li F, Wang XW. Interferon functional analog activates antiviral Jak/Stat signaling through integrin in an arthropod. Cell Rep 2021;36:109761. DOI: https://doi.org/10.1016/j.celrep.2021.109761
Altme S, Aghajanova L. Growth hormone and endometrial receptivity. Front Endocrinol (Lausanne) 2019;10:653. DOI: https://doi.org/10.3389/fendo.2019.00653
Zhao Y, He D, Zeng H, Luo J, Yang S, Chen J, et al. Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window. Reprod Biol Endocrinol 2021;19:138. DOI: https://doi.org/10.1186/s12958-021-00820-2
Chim CS, Wong ASY, Kwong YL. Epigenetic dysregulation of the Jak/STAT pathway by frequent aberrant methylation of SHP1 but not SOCS1 in acute leukaemias. Ann Hematol 2004;83:527-32. DOI: https://doi.org/10.1007/s00277-004-0843-1
Liu FT, Wu Z, Yan J, Norman RJ, Li R. The potential role of growth hormone on the endometrium in assisted reproductive technology. Front Endocrinol (Lausanne) 2020;11:49. DOI: https://doi.org/10.3389/fendo.2020.00049
Lan KC, Lin PY, Chang YC, Chen YJ, Tsai YR, Ismaeil Mohamed IS, et al. Growth hormone supplementation may improve the pregnancy rate and endometrial receptivity among women aged more than 40 years undergoing in vitro fertilization. Biomed J. 2019;42:411-6. DOI: https://doi.org/10.1016/j.bj.2019.05.003
Evans A, Jamieson SM, Liu DX, Wilson WR, Perry JK. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model. Cancer Lett 2016;379:117-23. DOI: https://doi.org/10.1016/j.canlet.2016.05.031
Altmäe S, Mendoza-Tesarik R, Mendoza C, Mendoza N, Cucinelli F, Tesarik J. Effect of growth hormone on uterine receptivity in women with repeated implantation failure in an oocyte donation program: A randomized controlled trial. J Endocr Soc 2017;2:96-105. DOI: https://doi.org/10.1210/js.2017-00359
Feng Q, Gao B, Huang H, Zou L, Zhao X, Zhu X, et al. Growth hormone promotes human endometrial glandular cells proliferation and motion through the GHR-STAT3/5 pathway. Ann Transl Med 2020;8:53. DOI: https://doi.org/10.21037/atm.2019.12.08
Song W, Wang J, Liu H, Zhu C, Xu F, Qian L, et al Effects of LncRNA Lnc-LIF-AS on cell proliferation, migration and invasion in a human cervical cancer cell line. Cytokine 2019;120:165-75. DOI: https://doi.org/10.1016/j.cyto.2019.05.004
Margioula-Siarkou C, Prapas Y, Petousis S, Milias S, Ravanos K, Dagklis T, et al. LIF endometrial expression is impaired in women with unexplained infertility while LIF-R expression in all infertility sub-groups. Cytokine 2017;96:166-72. DOI: https://doi.org/10.1016/j.cyto.2017.04.009
Cambra JM, Jauregi-Miguel A, Alvarez-Rodriguez M, Parrilla I, Gil MA, Martinez EA, et al. Allogeneic embryos disregulate leukemia inhibitory factor (LIF) and its receptor in the porcine endometrium during implantation. Front Vet Sci 2020;7:611598. DOI: https://doi.org/10.3389/fvets.2020.611598
Monsivais D, Nagashima T, Prunskaite-Hyyryläinen R, Nozawa K, Shimada K, Tang S, et al. Endometrial receptivity and implantation require uterine BMP signaling through an ACVR2A-SMAD1/SMAD5 axis. Nat Commun 2021;12:3386. DOI: https://doi.org/10.1038/s41467-021-23571-5
Yang D, Liu A, Wu Y, Li B, Nan S, Yin R, et al. BCL2L15 depletion inhibits endometrial receptivity via the STAT1 signaling pathway. Genes (Basel) 2020;11:816. DOI: https://doi.org/10.3390/genes11070816

How to Cite

Li, H., Sun, N., Zhu, Y. ., Wang, W., Cai, M. ., Luo, X. ., … Quan, S. . (2022). Growth hormone inhibits the JAK/STAT3 pathway by regulating SOCS1 in endometrial cells <em>in vitro</em>: a clue to enhance endometrial receptivity in recurrent implantation failure. European Journal of Histochemistry, 67(1). https://doi.org/10.4081/ejh.2023.3580
Copyright (c) 2022 The Author(s) Creative Commons License

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

PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.