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FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition

The FK506-binding protein 51 (FKBP51) binds progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. We evaluated FKBP51 expression and function in human leiomyoma vs. myometrial tissues and primary cultures to discover FKBP51...

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Autores principales: New, Erika P., Semerci, Nihan, Ozmen, Asli, Guo, Xiaofang, Jonnalagadda, Venkata A., Kim, Joung Woul, Anderson, Matthew L., Guzeloglu-Kayisli, Ozlem, Imudia, Anthony N., Lockwood, Charles J., Kayisli, Umit A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009985/
https://www.ncbi.nlm.nih.gov/pubmed/35426036
http://dx.doi.org/10.1007/s43032-022-00921-2
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author New, Erika P.
Semerci, Nihan
Ozmen, Asli
Guo, Xiaofang
Jonnalagadda, Venkata A.
Kim, Joung Woul
Anderson, Matthew L.
Guzeloglu-Kayisli, Ozlem
Imudia, Anthony N.
Lockwood, Charles J.
Kayisli, Umit A.
author_facet New, Erika P.
Semerci, Nihan
Ozmen, Asli
Guo, Xiaofang
Jonnalagadda, Venkata A.
Kim, Joung Woul
Anderson, Matthew L.
Guzeloglu-Kayisli, Ozlem
Imudia, Anthony N.
Lockwood, Charles J.
Kayisli, Umit A.
author_sort New, Erika P.
collection PubMed
description The FK506-binding protein 51 (FKBP51) binds progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. We evaluated FKBP51 expression and function in human leiomyoma vs. myometrial tissues and primary cultures to discover FKBP51 role(s) in the pathogenesis of leiomyomas. Quantification of in situ FKBP51 mRNA and protein levels inpaired myometrial vs. leiomyoma tissues from proliferative and secretory phases were analyzed by qPCR (n = 14), immunoblotting (n = 20), and immunohistochemistry (n = 12). Control (scramble) vs. FKBP5 siRNA-transfected leiomyoma cell cultures were assessed for proliferation, apoptosis, and mRNA levels of genes involved in cell survival and extracellular matrix (ECM) formation. Significantly higher FKBP5 mRNA levels were detected in leiomyoma vs. paired myometrium (P < 0.001). Immunoblot (P = 0.001) and immunostaining (P ≤ 0.001) confirmed increased FKBP51 levels in leiomyoma vs. paired myometrium. Compared to control siRNA transfection, FKBP5-silenced leiomyoma cell cultures displayed significantly decreased cell survival factors and reduced proliferation (P < 0.05). Moreover, qPCR analysis revealed significantly lower mRNA levels of ECM, TIPM1, and TIPM3 proteins in FKBP5-silenced leiomyoma cell cultures (P < 0.05). Increased FKBP51 expression in leiomyoma likely involves dysregulation of steroid signaling by blocking GR and PR action and promoting proliferation and ECM production. Evaluating the effect of FKBP51 inhibition in preclinical studies will clarify its significance as a potential therapeutic approach against leiomyoma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43032-022-00921-2.
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spelling pubmed-90099852022-04-15 FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition New, Erika P. Semerci, Nihan Ozmen, Asli Guo, Xiaofang Jonnalagadda, Venkata A. Kim, Joung Woul Anderson, Matthew L. Guzeloglu-Kayisli, Ozlem Imudia, Anthony N. Lockwood, Charles J. Kayisli, Umit A. Reprod Sci Fibroid: Original Article The FK506-binding protein 51 (FKBP51) binds progesterone receptor (PR), glucocorticoid receptor (GR), and androgen receptor (AR) to coregulate their transcriptional activity. We evaluated FKBP51 expression and function in human leiomyoma vs. myometrial tissues and primary cultures to discover FKBP51 role(s) in the pathogenesis of leiomyomas. Quantification of in situ FKBP51 mRNA and protein levels inpaired myometrial vs. leiomyoma tissues from proliferative and secretory phases were analyzed by qPCR (n = 14), immunoblotting (n = 20), and immunohistochemistry (n = 12). Control (scramble) vs. FKBP5 siRNA-transfected leiomyoma cell cultures were assessed for proliferation, apoptosis, and mRNA levels of genes involved in cell survival and extracellular matrix (ECM) formation. Significantly higher FKBP5 mRNA levels were detected in leiomyoma vs. paired myometrium (P < 0.001). Immunoblot (P = 0.001) and immunostaining (P ≤ 0.001) confirmed increased FKBP51 levels in leiomyoma vs. paired myometrium. Compared to control siRNA transfection, FKBP5-silenced leiomyoma cell cultures displayed significantly decreased cell survival factors and reduced proliferation (P < 0.05). Moreover, qPCR analysis revealed significantly lower mRNA levels of ECM, TIPM1, and TIPM3 proteins in FKBP5-silenced leiomyoma cell cultures (P < 0.05). Increased FKBP51 expression in leiomyoma likely involves dysregulation of steroid signaling by blocking GR and PR action and promoting proliferation and ECM production. Evaluating the effect of FKBP51 inhibition in preclinical studies will clarify its significance as a potential therapeutic approach against leiomyoma. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43032-022-00921-2. Springer International Publishing 2022-04-14 /pmc/articles/PMC9009985/ /pubmed/35426036 http://dx.doi.org/10.1007/s43032-022-00921-2 Text en © Society for Reproductive Investigation 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Fibroid: Original Article
New, Erika P.
Semerci, Nihan
Ozmen, Asli
Guo, Xiaofang
Jonnalagadda, Venkata A.
Kim, Joung Woul
Anderson, Matthew L.
Guzeloglu-Kayisli, Ozlem
Imudia, Anthony N.
Lockwood, Charles J.
Kayisli, Umit A.
FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title_full FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title_fullStr FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title_full_unstemmed FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title_short FKBP51 Contributes to Uterine Leiomyoma Pathogenesis by Inducing Cell Proliferation and Extracellular Matrix Deposition
title_sort fkbp51 contributes to uterine leiomyoma pathogenesis by inducing cell proliferation and extracellular matrix deposition
topic Fibroid: Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009985/
https://www.ncbi.nlm.nih.gov/pubmed/35426036
http://dx.doi.org/10.1007/s43032-022-00921-2
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