Regulation of Aromatase P450 Expression in Endometriotic and Endometrial Stromal Cells by CCAAT/Enhancer Binding Proteins (C/EBPs): Decreased C/EBPβ in Endometriosis Is Associated with Overexpression of Aromatase
Abstract
In human endometriotic stromal cells, markedly high levels of aromatase P450 (P450arom) mRNA and promoter II activity are present and can be vigorously stimulated by PGE(2) via a cAMP-dependent pathway to give rise to physiologically significant estrogen biosynthesis. Stromal cells of eutopic endometrium, on the other hand, do not express sufficient levels of P450arom for detectable enzyme activity. Because P450arom is up-regulated in the ovaries of CCAAT/enhancer binding protein (C/EBP) beta knockout mice and activation of the ovarian-type P450arom promoter (II) is responsible for aberrant P450arom expression in endometriosis, we sought here to evaluate the possible roles of C/EBP isoforms in the regulation of P450arom expression in endometriotic vs. eutopic endometrial stromal cells. We previously found that the -517-bp flanking region of promoter II contained the critical cis-acting elements for baseline and cAMP (analog)-induced activity. In this study, we disrupted several potential sequences and found that mutations of a -211/-197-bp cAMP-response element (CRE) and a -317/-304-bp C/EBP binding site abolished both baseline and cAMP-induced promoter II activity. Ectopic expression of C/EBPalpha increased both baseline and cAMP-dependent promoter II activity significantly in endometriotic cells, whereas ectopic expression of C/EBPbeta or C/EBPdelta abolished promoter II activity in both untreated and cAMP-treated endometriotic stromal cells. Comparable changes in promoter II activity were observed using endometrial stromal cells, which showed, however, seemingly diminished levels of baseline and cAMP-induced promoter II activity in comparison with endometriotic cells. EMSA using a probe containing the critical -317/-304-bp C/EBP site upstream of promoter II demonstrated a distinct DNA-protein complex in endometriotic, but not in endometrial stromal cells. This specific complex, however, could not be altered using antibodies against C/EBPalpha, -beta, or -delta. Because CRE is another potential DNA motif that can bind C/EBP isoforms, we next used EMSA using a probe containing the -211/-197-bp CRE and demonstrated that specific DNA-protein complexes contained C/EBPalpha but not C/EBPbeta or C/EBPdelta in endometriotic stromal cells. In contrast, C/EBPbeta and C/EBPdelta but not C/EBPalpha were detected in DNA-protein complexes using nuclear extracts from endometrial stromal cells. Western blotting and immunohistochemistry demonstrated expression of C/EBPalpha, -beta, and -delta in human endometriotic and endometrial stroma and epithelium. Intriguingly, C/EBPbeta was expressed at increased levels in stromal cells of human eutopic endometrium compared with simultaneously biopsied endometriotic tissues. We conclude that both -317/-304 and -211/-197-bp elements in promoter II are critical for the robust cAMP-dependent induction in endometriosis. C/EBPalpha up-regulates, whereas C/EBPbeta and C/EBPdelta inhibit P450arom promoter activity via binding primarily to the -211/-197-bp CRE under in vitro conditions. In vivo down-regulation of C/EBPbeta in endometriotic stromal cells and its up-regulation in endometrial stromal cells may in part account for the induction of P450arom expression in endometriosis and its inhibition in endometrium.
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There is a positive feed-forward loop involving local biosynthesis of both estradiol (E2) and prostaglandin E2 in endometriosis lesions.
“there are a number of reports that aromatase is expressed in endometriosis lesions with evidence of a positive feed-forward loop involving local biosynthesis of both E2 and the pro-inflammatory regulator prostaglandin E2 [69,98].”
From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [98]
Aromatase is expressed in endometriosis lesions.
“there are a number of reports that aromatase is expressed in endometriosis lesions with evidence of a positive feed-forward loop involving local biosynthesis of both E2 and the pro-inflammatory regulator prostaglandin E2 [69,98].”
From Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders (2018) · cites this paper as [98]
In vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression.
“Previously, we demonstrated that in vitro overexpression studies reflected the in vivo effects of these factors on differential P450arom expression (16,17,22).”
From Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis (2009) · cites this paper as [22]
Similar transcription factors (SF1, C/EBPs, and CREB) mediate PGE2-dependent regulation of both the StAR and aromatase promoters.
“Additionally, similar transcription factors (SF1, C/EBPs, and CREB) mediate PGE 2 -dependent regulation of both promoters (19 -22).”
From Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis (2009) · cites this paper as [22]
PGE2 activates PKA signaling via raising intracellular cAMP, which can enhance binding of SF-1 to promoters of steroidogenic genes and induce phosphorylation of CREB.
“PGE2 activates the protein kinase A (PKA) signaling pathway via raising the intracellular levels of cyclic adenosine 3′,5′-monophosphate (cAMP)12–14, which can enhance the binding of steroidogenic factor-1 (SF-1) to promoters of these steroidogenic genes15, and induce phosphorylation of the transcriptional activator cAMP-response element-binding protein (CREB)16.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [13]
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“For example, there are a number of reports that aromatase is expressed in endometriosis lesions with evidence of a positive feed-forward loop involving local biosynthesis of both E2 and the pro-inflammatory regulator prostaglandin E2 [69,98].”
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- Authors
- Yang, S., Fang, Z., Suzuki, T., Sasano, H., Zhou, J., Gurates, B., Tamura, M., Ferrer, K., & Bulun, S.
- Affiliations
- University of Illinois Chicago (US)
- Tohoku University (JP)
- Corresponding author
- Bulun, Serdar
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2002-05
- Volume
- 87
- Issue
- 5
- Pages
- 2336-2345
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1964930501
- Cited by
- 77
- References
- 32
- Citations by year
- 2022: 1 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 3
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Illinois at Chicago
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-38691)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- endometriosis, aromatase, C/EBPβ, C/EBPα, C/EBPδ, endometrial stromal cells, cAMP response element, estrogen synthesis, prostaglandin E2, transcriptional regulation, protein-DNA complex, eutopic endometrium
- MeSH terms
- Cyclic AMP, Adult, Aromatase, Cells, Cultured, Endometriosis, Endometrium, Female, Gene Expression Regulation, Humans, Nuclear Proteins, Promoter Regions, Genetic, Tissue Distribution, Transcription, Genetic, Stromal Cells, Response Elements, CCAAT-Enhancer-Binding Proteins, CCAAT-Enhancer-Binding Protein-alpha, CCAAT-Enhancer-Binding Protein-beta
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