RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth

Ikhena, Deborah E.; Liu, Shimeng; Kujawa, Stacy; Esencan, Ecem; Coon, John S.; Robins, Jared C.; Bulun, Serdar E.; Yin, Ping

doi:10.1210/jc.2017-01585

Cited by 21 publications

(30 citation statements)

References 19 publications

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“…Our finding that RANKL plays a critical role in regulating LSC function and LM tumorigenesis prompted us to further explore the mechanism underlying dysregulated RANKL gene expression in LM [11]. RANKL is a known P4/PR target gene in mammary glands [20, 21]; therefore, we postulated that the RANKL gene responds to P4/PR signaling differentially between LM and MM tissues, leading to higher RANKL expressions in LM.…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that RANKL is preferentially expressed and specifically upregulated by R5020 in LIC [11], we went on investigating whether the same mechanism (DNA methylation difference in the DMR adjacent to the distal PRBS of RANKL gene) was also involved. We examined the DNA methylation levels and the effects of 5ʹ-aza treatment on RANKL expression in each LM cell population.…”

Section: Resultsmentioning

confidence: 99%

“…Later studies in humans have demonstrated the positive correlation between serum P4 levels and RANKL mRNA and protein levels in normal and malignant breast tissues [9, 10]. We recently demonstrated that blocking the RANKL/RANK pathway inhibits steroid hormone-mediated LM development in a xenograft mouse model, indicating that this pathway plays a critical role in LM pathogenesis [11]. However, the mechanisms responsible for the hormone responsiveness of RANKL gene expression and the role of RANKL in LM formation require further elucidation.…”

Section: Introductionmentioning

confidence: 99%

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Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma

et al. 2018

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Progesterone and its receptor, PR, are essential for uterine leiomyoma (LM, a.k.a., fibroid) tumorigenesis, but the underlying cellular and molecular mechanisms remain unclear. The receptor activator of NF-κB (RANKL) was recently identified as a novel progesterone/PR-responsive gene that plays an important role in promoting LM growth. Here, we used RANKL as a representative gene to investigate how steroid hormone, genetic, and epigenetic signals are integrated to regulate LM stem cell (LSC) function. We demonstrated that RANKL specifically upregulates LSC proliferation through activation of Cyclin D1. RANKL gene transcription was robustly induced by the progesterone agonist R5020, leading to a dramatically higher RANKL expression in LM compared to adjacent myometrial (MM) tissue. MethylCap-Seq revealed a differentially methylated region (DMR) adjacent to the distal PR-binding site (PRBS) 87 kb upstream of the RANKL transcription start site. Hypermethylation of the DMR inhibited recruitment of PR to the adjacent PRBS. Luciferase assays indicated that the DMR and distal PRBS constitute a novel RANKL distal regulatory element that actively regulates RANKL expression. Furthermore, MED12 physically interacts with PR in LM tissue. The interaction between MED12 and PR, binding of PR and MED12 to PRBS, and RANKL gene expression are significantly higher in LM containing a distinct MED12 mutation (G44D) than in LM with wild-type MED12. In summary, our findings suggest that DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PR-mediated RANKL gene expression, with an important role in activating stem cell proliferation and fibroid tumor development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma

et al. 2018

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“…The suggested mechanism for hormone action on leiomyoma stem cells proposes that differentiated stromal cells respond to circulating steroid hormones by secreting paracrine factors, which in turn stimulate stem cell proliferation and tumor expansion (Bulun, 2013). Supporting this model, it was recently shown that a PGR-positive group of cells in uterine leiomyomas secrete receptor activator of nuclear factor kappa-Β ligand (RANKL) following progestin treatment, which induces proliferation of leiomyoma stem cells through its receptor RANK (Ikhena et al, 2018). Endometrial or endometriosis stem cells, which are also deficient in steroid receptors, may also be stimulated via unique paracrine signaling originating from the surrounding steroid receptor-positive cells.…”

Section: Nrs In Endometrial Stem Cellsmentioning

confidence: 99%

Endometriosis and nuclear receptors

Yilmaz

Bulun

2019

Human Reproduction Update

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BACKGROUND Endometriosis is recognized as a steroid-dependent disorder; however, the precise roles of nuclear receptors (NRs) in steroid responsiveness and other signaling pathways are not well understood. OBJECTIVE AND RATIONALE Over the past several years, a number of paradigm-shifting breakthroughs have occurred in the area of NRs in endometriosis. We review and clarify new information regarding the mechanisms responsible for: (i) excessive estrogen biosynthesis, (ii) estrogen-dependent inflammation, (iii) defective differentiation due to progesterone resistance and (iv) enhanced survival due to deficient retinoid production and action in endometriosis. We emphasize the roles of the relevant NRs critical for these pathological processes in endometriosis. SEARCH METHODS We conducted a comprehensive search using PubMed for human, animal and cellular studies published until 2018 in the following areas: endometriosis; the steroid and orphan NRs, estrogen receptors alpha (ESR1) and beta (ESR2), progesterone receptor (PGR), steroidogenic factor-1 (NR5A1) and chicken ovalbumin upstream promoter-transcription factor II (NR2F2); and retinoids. OUTCOMES Four distinct abnormalities in the intracavitary endometrium and extra-uterine endometriotic tissue underlie endometriosis progression: dysregulated differentiation of endometrial mesenchymal cells, abnormal epigenetic marks, inflammation activated by excess estrogen and the development of progesterone resistance. Endometriotic stromal cells compose the bulk of the lesions and demonstrate widespread epigenetic abnormalities. Endometriotic stromal cells also display a wide range of abnormal NR expression. The orphan NRs NR5A1 and NR2F2 compete to regulate steroid-synthesizing genes in endometriotic stromal cells; NR5A1 dominance gives rise to excessive estrogen formation. Endometriotic stromal cells show an abnormally low ESR1:ESR2 ratio due to excessive levels of ESR2, which mediates an estrogen-driven inflammatory process and prostaglandin formation. These cells are also deficient in PGR, leading to progesterone resistance and defective retinoid synthesis. The pattern of NR expression, involving low ESR1 and PGR and high ESR2, is reminiscent of uterine leiomyoma stem cells. This led us to speculate that endometriotic stromal cells may display stem cell characteristics found in other uterine tissues. The biologic consequences of these abnormalities in endometriotic tissue include intense inflammation, defective differentiation and enhanced survival. WIDER IMPLICATIONS Steroid- and other NR-related abnormalities exert genome-wide biologic effects via interaction with defective epigenetic programming and enhance inflammation in endometriotic stromal cells. New synthetic ligands, targeting PGR, retinoic acid receptors and ESR2, may offer novel treatment options.

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“…In the paper published in this issue of Endocrinology by Shimeng Liu and coworkers, the Bulun’s team explore a possible way of reducing leiomyoma lesions through a treatment by an epigenetic modulator, 5’-Aza-Cytidine ( 3 ). Building on their previous results and know-how ( 4 , 5 ), the Bulun’s team was able to separate, from human samples, 3 cell populations by fluorescence assisted cell sorting (FACs) using CD34 and CD49: stem-cell like cells (LSCs), intermediate cells (LICs), and differentiated cells (LDs) that were globally evaluated by transcriptome and methylome analyses. Ribonucleic acid sequencing (RNA-seq) was used for the transcription analysis and MethylCap-Seq for the methylation analysis.…”

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confidence: 99%