RANKL/RANK pathway and its inhibitor RANK-Fc in uterine leiomyoma growth
Open accessAbstract
Context: Uterine leiomyomas are the most common type of gynecologic tumor in women. Objective: To determine the role of the cytokine receptor activator of nuclear factor κ-Β ligand (RANKL); its receptor, receptor activator of nuclear factor κ-Β (RANK); and the RANKL/RANK pathway inhibitor RANK-Fc in leiomyoma growth. Design: Messenger RNA (mRNA) or protein levels of RANKL, RANK, and proliferation markers cyclin D1 and Ki67 were assessed in various leiomyoma tissues and cell populations. Human xenograft experiments were performed to determine the effects of RANK-Fc on leiomyoma growth in vivo. Setting: Research laboratory. Patients: Twenty-four regularly cycling premenopausal women (age 28 to 49 years) who were not receiving hormone therapy. Interventions: None. Main Outcome Measure: Tumor growth in a murine xenograft model following targeting of the RANKL/RANK pathway with RANK-Fc. Results: RANKL mRNA levels in leiomyoma were significantly higher than those in myometrial tissues. The highest RANK levels were found in the leiomyoma stem cell population, which is deficient in progesterone receptor (PR). Conversely, the highest RANKL levels were found in the PR-rich leiomyoma intermediate cell (LIC) population. R5020, a PR agonist, specifically increased RANKL expression in LICs. RANK-Fc blocked RANKL-induced expression of the proliferative gene cyclin D1. Treatment with RANK-Fc also significantly decreased tumor growth in vivo and diminished the expression of proliferation marker Ki67 in tumors (P < 0.01; n = 4). Conclusions: Treatment with the RANKL/RANK pathway inhibitor RANK-Fc significantly decreased human leiomyoma cell proliferation and tumor growth. This suggests that the RANKL/RANK pathway could serve as a potential target for the prevention and treatment of uterine leiomyoma.
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A PGR-positive group of cells in uterine leiomyomas secrete RANKL following progestin treatment, which induces proliferation of leiomyoma stem cells through its receptor RANK.
“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).”
From Endometriosis and nuclear receptors (2019) · cites this paper as Ikhena et al., 2018
The progestin-response section reports increased RANKL expression in progesterone-receptor-positive leiomyoma intermediate cells, and the RANK-expression section finds RANK preferentially in leiomyoma stem cells (pages unavailable). The Discussion describes activation of stem cells by intermediate-cell-derived RANKL as a potential paracrine interaction. It does not establish RANKL secretion after progestin treatment or directly show that this treatment induces stem-cell proliferation through RANK. (LLM, conf=0.86)
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References 19 · Cited by 26
Research works printed but not linked: 1
- Hann HW, Stahlhut MW, Rubin R, Maddrey WC. Antitumor effect of deferoxamine on human hepatocellular carcinoma growing in athymic nude mice. Cancer. 1992;70(8):2051-2056.
- Authors
- Ikhena, D. E., Liu, S., Kujawa, S., Esencan, E., Coon, J. S., Robins, J., Bulun, S. E., & Yin, P.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Yin, Ping
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-03-14
- Volume
- 103
- Issue
- 5
- Pages
- 1842-1849
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC6276708
- OpenAlex
- W2793470639
- Cited by
- 26
- References
- 19
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 1
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Northwestern University (CA060553)
- National Institutes of Health (CA-060553)
- National Cancer Institute (CA 060553, P30CA060553)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD057877)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Uterine Myomas and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- uterine fibroids, leiomyoma growth, progesterone receptor, cyclin D1, Ki-67, tumor cell proliferation, R5020, tumor heterogeneity, xenograft tumor growth, NF-κB signaling
- MeSH terms
- Adult, Cells, Cultured, Female, Humans, Leiomyoma, Middle Aged, Recombinant Fusion Proteins, Uterine Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Case-Control Studies, Cell Proliferation, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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