TY - JOUR
T1 - Paracrine pathways in uterine leiomyoma stem cells involve insulinlike growth factor 2 and insulin receptor a
AU - Moravek, Molly B.
AU - Yin, Ping
AU - Coon, John S.
AU - Ono, Masanori
AU - Druschitz, Stacy A.
AU - Malpani, Saurabh S.
AU - Dyson, Matthew T.
AU - Rademaker, Alfred W.
AU - Robins, Jared C.
AU - Wei, Jian Jun
AU - Kim, J. Julie
AU - Bulun, Serdar E.
N1 - Funding Information:
This work was supported by the National Institutes of Health/National Institute of Child Health and Human Development Grant P01-HD057877 (S.E.B.) and American Society for Reproductive Medicine In-Training Grant in Heavy Menstrual Bleeding (M.B.M.).
Publisher Copyright:
© 2017 Endocrine Society.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - Context: Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. Objective: To define differential gene expression and signaling pathways in leiomyoma cell populations. Design: Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, realtime quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-20-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma. Setting: Research laboratory. Patients: Eight African American women. Interventions: None Main Outcomes Measures: Gene expression patterns, cell proliferation, and differentiation. Results: Atotal of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P , 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD342/CD49b2 cells (15-fold and 0.35-fold, respectively; P , 0.05). IGF2 significantly increased cell number (1.4-fold; P , 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation. Conclusions: IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas. (J Clin Endocrinol Metab 102: 1588-1595, 2017).
AB - Context: Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. Objective: To define differential gene expression and signaling pathways in leiomyoma cell populations. Design: Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, realtime quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-20-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma. Setting: Research laboratory. Patients: Eight African American women. Interventions: None Main Outcomes Measures: Gene expression patterns, cell proliferation, and differentiation. Results: Atotal of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P , 0.05). Insulin receptor A (IR-A) expression was higher and IGF1 receptor lower in CD34+/CD49b+ vs CD342/CD49b2 cells (15-fold and 0.35-fold, respectively; P , 0.05). IGF2 significantly increased cell number (1.4-fold; P , 0.001), proliferation indices, and extracellular signal-regulated kinase (ERK) phosphorylation. ERK inhibition decreased IGF2-stimulated cell proliferation. Conclusions: IGF2 and IR-A are important for leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas. (J Clin Endocrinol Metab 102: 1588-1595, 2017).
UR - http://www.scopus.com/inward/record.url?scp=85019149734&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019149734&partnerID=8YFLogxK
U2 - 10.1210/jc.2016-3497
DO - 10.1210/jc.2016-3497
M3 - Article
C2 - 28324020
AN - SCOPUS:85019149734
VL - 102
SP - 1588
EP - 1595
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 5
ER -