Inhibition of tumor cell proliferation in human uterine leiomyomas by vitamin D via Wnt/β-catenin pathway

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Authors:

Ana Corachán, M.Sc., Hortensia Ferrero, Ph.D., Alejandra Aguilar, M.D., Nuria Garcia, M.D., Javier Monleon, M.D., Amparo Faus, B.Sc., Irene Cervelló, Ph.D.†, Antonio Pellicer, MD

Abstract:

Objective

To assess the effect of vitamin D (VitD) on human uterine leiomyomas through Wnt/β-catenin pathway inhibition, apoptosis induction, and cell growth arrest.

Design

A prospective study comparing leiomyoma vs. myometrium tissues. Paired design study comparing human uterine leiomyoma primary (HULP) cells treated with or without VitD.

Setting

Hospital Universitario-Politécnico La Fe, Fundación IVI/INCLIVA, Universidad de Valencia, Valencia, Spain.

Patient(s)

Human uterine leiomyoma and myometrium were collected from women (aged 35−52 years) without hormonal treatment.

Intervention(s)

Samples were collected from women undergoing surgery due to symptomatic uterine leiomyoma pathology.

Main Outcome Measure(s)

Uterine leiomyoma and myometrium tissues were analyzed by western blot (WB) to determine proliferation, Wnt/β-catenin, and apoptosis pathways. HULP cells were used to study VitD effect in cell proliferation (WB), cell cycle (flow cytometry), Wnt/β-catenin and apoptosis genes (polymerase chain reaction arrays), Wnt-related proteins (protein array), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL] assay).

Results

Human leiomyoma tissues compared with matched myometrium showed higher proliferation (fold change = 8.16; P=.0006) and altered Wnt/β-catenin pathway (fold change = 5.5; P<.0001), whereas no differences in apoptosis were observed. VitD induced cell growth arrest and decreased proliferation in HULP cells (fold change = 0.74; P=.007). Moreover, VitD decreased Wnt-pathway expression in HULP cells at gene (activity score = −0.775; P<.001) and protein levels. However, VitD did not induce apoptosis expression.

Conclusion

Increased proliferation and Wnt/β-catenin pathway deregulation play a role in the development and growth of leiomyomas, whereas apoptosis appears not to contribute. VitD exerts an antiproliferative action on HULP cells through cell growth arrest and Wnt/β-catenin pathway inhibition, but not through apoptosis regulation, suggesting VitD as an effective therapy to stabilize leiomyoma size and prevent its growth.


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