Ana Corachán1, Hortensia Ferrero2, Alejandra Aguilar3, Nuria Garcia3, Javier Monleon3, Amparo Faus4, Irene Cervelló4, Antonio Pellicer5. 1. Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain. 2. Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia; Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain. Electronic address: hortensia.ferrero@ivirma.com. 3. Hospital Universitario y Politécnico La Fe, Valencia. 4. Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia. 5. Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia; Hospital Universitario y Politécnico La Fe, Valencia.
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: University hospital. 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.
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: University hospital. 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:Humanleiomyoma 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.
Authors: Phyllis C Leppert; Ayman Al-Hendy; Donna D Baird; Serdar Bulun; William Catherino; Darlene Dixon; Merrick Ducharme; Quaker E Harmon; Friederike L Jayes; Emmanuel Paul; Aymara Mas Perucho; James Segars; Carlos Simón; Elizabeth A Stewart; Jose Teixeira; Andrea Tinelli; Daniel Tschumperlin; Ami R Zota Journal: F S Sci Date: 2020-11-07