Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia; Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain.
Fundación IVI, Instituto Universitario IVI, Universidad de Valencia, Valencia; Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain.
Fertil Steril. 2019 Feb;111(2):397-407. doi: 10.1016/j.fertnstert.2018.10.008. Epub 2018 Nov 17.
To assess the effect of vitamin D (VitD) on human uterine leiomyomas through Wnt/β-catenin pathway inhibition, apoptosis induction, and cell growth arrest.
A prospective study comparing leiomyoma vs. myometrium tissues. Paired design study comparing human uterine leiomyoma primary (HULP) cells treated with or without VitD.
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).
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.
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.
通过抑制 Wnt/β-连环蛋白通路、诱导细胞凋亡和抑制细胞生长来评估维生素 D（VitD）对人子宫肌瘤的作用。
比较子宫肌瘤与子宫肌层组织的前瞻性研究。比较用或不用 VitD 处理的人子宫肌瘤原代（HULP）细胞的配对设计研究。
大学医院。
收集因症状性子宫肌瘤病理而行手术的女性（年龄 35-52 岁）的人子宫肌瘤和子宫肌层组织。
收集因症状性子宫肌瘤病理而行手术的女性的组织样本。
通过 Western blot（WB）分析人子宫肌瘤和子宫肌层组织以确定增殖、Wnt/β-连环蛋白和细胞凋亡途径。使用 HULP 细胞研究 VitD 对细胞增殖（WB）、细胞周期（流式细胞术）、Wnt/β-连环蛋白和细胞凋亡基因（聚合酶链反应阵列）、Wnt 相关蛋白（蛋白质阵列）和细胞凋亡（末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记[TUNEL]测定）的影响。
与配对的子宫肌层组织相比，人子宫肌瘤组织显示出更高的增殖（倍数变化=8.16；P=.0006）和改变的 Wnt/β-连环蛋白通路（倍数变化=5.5；P<.0001），而凋亡无差异。VitD 诱导 HULP 细胞生长停滞和增殖减少（倍数变化=0.74；P=.007）。此外，VitD 在基因（活性评分=-0.775；P<.001）和蛋白水平上降低了 HULP 细胞的 Wnt 通路表达。然而，VitD 并没有诱导细胞凋亡的表达。
增殖增加和 Wnt/β-连环蛋白通路失调在子宫肌瘤的发生和生长中起作用，而凋亡似乎不起作用。VitD 通过细胞生长停滞和 Wnt/β-连环蛋白通路抑制对 HULP 细胞发挥抗增殖作用，但不通过细胞凋亡调节，提示 VitD 是一种有效的治疗方法，可稳定子宫肌瘤大小并防止其生长。
