Vitamin D as an effective treatment in human uterine leiomyomas independent of mediator complex subunit 12 mutation

Abstract

Objective: To study whether vitamin D (VitD) inhibits cell proliferation and Wnt/β-catenin and transforming growth factor-β (TGFβ) signaling pathways in uterine leiomyomas independent of mediator complex subunit 12 (MED12) mutation status.

Design: Prospective study comparing leiomyoma vs. myometrial tissues and human uterine leiomyoma primary (HULP) cells treated with or without VitD and analyzed by MED12 mutation status.

Setting: Hospital and university laboratories.

Patient(s): Women with uterine leiomyoma without any treatment (n = 37).

Intervention(s): Uterine leiomyoma and myometrium samples were collected from women undergoing surgery because of symptomatic leiomyoma pathology.

Main outcome measure(s): Analysis of Wnt/β-catenin and TGFβ pathways and proliferation by quantitative real-time polymerase chain reaction in leiomyoma and myometrial tissue as well as in VitD-treated HULP cells analyzed by Sanger sequencing.

Results: Sequencing data showed that 46% of leiomyomas presented MED12 mutation, whereas no mutations were detected in adjacent myometrium. Expression of Wnt/β-catenin and TGFβ pathway genes was significantly increased in MED12-mutated leiomyomas compared to matched myometrium; no significant differences were found in wild-type (WT) leiomyomas. In HULP cells, VitD significantly decreased PCNA expression of both MED12-mutated and WT groups. VitD treatment decreased WNT4 and β-catenin expression in both groups compared to controls, with significance for WNT4 expression in MED12-mutated samples. Similarly, VitD significantly inhibited TGFβ3 expression in cells from both groups. MMP9 expression also decreased.

Conclusion: Despite molecular differences between MED12-mutated and WT leiomyomas, VitD inhibited Wnt/β-catenin and TGFβ pathways in HULP cells, suggesting VitD as an effective treatment to reduce proliferation and extracellular matrix formation in different molecular subtypes of uterine leiomyomas.

Keywords: MED12 mutation; TGFβ signaling pathway; Uterine leiomyoma; Wnt/β-catenin pathway; cell proliferation.