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

Corachan, A, Trejo, M G, Carbajo-Garcia, M C, Monleon, J, Escrig, J, Faus, A, Pellicer, A, Cervello, I, Ferrero, H,
Fertil Steril. Feb. 2021 doi: 10.1016/j.fertnstert.2020.07.049


OBJECTIVE: To study whether vitamin D (VitD) inhibits cell proliferation and Wnt/beta-catenin and transforming growth factor-beta (TGFbeta) 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/beta-catenin and TGFbeta 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/beta-catenin and TGFbeta 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 beta-catenin expression in both groups compared to controls, with significance for WNT4 expression in MED12-mutated samples. Similarly, VitD significantly inhibited TGFbeta3 expression in cells from both groups. MMP9 expression also decreased. CONCLUSION: Despite molecular differences between MED12-mutated and WT leiomyomas, VitD inhibited Wnt/beta-catenin and TGFbeta pathways in HULP cells, suggesting VitD as an effective treatment to reduce proliferation and extracellular matrix formation in different molecular subtypes of uterine leiomyomas.