MED12 somatic mutation promotes human uterine leiomyoma’s growth by trigging canonical Wnt4/β-catenin and TGF-β signaling through the EMT pathway

Background: Somatic mutations in the Mediator complex subunit 12 (MED12) genes are major contributor in the uterine leiomyomas (UL) pathogenesis. However, the molecular mechanism by which exon 2 missense variant (c.131G>A;Gly44Asp) promote UL growth remain unclear. Objective: The objective of present study is to explore the molecular mechanism of UL growth promoted by missense variant in exon2 of MED12 gene. Materials and methods: In this study, patient-derived primary cultures from UL tissues were established and MED12 mutations were confirmed by Sanger sequencing categorizing samples as MED12-mutant (MED12-mut) and MED12 wild type (MED12-WT). Results: Functional analysis revealed that MED12-mut UL cells displayed enhanced activation of canonical Wnt4/β-catenin and TGF-β signaling pathways compared with MED12-mut UL cells. This dual activation promoted cell proliferation, extracellular matrix (ECM) deposition, and epithelial-mesenchymal transition (EMT). Protein expression analyses further revealed significantly elevated levels of Vimentin, MMP-2, MMP-9, and α-SMA in MED12-mut tissues, consistent with increased remodeling and tumor aggressiveness. Conclusions: Our findings reveal that MED12 somatic mutation drives UL progression through coordinated activation of Wnt4/β-catenin and TGF-β signaling pathways, facilitating EMT and ECM remodeling. Targeting these intersecting signaling networks may represent a promising therapeutic strategy for the treatment of MED12 mutant uterine leiomyomas.