Abstract
Adenomyosis is defined as the presence of ectopic nests of endometrial glands and stroma within the myometrium. Adenomyosis is a common cause of dysmenorrhea, menorrhagia, and chronic pelvic pain but is often underdiagnosed. Despite its prevalence and severity of symptoms, its pathogenesis and etiology are poorly understood. Our previous study showed that aberrant activation of β-catenin results in adenomyosis through epithelial–mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-β signaling in the uteri of mutant mice that expressed dominant stabilized β-catenin in the uterus. There was a strong positive correlation between β-catenin and TGF-β2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-β inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear β-catenin. Our results suggest that β-catenin activates TGF-β-induced epithelial–mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-β as a potential therapeutic target for adenomyosis.
Highlights
Adenomyosis is a common benign heterogeneous gynecological disorder defined by the presence of endometrial glandular and stromal tissue found in the myometrium[1,2]
It is a useful model system to investigate the genetic and molecular events involved in the transition from normal uterine structure to adenomyosis. β-catenin has a dual function, regulating both the coordination of cell–cell adhesion and gene transcription, depending on its localization in the cell
Since TGF-β2 was identified as a direct target of β-catenin, we examined the relationship between β-catenin and TGF-β2 proteins in adenomyosis patients
Summary
Adenomyosis is a common benign heterogeneous gynecological disorder defined by the presence of endometrial glandular and stromal tissue found in the myometrium[1,2]. Adenomyosis is diagnosed in 10 to 66% of women at the time of hysterectomy[3]. It is systematically associated with menorrhagia, dysmenorrhea, chronic pelvic pain and dyspareunia[4,5], and can interfere with embryo implantation and cause subfertility[6,7]. Adenomyosis is more frequently diagnosed in infertile patients by transvaginal ultrasonography and magnetic resonance imaging[8]. There have been several studies in mice using hormonal treatment that have shown an increased incidence of adenomyosis[12,13,14]. The molecular mechanism for the development and progression of adenomyosis is still unclear. Mice with uterine conditional activation of β-catenin (Pgrcre/+Ctnnβf(ex3)/+) develop adenomyosis[15].
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