β-catenin activates TGF-β-induced epithelial-mesenchymal transition in adenomyosis

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 beta-catenin results in adenomyosis through epithelial-mesenchymal transition. Using transcriptomic and ChIP-seq analysis, we identified activation of TGF-beta signaling in the uteri of mutant mice that expressed dominant stabilized beta-catenin in the uterus. There was a strong positive correlation between beta-catenin and TGF-beta 2 proteins in women with adenomyosis. Furthermore, treatment with pirfenidone, a TGF-beta inhibitor, increased E-cadherin expression and reduced cell invasiveness in Ishikawa cells with nuclear beta-catenin. Our results suggest that beta-catenin activates TGF-beta-induced epithelial-mesenchymal transition in adenomyosis. This finding describes the molecular pathogenesis of adenomyosis and the use of TGF-beta as a potential therapeutic target for adenomyosis. Uterine disease: Regulatory pathways identified A regulatory link between two proteins involved in the progression of a debilitating uterine condition highlights a potential therapeutic target. Adenomyosis involves the invasion of cells from the inner lining of the uterus (the endometrium) into the uterine muscle wall (the myometrium), resulting in heavy, prolonged periods and chronic pain. The aberrent activation of a protein called beta-catenin triggers adenomyosis, but the precise mechanisms are unclear. A team led by Jung-Ho Shin at the Korea University Medical Center, Seoul, South Korea, and Jae-Wook Jeong, Michigan State University, Grand Rapids, USA, used sequencing techniques in mice and human tissue samples to identify the pathways governed by beta-catenin in adenomyosis. They found that theTgf-beta 2gene is directly regulated by beta-catenin in the uterus. TGF-beta 2 levels were elevated in human adenomyosis lesions, suggesting the protein could be a therapeutic target.