Activation of β-catenin signaling and its cross talk with estrogen and histone deacetylases in human uterine fibroids

Context: Uterine Fibroid (UF) is the most common benign tumor in myometrium (MM) of reproductive age women. However, mechanism underlying disease pathogenesis is largely unknown. Objective: To explore the link between nuclear β-catenin and UF phenotype and β-catenin cross-talk with estrogen and histone deacetylases (HDACs). Design protein/RNA levels of β-catenin (CTNNB1), its responsive markers [CyclinD1, c-Myc], Androgen receptor (AR), p27 and class-I HDACs were measured in matched UF/MM tissues or cell populations. Chemical inhibition/activation and genetic knockdown (KD) of CTNNB1 were performed and their effects on UF phenotype were measured. Anti-UF Effect of two HDAC inhibitors (HDACis) was evaluated. Main Outcome Measure: β-catenin nuclear translocation in response to β-catenin inhibition/activation, estrogen and HDACis in UF cells. Results: UF tissues/cells showed significantly higher expression of nuclear β-catenin, CyclinD1, C-Myc, and HDACs (1, 2, 3, 8) than MM. Estradiol ind...研究背景：子宫肌瘤（Uterine Fibroid, UF）是育龄女性子宫肌层（Myometrium, MM）最常见的良性肿瘤，但其发病机制目前尚不明确。研究目标：探讨核β-连环蛋白与子宫肌瘤表型之间的关联，以及β-连环蛋白与雌激素、组蛋白去乙酰化酶（Histone Deacetylases, HDACs）的交叉调控作用。实验方案：在配对的子宫肌瘤/子宫肌层组织或细胞群中，检测β-连环蛋白（CTNNB1）及其响应标志物[细胞周期蛋白D1（CyclinD1）、c-Myc]、雄激素受体（Androgen Receptor, AR）、p27与I类组蛋白去乙酰化酶的蛋白及RNA表达水平；开展β-连环蛋白（CTNNB1）的化学抑制/激活实验与基因敲低（Knockdown, KD）实验，并检测其对子宫肌瘤表型的影响；同时评估两种组蛋白去乙酰化酶抑制剂（HDAC inhibitors, HDACis）的抗子宫肌瘤活性。主要观测指标：子宫肌瘤细胞中，β-连环蛋白在经β-连环蛋白抑制/激活、雌激素及组蛋白去乙酰化酶抑制剂处理后的核转位情况。实验结果：子宫肌瘤组织/细胞的核β-连环蛋白、细胞周期蛋白D1、c-Myc以及组蛋白去乙酰化酶1、2、3、8的表达水平均显著高于子宫肌层。雌二醇（Estradiol）……