CXADR promote epithelial–mesenchymal transition in endometriosis by modulating AKT/GSK-3β signaling

Endometriosis is a benign high prevalent disease exhibiting malignant features. However, the underlying pathogenesis and key molecules of endometriosis remain unclear. By integrating and analysis of existing expression profile datasets, we identified coxsackie and adenovirus receptor (CXADR), as a novel key gene in endometriosis. Based on the results of immunohistochemistry (IHC), we confirmed significant down-regulation of CXADR in ectopic endometrial tissues obtained from women with endometriosis compared with healthy controls. Further in vitro investigation indicated that CXADR regulated the stability and function of the phosphatases and AKT inhibitors PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2) and PTEN (phosphatase and tensin homolog). Loss of CXADR led to phosphorylation of AKT and glycogen synthase kinase-3β (GSK-3β), which resulted in stabilization of an epithelial–mesenchymal transition (EMT) factor, SNAIL1 (snail family transcriptional repressor 1). Therefore, EMT processs was induced, and the proliferation, migration and invasion of Ishikawa cells were enhanced. Over-expression of CXADR showed opposite effects. These findings suggest a previously undefined role of AKT/GSK-3β signaling axis in regulating EMT and reveal the involvement of a CXADR-induced EMT, in pathogenic progression of endometriosis.子宫内膜异位症（Endometriosis）是一种具有恶性表型的良性高患病率疾病，但其潜在发病机制与关键分子仍未明确。通过整合分析现有表达谱数据集，我们鉴定出柯萨奇病毒与腺病毒受体（CXADR）为子宫内膜异位症的新型关键基因。基于免疫组织化学（IHC）结果，我们证实相较于健康对照，子宫内膜异位症患者的异位子宫内膜组织中CXADR的表达显著下调。进一步的体外实验表明，CXADR可调控磷酸酶及AKT抑制剂PHLPP2（pleckstrin同源结构域与亮氨酸富集重复蛋白磷酸酶2）和PTEN（张力蛋白同源缺失的磷酸酶）的稳定性与功能。CXADR的缺失会导致AKT及糖原合成激酶3β（GSK-3β）发生磷酸化，进而稳定上皮间质转化（EMT）因子SNAIL1（蜗牛家族转录抑制因子1）。因此，上皮间质转化过程被诱导，Ishikawa细胞的增殖、迁移与侵袭能力增强。过表达CXADR则呈现相反的效应。上述研究结果表明，AKT/GSK-3β信号轴在调控上皮间质转化中存在此前未被阐明的作用，并揭示了CXADR介导的上皮间质转化参与子宫内膜异位症的致病进程。