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

ABSTRACT

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.

KEYWORDS:

• Endometriosis
• CXADR, EMT
• AKT-signaling pathway

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contribution statement

HJ-T and HM-X performed study concept and design; HJ-T, ZH-D and HW-D performed development of methodology and writing, review and revision of the paper; CZ provided acquisition, analysis and interpretation of data, and statistical analysis. All authors read and approved the final paper.

Data availability statement

The data that support the findings of this study are openly available in Gene Expression Omnibus (GEO) database (https://www. ncbi.nlm.nih.gov/geo). All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Ethics statement

This study was approved by the Ethics Committees of School of basic medicine, Central South University (2022-KT109), and written informed consent was obtained from all patients before surgical procedures and sample collection.

Supplementary information

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2023.2296242

Additional information

Funding

This research was funded by the National Key R&D Program of China [2017YFC1001100].