Introduction PAX2 (Paired box 2) and PTEN inactivation were reportedly as important biomarkers for endometrioid intraepithelial neoplasia (EIN) and Endometrioid endometrial carcinoma (EEC). However, though PTEN was extensively studied, the role of PAX2 in EEC carcinogenesis still remains unclear.
Methods Public databases and clinical paired paraffin-embedded tissues were used to analyze PAX2 expression in EEC. Cell function tests and mouse xenograft models were utilized to study the biological functions of PAX2. Pyrosequencing and demethylating drug 5-Aza-dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay.
Results PAX2 expression was significantly down-regulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation.
Conclusion/Implications Our findings elucidated the expression and function of PAX2 in EEC and firstly provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression.
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