PTEN overexpression and nuclear β-catenin stabilization promote morular differentiation through induction of epithelial–mesenchymal transition and cancer stem cell-like properties in endometrial carcinoma

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Although a lack of functional PTEN contributes to tumorigenesis in a wide spectrum of human malignancies, little is known about the functional role of its overexpression in the tumors. The current study focused on PTEN overexpression in endometrial carcinoma (Em Ca). </jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>The functional impact of PTEN overexpression was assessed by Em Ca cell lines. Immunohistochemical analyses were also conducted using 38 Em Ca with morular lesions. </jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Em Ca cell lines stably overexpressing PTEN (H6-PTEN) exhibited epithelial–mesenchymal transition (EMT)-like features, probably through β-catenin/Slug-meditated suppression of E-cadherin. PTEN overexpression also inhibited cell proliferation, accelerated cellular senescence, increased apoptotic features, and enhanced migration capability. Moreover, H6-PTEN cells exhibited cancer stem cell (CSC)-like properties, along with high expression of aldehyde dehydrogenase 1 and CD44s, a large ALDH 1<jats:sup>high</jats:sup> population, enriched spheroid formation, and β-catenin-mediated upregulation of cyclin D2, which is required for persistent CSC growth. In clinical samples, immunoreactivities for PTEN, as well as CSC-related molecules, were significantly higher in morular lesions as compared to the surrounding carcinomas. PTEN score was positively correlated with expression of nuclear β-catenin, cytoplasmic CD133, and CD44v6, and negatively with cell proliferation. Finally, estrogen receptor-α (ERα)-dependent expression of Ezrin-radixin-moesin-binding phophoprotein-50 (EBP50), a multifunctional scaffolding protein, acts as a negative regulator of morular formation by Em Ca cells through interacting with PTEN and β-catenin.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>In the abscess of ERα/EBP50 expression, PTEN overexpression and nuclear β-catenin stabilization promote the establishment and maintenance of morular phenotype associated with EMT/CSC-like features in Em Ca cells.</jats:p> </jats:sec>