Cell Communication and Signaling (Nov 2022)

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

  • Ako Yokoi,
  • Marina Minami,
  • Miki Hashimura,
  • Yasuko Oguri,
  • Toshihide Matsumoto,
  • Yoshinori Hasegawa,
  • Mayu Nakagawa,
  • Yu Ishibashi,
  • Takashi Ito,
  • Kensuke Ohhigata,
  • Youhei Harada,
  • Naomi Fukagawa,
  • Makoto Saegusa

DOI
https://doi.org/10.1186/s12964-022-00999-w
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 14

Abstract

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Abstract Background 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). Methods 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. Results 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 1high 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. Conclusion 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. Video Abstract

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