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β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation

Abstract

The Wnt/β-catenin signaling is essential for various organogenesis and is often implicated during tumorigenesis. Dysregulated β-catenin signaling is associated with the formation of endometrial adenocarcinomas (EACs), which is considered as the common form of endometrial cancer in women. In the current study, we investigate the downstream target of Wnt/β-catenin signaling in the uterine epithelia and the mechanism leading to the formation of endometrial hyperplasia. We report that conditional ablation and activation of β-catenin in the uterine epithelia lead to aberrant epithelial structures and endometrial hyperplasia formation, respectively. We demonstrate that β-catenin regulates Foxa2 with its candidate upstream region for the uterine epithelia. Furthermore, knockdown of Foxa2 leads to defects in cell cycle regulation, suggesting a possible function of Foxa2 in the control of cell proliferation. We also observe that β-catenin and Foxa2 expression levels are augmented in the human specimens of complex atypical endometrial hyperplasia, which is considered to have a greater risk of progression to EACs. Thus, our study indicates that β-catenin regulates Foxa2 expression, and this interaction is possibly essential to control cell cycle progression during endometrial hyperplasia formation. Altogether, the augmented expression levels of β-catenin and Foxa2 are essential features during the formation of endometrial hyperplasia.

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Acknowledgements

We thank Drs R Behringer, H Sasaki, M M Taketo, W Birchmeier, A Santin, R Nishinakamura, Y Yoshimura, T Kurita, N Shiraki, K Maehara, H Nishida-Fukuda, K Yoshinaga, MA Suico, S Ohta, A Murashima, L Liu, A Omori, M Harada and D Matsumaru for their constructive criticisms We also thank E Chun, Y Sakamoto, Y Yamakawa, T Seki, M Aoki, S Usuki, M Matsumuto, M Etoh, S Fujikawa, Y Endo, S Miyaji and T Iba for technical help. This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas: molecular mechanisms for the establishment of Sex Differences (22132006), Global Center of Excellence program ‘Cell Fate Regulation Research and Education Unit’ and Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. This work was also supported by the National Institutes Health grant R01ES016597-01A1.

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Correspondence to G Yamada.

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Villacorte, M., Suzuki, K., Hirasawa, A. et al. β-Catenin signaling regulates Foxa2 expression during endometrial hyperplasia formation. Oncogene 32, 3477–3482 (2013). https://doi.org/10.1038/onc.2012.376

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  • DOI: https://doi.org/10.1038/onc.2012.376

Keywords

  • uterine gland
  • Wnt/β-catenin
  • Foxa2
  • cyclin
  • endometrial hyperplasia

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