Human Cell

, Volume 32, Issue 3, pp 367–378 | Cite as

Proliferation of poorly differentiated endometrial cancer cells through autocrine activation of FGF receptor and HES1 expression

  • Michihiro MoriEmail author
  • Toshinori Mori
  • Aina Yamamoto
  • Shoji Takagi
  • Masatsugu Ueda
Research Article


Patients with poorly differentiated endometrial cancer show poor prognosis, and effective molecular target-based therapies are needed. Endometrial cancer cells proliferate depending on the activation of HES1 (hairy and enhancer of split-1), which is induced by several pathways, such as the Notch and fibroblast growth factor receptor (FGFR) signaling pathways. In addition, aberrant, ligand-free activation of the FGFR signaling pathway resulting from mutations in FGFR2 was also reported in endometrial cancer. However, a clinical trial showed that there was no difference in the effectiveness of FGFR inhibitors between patients with and without the FGFR2 mutation, suggesting a presence of another signaling pathway for the FGFR activation. Here, we investigated the signaling pathway regulating the expression of HES1 and proliferation of poorly and well-differentiated endometrial cancer cell lines Ishikawa and HEC-50B, respectively. Whereas Ishikawa cells proliferated and expressed HES1 in a Notch signaling-dependent manner, Notch signaling was not involved in HES1 and proliferation of HEC-50B cells. The FGFR inhibitor, NVP-BGJ398, decreased HES1 expression and proliferation of HEC-50B cells; however, HEC50B cells had no mutations in the FGFR2 gene. Instead, HEC-50B cells highly expressed ligands for FGFR2, suggesting that FGFR2 is activated by an autocrine manner, not by ligand-free activation. This autocrine pathway activated Akt downstream of FGFR for cell proliferation. Our findings suggest the usefulness of HES1 as a marker for the proliferation signaling and that FGFR inhibitor may be effective for poorly differentiated endometrial cancers that harbor wild-type FGFR.


HES1 FGF/FGFR FGFR2 Endometrial cancer NVP-BGJ398 



We thank Masayoshi Okada and Edanz Group ( for editing a draft of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Michihiro Mori
    • 1
    • 2
    Email author
  • Toshinori Mori
    • 3
    • 4
  • Aina Yamamoto
    • 4
  • Shoji Takagi
    • 1
    • 2
  • Masatsugu Ueda
    • 5
    • 6
  1. 1.Department of Medical Life Science, College of Life ScienceKurashiki University of Science and the ArtsOkayamaJapan
  2. 2.Kake Institute of CytopathologyOkayamaJapan
  3. 3.Department of Clinical LaboratoryMihara Medical Associations HospitalHiroshimaJapan
  4. 4.Department of Chemical Technology, Graduate School of Science and Industrial TechnologyKurashiki University of Science and the ArtsOkayamaJapan
  5. 5.Faculty of Health SciencesKio UniversityNaraJapan
  6. 6.Graduate School of Health SciencesKio UniversityNaraJapan

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