Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Stem Cell Properties of Gastric Cancer Stem-Like Cells under Stress Conditions Are Regulated via the c-Fos/UCH-L3/β-Catenin Axis

  • Jae Hyeong Lee (Department of Molecular Bioscience, Kangwon National University) ;
  • Sang-Ah Park (Graduate School of Medical Science & Engineering, Korea Advanced Institute of Science and Technology) ;
  • Il-Geun Park (Graduate School of Medical Science & Engineering, Korea Advanced Institute of Science and Technology) ;
  • Bo Kyung Yoon (Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine) ;
  • Jung-Shin Lee (Department of Molecular Bioscience, Kangwon National University) ;
  • Ji Min Lee (Graduate School of Medical Science & Engineering, Korea Advanced Institute of Science and Technology)
  • Received : 2023.01.12
  • Accepted : 2023.05.24
  • Published : 2023.08.31
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Abstract

Gastric cancer stem-like cells (GCSCs) possess stem cell properties, such as self-renewal and tumorigenicity, which are known to induce high chemoresistance and metastasis. These characteristics of GCSCs are further enhanced by autophagy, worsening the prognosis of patients. Currently, the mechanisms involved in the induction of stemness in GCSCs during autophagy remain unclear. In this study, we compared the cellular responses of GCSCs with those of gastric cancer intestinal cells (GCICs) whose stemness is not induced by autophagy. In response to glucose starvation, the levels of β-catenin and stemness-related genes were upregulated in GCSCs, while the levels of β-catenin declined in GCICs. The pattern of deubiquitinase ubiquitin C-terminal hydrolase-L3 (UCH-L3) expression in GCSCs and GCICs was similar to that of β-catenin expression depending on glucose deprivation. We also observed that inhibition of UCH-L3 activity reduced β-catenin protein levels. The interaction between UCH-L3 and β-catenin proteins was confirmed, and it reduced the ubiquitination of β-catenin. Our results suggest that UCH-L3 induces the stabilization of β-catenin, which is required to promote stemness during autophagy activation. Also, UCH-L3 expression was regulated by c-Fos, and the levels of c-Fos increased in response to autophagy activation. In summary, our findings suggest that the inhibition of UCH-L3 during nutrient deprivation could suppress stress resistance of GCSCs and increase the survival rates of gastric cancer patients.

Keywords

Acknowledgement

This work was supported by the Basic Science Research Program NRF-2021R1C1C1008780 to J.M.L. from the National Research Foundation (NRF) grant funded by the Korean government.

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