STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma

Authors

  • Li Wang a Department of Obstetrics and Gynecology, Center of Genetics and Prenatal Diagnosis, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
  • Qiao-Feng Zhao b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China; c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China
  • Bing-Bing Yang b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China;c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China; d State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, P. R. China
  • Hui-Jie Liang b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China; c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China
  • Xian-E Zhang b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China;c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China; e Second People’s Hospital of Henan Province, Zhengzhou, P. R. China
  • Xiao-Yan Zhang b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China; c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China
  • Wan-Jing Yang b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China; c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China
  • Zhi-Yu Guo f SanQuan College of XinXiang Medical University, Xinxiang, P. R. China
  • Xin Xu g College of Biotechnology, Center for Self-Propelled Nanotechnologies, Suzhou Industrial Park Institute of Services Outsourcing, Suzhou, P. R. China; h Translational Cancer Research Laboratory, Suzhou Acumen Medical Technology, Suzhou, P. R. China
  • Fang Tian b Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, P. R. China;c Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, P. R. China; d State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, P. R. China
  • Qing-Hua Wu a Department of Obstetrics and Gynecology, Center of Genetics and Prenatal Diagnosis, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China

DOI:

https://doi.org/10.1080/0284186X.2023.2259601

Keywords:

STAT3, EphA7, transcription, ESCC, promoter

Abstract

Background

Our previous study has revealed that EphA7 was upregulated in patient-derived esophageal squamous cell carcinoma (ESCC) xenografts with hyper-activated STAT3, but its mechanism was still unclear.

Materials and methods

To assess the association between EphA7 and STAT3, western blotting, immunofluorescence, ChIP assay, and qRT-PCR were conducted. Truncated mutation and luciferase assay were performed to examine the promoter activity of EphA7. CCK-8 assay and colony formation were performed to assess the proliferation of ESCC. Cell-derived xenograft models were established to evaluate the effects of EphA7 on ESCC tumor growth. RNA-seq analyses were used to assess the effects of EphA7 on related signals.

Results

In this study, EphA7 was found upregulated in ESCC cell lines with high STAT3 activation, and immunofluorescence also showed that EphA7 was co-localized with phospho-STAT3 in ESCC cells. Interestingly, suppressing STAT3 activation by the STAT3 inhibitor Stattic markedly inhibited the protein expression of EphA7 in ESCC cells, in contrast, activation of STAT3 by IL-6 obviously upregulated the protein expression of EphA7. Moreover, the transcription of EphA7 was also mediated by the activation of STAT3 in ESCC cells, and the −2000∼−1500 region was identified as the key promoter of EphA7. Our results also indicated that EphA7 enhanced the cell proliferation of ESCC, and silence of EphA7 significantly suppressed ESCC tumor growth. Moreover, EphA7 silence markedly abolished STAT3 activation-derived cell proliferation of ESCC. Additionally, RNA-seq analyses indicated that several tumor-related signaling pathways were significantly changed after EphA7 downregulation in ESCC cells.

Conclusion

Our results showed that the transcriptional expression of EphA7 was increased by activated STAT3, and the STAT3 signaling may act through EphA7 to promote the development of ESCC.

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Published

2023-12-02

How to Cite

Wang, L., Zhao, Q.-F., Yang, B.-B., Liang, H.-J., Zhang, X.-E., Zhang, X.-Y., … Wu, Q.-H. (2023). STAT3-EphA7 axis contributes to the progression of esophageal squamous cell carcinoma. Acta Oncologica, 62(12), 1757–1766. https://doi.org/10.1080/0284186X.2023.2259601

Issue

Vol. 62 No. 12 (2023): Acta Oncologica

Section

Articles