Rel Family Transcription Factor NFAT5 Upregulates COX2 via HIF-1α Activity in Ishikawa and HEC1a Cells

Toshiyuki Okumura, Janet P. Raja Xavier, Jana Pasternak, Zhiqi Yang, Cao Hang, Bakhtiyor Nosirov, Yogesh Singh, Jakob Admard, Sara Y. Brucker, Stefan Kommoss, Satoru Takeda, Annette Staebler, Florian Lang, Madhuri S. Salker*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5—HIF-1α—COX2 axis could promote endometrial cancer progression.

Original languageEnglish
Article number3666
JournalInternational Journal of Molecular Sciences
Volume25
Issue number7
DOIs
Publication statusPublished - 25 Mar 2024

Keywords

  • cyclooxygenase 2
  • endometrial cancer
  • hypoxia inducible factor 1α

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