Reduced DEFA5 Expression and STAT3 Activation Underlie the Submucosal Invasion of Early Gastric Cancers

Sayaka Nagao, Yu Takahashi, Tamami Denda, Yukihisa Tanaka, Yuko Miura, Hiroya Mizutani, Daisuke Ohki, Yoshiki Sakaguchi, Seiichi Yakabi, Yosuke Tsuji, Keiko Niimi, Naomi Kakushima, Nobutake Yamamichi, Yasunori Ota, Kazuhiko Koike, Mitsuhiro Fujishiro

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Submucosal invasion is a core hallmark of early gastric cancer (EGC) with poor prognosis. However, the molecular mechanism of the progression from intramucosal gastric cancer (IMGC) to early submucosal-invasive gastric cancer (SMGC) is not fully understood. The objective of this study was to identify genes and pathways involved in the submucosal invasion in EGC using comprehensive gene expression analysis. Methods: Gene expression profiling was performed for eight cases of IMGC and eight cases of early SMGC with submucosal invasion ≥500 μm. To validate the findings of gene expression analysis and to examine the gene expression pattern in tissues, immunohistochemical (IHC) staining was performed for 50 cases of IMGC and SMGC each. Results: Gene expression analysis demonstrated that the expression levels of small intestine-specific genes were significantly decreased in SMGC. Among them, defensin alpha 5 (DEFA5) was the most downregulated gene in SMGC, which was further validated in SMGC tissues by IHC staining. Gene set enrichment analysis showed a strong association between SMGC, the JAK-STAT signaling pathway, and the upregulation of STAT3-activating cytokines. The expression of phosphorylated STAT3 was significant in the nucleus of tumor cells in SMGC tissues but not in areas expressing DEFA5. Conclusion: The results of this study strongly suggest that the downregulation of DEFA5 and the activation of STAT3 play a significant role in the submucosal invasion of EGC.

Original languageEnglish
Pages (from-to)480-493
Number of pages14
JournalDigestion
Volume104
Issue number6
DOIs
Publication statusPublished - 1 Dec 2023
Externally publishedYes

Keywords

  • DEFA5
  • Gastric cancer
  • STAT3
  • Submucosal invasion

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