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Background <p>Esophageal cancer is the 11th most common malignancy and the 7th leading cause of cancer-related death globally. Identifying key molecules and underlying mechanisms in the progression of esophageal cancer represents an effective strategy for developing novel therapeutic approaches.</p> Methods <p><i>DDX18</i> expression in clinical specimens was evaluated by immunohistochemistry and western blot analysis. Functional assays were performed in cells with either <i>DDX18</i> knockdown or overexpression. Dual luciferase reporter assays and chromatin immunoprecipitation (ChIP) were conducted to validate the interaction between <i>YY1</i> and the <i>DDX18</i> promoter. A xenograft tumor model was utilized to investigate the role of <i>DDX18</i> in vivo in esophageal cancer.</p> Results <p><i>DDX18</i> was found to be markedly overexpressed in esophageal cancer, with its levels significantly higher in patients with pathological grade III compared to those with grades I–II. In vitro, <i>DDX18</i> enhanced cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Furthermore, <i>DDX18</i> promoted epithelial–mesenchymal transition (EMT) and activated the <i>AKT</i>/<i>mTOR</i> signaling pathway. The use of <i>AKT</i> inhibitors effectively abrogated the oncogenic effects of <i>DDX18</i>. Dual luciferase and ChIP assays confirmed that <i>YY1</i> binds to and stimulates <i>DDX18</i> transcription. In rescue experiments, <i>YY1</i> countered the inhibitory effects of <i>DDX18</i> knockdown on cell proliferation, EMT, and <i>AKT</i>/<i>mTOR</i> activation. In vivo, <i>DDX18</i> knockdown resulted in reduced tumor growth.</p> Conclusions <p>The transcription of <i>DDX18</i> was activated by <i>YY1</i>, and <i>DDX18</i> promoted tumor cell growth and EMT through the <i>AKT</i>/<i>mTOR</i> signaling pathway in esophageal cancer cells.</p>

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YY1-induced DDX18 modulates EMT via the AKT/mTOR pathway in esophageal cancer: a novel therapeutic target

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Xiaochao Ma,
  • Yulu He,
  • Yue Yang,
  • Tianyu Lu,
  • Ze Tang,
  • Youbin Cui,
  • Rui Wang

摘要

Background

Esophageal cancer is the 11th most common malignancy and the 7th leading cause of cancer-related death globally. Identifying key molecules and underlying mechanisms in the progression of esophageal cancer represents an effective strategy for developing novel therapeutic approaches.

Methods

DDX18 expression in clinical specimens was evaluated by immunohistochemistry and western blot analysis. Functional assays were performed in cells with either DDX18 knockdown or overexpression. Dual luciferase reporter assays and chromatin immunoprecipitation (ChIP) were conducted to validate the interaction between YY1 and the DDX18 promoter. A xenograft tumor model was utilized to investigate the role of DDX18 in vivo in esophageal cancer.

Results

DDX18 was found to be markedly overexpressed in esophageal cancer, with its levels significantly higher in patients with pathological grade III compared to those with grades I–II. In vitro, DDX18 enhanced cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Furthermore, DDX18 promoted epithelial–mesenchymal transition (EMT) and activated the AKT/mTOR signaling pathway. The use of AKT inhibitors effectively abrogated the oncogenic effects of DDX18. Dual luciferase and ChIP assays confirmed that YY1 binds to and stimulates DDX18 transcription. In rescue experiments, YY1 countered the inhibitory effects of DDX18 knockdown on cell proliferation, EMT, and AKT/mTOR activation. In vivo, DDX18 knockdown resulted in reduced tumor growth.

Conclusions

The transcription of DDX18 was activated by YY1, and DDX18 promoted tumor cell growth and EMT through the AKT/mTOR signaling pathway in esophageal cancer cells.