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<p>Chemoresistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC) and is often associated with poor clinical outcomes. This resistance is closely linked to cancer stem cell (CSC)-like properties, such as the ability to evade anoikis. In this study, we identify dual-specificity phosphatase 23 (DUSP23) as a critical regulator of CSC-like traits and chemoresistance. DUSP23 expression was significantly elevated in cell clusters grown under ultra-low adhesion conditions that mimic CSC-promoting environments. <i>DUSP23</i> knockdown impaired cluster formation, and suppressed the expression of SOX2, a representative marker for CSC-like property, and lung tumorigenesis in vivo. In cisplatin-resistant NSCLC cells, <i>DUSP23</i> knockdown further decreased invasive behavior and induced apoptosis. Mechanistically, DUSP23 promoted STAT3 phosphorylation, thereby enhancing <i>SOX2</i> transcription in cisplatin-resistant cells. Clinically, a DUSP23–SOX2 target gene signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly shorter overall and disease-free survival. Collectively, our findings indicate that DUSP23 plays a central role in maintaining CSC-like properties and chemoresistance through the regulation of SOX2. Targeting DUSP23 may provide a novel therapeutic approach to overcome treatment resistance and improve outcomes for patients with NSCLC.</p>

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Targeting dual-specificity phosphatase 23 to overcome chemoresistance and stem cell-like behavior in non-small cell lung cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月19日

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  • Seula Keum,
  • Yujin Hwang,
  • Minwoo Lee,
  • Seongeun Song,
  • Jangho Jeong,
  • Ye Eun Hwang,
  • Jee-Hye Choi,
  • Jung-Woong Kim,
  • Sangmyung Rhee

摘要

Chemoresistance remains a significant challenge in the treatment of non-small cell lung cancer (NSCLC) and is often associated with poor clinical outcomes. This resistance is closely linked to cancer stem cell (CSC)-like properties, such as the ability to evade anoikis. In this study, we identify dual-specificity phosphatase 23 (DUSP23) as a critical regulator of CSC-like traits and chemoresistance. DUSP23 expression was significantly elevated in cell clusters grown under ultra-low adhesion conditions that mimic CSC-promoting environments. DUSP23 knockdown impaired cluster formation, and suppressed the expression of SOX2, a representative marker for CSC-like property, and lung tumorigenesis in vivo. In cisplatin-resistant NSCLC cells, DUSP23 knockdown further decreased invasive behavior and induced apoptosis. Mechanistically, DUSP23 promoted STAT3 phosphorylation, thereby enhancing SOX2 transcription in cisplatin-resistant cells. Clinically, a DUSP23–SOX2 target gene signature stratified patients into high- and low-risk groups, with high-risk patients showing significantly shorter overall and disease-free survival. Collectively, our findings indicate that DUSP23 plays a central role in maintaining CSC-like properties and chemoresistance through the regulation of SOX2. Targeting DUSP23 may provide a novel therapeutic approach to overcome treatment resistance and improve outcomes for patients with NSCLC.