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<p>Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis. Transfer RNA-derived small RNAs (tsRNAs) are implicated in tumorigenesis, but their precise mechanistic roles in GC progression remain incompletely understood. We performed high-throughput sequencing in four paired GC/normal tissues to profile tsRNAs. The functional and mechanistic role of a candidate tsRNA was systematically investigated, alongside a suite of techniques including fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. We identified a novel tsRNA, tRF-Ser, that was significantly downregulated in GC tissues and cell lines, and its expression was correlated with favorable survival. Functionally, tRF-Ser acted as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT), inducing ferroptosis, and enhancing sensitivity to 5-fluorouracil chemotherapy. Mechanistically, tRF-Ser directly bound to the cellular nucleic acid-binding protein CNBP (a transcription factor), promoting its accumulation in the cytoplasm and preventing its binding to the HSPA8 promoter to downregulate HSPA8. Then, the tRF-Ser/CNBP/HSPA8 axis suppressed EMT by inhibiting β-catenin nuclear translocation and promoted ferroptosis by facilitating STUB1-mediated ubiquitination degradation of GPX4. Our study unveils that the tRF-Ser/CNBP/HSPA8 axis may constrain GC progression by regulating energy metabolism, which highlights the therapeutic potential of targeting this axis for GC treatment.</p>

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A new candidate tumor suppressor tRF-Ser inhibits gastric cancer progression by regulating the CNBP/HSPA8 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Jian Jiao,
  • Guangchuan Wang,
  • Jin Liu,
  • Kun Xiao,
  • Zi Gao,
  • Daocong Dong,
  • Keshu Shan,
  • Huaiping Cui,
  • Liang Shang,
  • Leping Li,
  • Chunqing Zhang

摘要

Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis. Transfer RNA-derived small RNAs (tsRNAs) are implicated in tumorigenesis, but their precise mechanistic roles in GC progression remain incompletely understood. We performed high-throughput sequencing in four paired GC/normal tissues to profile tsRNAs. The functional and mechanistic role of a candidate tsRNA was systematically investigated, alongside a suite of techniques including fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. We identified a novel tsRNA, tRF-Ser, that was significantly downregulated in GC tissues and cell lines, and its expression was correlated with favorable survival. Functionally, tRF-Ser acted as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT), inducing ferroptosis, and enhancing sensitivity to 5-fluorouracil chemotherapy. Mechanistically, tRF-Ser directly bound to the cellular nucleic acid-binding protein CNBP (a transcription factor), promoting its accumulation in the cytoplasm and preventing its binding to the HSPA8 promoter to downregulate HSPA8. Then, the tRF-Ser/CNBP/HSPA8 axis suppressed EMT by inhibiting β-catenin nuclear translocation and promoted ferroptosis by facilitating STUB1-mediated ubiquitination degradation of GPX4. Our study unveils that the tRF-Ser/CNBP/HSPA8 axis may constrain GC progression by regulating energy metabolism, which highlights the therapeutic potential of targeting this axis for GC treatment.