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<p>Endometrial cancer (EC) remains a lethal gynecological malignancy with limited therapeutic options owing to unresolved pathogenesis. Cellular senescence acts as a key barrier against tumorigenesis in cancer cells, thus investigating its role in EC progression represents a pivotal research avenue to address these challenges. This study reveals the critical role of cellular senescence in EC progression through multi-omics profiling and functional validation. The integrative analysis of RNA-seq and clinical datasets identified Na<sup>+</sup>/H<sup>+</sup> exchanger 7 (NHE7) as a prognostic biomarker that was significantly overexpressed in EC tissues. Functional studies demonstrated that <i>NHE7</i> overexpression drives proliferation, cell motility, and cell cycle progression while suppressing senescence-associated markers and cytokine secretion. Conversely, <i>NHE7</i> knockdown reversed these oncogenic phenotypes. Mechanistically, NHE7 binds to a cAMP-related transcription factor, thereby increasing <i>GRIN2B</i> expression to elevate intracellular Ca²⁺ levels influx, which delays cell senescence and promotes cancer progression in vitro and in vivo. Our findings suggest that NHE7 plays a crucial role in delaying cellular senescence and advancing EC progression through the cAMP pathway, uncovering critical mechanistic drivers of EC pathogenesis and highlighting actionable therapeutic targets.</p><p></p>

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NHE7 drives endometrial cancer progression by delaying senescence through cAMP/CREB/GRIN2B axis-mediated Ca²⁺ influx

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月5日

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  • Shizhou Yang,
  • Tao Shen,
  • Minghua Yu,
  • Tingting Wu,
  • Linhua Qian,
  • Wu Liu,
  • Ting Wang,
  • Xiufeng Huang

摘要

Endometrial cancer (EC) remains a lethal gynecological malignancy with limited therapeutic options owing to unresolved pathogenesis. Cellular senescence acts as a key barrier against tumorigenesis in cancer cells, thus investigating its role in EC progression represents a pivotal research avenue to address these challenges. This study reveals the critical role of cellular senescence in EC progression through multi-omics profiling and functional validation. The integrative analysis of RNA-seq and clinical datasets identified Na+/H+ exchanger 7 (NHE7) as a prognostic biomarker that was significantly overexpressed in EC tissues. Functional studies demonstrated that NHE7 overexpression drives proliferation, cell motility, and cell cycle progression while suppressing senescence-associated markers and cytokine secretion. Conversely, NHE7 knockdown reversed these oncogenic phenotypes. Mechanistically, NHE7 binds to a cAMP-related transcription factor, thereby increasing GRIN2B expression to elevate intracellular Ca²⁺ levels influx, which delays cell senescence and promotes cancer progression in vitro and in vivo. Our findings suggest that NHE7 plays a crucial role in delaying cellular senescence and advancing EC progression through the cAMP pathway, uncovering critical mechanistic drivers of EC pathogenesis and highlighting actionable therapeutic targets.