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<p>Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy, in which patient prognosis is critically influenced by metastasis. While Keratin 17 (KRT17) has been implicated in tumor progression across various cancers, prior studies have primarily focused on its cytoplasmic roles. The mechanisms underlying nuclear KRT17-driven metastasis in ESCC remain unclear. Here, we demonstrate that KRT17 translocates to the nucleus via its nuclear localization sequence (NLS), thereby promoting the redistribution of heterogeneous nuclear ribonucleoprotein K (hnRNP K) from the nucleus to the cytoplasm. This shift upregulates the CXCR3 ligands CXCL9, CXCL10, and CXCL11, leading to subsequent activation of the CXCR3 signaling pathway and a marked enhancement of ESCC cell migration and invasion. In contrast, an NLS mutant (KRT17-K399A) that fails to enter the nucleus does not induce hnRNP K cytoplasmic accumulation or activate CXCR3 signaling. Furthermore, silencing hnRNP K or inhibiting the CXCR3 pathway reverses the pro-metastatic effects of KRT17, whereas exogenous CXCL11 partially rescues cell migration. Collectively, our findings unveil a novel mechanism by which overexpressed KRT17 facilitates ESCC metastasis through a nuclear localization-dependent KRT17-hnRNP K-CXCR3 axis, providing a theoretical foundation for targeting this pathway as a promising therapeutic strategy.</p>

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A novel KRT17-hnRNP K-CXCR3 axis promotes esophageal squamous cell carcinoma metastasis via nuclear-cytoplasmic redistribution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月12日

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  • Shaobin Yu,
  • Lin Ye,
  • Jin Huang,
  • Hui Xu,
  • Weiqing Wu,
  • Meicheng Jiang,
  • Mingqiang Kang

摘要

Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy, in which patient prognosis is critically influenced by metastasis. While Keratin 17 (KRT17) has been implicated in tumor progression across various cancers, prior studies have primarily focused on its cytoplasmic roles. The mechanisms underlying nuclear KRT17-driven metastasis in ESCC remain unclear. Here, we demonstrate that KRT17 translocates to the nucleus via its nuclear localization sequence (NLS), thereby promoting the redistribution of heterogeneous nuclear ribonucleoprotein K (hnRNP K) from the nucleus to the cytoplasm. This shift upregulates the CXCR3 ligands CXCL9, CXCL10, and CXCL11, leading to subsequent activation of the CXCR3 signaling pathway and a marked enhancement of ESCC cell migration and invasion. In contrast, an NLS mutant (KRT17-K399A) that fails to enter the nucleus does not induce hnRNP K cytoplasmic accumulation or activate CXCR3 signaling. Furthermore, silencing hnRNP K or inhibiting the CXCR3 pathway reverses the pro-metastatic effects of KRT17, whereas exogenous CXCL11 partially rescues cell migration. Collectively, our findings unveil a novel mechanism by which overexpressed KRT17 facilitates ESCC metastasis through a nuclear localization-dependent KRT17-hnRNP K-CXCR3 axis, providing a theoretical foundation for targeting this pathway as a promising therapeutic strategy.