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Background <p>Stromal interaction molecule 1 (STIM1)-mediated Ca<sup>2+</sup> signaling modulates the malignant features of nasopharyngeal carcinoma (NPC), a unique Epstein-Barr virus (EBV)-associated human malignancy. Integrin-β4 is involved in EBV-promoted motility in NPC cells. However, the underlying mechanism through which STIM1 signaling manipulates the invasive characteristics of NPC cells and the implication of integrin-β4 remains elusive. The present study aimed to characterize the role of integrin-β4 in the phenotypic plasticity for the epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET), and determine whether STIM1 signaling enhances invasive potential by modulating integrin-β4 cleavage in NPC cells.</p> Methods <p>Western blotting of epithelial and mesenchymal markers, cell migration and colony formation assays were performed to evaluate the EGF-stimulated EMT and laminin-induced MET in vitro. A zebrafish xenograft model was employed to elucidate the proliferation of transplanted NPC cell spheroids in vivo. A tail vein injection-lung metastasis mouse model was utilized to determine the capacity for distant metastatic colonization of NPC cells. Immunohistochemical analysis was conducted to detect the expression level of integrin-β4 in NPC tissues.</p> Results <p>Integrin-β4 was required for the bi-directional epithelial-mesenchymal transition in NPC cells. Silencing of integrin-β4 inhibited cell migration and clonogenicity in vitro, reduced clonal expansion of tumor cell clusters in zebrafishes, and eliminated distant metastatic colonization in mice. STIM1 Ca<sup>2+</sup> signaling modulated the redistribution of integrin-β4 in migrating NPC cells. Mechanistically, STIM1-mediated Ca<sup>2+</sup> influx enhanced aggregation of integrin-β4 at the cell membranes by promoting the calpain-dependent cleavage of integrin-β4. Clinically, we confirmed that integrin-β4 was highly expressed in primary tumors and cervical lymph node metastases.</p> Conclusion <p>STIM1 signaling promotes invasiveness by enabling accelerated subcellular integrin-β4 redistribution, which is essential for maintaining the invasive plasticity of NPC cells.</p>

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STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月4日

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  • Weiming Deng,
  • Wenlin Huang,
  • Yujuan Huang,
  • Lihong Huang,
  • Linsong Ye,
  • Fei Liu,
  • Min Li,
  • Jingjin Weng,
  • Qian He,
  • Jinyan Zhang,
  • Shenhong Qu,
  • Jiazhang Wei

摘要

Background

Stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling modulates the malignant features of nasopharyngeal carcinoma (NPC), a unique Epstein-Barr virus (EBV)-associated human malignancy. Integrin-β4 is involved in EBV-promoted motility in NPC cells. However, the underlying mechanism through which STIM1 signaling manipulates the invasive characteristics of NPC cells and the implication of integrin-β4 remains elusive. The present study aimed to characterize the role of integrin-β4 in the phenotypic plasticity for the epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET), and determine whether STIM1 signaling enhances invasive potential by modulating integrin-β4 cleavage in NPC cells.

Methods

Western blotting of epithelial and mesenchymal markers, cell migration and colony formation assays were performed to evaluate the EGF-stimulated EMT and laminin-induced MET in vitro. A zebrafish xenograft model was employed to elucidate the proliferation of transplanted NPC cell spheroids in vivo. A tail vein injection-lung metastasis mouse model was utilized to determine the capacity for distant metastatic colonization of NPC cells. Immunohistochemical analysis was conducted to detect the expression level of integrin-β4 in NPC tissues.

Results

Integrin-β4 was required for the bi-directional epithelial-mesenchymal transition in NPC cells. Silencing of integrin-β4 inhibited cell migration and clonogenicity in vitro, reduced clonal expansion of tumor cell clusters in zebrafishes, and eliminated distant metastatic colonization in mice. STIM1 Ca2+ signaling modulated the redistribution of integrin-β4 in migrating NPC cells. Mechanistically, STIM1-mediated Ca2+ influx enhanced aggregation of integrin-β4 at the cell membranes by promoting the calpain-dependent cleavage of integrin-β4. Clinically, we confirmed that integrin-β4 was highly expressed in primary tumors and cervical lymph node metastases.

Conclusion

STIM1 signaling promotes invasiveness by enabling accelerated subcellular integrin-β4 redistribution, which is essential for maintaining the invasive plasticity of NPC cells.