STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells
Abstract 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...
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BMC
2025-07-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-025-03890-z |
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| author | Weiming Deng Wenlin Huang Yujuan Huang Lihong Huang Linsong Ye Fei Liu Min Li Jingjin Weng Qian He Jinyan Zhang Shenhong Qu Jiazhang Wei |
| author_facet | Weiming Deng Wenlin Huang Yujuan Huang Lihong Huang Linsong Ye Fei Liu Min Li Jingjin Weng Qian He Jinyan Zhang Shenhong Qu Jiazhang Wei |
| author_sort | Weiming Deng |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-4753022079ea45ef87f1a17d8f97a817 |
| institution | Kabale University |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-4753022079ea45ef87f1a17d8f97a8172025-08-20T04:01:40ZengBMCCancer Cell International1475-28672025-07-0125111510.1186/s12935-025-03890-zSTIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cellsWeiming Deng0Wenlin Huang1Yujuan Huang2Lihong Huang3Linsong Ye4Fei Liu5Min Li6Jingjin Weng7Qian He8Jinyan Zhang9Shenhong Qu10Jiazhang Wei11Department of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Science Research, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionResearch Center of Medical Sciences, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionInstitute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate SchoolDepartment of Medical Oncology, Guangxi Medical University Cancer HospitalDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionDepartment of Otolaryngology & Head and Neck, The People’s Hospital of Guangxi Zhuang Autonomous RegionAbstract 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.https://doi.org/10.1186/s12935-025-03890-zIntegrin-β4Invasive plasticityStromal interaction molecule 1Nasopharyngeal carcinoma |
| spellingShingle | Weiming Deng Wenlin Huang Yujuan Huang Lihong Huang Linsong Ye Fei Liu Min Li Jingjin Weng Qian He Jinyan Zhang Shenhong Qu Jiazhang Wei STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells Cancer Cell International Integrin-β4 Invasive plasticity Stromal interaction molecule 1 Nasopharyngeal carcinoma |
| title | STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells |
| title_full | STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells |
| title_fullStr | STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells |
| title_full_unstemmed | STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells |
| title_short | STIM1 signaling modulates invasive phenotypic plasticity by regulating calpain-dependent cleavage of integrin-β4 in nasopharyngeal carcinoma cells |
| title_sort | stim1 signaling modulates invasive phenotypic plasticity by regulating calpain dependent cleavage of integrin β4 in nasopharyngeal carcinoma cells |
| topic | Integrin-β4 Invasive plasticity Stromal interaction molecule 1 Nasopharyngeal carcinoma |
| url | https://doi.org/10.1186/s12935-025-03890-z |
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