S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma
Abstract Background Sphingosine-1-phosphate receptor 3 (S1PR3) has been implicated in promoting tumor progression in various cancers. However, the role and molecular mechanisms of S1PR3 in oral squamous cell carcinoma (OSCC) remain poorly understood. The aims of this study were to investigate the fu...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06582-4 |
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| author | Xinxia Zhou Jinghao Liu Xu Chen Xinyu Zhou Beihui Xu Guifang Gan Fuxiang Chen |
| author_facet | Xinxia Zhou Jinghao Liu Xu Chen Xinyu Zhou Beihui Xu Guifang Gan Fuxiang Chen |
| author_sort | Xinxia Zhou |
| collection | DOAJ |
| description | Abstract Background Sphingosine-1-phosphate receptor 3 (S1PR3) has been implicated in promoting tumor progression in various cancers. However, the role and molecular mechanisms of S1PR3 in oral squamous cell carcinoma (OSCC) remain poorly understood. The aims of this study were to investigate the function of S1PR3 in OSCC progression and its potential as a therapeutic target. Method The expression of S1PR3 was determined through qPCR, Western blotting analysis, immunohistochemistry (IHC), and the TCGA database. The correlation between S1PR3 expression and clinical prognosis was analyzed using the TCGA database and IHC. The effects of S1PR3 on OSCC cell proliferation and cell cycle were investigated through CCK-8 assay, colony formation assay, EdU incorporation assay, cell cycle analysis, and a xenograft mouse model. The potential mechanisms through which S1PR3 affects the OSCC cell cycle were explored using RNA-seq and a cell cycle array. The effects of combining S1PR3 antagonist with cisplatin on OSCC cell growth were examined through CCK-8 and EdU incorporation assays. Results S1PR3 was overexpressed in OSCC and the upregulation of S1PR3 in OSCC was correlated with unfavorable clinicopathological characteristics and adverse prognosis. Targeting S1PR3 reduced AKT phosphorylation, which led to a downregulation of WEE1, a kinase involved in cell cycle regulation. This downregulation resulted in reducing CDC2 phosphorylation, disrupting the G2/M cell cycle checkpoint and inhibiting OSCC cell proliferation. Furthermore, the combination of S1PR3 antagonist exhibited synergistic inhibitory effects on OSCC cell growth when combined with cisplatin. Conclusions These findings reveal a critical role for S1PR3 in regulating OSCC cell cycle via the AKT/WEE1/CDC2 pathway, thus offering a basis for developing treatment strategies for OSCC patients. |
| format | Article |
| id | doaj-art-2a41753f785e4867b040e95cc59c703c |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-2a41753f785e4867b040e95cc59c703c2025-08-20T03:08:44ZengBMCJournal of Translational Medicine1479-58762025-05-0123111910.1186/s12967-025-06582-4S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinomaXinxia Zhou0Jinghao Liu1Xu Chen2Xinyu Zhou3Beihui Xu4Guifang Gan5Fuxiang Chen6Department of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, College of Stomatology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineAbstract Background Sphingosine-1-phosphate receptor 3 (S1PR3) has been implicated in promoting tumor progression in various cancers. However, the role and molecular mechanisms of S1PR3 in oral squamous cell carcinoma (OSCC) remain poorly understood. The aims of this study were to investigate the function of S1PR3 in OSCC progression and its potential as a therapeutic target. Method The expression of S1PR3 was determined through qPCR, Western blotting analysis, immunohistochemistry (IHC), and the TCGA database. The correlation between S1PR3 expression and clinical prognosis was analyzed using the TCGA database and IHC. The effects of S1PR3 on OSCC cell proliferation and cell cycle were investigated through CCK-8 assay, colony formation assay, EdU incorporation assay, cell cycle analysis, and a xenograft mouse model. The potential mechanisms through which S1PR3 affects the OSCC cell cycle were explored using RNA-seq and a cell cycle array. The effects of combining S1PR3 antagonist with cisplatin on OSCC cell growth were examined through CCK-8 and EdU incorporation assays. Results S1PR3 was overexpressed in OSCC and the upregulation of S1PR3 in OSCC was correlated with unfavorable clinicopathological characteristics and adverse prognosis. Targeting S1PR3 reduced AKT phosphorylation, which led to a downregulation of WEE1, a kinase involved in cell cycle regulation. This downregulation resulted in reducing CDC2 phosphorylation, disrupting the G2/M cell cycle checkpoint and inhibiting OSCC cell proliferation. Furthermore, the combination of S1PR3 antagonist exhibited synergistic inhibitory effects on OSCC cell growth when combined with cisplatin. Conclusions These findings reveal a critical role for S1PR3 in regulating OSCC cell cycle via the AKT/WEE1/CDC2 pathway, thus offering a basis for developing treatment strategies for OSCC patients.https://doi.org/10.1186/s12967-025-06582-4Oral squamous cell carcinomaSphingosine-1-phosphate receptor 3AKT signaling pathwayWEE1Cell cycle |
| spellingShingle | Xinxia Zhou Jinghao Liu Xu Chen Xinyu Zhou Beihui Xu Guifang Gan Fuxiang Chen S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma Journal of Translational Medicine Oral squamous cell carcinoma Sphingosine-1-phosphate receptor 3 AKT signaling pathway WEE1 Cell cycle |
| title | S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma |
| title_full | S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma |
| title_fullStr | S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma |
| title_full_unstemmed | S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma |
| title_short | S1PR3 inhibition impairs cell cycle checkpoint via the AKT/WEE1 pathway in oral squamous cell carcinoma |
| title_sort | s1pr3 inhibition impairs cell cycle checkpoint via the akt wee1 pathway in oral squamous cell carcinoma |
| topic | Oral squamous cell carcinoma Sphingosine-1-phosphate receptor 3 AKT signaling pathway WEE1 Cell cycle |
| url | https://doi.org/10.1186/s12967-025-06582-4 |
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