GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation
Abstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal...
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03288-9 |
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| author | Yikai Shen Jie Lin Tianlu Jiang Xusheng Shen Ying Li Yiwang Fu Penghui Xu Lang Fang Zetian Chen Hongxin Huang Yiwen Xia Zekuan Xu Linjun Wang |
| author_facet | Yikai Shen Jie Lin Tianlu Jiang Xusheng Shen Ying Li Yiwang Fu Penghui Xu Lang Fang Zetian Chen Hongxin Huang Yiwen Xia Zekuan Xu Linjun Wang |
| author_sort | Yikai Shen |
| collection | DOAJ |
| description | Abstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal circRNAs in gastric cancer (GC) progression has not been completely clarified. Methods The exosomal circRNAs enriched in GC were identified using exosomal circRNA sequencing. The biological function of circMAN1A2 in GC was investigated using a series of in vitro and in vivo experiments. PKH-67 staining was used to label the exosomes. The molecular mechanism of exosomal circMAN1A2 was investigated via mass spectrometry, immunoprecipitation, Western blot, and single-cell RNA-sequencing data analyses. Results In our study, we determined that circMAN1A2 (hsa_circ_0000118) was enriched in GC-derived exosomes. Higher circMAN1A2 expression was related to poor survival in GC patients (HR = 2.917, p = 0.0120). Exosomal circMAN1A2 promoted GC progression in vitro and in vivo and suppressed the antitumour activity of T cells. Moreover, circMAN1A2 bound to SFPQ in GC cells and T cells, promoting the G1/S phase transition of the cell cycle in GC cells while inhibiting the activation of the T cell receptor signalling pathway in T cells to decrease antitumour activity. Mechanistically, circMAN1A2 competed with FBXW11 for binding to SFPQ, preventing FBXW11-mediated k48-linked ubiquitination and SFPQ protein degradation, thereby stabilizing SFPQ expression. Conclusions Our work confirms the critical role of exosomal circMAN1A2 in the progression and immunosuppression of GC. This novel axis of circMAN1A2-SFPQ provides new insights into exosomal circRNA-based GC diagnostic and therapeutic strategies. |
| format | Article |
| id | doaj-art-eb1ea939c9554f519e9a32f11c3b6b45 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-eb1ea939c9554f519e9a32f11c3b6b452025-01-26T12:57:54ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144112810.1186/s13046-025-03288-9GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradationYikai Shen0Jie Lin1Tianlu Jiang2Xusheng Shen3Ying Li4Yiwang Fu5Penghui Xu6Lang Fang7Zetian Chen8Hongxin Huang9Yiwen Xia10Zekuan Xu11Linjun Wang12Gastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityThe Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi People’s HospitalGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityGastric Cancer Center, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Background Exosomes, as extracellular membrane vesicles, play important roles in intercellular communication and can influence tumour progression. Circular RNAs (circRNAs) have been reported in various malignancies and are also important components of exosomes. However, the role of exosomal circRNAs in gastric cancer (GC) progression has not been completely clarified. Methods The exosomal circRNAs enriched in GC were identified using exosomal circRNA sequencing. The biological function of circMAN1A2 in GC was investigated using a series of in vitro and in vivo experiments. PKH-67 staining was used to label the exosomes. The molecular mechanism of exosomal circMAN1A2 was investigated via mass spectrometry, immunoprecipitation, Western blot, and single-cell RNA-sequencing data analyses. Results In our study, we determined that circMAN1A2 (hsa_circ_0000118) was enriched in GC-derived exosomes. Higher circMAN1A2 expression was related to poor survival in GC patients (HR = 2.917, p = 0.0120). Exosomal circMAN1A2 promoted GC progression in vitro and in vivo and suppressed the antitumour activity of T cells. Moreover, circMAN1A2 bound to SFPQ in GC cells and T cells, promoting the G1/S phase transition of the cell cycle in GC cells while inhibiting the activation of the T cell receptor signalling pathway in T cells to decrease antitumour activity. Mechanistically, circMAN1A2 competed with FBXW11 for binding to SFPQ, preventing FBXW11-mediated k48-linked ubiquitination and SFPQ protein degradation, thereby stabilizing SFPQ expression. Conclusions Our work confirms the critical role of exosomal circMAN1A2 in the progression and immunosuppression of GC. This novel axis of circMAN1A2-SFPQ provides new insights into exosomal circRNA-based GC diagnostic and therapeutic strategies.https://doi.org/10.1186/s13046-025-03288-9Gastric cancerExosomescircMAN1A2Antitumour immunity |
| spellingShingle | Yikai Shen Jie Lin Tianlu Jiang Xusheng Shen Ying Li Yiwang Fu Penghui Xu Lang Fang Zetian Chen Hongxin Huang Yiwen Xia Zekuan Xu Linjun Wang GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation Journal of Experimental & Clinical Cancer Research Gastric cancer Exosomes circMAN1A2 Antitumour immunity |
| title | GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation |
| title_full | GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation |
| title_fullStr | GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation |
| title_full_unstemmed | GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation |
| title_short | GC-derived exosomal circMAN1A2 promotes cancer progression and suppresses T-cell antitumour immunity by inhibiting FBXW11-mediated SFPQ degradation |
| title_sort | gc derived exosomal circman1a2 promotes cancer progression and suppresses t cell antitumour immunity by inhibiting fbxw11 mediated sfpq degradation |
| topic | Gastric cancer Exosomes circMAN1A2 Antitumour immunity |
| url | https://doi.org/10.1186/s13046-025-03288-9 |
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