Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis
Abstract Numerous aberrant splicing events are implicated in tumor progression, yet comprehensive reports on splicing factors and events associated with peritoneal metastasis in gastric cancer (GCPM) are lacking. In this study, PTBP3 is found to be significantly overexpressed in peritoneal metastati...
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| Format: | Article |
| Language: | English |
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202415983 |
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| author | Yajing Zhou Chao Dong Xiaochun Shen Pengbo Wang Tao Chen Weikang Li Xiaotong Sun Peiyuan Li Chengxiang Xu Kaipeng Duan Dongbao Li Jin Zhou |
| author_facet | Yajing Zhou Chao Dong Xiaochun Shen Pengbo Wang Tao Chen Weikang Li Xiaotong Sun Peiyuan Li Chengxiang Xu Kaipeng Duan Dongbao Li Jin Zhou |
| author_sort | Yajing Zhou |
| collection | DOAJ |
| description | Abstract Numerous aberrant splicing events are implicated in tumor progression, yet comprehensive reports on splicing factors and events associated with peritoneal metastasis in gastric cancer (GCPM) are lacking. In this study, PTBP3 is found to be significantly overexpressed in peritoneal metastatic tissues of gastric cancer compared to primary tumor tissues, and higher PTBP3 expression correlates with poorer prognosis. Using gastric cancer cells and patient‐derived organoids (PDO), the role of PTBP3 in promoting tumor invasion and proliferation is investigated. Mechanistically, through full‐length transcriptome sequencing, PTBP3 mediates exon 4 skipping in its target gene COX11, leading to shorter transcripts that impair COX11 protein function, reducing mitochondrial copper content and enabling tumor cells to evade cuproptosis. Antisense oligonucleotide (ASO) drugs targeting the short COX11 transcripts effectively degrade mRNA, disrupting copper homeostasis. In PDO‐based xenograft models, exogenous copper ionophores combined with ASO drugs induce excessive copper accumulation in mitochondria, triggering proteotoxic stress and cuproptosis. Overall, PTBP3‐mediated exon 4 skipping in COX11 pre‐mRNA is critical for tumor cell survival and progression in GCPM, offering potential therapeutic strategies targeting copper metabolism. |
| format | Article |
| id | doaj-art-2394a7d421af4d7dab58ff147bd2039c |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2394a7d421af4d7dab58ff147bd2039c2025-08-20T02:02:58ZengWileyAdvanced Science2198-38442025-06-011221n/an/a10.1002/advs.202415983Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal MetastasisYajing Zhou0Chao Dong1Xiaochun Shen2Pengbo Wang3Tao Chen4Weikang Li5Xiaotong Sun6Peiyuan Li7Chengxiang Xu8Kaipeng Duan9Dongbao Li10Jin Zhou11Department of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of Pulmonary and Critical Care MedicineThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaDepartment of General SurgeryThe First Affiliated Hospital of Soochow University899 Pinghai Road Suzhou Jiangsu Province 215031 ChinaAbstract Numerous aberrant splicing events are implicated in tumor progression, yet comprehensive reports on splicing factors and events associated with peritoneal metastasis in gastric cancer (GCPM) are lacking. In this study, PTBP3 is found to be significantly overexpressed in peritoneal metastatic tissues of gastric cancer compared to primary tumor tissues, and higher PTBP3 expression correlates with poorer prognosis. Using gastric cancer cells and patient‐derived organoids (PDO), the role of PTBP3 in promoting tumor invasion and proliferation is investigated. Mechanistically, through full‐length transcriptome sequencing, PTBP3 mediates exon 4 skipping in its target gene COX11, leading to shorter transcripts that impair COX11 protein function, reducing mitochondrial copper content and enabling tumor cells to evade cuproptosis. Antisense oligonucleotide (ASO) drugs targeting the short COX11 transcripts effectively degrade mRNA, disrupting copper homeostasis. In PDO‐based xenograft models, exogenous copper ionophores combined with ASO drugs induce excessive copper accumulation in mitochondria, triggering proteotoxic stress and cuproptosis. Overall, PTBP3‐mediated exon 4 skipping in COX11 pre‐mRNA is critical for tumor cell survival and progression in GCPM, offering potential therapeutic strategies targeting copper metabolism.https://doi.org/10.1002/advs.202415983alternative splicingantisense oligonucleotide drugscuproptosisgastric cancer peritoneal metastasispatient‐derived organoids‐based xenograft |
| spellingShingle | Yajing Zhou Chao Dong Xiaochun Shen Pengbo Wang Tao Chen Weikang Li Xiaotong Sun Peiyuan Li Chengxiang Xu Kaipeng Duan Dongbao Li Jin Zhou Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis Advanced Science alternative splicing antisense oligonucleotide drugs cuproptosis gastric cancer peritoneal metastasis patient‐derived organoids‐based xenograft |
| title | Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis |
| title_full | Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis |
| title_fullStr | Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis |
| title_full_unstemmed | Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis |
| title_short | Targeting PTBP3‐Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal Metastasis |
| title_sort | targeting ptbp3 mediated alternative splicing of cox11 induces cuproptosis for inhibiting gastric cancer peritoneal metastasis |
| topic | alternative splicing antisense oligonucleotide drugs cuproptosis gastric cancer peritoneal metastasis patient‐derived organoids‐based xenograft |
| url | https://doi.org/10.1002/advs.202415983 |
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