KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells
Abstract Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on ora...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-05-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07689-8 |
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| author | Xin Qi Jiang Zhou Pan Wang Yunyan Li Haoran Li Yuwen Miao XiaoQing Ma Xiayan Luo Zhiling Zhang Yanling He Wenyi Shen Wenquan Zhao Rutao Cui Cang Li Huiyong Zhu Jiong Lyu |
| author_facet | Xin Qi Jiang Zhou Pan Wang Yunyan Li Haoran Li Yuwen Miao XiaoQing Ma Xiayan Luo Zhiling Zhang Yanling He Wenyi Shen Wenquan Zhao Rutao Cui Cang Li Huiyong Zhu Jiong Lyu |
| author_sort | Xin Qi |
| collection | DOAJ |
| description | Abstract Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. Upon binding to its extracellular matrix (ECM) ligand, type I collagen, ITGA2 activates stemness-associated signaling pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, a small-molecule inhibitor of the ITGA2-collagen interaction, significantly sensitizes oral squamous cell carcinoma (OSCC) to cisplatin in xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy. |
| format | Article |
| id | doaj-art-2a5a9d1b9bb04bb88f37c7624fcf9a5f |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-2a5a9d1b9bb04bb88f37c7624fcf9a5f2025-08-20T02:10:53ZengNature Publishing GroupCell Death and Disease2041-48892025-05-0116111310.1038/s41419-025-07689-8KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cellsXin Qi0Jiang Zhou1Pan Wang2Yunyan Li3Haoran Li4Yuwen Miao5XiaoQing Ma6Xiayan Luo7Zhiling Zhang8Yanling He9Wenyi Shen10Wenquan Zhao11Rutao Cui12Cang Li13Huiyong Zhu14Jiong Lyu15Zhejiang University, School of Medicine, First Affiliated HospitalCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Stomatology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineZhejiang University, School of Medicine, First Affiliated HospitalZhejiang University, School of Medicine, Affiliated Stomatology HospitalCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineZhejiang University, School of Medicine, First Affiliated HospitalCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineZhejiang University, School of Medicine, First Affiliated HospitalZhejiang University, School of Medicine, First Affiliated HospitalZhejiang University, School of Medicine, First Affiliated HospitalCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of MedicineZhejiang University, School of Medicine, First Affiliated HospitalZhejiang University, School of Medicine, First Affiliated HospitalAbstract Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. Upon binding to its extracellular matrix (ECM) ligand, type I collagen, ITGA2 activates stemness-associated signaling pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, a small-molecule inhibitor of the ITGA2-collagen interaction, significantly sensitizes oral squamous cell carcinoma (OSCC) to cisplatin in xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy.https://doi.org/10.1038/s41419-025-07689-8 |
| spellingShingle | Xin Qi Jiang Zhou Pan Wang Yunyan Li Haoran Li Yuwen Miao XiaoQing Ma Xiayan Luo Zhiling Zhang Yanling He Wenyi Shen Wenquan Zhao Rutao Cui Cang Li Huiyong Zhu Jiong Lyu KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells Cell Death and Disease |
| title | KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells |
| title_full | KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells |
| title_fullStr | KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells |
| title_full_unstemmed | KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells |
| title_short | KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells |
| title_sort | klf7 regulated itga2 as a therapeutic target for inhibiting oral cancer stem cells |
| url | https://doi.org/10.1038/s41419-025-07689-8 |
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