ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis
Abstract Background Osteosarcoma (OS) is a primary bone malignancy characterized by early metastasis and generally poor prognosis. ESPN is highly expressed and plays an important role in regulating the aggressive phenotypes of several cancer cell types. However, little is known about the molecular m...
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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/s12967-025-06500-8 |
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| author | Ruikai Zhou Hongyu Wu Hao You Xiaofei Wang Xiuchen Yuan Zhengyi Sun Dong Zhou Yuqing Jiang Yifei Shen |
| author_facet | Ruikai Zhou Hongyu Wu Hao You Xiaofei Wang Xiuchen Yuan Zhengyi Sun Dong Zhou Yuqing Jiang Yifei Shen |
| author_sort | Ruikai Zhou |
| collection | DOAJ |
| description | Abstract Background Osteosarcoma (OS) is a primary bone malignancy characterized by early metastasis and generally poor prognosis. ESPN is highly expressed and plays an important role in regulating the aggressive phenotypes of several cancer cell types. However, little is known about the molecular mechanisms underlying ESPN-mediated migration and invasion in OS cells. Methods In this study, we first analyzed the survival of osteosarcoma patients using Kaplan-Meier analysis to assess the prognostic relevance of ESPN. To further evaluate its clinical significance, we performed immunohistochemical analysis on osteosarcoma tissue samples and benign osteochondroma (OC) tissues. The biological function of ESPN in osteosarcoma was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we explored the underlying molecular mechanisms through Western blotting, co-immunoprecipitation, immunofluorescence, and PCR, revealing key downstream signaling pathways. Results In this study, we demonstrate that ESPN, acting as an oncogene, is highly expressed in OS cell lines and tissues, promoting OS cell proliferation and metastasis. Mechanistically, ESPN promoted the phosphorylation of PI3K by direct interaction with it and active the AKT/mTOR pathway, which enhanced the expression of the transcription factor ZEB1 and initiating the epithelial-mesenchymal transition (EMT) cascade. Furthermore, we validated that mTOR-mediated activation of p70 ribosomal protein S6 kinase (p70S6K) promotes the translation of ZEB1, thereby enhancing the growth and motility of OS cells. Conclusions Our findings reveal a previously unrecognized function of ESPN in OS, closely linked with EMT and cancer metastasis progression. Targeting ESPN may represent a potential therapeutic approach for patients with OS. |
| format | Article |
| id | doaj-art-3acba2cf145a411bb1bb828d9fba7b6e |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-3acba2cf145a411bb1bb828d9fba7b6e2025-08-20T03:09:20ZengBMCJournal of Translational Medicine1479-58762025-05-0123111510.1186/s12967-025-06500-8ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasisRuikai Zhou0Hongyu Wu1Hao You2Xiaofei Wang3Xiuchen Yuan4Zhengyi Sun5Dong Zhou6Yuqing Jiang7Yifei Shen8Department of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityDepartment of Orthopedics, Changzhou Medical Center, The Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Nanjing Medical UniversityAbstract Background Osteosarcoma (OS) is a primary bone malignancy characterized by early metastasis and generally poor prognosis. ESPN is highly expressed and plays an important role in regulating the aggressive phenotypes of several cancer cell types. However, little is known about the molecular mechanisms underlying ESPN-mediated migration and invasion in OS cells. Methods In this study, we first analyzed the survival of osteosarcoma patients using Kaplan-Meier analysis to assess the prognostic relevance of ESPN. To further evaluate its clinical significance, we performed immunohistochemical analysis on osteosarcoma tissue samples and benign osteochondroma (OC) tissues. The biological function of ESPN in osteosarcoma was confirmed by a series of experiments conducted both in vitro and in vivo. Additionally, we explored the underlying molecular mechanisms through Western blotting, co-immunoprecipitation, immunofluorescence, and PCR, revealing key downstream signaling pathways. Results In this study, we demonstrate that ESPN, acting as an oncogene, is highly expressed in OS cell lines and tissues, promoting OS cell proliferation and metastasis. Mechanistically, ESPN promoted the phosphorylation of PI3K by direct interaction with it and active the AKT/mTOR pathway, which enhanced the expression of the transcription factor ZEB1 and initiating the epithelial-mesenchymal transition (EMT) cascade. Furthermore, we validated that mTOR-mediated activation of p70 ribosomal protein S6 kinase (p70S6K) promotes the translation of ZEB1, thereby enhancing the growth and motility of OS cells. Conclusions Our findings reveal a previously unrecognized function of ESPN in OS, closely linked with EMT and cancer metastasis progression. Targeting ESPN may represent a potential therapeutic approach for patients with OS.https://doi.org/10.1186/s12967-025-06500-8ESPNEpithelial-mesenchymal transitionmTOROsteosarcomaMetastasis |
| spellingShingle | Ruikai Zhou Hongyu Wu Hao You Xiaofei Wang Xiuchen Yuan Zhengyi Sun Dong Zhou Yuqing Jiang Yifei Shen ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis Journal of Translational Medicine ESPN Epithelial-mesenchymal transition mTOR Osteosarcoma Metastasis |
| title | ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis |
| title_full | ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis |
| title_fullStr | ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis |
| title_full_unstemmed | ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis |
| title_short | ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis |
| title_sort | espn activates zeb1 mediated emt through the pi3k akt mtor axis to promote osteosarcoma metastasis |
| topic | ESPN Epithelial-mesenchymal transition mTOR Osteosarcoma Metastasis |
| url | https://doi.org/10.1186/s12967-025-06500-8 |
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