The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway
Abstract Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of gli...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05556-y |
| _version_ | 1797952349647405056 |
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| author | Hao Li Yang Jiang Jinpeng Hu Jinkun Xu Lian Chen Guoqing Zhang Junshuang Zhao Shengliang Zong Zhengting Guo Xinqiao Li Xiang Zhao Zhitao Jing |
| author_facet | Hao Li Yang Jiang Jinpeng Hu Jinkun Xu Lian Chen Guoqing Zhang Junshuang Zhao Shengliang Zong Zhengting Guo Xinqiao Li Xiang Zhao Zhitao Jing |
| author_sort | Hao Li |
| collection | DOAJ |
| description | Abstract Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of glioma stem cells. We used bioinformatics analysis to identify circRNAs and potential RNA-binding proteins (RBPs) in glioma. qRT-PCR, western blotting, RNA FISH, RNA pull-down, RNA immunoprecipitation assay, ChIP, immunohistochemistry, and immunofluorescence methods were used to quantified the expression of circNCAPG, U2AF65, RREB1 and TGF-β1, and the underlying mechanisms between them. MTS, EDU, neurosphere formation, limiting dilution neurosphere formation and transwell assays examined the proliferation and invasive capability of GSCs, respectively. We identified a novel circRNA named circNCAPG was overexpressed and indicated the poor prognosis in glioma patients. Upregulating circNCAPG promoted the malignant progression of GSCs. RNA binding protein U2AF65 could stabilize circNCAPG by direct binding. Mechanically, circNCAPG interacted with and stabilized RREB1, as well as stimulated RREB1 nuclear translocation to activate TGF-β1 signaling pathway. Furthermore, RREB1 transcriptionally upregulated U2AF65 expression to improve the stability of circNCAPG in GSCs, which established a feedback loop involving U2AF65, circNCAPG and RREB1. Since circRNA is more stable than mRNA and can execute its function continuously, targeting circNCAPG in glioma may be a novel promising therapeutic. |
| first_indexed | 2024-04-10T22:44:55Z |
| format | Article |
| id | doaj.art-77098c59b6a047528f749df6c65ccbd7 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T22:44:55Z |
| publishDate | 2023-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-77098c59b6a047528f749df6c65ccbd72023-01-15T12:22:34ZengNature Publishing GroupCell Death and Disease2041-48892023-01-0114111510.1038/s41419-023-05556-yThe U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathwayHao Li0Yang Jiang1Jinpeng Hu2Jinkun Xu3Lian Chen4Guoqing Zhang5Junshuang Zhao6Shengliang Zong7Zhengting Guo8Xinqiao Li9Xiang Zhao10Zhitao Jing11Department of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of MedicineDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityDepartment of Neurosurgery, The First Hospital of China Medical UniversityAbstract Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of glioma stem cells. We used bioinformatics analysis to identify circRNAs and potential RNA-binding proteins (RBPs) in glioma. qRT-PCR, western blotting, RNA FISH, RNA pull-down, RNA immunoprecipitation assay, ChIP, immunohistochemistry, and immunofluorescence methods were used to quantified the expression of circNCAPG, U2AF65, RREB1 and TGF-β1, and the underlying mechanisms between them. MTS, EDU, neurosphere formation, limiting dilution neurosphere formation and transwell assays examined the proliferation and invasive capability of GSCs, respectively. We identified a novel circRNA named circNCAPG was overexpressed and indicated the poor prognosis in glioma patients. Upregulating circNCAPG promoted the malignant progression of GSCs. RNA binding protein U2AF65 could stabilize circNCAPG by direct binding. Mechanically, circNCAPG interacted with and stabilized RREB1, as well as stimulated RREB1 nuclear translocation to activate TGF-β1 signaling pathway. Furthermore, RREB1 transcriptionally upregulated U2AF65 expression to improve the stability of circNCAPG in GSCs, which established a feedback loop involving U2AF65, circNCAPG and RREB1. Since circRNA is more stable than mRNA and can execute its function continuously, targeting circNCAPG in glioma may be a novel promising therapeutic.https://doi.org/10.1038/s41419-023-05556-y |
| spellingShingle | Hao Li Yang Jiang Jinpeng Hu Jinkun Xu Lian Chen Guoqing Zhang Junshuang Zhao Shengliang Zong Zhengting Guo Xinqiao Li Xiang Zhao Zhitao Jing The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway Cell Death and Disease |
| title | The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway |
| title_full | The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway |
| title_fullStr | The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway |
| title_full_unstemmed | The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway |
| title_short | The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway |
| title_sort | u2af65 circncapg rreb1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the tgf β pathway |
| url | https://doi.org/10.1038/s41419-023-05556-y |
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