AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide
Abstract Glioma is the most frequent primary malignancy in the brain; temozolomide (TMZ) is the first-line chemotherapeutic agent used to combat this tumor. We showed here that astrocyte elevated gene-1 (AEG-1) was overexpressed in glioma tissues and associated with a worse subtype and a poor progno...
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| Format: | Article |
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Nature Portfolio
2021-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-96647-3 |
| _version_ | 1818683740648374272 |
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| author | Jing Li Yuchen Sun Xuanzi Sun Xu Zhao Yuan Ma Yuzhu Wang Xiaozhi Zhang |
| author_facet | Jing Li Yuchen Sun Xuanzi Sun Xu Zhao Yuan Ma Yuzhu Wang Xiaozhi Zhang |
| author_sort | Jing Li |
| collection | DOAJ |
| description | Abstract Glioma is the most frequent primary malignancy in the brain; temozolomide (TMZ) is the first-line chemotherapeutic agent used to combat this tumor. We showed here that astrocyte elevated gene-1 (AEG-1) was overexpressed in glioma tissues and associated with a worse subtype and a poor prognosis. CCK-8 proliferation assays and clone formation experiments presented that AEG-1 knockdown sensitizes glioma cells to TMZ. The γH2AX foci formation assays indicated that AEG-1 silencing promotes TMZ-induced DNA damage in glioma cells. Glioma-associated microglia/macrophages (GAMs), the largest subpopulation infiltrating glioma, play important roles in the tumor microenvironment. Bioinformatics analyses and functional studies demonstrated that AEG-1 silencing decreased M2-polarization of HMC3 microglia and the secretion of tumor supportive cytokines IL-6 and TGF-β1. The expression of AEG-1 was positively associated with M2 markers in glioma tissues varified by IHC staining. Based on the results of Affymetrix microarray and GSEA analyses, Western blot and Co-Immunoprecipitation assays were conducted to show that AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β. The co-localization of AEG-1 and GSK-3β in the cytoplasm of glioma cells was detected through immunofluorescence staining. This study raises the possibility that targeting AEG-1 might improve the efficiency of chemotherapy and reduce immunosuppressive M2 GAMs in glioma. |
| first_indexed | 2024-12-17T10:39:33Z |
| format | Article |
| id | doaj.art-1a91033503a44d64b19981a01dc387a6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:39:33Z |
| publishDate | 2021-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1a91033503a44d64b19981a01dc387a62022-12-21T21:52:17ZengNature PortfolioScientific Reports2045-23222021-08-0111111210.1038/s41598-021-96647-3AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomideJing Li0Yuchen Sun1Xuanzi Sun2Xu Zhao3Yuan Ma4Yuzhu Wang5Xiaozhi Zhang6Department of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Radiation Oncology, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Glioma is the most frequent primary malignancy in the brain; temozolomide (TMZ) is the first-line chemotherapeutic agent used to combat this tumor. We showed here that astrocyte elevated gene-1 (AEG-1) was overexpressed in glioma tissues and associated with a worse subtype and a poor prognosis. CCK-8 proliferation assays and clone formation experiments presented that AEG-1 knockdown sensitizes glioma cells to TMZ. The γH2AX foci formation assays indicated that AEG-1 silencing promotes TMZ-induced DNA damage in glioma cells. Glioma-associated microglia/macrophages (GAMs), the largest subpopulation infiltrating glioma, play important roles in the tumor microenvironment. Bioinformatics analyses and functional studies demonstrated that AEG-1 silencing decreased M2-polarization of HMC3 microglia and the secretion of tumor supportive cytokines IL-6 and TGF-β1. The expression of AEG-1 was positively associated with M2 markers in glioma tissues varified by IHC staining. Based on the results of Affymetrix microarray and GSEA analyses, Western blot and Co-Immunoprecipitation assays were conducted to show that AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β. The co-localization of AEG-1 and GSK-3β in the cytoplasm of glioma cells was detected through immunofluorescence staining. This study raises the possibility that targeting AEG-1 might improve the efficiency of chemotherapy and reduce immunosuppressive M2 GAMs in glioma.https://doi.org/10.1038/s41598-021-96647-3 |
| spellingShingle | Jing Li Yuchen Sun Xuanzi Sun Xu Zhao Yuan Ma Yuzhu Wang Xiaozhi Zhang AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide Scientific Reports |
| title | AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide |
| title_full | AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide |
| title_fullStr | AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide |
| title_full_unstemmed | AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide |
| title_short | AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide |
| title_sort | aeg 1 silencing attenuates m2 polarization of glioma associated microglia macrophages and sensitizes glioma cells to temozolomide |
| url | https://doi.org/10.1038/s41598-021-96647-3 |
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