DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context
Background: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gli...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239641930043X |
| _version_ | 1818875101503815680 |
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| author | Xiangqi Meng Chunbin Duan Hengyuan Pang Qun Chen Bo Han Caijun Zha Magafurov Dinislam Pengfei Wu Ziwei Li Shihong Zhao Ruijia Wang Lin Lin Chuanlu Jiang Jinquan Cai |
| author_facet | Xiangqi Meng Chunbin Duan Hengyuan Pang Qun Chen Bo Han Caijun Zha Magafurov Dinislam Pengfei Wu Ziwei Li Shihong Zhao Ruijia Wang Lin Lin Chuanlu Jiang Jinquan Cai |
| author_sort | Xiangqi Meng |
| collection | DOAJ |
| description | Background: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment. Methods: Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma. Findings: DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment. Interpretation: Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. Fund: This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017–201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03). Keywords: DNA damage repair, Microglia, Glioma microenvironment, p53, Midkine |
| first_indexed | 2024-12-19T13:21:09Z |
| format | Article |
| id | doaj.art-801ac82732f3487a8e14d643b924f458 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-19T13:21:09Z |
| publishDate | 2019-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-801ac82732f3487a8e14d643b924f4582022-12-21T20:19:42ZengElsevierEBioMedicine2352-39642019-03-0141185199DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in contextXiangqi Meng0Chunbin Duan1Hengyuan Pang2Qun Chen3Bo Han4Caijun Zha5Magafurov Dinislam6Pengfei Wu7Ziwei Li8Shihong Zhao9Ruijia Wang10Lin Lin11Chuanlu Jiang12Jinquan Cai13Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Laboratory Diagnosis, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neurosurgical department, Bashkir State Medical University, Ufa 450008, RussiaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China; Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin, China.Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China; Neuroscience Institute, Heilongjiang Academy of Medical Sciences, Harbin 150086, China; Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin, China.Background: DNA damage repair (DDR) alterations are important events in cancer initiation, progression, and therapeutic resistance. However, the involvement of DDR alterations in glioma malignancy needs further investigation. This study aims to characterize the clinical and molecular features of gliomas with DDR alterations and elucidate the biological process of DDR alterations that regulate the cross talk between gliomas and the tumor microenvironment. Methods: Integrated transcriptomic and genomic analyses were undertaken to conduct a comprehensive investigation of the role of DDR alterations in glioma. The prognostic DDR-related cytokines were identified from multiple datasets. In vivo and in vitro experiments validated the role of p53, the key molecule of DDR, regulating M2 polarization of microglia in glioma. Findings: DDR alterations are associated with clinical and molecular characteristics of glioma. Gliomas with DDR alterations exhibit distinct immune phenotypes, and immune cell types and cytokine processes. DDR-related cytokines have an unfavorable prognostic implication for GBM patients and are synergistic with DDR alterations. Overexpression of MDK mediated by p53, the key transcriptional factor in DDR pathways, remodels the GBM immunosuppressive microenvironment by promoting M2 polarization of microglia, suggesting a potential role of DDR in regulating the glioma microenvironment. Interpretation: Our work suggests that DDR alterations significantly contribute to remodeling the glioma microenvironment via regulating the immune response and cytokine pathways. Fund: This study was supported by: 1. The National Key Research and Development Plan (No. 2016YFC0902500); 2. National Natural Science Foundation of China (No. 81702972, No. 81874204, No. 81572701, No. 81772666); 3. China Postdoctoral Science Foundation (2018M640305); 4. Special Fund Project of Translational Medicine in the Chinese-Russian Medical Research Center (No. CR201812); 5. The Research Project of the Chinese Society of Neuro-oncology, CACA (CSNO-2016-MSD12); 6. The Research Project of the Health and Family Planning Commission of Heilongjiang Province (2017–201); and 7. Harbin Medical University Innovation Fund (2017LCZX37, 2017RWZX03). Keywords: DNA damage repair, Microglia, Glioma microenvironment, p53, Midkinehttp://www.sciencedirect.com/science/article/pii/S235239641930043X |
| spellingShingle | Xiangqi Meng Chunbin Duan Hengyuan Pang Qun Chen Bo Han Caijun Zha Magafurov Dinislam Pengfei Wu Ziwei Li Shihong Zhao Ruijia Wang Lin Lin Chuanlu Jiang Jinquan Cai DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context EBioMedicine |
| title | DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context |
| title_full | DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context |
| title_fullStr | DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context |
| title_full_unstemmed | DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context |
| title_short | DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in gliomaResearch in context |
| title_sort | dna damage repair alterations modulate m2 polarization of microglia to remodel the tumor microenvironment via the p53 mediated mdk expression in gliomaresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S235239641930043X |
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