1. DNA damage repair alterations modulate M2 polarization of microglia to remodel the tumor microenvironment via the p53-mediated MDK expression in glioma
- Author
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Jinquan Cai, Ruijia Wang, Lin Lin, Hengyuan Pang, Magafurov Dinislam, Ziwei Li, Shihong Zhao, Qun Chen, Chuanlu Jiang, Pengfei Wu, Caijun Zha, Chunbin Duan, Xiangqi Meng, and Bo Han
- Subjects
Research paper ,DNA Repair ,Cellular differentiation ,medicine.medical_treatment ,ATRX, alpha thalassemia/mental retardation syndrome X-linked ,SAA1, serum amyloid A1 ,Transcriptome ,Mice ,0302 clinical medicine ,GSEA, gene set enrichment analysis ,GME, glioma microenvironment ,MEM, Minimum Essential Media ,BER, base excision repair ,Midkine ,TNFSF4, TNF superfamily member 4 ,NADP, nicotinamide adenine dinucleotide phosphate ,General Medicine ,DSBR, DNA double-strand break repair ,030220 oncology & carcinogenesis ,NHEJ, nonhomologous end joining ,Microglia ,IHC, immunohistochemistry ,γH2AX, phosphorylated on serine 139 on H2A histone family member X ,CNV, copy number variation ,IL6, interleukin 6 ,ATM, ataxia telangiectasia-mutated gene ,IGV, Integrative Genomics Viewer ,MDK, midkine ,KEGG, Kyoto Encyclopedia of Genes and Genomes ,PI, protease inhibitor ,DDR, DNA damage response ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mrc1, mannose receptor C-type 1 ,NER, nucleotide excision repair ,Glioma ,Humans ,PTEN ,IF, immunofluorescence ,GCM, glioma-conditioned medium ,IDH, isocitrate dehydrogenase (NADP(+)) ,Tumor microenvironment ,SSBR, DNA single-strand break repair ,TMZ, temozolomide ,Macrophages ,medicine.disease ,Mice, Inbred C57BL ,body regions ,030104 developmental biology ,Pen/Strep, penicillin/streptomycin ,HR, homologous recombination ,DAPI, 4′,6-diamidino-2-phenylindole ,p53 ,0301 basic medicine ,ATR, Ataxia Telangiectasia And Rad3-Related Protein ,qRT-PCR, Quantitative real-time reverse transcription-polymerase chain reaction ,DAB, Diaminobenzidine ,ChIP, Chromatin immunoprecipitation ,Tumor Microenvironment ,DNA damage repair ,FA, Fanconi anemia ,MGMT, O6-methylguanine-DNA methyltransferase ,biology ,LGG, lower grade glioma ,TLS, trans-lesion synthesis ,TP53, tumor protein P53 ,HRP, horseradish peroxidase ,Cell Differentiation ,Fizz1, found in inflammatory zone 1 ,SNP, single nucleotide polymorphism ,TCGA, The Cancer Genome Atlas dataset ,Cytokine ,TNFA, tumor necrosis factor alpha ,Female ,Arg1, arginase 1 ,DNA repair ,SWI/SNF, SWItch/Sucrose Non-Fermentable ,MMR, mismatch repair ,DMEM, Dulbecco's Modified Eagle Medium ,AKT, protein kinase B ,CCL2, C-C motif chemokine ligand 2 ,CGGA, The Chinese Glioma Genome Atlas dataset ,C5, Complement C5 ,Cell Line ,Glioma microenvironment ,VEGFA, vascular endothelial growth factor A ,FBS, fetal bovine serum ,PBS, phosphate buffered saline ,Cell Line, Tumor ,medicine ,Animals ,ELISA, Enzyme-Linked Immunosorbent Assay ,DR, direct repair ,GO, gene ontology ,ssGSEA, single sample gene set enrichment analysis ,FC, fold change ,PTEN, phosphatase and tensin homolog ,EGFR, epidermal growth factor receptor ,TBST, Tris-buffered Saline with Tween 20 ,NFκB, nuclear factor kappa B ,biology.protein ,Cancer research ,GBM, glioblastoma ,EM/PM classification, EGFR module / PDGFRA (platelet derived growth factor receptor A) -based molecular classification ,Tumor Suppressor Protein p53 - Abstract
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)., Highlights • Gliomas with DNA damage repair alterations had distinct genomic variation spectrum. • DDR alterations exhibit distinct immune phenotypes, cytokine processes and immune cell types in glioma. • DDR-related cytokines in GME have an unfavorable prognostic implication for GBM patients. • P53-mediated midkine expression derived from glioma cells promotes M2 polarization of microglia.
- Published
- 2019
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