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Brase L, Yu Y, McDade E, Harari O, Benitez BA. Comparative gene regulatory networks modulating APOE expression in microglia and astrocytes. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.04.19.24306098. [PMID: 38699303 PMCID: PMC11065001 DOI: 10.1101/2024.04.19.24306098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2024]
Abstract
Background Single-cell technologies have unveiled various transcriptional states in different brain cell types. Transcription factors (TFs) regulate the expression of related gene sets, thereby controlling these diverse expression states. Apolipoprotein E (APOE), a pivotal risk-modifying gene in Alzheimer's disease (AD), is expressed in specific glial transcriptional states associated with AD. However, it is still unknown whether the upstream regulatory programs that modulate its expression are shared across brain cell types or specific to microglia and astrocytes. Methods We used pySCENIC to construct state-specific gene regulatory networks (GRNs) for resting and activated cell states within microglia and astrocytes based on single-nucleus RNA sequencing data from AD patients' cortices from the Knight ADRC-DIAN cohort. We then identified replicating TF using data from the ROSMAP cohort. We identified sets of genes co-regulated with APOE by clustering the GRN target genes and identifying genes differentially expressed after the virtual knockout of TFs regulating APOE. We performed enrichment analyses on these gene sets and evaluated their overlap with genes found in AD GWAS loci. Results We identified an average of 96 replicating regulators for each microglial and astrocyte cell state. Our analysis identified the CEBP, JUN, FOS, and FOXO TF families as key regulators of microglial APOE expression. The steroid/thyroid hormone receptor families, including the THR TF family, consistently regulated APOE across astrocyte states, while CEBP and JUN TF families were also involved in resting astrocytes. AD GWAS-associated genes (PGRN, FCGR3A, CTSH, ABCA1, MARCKS, CTSB, SQSTM1, TSC22D4, FCER1G, and HLA genes) are co-regulated with APOE. We also uncovered that APOE-regulating TFs were linked to circadian rhythm (BHLHE40, DBP, XBP1, CREM, SREBF1, FOXO3, and NR2F1). Conclusions Our findings reveal a novel perspective on the transcriptional regulation of APOE in the human brain. We found a comprehensive and cell-type-specific regulatory landscape for APOE, revealing distinct and shared regulatory mechanisms across microglia and astrocytes, underscoring the complexity of APOE regulation. APOE-co-regulated genes might also affect AD risk. Furthermore, our study uncovers a potential link between circadian rhythm disruption and APOE regulation, shedding new light on the pathogenesis of AD.
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Affiliation(s)
- Logan Brase
- Department of Psychiatry, Washington University, Saint Louis, St. Louis, Missouri, United States of America
- The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St. Louis, Missouri, United States of America
| | - Yanbo Yu
- Department of Psychiatry, Washington University, Saint Louis, St. Louis, Missouri, United States of America
- The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St. Louis, Missouri, United States of America
| | - Eric McDade
- Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | | | - Oscar Harari
- Department of Psychiatry, Washington University, Saint Louis, St. Louis, Missouri, United States of America
- The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, St. Louis, Missouri, United States of America
- Department of Neurology, Division of Neurogenetics, The Ohio State University, Columbus, OH, United States of America
| | - Bruno A. Benitez
- Department of Neurology and Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America
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Qiao H, Li H. PLP2 Could Be a Prognostic Biomarker and Potential Treatment Target in Glioblastoma Multiforme. Pharmgenomics Pers Med 2023; 16:991-1009. [PMID: 37964785 PMCID: PMC10642424 DOI: 10.2147/pgpm.s425251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
Objective This study aimed to discern the association between PLP2 expression, its biological significance, and the extent of immune infiltration in human GBM. Methods Utilizing the GEPIA2 and TCGA databases, we contrasted the expression levels of PLP2 in GBM against normal tissue. We utilized GEPIA2 and LinkedOmics for survival analysis, recognized genes co-expressed with PLP2 via cBioPortal and GEPIA2, and implemented GO and KEGG analyses. The STRING database facilitated the construction of protein-protein interaction networks. We evaluated the relationship of PLP2 with tumor immune infiltrates using ssGSEA and the TIMER 2.0 database. An IHC assay assessed PLP2 and PDL-1 expression in GBM tissue, and the Drugbank database aided in identifying potential PLP2-targeting compounds. Molecular docking was accomplished using Autodock Vina 1.2.2. Results PLP2 expression was markedly higher in GBM tissues in comparison to normal tissues. High PLP2 expression correlated with a decrease in overall survival across two databases. Functional analyses highlighted a focus of PLP2 functions within leukocyte. Discrepancies in PLP2 expression were evident in immune infiltration, impacting CD4+ T cells, neutrophils, myeloid dendritic cells, and macrophages. There was a concomitant increase in PLP2 and PD-L1 expression in GBM tissues, revealing a link between the two. Molecular docking with ethosuximide and praziquantel yielded scores of -7.441 and -4.295 kcal/mol, correspondingly. Conclusion PLP2's upregulation in GBM may adversely influence the lifespan of GBM patients. The involvement of PLP2 in pathways linked to leukocyte function is suggested. The positive correlation between PLP2 and PD-L1 could provide insights into PLP2's role in glioma modulation. Our research hints at PLP2's potential as a therapeutic target for GBM, with ethosuximide and praziquantel emerging as potential treatment candidates, especially emphasizing the potential of these compounds in GBM treatment targeting PLP2.
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Affiliation(s)
- Hao Qiao
- The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
| | - Huanting Li
- The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China
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Qing F, Liu Z. Interferon regulatory factor 7 in inflammation, cancer and infection. Front Immunol 2023; 14:1190841. [PMID: 37251373 PMCID: PMC10213216 DOI: 10.3389/fimmu.2023.1190841] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/26/2023] [Indexed: 05/31/2023] Open
Abstract
Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factors (IRFs) family, is located downstream of the pattern recognition receptors (PRRs)-mediated signaling pathway and is essential for the production of type I interferon (IFN-I). Activation of IRF7 inhibits various viral and bacterial infections and suppresses the growth and metastasis of some cancers, but it may also affect the tumor microenvironment and promote the development of other cancers. Here, we summarize recent advances in the role of IRF7 as a multifunctional transcription factor in inflammation, cancer and infection by regulating IFN-I production or IFN-I-independent signaling pathways.
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Shrivastava R, Gandhi P, Gothalwal R. The road-map for establishment of a prognostic molecular marker panel in glioma using liquid biopsy: current status and future directions. Clin Transl Oncol 2022; 24:1702-1714. [PMID: 35653004 DOI: 10.1007/s12094-022-02833-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/02/2022] [Indexed: 11/24/2022]
Abstract
Gliomas are primary intracranial tumors with defined molecular markers available for precise diagnosis. The prognosis of glioma is bleak as there is an overlook of the dynamic crosstalk between tumor cells and components of the microenvironment. Herein, different phases of gliomagenesis are presented with reference to the role and involvement of secreted proteomic markers at various stages of tumor initiation and development. The secreted markers of inflammatory response, namely interleukin-6, tumor necrosis factor-α, interferon-ϒ, and kynurenine, proliferation markers human telomerase reverse transcriptase and microtubule-associated-protein-Tau, and stemness marker human-mobility-group-AThook-1 are involved in glial tumor initiation and growth. Further, hypoxia and angiogenic factors, heat-shock-protein-70, endothelial-growth-factor-receptor-1 and vascular endothelial growth factor play a major role in promoting vascularization and tumor volume expansion. Eventually, molecules such as matrix-metalloprotease-7 and intercellular adhesion molecule-1 contribute to the degradation and remodeling of the extracellular matrix, ultimately leading to glioma progression. Our study delineates the roadmap to develop and evaluate a non-invasive panel of secreted biomarkers using liquid biopsy for precisely evaluating disease progression, to accomplish a clinical translation.
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Affiliation(s)
- Richa Shrivastava
- Department of Research, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, Bhopal, M.P., 462038, India
| | - Puneet Gandhi
- Department of Research, Bhopal Memorial Hospital and Research Centre, Raisen Bypass Road, Bhopal, M.P., 462038, India.
| | - Ragini Gothalwal
- Department of Biotechnology, Barkatullah University, Bhopal, M.P., 462026, India
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Wang H, Zhang D, Cui X, Dai Y, Wang C, Feng W, Lv X, Li Y, Wang L, Ru Y, Zhang Y, Ren Q, Zheng G. Loss of IRF7 accelerates acute myeloid leukemia progression and induces VCAM1-VLA-4 mediated intracerebral invasion. Oncogene 2022; 41:2303-2314. [PMID: 35256780 PMCID: PMC9010288 DOI: 10.1038/s41388-022-02233-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/21/2022] [Accepted: 02/03/2022] [Indexed: 01/06/2023]
Abstract
Interferon regulatory factor 7 (IRF7) is widely studied in inflammatory models. Its effects on malignant progression have been documented mainly from the perspective of the microenvironment. However, its role in leukemia has not been established. Here we used MLL-AF9-induced acute myeloid leukemia (AML) mouse models with IRF7 knockout or overexpression and xenograft mouse models to explore the intrinsic effects of IRF7 in AML. AML-IRF7−/− mice exhibited accelerated disease progression with intracerebral invasion of AML cells. AML-IRF7−/− cells showed increased proliferation and elevated leukemia stem cell (LSC) levels. Overexpression of IRF7 in AML cells decreased cell proliferation and LSC levels. Furthermore, overexpression of transforming growth-interacting factor 1 (TGIF1) rescued the enhanced proliferation and high LSC levels caused by IRF7 deficiency. Moreover, upregulation of vascular cell adhesion molecule 1 (VCAM1), which correlated with high LSC levels, was detected in AML-IRF7−/− cells. In addition, blocking VCAM1-very late antigen 4 (VLA-4) axis delayed disease progression and attenuated intracerebral invasion of AML cells. Therefore, our findings uncover the intrinsic effects of IRF7 in AML and provide a potential strategy to control central nervous system myeloid leukemia.
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Gandhi P, Shrivastava R, Garg N, Sorte SK. Novel molecular panel for evaluating systemic inflammation and survival in therapy naïve glioma patients. World J Clin Oncol 2021; 12:947-959. [PMID: 34733616 PMCID: PMC8546655 DOI: 10.5306/wjco.v12.i10.947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/21/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammation is crucial to tumor progression. A traumatic event at a specific site in the brain activates the signaling molecules, which triggers inflammation as the initial response within the tumor and its surroundings. The educated immune cells and secreted proteins then initiate the inflammatory cascade leading to persistent chronic inflammation. Therefore, estimation of the circulating inflammatory indicators kynurenine (KYN), interleukin-6 (IL-6), tissue-inhibitor of matrix-metalloproteinase-1 and human telomerase reverse transcriptase (hTERT) along with neutrophil-lymphocyte ratio (NLR) has prognostic value. AIM To assess the utility of chosen inflammatory marker panel in estimating systemic inflammation. METHODS The chosen markers were quantitatively evaluated in 90 naive, molecularly sub-typed plasma samples of glioma. A correlation between the markers and confounders was assessed to establish their prognostication power. Follow-up on the levels of the indicators was done 3-mo post-surgery. To establish the validity of circulating KYN, it was also screened qualitatively by dot-immune-assay and by immunofluorescence-immunohistochemistry in tumor tissues. RESULTS Median values of circulating KYN, IL-6, hTERT, tissue-inhibitor of matrix-metalloproteinase-1 and NLR in isocitrate-dehydrogenase-mutant/wildtype and within the astrocytic sub-groups were estimated, which differed from controls, reaching statistical significance (P < 0.0001). All markers negatively correlated with mortality (P < 0.0001). Applying combination-statistics, the panel of KYN, IL-6, hTERT and NLR achieved higher sensitivity and specificity (> 90%) than stand-alone markers, to define survival. The inflammatory panel could discriminate between WHO grades, and isocitrate-dehydrogenase-mutant/wildtype and define differential survival between astrocytic isocitrate-dehydrogenase-mutant/wildtype. Therefore, its assessment for precise disease prognosis is indicated. Association of KYN with NLR, IL-6 and hTERT was significant. Cox-regression described KYN, IL-6, NLR, and hTERT as good prognostic markers, independent of confounders. Multivariate linear-regression analysis confirmed the association of KYN and hTERT with inflammation marker IL-6.There was a concomitant significant decrease in their levels in a 3-mo follow-up. CONCLUSION The first evidence-based study of circulating-KYN in molecularly defined gliomas, wherein the tissue expression was found to be concomitant with plasma levels. A non-invasive model for assessing indicators of chronic systemic inflammation is proposed.
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Affiliation(s)
- Puneet Gandhi
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Richa Shrivastava
- Department of Research, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Nitin Garg
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
| | - Sandeep K Sorte
- Department of Neurosurgery, Bhopal Memorial Hospital and Research Centre, Bhopal 462038, Madhya Pradesh, India
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Wang Y, Yang F, Yin H, He Q, Lu Y, Zhu Q, Lan X, Zhao X, Li D, Liu Y, Xu H. Chicken interferon regulatory factor 7 (IRF7) can control ALV-J virus infection by triggering type I interferon production through affecting genes related with innate immune signaling pathway. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 119:104026. [PMID: 33497733 DOI: 10.1016/j.dci.2021.104026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/20/2021] [Accepted: 01/20/2021] [Indexed: 06/12/2023]
Abstract
In order to breed new birds with strong disease resistance, it is necessary to first understand the mechanism of avian antiviral response. Interferon regulatory factor 7 (IRF7) is not only a member of type I interferons (IFNs) regulatory factor (IRFs) family, but also a major regulator of the IFN response in mammals. However, whether IRF7 is involved in the host innate immune response remains unclear in poultry, due to the absence of IRF3. Here, we first observed by HE stains that with the increase of the time of ALV-J challenge, the thymus was obviously loose and swollen, the arrangement of liver cell was disordered, and the bursa of fabricius formed vacuolated. Real-time PCR detection showed that the expression level of IRF7 gene and related immune genes in ALV-J group was significantly higher than that in control group (P < 0.05). To further study the role of chicken IRF7 during avian leukosis virus subgroup J (ALV-J) infection, we constructed an induced IRF7 overexpression and interfered chicken embryo fibroblasts (CEFs) cell and performed in vitro infection using low pathogenic ALV-J and virus analog poly(I:C). In ALV-J and poly(I:C) stimulated CEFs cells, the expression level of STAT1, IFN-α, IFN-β, TLR3 and TLR7 were increased after IRF7 overexpressed, while the results were just the opposite after IRF7 interfered, which indicating that IRF7 may be associated with Toll-like receptor signaling pathway and JAK-STAT signaling pathway. These findings suggest that chicken IRF7 is an important regulator of IFN and is involved in chicken anti-ALV-J innate immunity.
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Affiliation(s)
- Yan Wang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Fuling Yang
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Huadong Yin
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Qijian He
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Yuxiang Lu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Qing Zhu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Xi Lan
- College of Animal Science and Technology, Southwest University, 2# Tiansheng Road, Beibei District Chongqing, 400715, China
| | - Xiaoling Zhao
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Diyan Li
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Yiping Liu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China
| | - Hengyong Xu
- Institute of Animal Genetics and Breeding, Sichuan Agricultural University, 211# Huimin Road, Chengdu, 611130, China.
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Deng Y, Guo SL, Li JQ, Xie SS, Zhou YC, Wei B, Wang Q, Wang F. Interferon regulatory factor 7 inhibits rat vascular smooth muscle cell proliferation and inflammation in monocrotaline-induced pulmonary hypertension. Life Sci 2021; 264:118709. [PMID: 33152351 DOI: 10.1016/j.lfs.2020.118709] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 10/24/2020] [Accepted: 10/30/2020] [Indexed: 12/28/2022]
Abstract
AIMS Although interferon regulatory factor 7 (IRF7) has known roles in regulating the inflammatory response, vascular smooth muscle cell proliferation, and apoptosis, its role in the pathogenesis of pulmonary hypertension (PH) is unclear. We hypothesized that IRF7 overexpression could inhibit pulmonary vascular remodeling and slow the progression of PH. MAIN METHODS IRF7 mRNA and protein levels in the lung samples and pulmonary artery smooth muscle cells (PASMCs) isolated from monocrotaline (MCT)-induced PH rats were assessed. We evaluated the effects of IRF7 on inflammation, proliferation, and apoptosis using an in vivo MCT-induced PH rat model and in vitro methods. KEY FINDINGS We noted decreased IRF7 mRNA and protein levels in the pulmonary vasculature of MCT-induced PH rats. IRF7 upregulation attenuated pulmonary vascular remodeling, decreased the pulmonary artery systolic pressure, and improved the right ventricular (RV) structure and function. Our findings suggest that nuclear factor kappa-Bp65 (NF-κBp65) deactivation could confer pulmonary vasculature protection, reduce proinflammatory cytokine (tumor necrosis factor-α, interleukin 6) release, and decrease PASMC proliferation and resistance to apoptosis via deactivating transcription factor 3 (ATF3) signaling. ATF3 deactivation induced the downregulation of the proliferation-dependent genes proliferating cell nuclear antigen (PCNA), cyclin D1, and survivin, coupled with increased levels of B cell lymphoma-2-associated X protein (Bax)/B cell lymphoma-2 (Bcl2) ratio, and cleaved caspase-3 in PASMCs. SIGNIFICANCE Our findings showed that IRF7 downregulation could initiate inflammation via NF-κBp65 signaling, causing PASMC proliferation via ATF3 signaling pathway activation. Therefore, IRF7 could be a potential molecular target for PH therapy.
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MESH Headings
- Activating Transcription Factor 3/metabolism
- Animals
- Apoptosis
- Caspase 3/metabolism
- Cell Proliferation
- Cells, Cultured
- Core Binding Factor Alpha 1 Subunit/metabolism
- Cyclin D1/metabolism
- Dependovirus/metabolism
- Heart Ventricles/pathology
- Heart Ventricles/physiopathology
- Hemodynamics
- Hypertension, Pulmonary/chemically induced
- Hypertension, Pulmonary/metabolism
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/physiopathology
- Inflammation/complications
- Inflammation/pathology
- Interferon Regulatory Factor-7/metabolism
- Lung/pathology
- Lung/physiopathology
- Male
- Monocrotaline
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Proliferating Cell Nuclear Antigen/metabolism
- Rats, Sprague-Dawley
- Receptor for Advanced Glycation End Products/metabolism
- Signal Transduction
- Survivin/metabolism
- Up-Regulation
- Vascular Remodeling
- bcl-2-Associated X Protein/metabolism
- Rats
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Affiliation(s)
- Yan Deng
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
| | - Sheng-Lan Guo
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jia-Quan Li
- The Experimental Center of Guangxi Medical University, Nanning, China
| | - Shan-Shan Xie
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ying-Chuan Zhou
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bin Wei
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qian Wang
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Fen Wang
- Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Wang Q, Jia S, Wang D, Chen X, Kalvakolanu DV, Zheng H, Wei X, Wen N, Liang H, Guo B, Zhang L. A Combination of BRD4 and HDAC3 Inhibitors Synergistically Suppresses Glioma Stem Cell Growth by Blocking GLI1/IL6/STAT3 Signaling Axis. Mol Cancer Ther 2020; 19:2542-2553. [PMID: 32999044 DOI: 10.1158/1535-7163.mct-20-0037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/31/2020] [Accepted: 09/16/2020] [Indexed: 11/16/2022]
Abstract
Glioma stem cells (GSC) are essential for tumor maintenance, invasiveness, and recurrence. Using a global epigenetic screening with an shRNA library, we identified HDAC3 as an essential factor for GSC stemness. Here, we demonstrated that GSCs poorly respond to an HDAC3 inhibitor, RGFP966 (HDAC3i), owing to the production of IL6 and STAT3 activation. To enhance GSC sensitivity to HDAC3i, we explored whether cotreatment with a BRD4 inhibitor, JQ1 (BRD4i), in GSCs produced a better antitumor effect. BRD4i synergistically inhibits GSC growth in association with HDAC3i. HDAC3 inhibition upregulated the acetylation of H3K27, which allowed the recruitment of BRD4 to the GLI1 gene promoter and induced its expression. GLI1, a transcription factor, turned on the expression of IL6, which led to the activation of STAT3 signaling pathways. However, BRD4i inhibited transcription of the GLI1 gene, thereby blocking the GLI1/IL6/STAT3 pathway. In vivo, the HDAC3i/BRD4i combination caused stronger tumor growth suppression than either drug alone. Thus, HDAC3i/BRD4i might provide promising therapies for GBM.
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Affiliation(s)
- Qian Wang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Shengnan Jia
- Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun, China
| | - Ding Wang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xuyang Chen
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Dhan V Kalvakolanu
- Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology University of Maryland School Medicine, Baltimore, Maryland
| | - Hongwu Zheng
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Xiaodong Wei
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Naiyan Wen
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Hang Liang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Baofeng Guo
- Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
| | - Ling Zhang
- Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, China.
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Grégoire H, Roncali L, Rousseau A, Chérel M, Delneste Y, Jeannin P, Hindré F, Garcion E. Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma. Front Pharmacol 2020; 11:368. [PMID: 32322199 PMCID: PMC7158850 DOI: 10.3389/fphar.2020.00368] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/10/2020] [Indexed: 12/11/2022] Open
Abstract
Glioblastoma (GB) is the most common and devastating form of brain cancer. Despite conventional treatments, progression or recurrences are systematic. In recent years, immunotherapies have emerged as an effective treatment in a number of cancers, leaving the question of their usefulness also faced with the particular case of brain tumors. The challenge here is major not only because the brain is the seat of our consciousness but also because of its isolation by the blood-brain barrier and the presence of a unique microenvironment that constitutes the central nervous system (CNS) with very specific constituent or patrolling cells. Much of the microenvironment is made up of immune cells or inflammation. Among these, tumor-associated macrophages (TAMs) are of significant interest as they are often involved in facilitating tumor progression as well as the development of resistance to standard therapies. In this review, the ubiquity of TAMs in GB will be discussed while the specific case of microglia resident in the brain will be also emphasized. In addition, the roles of TAMs as accomplices in the progression of GB and resistance to treatment will be presented. Finally, clinical trials targeting TAMs as a means of treating cancer will be discussed.
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Affiliation(s)
- Hélène Grégoire
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Loris Roncali
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Audrey Rousseau
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,Département de Pathologie Cellulaire et Tissulaire, CHU Angers, Angers, France
| | - Michel Chérel
- CRCINA, INSERM, Université d'Angers, Université de Nantes, Nantes, France
| | - Yves Delneste
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,Laboratoire d'Immunologie et Allergologie, CHU d'Angers, Angers, France
| | - Pascale Jeannin
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,Laboratoire d'Immunologie et Allergologie, CHU d'Angers, Angers, France
| | - François Hindré
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,PRIMEX, Plateforme de radiobiologie et d'imagerie expérimentale, SFR ICAT, Université d'Angers, Angers, France
| | - Emmanuel Garcion
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,PACeM, Plateforme d'analyses cellulaires et moléculaires, SFR ICAT, Université d'Angers, Angers, France
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Involvement of Interferon Regulatory Factor 7 in Nicotine's Suppression of Antiviral Immune Responses. J Neuroimmune Pharmacol 2019; 14:551-564. [PMID: 31154625 DOI: 10.1007/s11481-019-09845-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 03/05/2019] [Indexed: 01/16/2023]
Abstract
Nicotine, the active ingredient in tobacco smoke, suppresses antiviral responses. Interferon regulatory factors (IRFs) regulate transcription of type I interferons (IFNs) and IFN-stimulated genes (ISGs) in this response. IRF7 is a key member of the IRF family. Expression of Irf7 is elevated in the brains of virus-infected animals, including human immunodeficiency virus-1 transgenic (HIV-1Tg) rats. We hypothesized that IRF7 affects nicotine's modulation of antiviral responses. Using CRISPR/Cas9 system, IRF7-mutant cell lines were created from human embryonic kidney 293FT cells in which 16 nicotinic acetylcholine receptors (nAChRs) were detected. Decreased expression of IRF7 was confirmed at both the mRNA and protein levels, as was IRF7-regulated cell growth in two IRF7-mutant cell lines, designated IRF7-Δ7 and IRF7-Δ11. In IRF7-Δ7 cells, expression of two nAChR genes, CHRNA3 and CHRNA9, changed modestly. After stimulation with polyinosinic-polycytidylic acid (poly I:C) (0.25 μg/ml) for 4 h to mimic viral infection, 293FT wild-type (WT) and IRF7-Δ7 cells were treated with 0, 1, or 100 μM nicotine for 24 h, which increased IFN-β expression in both types of cells but elevation was higher in WT cells (p < 0.001). Expression was significantly suppressed in WT cells (p < 0.001) but not in IRF7-Δ7 cells by 24-h nicotine exposure. Poly I:C stimulation increased mRNA expression of retinoic-acid-inducible protein I (RIG-I), melanoma-differentiation-associated gene 5 (MDA5), IFN-stimulated gene factor 3 (ISG3) complex, and IFN-stimulated genes (IRF7, ISG15, IFIT1, OAS1); nicotine attenuated mRNA expression only in WT cells. Overall, IRF7 is critical to nicotine's effect on the antiviral immune response. Graphical Abstract Involvement of IRF7 in nicotine's suppression of poly I:C-induced antiviral immune responses. PAMPs, such as a synthetic viral analogue of dsRNA poly I:C attack cells, will be recognized by PRRs, and the host innate immunity against viral infection will be activated. PRRs signaling trigger phosphorylation of IRF7 and IRF3 to induce their translocation to the nucleus and result in the production of type I IFNs. Then IFNs bind to IFNAR to activate the transcription factor ISGF3, a complex consisting of STAT1, STAT2, and IRF9. Further, it induces the expression of ISGs, including IFIT1, OAS1, IRF7, ISG15, etc. Nicotine suppresses the immune responses stimulated by poly I:C. In the IRF7-mutant cells, nicotine's suppressive effects on poly I:C-stimulated immune responses were restrained.
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Saint Fleur-Lominy S, Maus M, Vaeth M, Lange I, Zee I, Suh D, Liu C, Wu X, Tikhonova A, Aifantis I, Feske S. STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia. Cell Rep 2018; 24:3045-3060.e5. [PMID: 30208327 PMCID: PMC6170166 DOI: 10.1016/j.celrep.2018.08.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 06/04/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.
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Affiliation(s)
- Shella Saint Fleur-Lominy
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA
| | - Mate Maus
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Martin Vaeth
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Ingo Lange
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Isabelle Zee
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - David Suh
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Cynthia Liu
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Xiaojun Wu
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Anastasia Tikhonova
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Iannis Aifantis
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Stefan Feske
- Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
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Chen PG, Guan YJ, Zha GM, Jiao XQ, Zhu HS, Zhang CY, Wang YY, Li HP. Swine IRF3/IRF7 attenuates inflammatory responses through TLR4 signaling pathway. Oncotarget 2017; 8:61958-61968. [PMID: 28977918 PMCID: PMC5617478 DOI: 10.18632/oncotarget.18740] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 05/22/2017] [Indexed: 01/22/2023] Open
Abstract
To explore the role of IRF3/IRF7 during inflammatory responses, we investigated the effects of swine IRF3/IRF7 on TLR4 signaling pathway and inflammatory factors expression in porcine kidney epithelial PK15 cell lines. We successfully constructed eukaryotic vectors PB-IRF3 and PB-IRF7, transfected these vectors into PK15 cells and observed GFP under a fluorescence microscope. In addition, RT-PCR was also used to detect transfection efficiency. We found that IRF3/IRF7 was efficiently overexpressed in PK15 cells. Moreover, we evaluated the effects of IRF3/IRF7 on the TLR4 signaling pathway and inflammatory factors by RT-PCR. Transfected cells were treated with lipopolysaccharide (LPS) alone, or in combination with a TBK1 inhibitor (LiCl). We revealed that IRF3/IRF7 enhanced IFNα production, and decreased IL-6 mRNA expression. Blocking the TBK1 pathway, inhibited the changes in IFNα, but not IL-6 mRNA. This illustrated that IRF3/IRF7 enhanced IFNα production through TLR4/TBK1 signaling pathway and played an anti-inflammatory role, while IRF3/IRF7 decreased IL-6 expression independent of the TBK1 pathway. Trends in MyD88, TRAF6, TBK1 and NFκB mRNA variation were similar in all treatments. LPS increased MyD88, TRAF6, TBK1 and NFκB mRNA abundance in PBR3/PBR7 and PBv cells, while LiCl blocked the LPS-mediated effects. The levels of these four factors in PBR3/PBR7 cells were higher than those in PBv. These results demonstrated that IRF3/IRF7 regulated the inflammatory response through the TLR4 signaling pathway. Overexpression of swine IRF3/IRF7 in PK15 cells induced type I interferons production, and attenuated inflammatory responses through TLR4 signaling pathway.
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Affiliation(s)
- Pei-Ge Chen
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - Yan-Jing Guan
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - Guang-Ming Zha
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - Xian-Qin Jiao
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - He-Shui Zhu
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - Cheng-Yu Zhang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - Yue-Ying Wang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
| | - He-Ping Li
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture, Henan Agricultural University, Zhengzhou, Henan, China
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