44 results on '"Receptor, Notch4 genetics"'
Search Results
2. Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.
- Author
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Zhu R, Shirley CM, Chu SH, Li L, Nguyen BH, Seo J, Wu M, Seale T, Duffield AS, Staudt LM, Levis M, Hu Y, and Small D
- Subjects
- Humans, Animals, Mice, Mutation, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Signal Transduction drug effects, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Receptor, Notch4 genetics, Xenograft Model Antitumor Assays
- Abstract
Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.) more...
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- 2024
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Catalog
3. Association of NOTCH4 and ACHE gene polymorphism in Alzheimer's disease of Gujarat cohort.
- Author
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Budhbhatti U, Chauhan A, Bhatt D, Parmar C, Damani V, Patel A, and Joshi C
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- Humans, Epistasis, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptor, Notch4 genetics, Alzheimer Disease genetics
- Abstract
Background: Alzheimer's Disease (AD) is the most common form of dementia, affecting cognitive and behavioral functions. AD is a complex disease resulting from the modest effect of gene interaction and environmental factors, as a result of which the exact pathogenesis is still unknown., Aim: The aim of the present study was to investigate the association between variants of 98 targeted genes with Alzheimer's disease phenotype., Method: A total of 98 genes from 32 AD cases and 11 controls were genotyped using the Haloplex target enrichment method and the PCR-RFLP approach.Association analysis was performed using the PLINK tool to identify the variant significantly associated with AD. Functional enrichment analysis and network analysis was performed using ClueGo and String database respectively. The Expression Quantitative Trait Loci (eQTL) analysis using the Genotype Tissue Expression (GTEx) dataset to explore the possible implication of the variant on the expression of one or more genes in different brain regions and whole blood., Result: Association analysis showed significant association of 19 variant assigned to 16 genes with Alzheimer's with p-value < 0.05 with rs367398/NOTCH4 only variant that passed multiple test corrections. Functional enrichment analysis showed association of these genes with AD. ClueGo and network analysis utilizing the String database suggested that genes are directly and indirectly linked to the AD pathogenesis. eQTL analysis revealed that the rs367398/NOTCH4 and rs1799806/ACHE variant showed significant eQTL for the neighbouring genes., Conclusion: The present study showed the possible role of 16 genes in AD pathogenesis, especially highlighting the role of rs367398/NOTCH4 and rs1799806/ACHE. However further investigation with large cohort is required to study and validate the implication of these variants in the AD pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.) more...
- Published
- 2023
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4. NOTCH4 ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1.
- Author
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Zhang B, Dong S, Wang J, Huang T, Zhao P, Xu J, Liu D, Fu L, Wang L, Wang G, and Zou C
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- Humans, ErbB Receptors metabolism, Down-Regulation, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cell Line, Tumor, Drug Resistance, Neoplasm genetics, Mutation, Transcription Factor HES-1 genetics, Transcription Factor HES-1 metabolism, Receptor, Notch4 genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms metabolism, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics
- Abstract
Resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) remains one of the major challenges in lung adenocarcinoma (LUAD) therapy. Here, we find an increased frequency of the L12_16 amino acid deletion mutation in the signal peptide region of NOTCH4 (NOTCH4
ΔL12_16 ) in EGFR-TKI-sensitive patients. Functionally, exogenous induction of NOTCH4ΔL12_16 in EGFR-TKI -resistant LUAD cells sensitizes them to EGFR-TKIs. This process is mainly mediated by the reduction of the intracellular domain of NOTCH4 (NICD4) caused by the NOTCH4ΔL12_16 mutation, which results in a lower localization of NOTCH4 in the plasma membrane. Mechanistically, NICD4 transcriptionally upregulates the expression of HES1 by competitively binding to the gene promoter relative to p-STAT3. Because p-STAT3 can downregulate the expression of HES1 in EGFR-TKI-resistant LUAD cells, the reduction of NICD4 induced by NOTCH4ΔL12_16 mutation leads to a decrease in HES1. Moreover, inhibition of the NOTCH4-HES1 pathway using inhibitors and siRNAs abolishes the resistance of EGFR-TKI. Overall, we report that the NOTCH4ΔL12_16 mutation sensitizes LUAD patients to EGFR-TKIs through transcriptional down-regulation of HES1 and that targeted blockade of this signaling cohort could reverse EGFR-TKI -resistance in LUAD, providing a potential approach to overcome resistance to EGFR-TKI -therapy., (© 2023. The Author(s).) more...- Published
- 2023
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5. Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties.
- Author
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Sargis T, Youn SW, Thakkar K, Naiche LA, Paik NY, Pajcini KV, and Kitajewski JK
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- Animals, Mice, Epidermal Growth Factor metabolism, Immunoprecipitation, Inflammation drug therapy, Inflammation genetics, Inflammation metabolism, Ligands, Neoplasms drug therapy, Neoplasms genetics, Neoplasms metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Retinal Vessels drug effects, Surface Plasmon Resonance, Angiogenesis Inhibitors genetics, Angiogenesis Inhibitors metabolism, Angiogenesis Inhibitors pharmacology, Endothelial Cells drug effects, Endothelial Cells metabolism, Receptor, Notch1 antagonists & inhibitors, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Receptor, Notch4 genetics, Receptor, Notch4 metabolism
- Abstract
The Notch signaling pathway is an important therapeutic target for the treatment of inflammatory diseases and cancer. We previously created ligand-specific inhibitors of Notch signaling comprised of Fc fusions to specific EGF-like repeats of the Notch1 extracellular domain, called Notch decoys, which bound ligands, blocked Notch signaling, and showed anti-tumor activity with low toxicity. However, the study of their function depended on virally mediated expression, which precluded dosage control and limited clinical applicability. We have refined the decoy design to create peptibody-based Notch inhibitors comprising the core binding domains, EGF-like repeats 10-14, of either Notch1 or Notch4. These Notch peptibodies showed high secretion properties and production yields that were improved by nearly 100-fold compared to previous Notch decoys. Using surface plasmon resonance spectroscopy coupled with co-immunoprecipitation assays, we observed that Notch1 and Notch4 peptibodies demonstrate strong but distinct binding properties to Notch ligands DLL4 and JAG1. Both Notch1 and Notch4 peptibodies interfere with Notch signaling in endothelial cells and reduce expression of canonical Notch targets after treatment. While prior DLL4 inhibitors cause hyper-sprouting, the Notch1 peptibody reduced angiogenesis in a 3-dimensional in vitro sprouting assay. Administration of Notch1 peptibodies to neonate mice resulted in reduced radial outgrowth of retinal vasculature, confirming anti-angiogenic properties. We conclude that purified Notch peptibodies comprising EGF-like repeats 10-14 bind to both DLL4 and JAG1 ligands and exhibit anti-angiogenic properties. Based on their secretion profile, unique Notch inhibitory activities, and anti-angiogenic properties, Notch peptibodies present new opportunities for therapeutic Notch inhibition., (© 2022. The Author(s).) more...
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- 2023
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6. Polymorphisms and gene expression of Notch4 in pulmonary tuberculosis.
- Author
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Fang W, Liu H, Qin L, Wang J, Huang X, Pan S, and Zheng R
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- Humans, Toll-Like Receptor 2 genetics, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression, Receptor, Notch4 genetics, Tuberculosis, Pulmonary microbiology, Tuberculosis genetics
- Abstract
Background: Tuberculosis (TB) is a serious public health problem to human health, but the pathogenesis of TB remains elusive., Methods: To identify novel candidate genes associated with TB susceptibility, we performed a population-based case control study to genotype 41SNPs spanning 21 genes in 435 pulmonary TB patients and 375 health donors from China., Results: We found Notch4 gene rs206018 and rs422951 polymorphisms were associated with susceptibility to pulmonary tuberculosis. The association was validated in another independent cohort including 790 TB patients and 1,190 healthy controls. Moreover, we identified that the rs206018 C allele was associated with higher level of Notch4 in PBMCs from pulmonary TB patients. Furthermore, Notch4 expression increased in TB patients and higher Notch4 expression correlated with the severer pulmonary TB. Finally, we explored the origin and signaling pathways involved in the regulation of Notch4 expression in response to Mycobacterium tuberculosis (Mtb) infection. We determine that Mtb induced Notch4 and its ligand Jagged1expression in macrophages, and Notch4 through TLR2/P38 signaling pathway and Jagged1 through TLR2/ERK signaling pathway., Conclusion: Our work further strengthens that Notch4 underlay an increased risk of TB in humans and is involved in the occurrence and development of TB, which could serve as a novel target for the host-targeted therapy of TB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fang, Liu, Qin, Wang, Huang, Pan and Zheng.) more...
- Published
- 2023
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7. NOTCH4 Single-Nucleotide Polymorphism Is Associated with Brain Arteriovenous Malformation in a Chinese Han Population.
- Author
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Zhong M, Zhang J, Li Z, Liu Z, Fan H, Su H, Meng H, Zhang X, Li X, Duan CZ, and He X
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- Humans, Polymorphism, Single Nucleotide, East Asian People, Brain pathology, Receptor, Notch4 genetics, Intracranial Arteriovenous Malformations surgery, Epilepsy
- Abstract
Introduction: Brain arteriovenous malformations (BAVMs) are high-flow intracranial vascular malformations characterized by the direct connection of arteries to veins without an intervening capillary bed. They are one of the main causes of intracranial hemorrhage and epilepsy, although morbidity is low. Angiogenesis, heredity, inflammation, and arteriovenous malformation syndromes play important roles in BAVM formation. Animal experiments and previous studies have confirmed that NOTCH4 may be associated with BAVM development. Our study identifies a connection between NOTCH4 gene polymorphisms and BAVM in a Chinese Han population., Methods: We enrolled 150 patients with BAVMs confirmed by digital subtraction angiography (DSA) in the Department of Neurosurgery, Zhujiang Hospital, Southern Medical University from June 2017 to July 2019. Simultaneously, 150 patients without cerebrovascular disease were confirmed by computed tomography angiography/magnetic resonance angiography/DSA. DNA was extracted from peripheral blood and NOTCH4 genotypes were identified by PCR-ligase detection reaction. The χ2 test or Fisher's exact test was used to evaluate the differences in allele and genotype frequencies between the BAVM group, control group, bleeding group, and other complications., Results: Two single-nucleotide polymorphisms (SNPs), rs443198 and rs438475, were significantly associated with BAVM. No SNP genotypes were significantly associated with hemorrhage or epilepsy. SNPs rs443198_AA-SNP and rs438475_AA-SNP may be associated with a lower risk of BAVM (p = 0.011, odds ratio (OR) = 0.459, 95% confidence interval (CI): 0.250-0.845; p = 0.033, OR = 0.759, 95% CI: 0.479-1.204)., Conclusion: NOTCH4 gene polymorphisms were associated with BAVM and may be a risk factor in a Chinese Han population., (© 2023 S. Karger AG, Basel.) more...
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- 2023
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8. The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer.
- Author
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Scheurlen KM, Chariker JH, Kanaan Z, Littlefield AB, George JB, Seraphine C, Rochet A, Rouchka EC, and Galandiuk S
- Subjects
- Adiponectin metabolism, Age of Onset, Carboxy-Lyases metabolism, Cell Line, Tumor, Cell Proliferation, GATA4 Transcription Factor genetics, GATA4 Transcription Factor metabolism, Gene Expression Regulation, Neoplastic, Humans, Obesity complications, Obesity metabolism, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt genetics, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Colorectal Neoplasms, Leptin metabolism
- Abstract
The early onset of colorectal cancer (CRC) in individuals younger than 50 years is an emerging phenomenon, and obesity is a strong risk factor. Inflammatory mechanisms are mediated by immune cells, with macrophages and their phenotypical changes playing a significant role in CRC. Obesity-related hormones, such as leptin and adiponectin, affect macrophage polarization and cytokine expression. Macrophage metabolism, and therefore polarization, directly affects tumor progression and survival in patients with CRC. Altered obesity-related hormone levels induce phosphoinositide kinase-3 (PI3K)/serine-threonine-protein kinase (AKT) activation in colon cancer, causing increased cell survival, hyperplasia, and proliferation. Investigating the effects of obesity-related mechanisms on PI3K/Akt signaling can provide new insights for targeting mechanisms in CRC and obesity among the young. Central molecules for the control of cell proliferation, differentiation, and tumorigenesis within the gastrointestinal tract include downstream targets of the PI3K/AKT pathway, such as Neurogenic locus notch homolog 4 (Notch4) and GATA binding proteins (GATA). Leptin and adiponectin both alter gene expression within this pathway, thereby affecting TAM-mediated CRC progression. Our goal is to introduce the NOTCH4-GATA4-IRG1 axis as a link between inflammation and sporadic CRC and to discuss this pathway as a new potential immunotherapeutic target in individuals affected with obesity and early-onset CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...
- Published
- 2022
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9. JAG1-NOTCH4 mechanosensing drives atherosclerosis.
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Souilhol C, Tardajos Ayllon B, Li X, Diagbouga MR, Zhou Z, Canham L, Roddie H, Pirri D, Chambers EV, Dunning MJ, Ariaans M, Li J, Fang Y, Jørgensen HF, Simons M, Krams R, Waltenberger J, Fragiadaki M, Ridger V, De Val S, Francis SE, Chico TJ, Serbanovic-Canic J, and Evans PC more...
- Subjects
- Animals, Coronary Vessels metabolism, Endothelial Cells metabolism, Humans, Mice, Signal Transduction, Swine, Atherosclerosis genetics, Atherosclerosis metabolism, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Plaque, Atherosclerotic metabolism, Receptor, Notch4 genetics, Receptor, Notch4 metabolism
- Abstract
Endothelial cell (EC) sensing of disturbed blood flow triggers atherosclerosis, a disease of arteries that causes heart attack and stroke, through poorly defined mechanisms. The Notch pathway plays a central role in blood vessel growth and homeostasis, but its potential role in sensing of disturbed flow has not been previously studied. Here, we show using porcine and murine arteries and cultured human coronary artery EC that disturbed flow activates the JAG1-NOTCH4 signaling pathway. Light-sheet imaging revealed enrichment of JAG1 and NOTCH4 in EC of atherosclerotic plaques, and EC-specific genetic deletion of Jag1 ( Jag1
ECKO ) demonstrated that Jag1 promotes atherosclerosis at sites of disturbed flow. Mechanistically, single-cell RNA sequencing in Jag1ECKO mice demonstrated that Jag1 suppresses subsets of ECs that proliferate and migrate. We conclude that JAG1-NOTCH4 sensing of disturbed flow enhances atherosclerosis susceptibility by regulating EC heterogeneity and that therapeutic targeting of this pathway may treat atherosclerosis. more...- Published
- 2022
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10. NOTCH4 mutation as predictive biomarker for immunotherapy benefits in NRAS wildtype melanoma.
- Author
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Li H, Zhang Q, Duan Q, Tan Y, Sun T, and Qi C
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- Biomarkers, Humans, Immunologic Factors therapeutic use, Immunotherapy methods, Mutation, Tumor Microenvironment genetics, GTP Phosphohydrolases genetics, Melanoma drug therapy, Melanoma genetics, Melanoma therapy, Membrane Proteins genetics, Receptor, Notch4 genetics
- Abstract
Background: NRAS wildtype melanoma accounts for approximately 80% of melanomas. Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy, while as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immunotherapy in NRAS wildtype melanoma remains indistinct., Objective: We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients., Method: This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy., Results: NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11-0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07-0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) ( P < 0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity., Conclusion: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness., Competing Interests: Authors QZ, QD, YT, TS, and CQ were employed by Jiangsu Simcere Diagnostics Co., Ltd., the Nanjing Simcere Medical Laboratory Science Co., Ltd., and The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhang, Duan, Tan, Sun and Qi.) more...
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- 2022
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11. Expression of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA is synergistically associated with T cell exclusion, immune checkpoint blockade efficacy and recurrence risk in ER-negative breast cancer.
- Author
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Liu D and Hofman P
- Subjects
- Biomarkers, Tumor biosynthesis, Biomarkers, Tumor genetics, Female, Humans, HLA-DR alpha-Chains biosynthesis, HLA-DR alpha-Chains genetics, HLA-DR alpha-Chains immunology, Receptor, Notch1 biosynthesis, Receptor, Notch1 genetics, Receptor, Notch1 immunology, Receptor, Notch4 biosynthesis, Receptor, Notch4 genetics, Receptor, Notch4 immunology, T-Lymphocytes immunology, T-Lymphocytes pathology, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology
- Abstract
Purpose: Reliable biomarkers to predict the outcome and treatment response of estrogen receptor (ER)-negative breast cancer (BC) are urgently needed. Since immune-related signaling plays an important role in the tumorigenesis of ER-negative BC, we asked whether Notch genes, alone or in combination with other immune genes, can be used to predict the clinical outcome and immune checkpoint blockade (ICB) for this type of cancer., Methods: We analyzed transcriptome data of 6918 BC samples from five independent cohorts, 81 xenograft triple-negative BC tumors that respond differently to ICB treatment and 754 samples of different cancer types from patients treated with ICB agents., Results: We found that among four Notch genes, the expression levels of NOTCH1 and NOTCH4 were positively associated with recurrence of ER-negative BC, and that combined expression of these two genes (named Notch14) further enhanced this association, which was comparable with that of the Notch pathway signature. Analysis of 1182 immune-related genes revealed that the expression levels of most HLA genes, particularly HLA-DMA and -DRA, were reversely associated with recurrence in ER-negative BC with low, but not high Notch14 expression. A combined expression signature of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA was more prognostic for ER-negative and triple-negative BCs than previously reported immune-related signatures. Furthermore, we found that the expression levels of these four genes were also synergistically associated with T cell exclusion score, infiltration of specific T cells and ICB efficacy in ER-negative BC, thereby providing a potential molecular mechanism for the synergistic effect of these genes on BC., Conclusions: Our data indicate that a gene signature composed of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA may serve as a potential promising biomarker for predicting ICB therapy efficacy and recurrence in ER-negative/triple-negative BCs., (© 2022. Springer Nature Switzerland AG.) more...
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- 2022
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12. Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension.
- Author
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Guo M, Zhang M, Cao X, Fang X, Li K, Qin L, He Y, Zhao J, Xu Y, Liu X, and Li X
- Subjects
- Animals, Apoptosis, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Hypertension, Pulmonary etiology, Hypertension, Pulmonary pathology, Hypoxia genetics, Hypoxia metabolism, MAP Kinase Signaling System, Male, Myocytes, Smooth Muscle pathology, Pulmonary Artery metabolism, Pulmonary Artery pathology, Pulmonary Artery physiopathology, Rats, Rats, Sprague-Dawley, Receptor, Notch4 biosynthesis, Signal Transduction, Up-Regulation, p38 Mitogen-Activated Protein Kinases biosynthesis, Gene Expression Regulation, Hypertension, Pulmonary genetics, Hypoxia complications, Myocytes, Smooth Muscle metabolism, Receptor, Notch4 genetics, Vascular Remodeling genetics, p38 Mitogen-Activated Protein Kinases genetics
- Abstract
Background: Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling., Methods: Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated., Results: In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats., Conclusions: These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH., (© 2022. The Author(s).) more...
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- 2022
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13. NOTCH4 Exhibits Anti-Inflammatory Activity in Activated Macrophages by Interfering With Interferon-γ and TLR4 Signaling.
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López-López S, Romero de Ávila MJ, Hernández de León NC, Ruiz-Marcos F, Baladrón V, Nueda ML, Laborda J, García-Ramírez JJ, Monsalve EM, and Díaz-Guerra MJM
- Subjects
- Animals, Blood Donors, Humans, Lipopolysaccharides pharmacology, Male, Mice, Mice, Inbred C57BL, Monocytes metabolism, RAW 264.7 Cells, Receptor, Notch4 genetics, Signal Transduction drug effects, Transfection, Interferon-gamma metabolism, Macrophage Activation genetics, Macrophages, Peritoneal immunology, Receptor, Notch4 metabolism, Signal Transduction genetics, Toll-Like Receptor 4 metabolism
- Abstract
NOTCH4 is a member of the NOTCH family of receptors whose expression is intensively induced in macrophages after their activation by Toll-like receptors (TLR) and/or interferon-γ (IFN-γ). In this work, we show that this receptor acts as a negative regulator of macrophage activation by diminishing the expression of proinflammatory cytokines, such as IL-6 and IL-12, and costimulatory proteins, such as CD80 and CD86. We have observed that NOTCH4 inhibits IFN-γ signaling by interfering with STAT1-dependent transcription. Our results show that NOTCH4 reprograms the macrophage response to IFN-γ by favoring STAT3 versus STAT1 phosphorylation without affecting their expression levels. This lower activation of STAT1 results in diminished transcriptional activity and expression of STAT1-dependent genes, including IRF1, SOCS1 and CXCL10. In macrophages, NOTCH4 inhibits the canonical NOTCH signaling pathway induced by LPS; however, it can reverse the inhibition exerted by IFN-γ on NOTCH signaling, favoring the expression of NOTCH-target genes, such as Hes1 . Indeed, HES1 seems to mediate, at least in part, the enhancement of STAT3 activation by NOTCH4. NOTCH4 also affects TLR signaling by interfering with NF-κB transcriptional activity. This effect could be mediated by the diminished activation of STAT1. These results provide new insights into the mechanisms by which NOTCH, TLR and IFN-γ signal pathways are integrated to modulate macrophage-specific effector functions and reveal NOTCH4 acting as a new regulatory element in the control of macrophage activation that could be used as a target for the treatment of pathologies caused by an excess of inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 López-López, Romero de Ávila, Hernández de León, Ruiz-Marcos, Baladrón, Nueda, Laborda, García-Ramírez, Monsalve and Díaz-Guerra.) more...
- Published
- 2021
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14. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
- Author
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Grosche S, Marenholz I, Esparza-Gordillo J, Arnau-Soler A, Pairo-Castineira E, Rüschendorf F, Ahluwalia TS, Almqvist C, Arnold A, Baurecht H, Bisgaard H, Bønnelykke K, Brown SJ, Bustamante M, Curtin JA, Custovic A, Dharmage SC, Esplugues A, Falchi M, Fernandez-Orth D, Ferreira MAR, Franke A, Gerdes S, Gieger C, Hakonarson H, Holt PG, Homuth G, Hubner N, Hysi PG, Jarvelin MR, Karlsson R, Koppelman GH, Lau S, Lutz M, Magnusson PKE, Marks GB, Müller-Nurasyid M, Nöthen MM, Paternoster L, Pennell CE, Peters A, Rawlik K, Robertson CF, Rodriguez E, Sebert S, Simpson A, Sleiman PMA, Standl M, Stölzl D, Strauch K, Szwajda A, Tenesa A, Thompson PJ, Ullemar V, Visconti A, Vonk JM, Wang CA, Weidinger S, Wielscher M, Worth CL, Xu CJ, and Lee YA more...
- Subjects
- Cytokine Receptor Common beta Subunit, Dual Specificity Phosphatase 1 chemistry, Dual Specificity Phosphatase 1 metabolism, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Matrix Attachment Region Binding Proteins, Polymorphism, Single Nucleotide, Rare Diseases genetics, Receptor, Notch4 chemistry, Receptor, Notch4 metabolism, Sodium-Hydrogen Exchangers chemistry, Sodium-Hydrogen Exchangers metabolism, Dual Specificity Phosphatase 1 genetics, Eczema diagnosis, Eczema genetics, Receptor, Notch4 genetics, Sodium-Hydrogen Exchangers genetics
- Abstract
Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema., (© 2021. The Author(s).) more...
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- 2021
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15. Unsuspected Associations of Variants within the Genes NOTCH4 and STEAP2-AS1 Uncovered by a GWAS in Endemic Pemphigus Foliaceus.
- Author
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Augusto DG, de Almeida RC, Farias TDJ, Magalhães WCS, Malheiros D, Lima-Costa MF, Barreto ML, Horta BL, Kumar V, Wittig M, Franke A, Busch H, Schmidt E, Roselino AM, Tarazona-Santos E, Boldt ABW, and Petzl-Erler ML more...
- Subjects
- Histocompatibility Antigens Class II genetics, Humans, Oxidoreductases, Pemphigus etiology, Genome-Wide Association Study, Pemphigus genetics, RNA, Long Noncoding physiology, Receptor, Notch4 genetics
- Published
- 2021
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16. Convergent lines of evidence support NOTCH4 as a schizophrenia risk gene.
- Author
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Zhang Y, Li S, Li X, Yang Y, Li W, Xiao X, Li M, Lv L, and Luo X
- Subjects
- Alleles, Animals, Brain metabolism, Case-Control Studies, Cells, Cultured, Chromosome Mapping, Computational Biology methods, Gene Expression, Gene Knockdown Techniques, Genome-Wide Association Study, Humans, Mice, Mice, Knockout, Molecular Sequence Annotation, Neural Stem Cells metabolism, Neurons metabolism, Polymorphism, Single Nucleotide, Population Surveillance, Quantitative Trait Loci, Schizophrenia diagnosis, Genetic Association Studies methods, Genetic Predisposition to Disease, Receptor, Notch4 genetics, Schizophrenia epidemiology, Schizophrenia genetics
- Abstract
The association between NOTCH4 and schizophrenia has been repeatedly reported. However, the results from different genetic studies are inconsistent, and the role of NOTCH4 in schizophrenia pathogenesis remains unknown. Here, we provide convergent lines of evidence that support NOTCH4 as a schizophrenia risk gene. We first performed a meta-analysis and found that a genetic variant (rs2071287) in NOTCH4 was significantly associated with schizophrenia (a total of 125 848 subjects, p=8.31×10
-17 ), with the same risk allele across all tested samples. Expression quantitative trait loci (eQTL) analysis showed that rs2071287 was significantly associated with NOTCH4 expression (p=1.08×10-14 ) in human brain tissues, suggesting that rs2071287 may confer schizophrenia risk through regulating NOTCH4 expression. Sherlock integrative analysis using a large-scale schizophrenia GWAS and eQTL data from human brain tissues further revealed that NOTCH4 was significantly associated with schizophrenia (p=4.03×10-7 in CMC dataset and p=3.06×10-6 in xQTL dataset), implying that genetic variants confer schizophrenia risk through modulating NOTCH4 expression. Consistently, we found that NOTCH4 was significantly downregulated in brains of schizophrenia patients compared with controls (p=2.53×10-3 ), further suggesting that dysregulation of NOTCH4 may have a role in schizophrenia. Finally, we showed that NOTCH4 regulates proliferation, self-renewal, differentiation and migration of neural stem cells, suggesting that NOTCH4 may confer schizophrenia risk through affecting neurodevelopment. Our study provides convergent lines of evidence that support the involvement of NOTCH4 in schizophrenia. In addition, our study also elucidates a possible mechanism for the role of NOTCH4 in schizophrenia pathogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2021
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17. Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis.
- Author
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Gragnani L, Lorini S, Marri S, Basile U, Santarlasci V, Monti M, Madia F, Petraccia L, Stasi C, Marello N, Napodano C, Annunziato F, and Zignego AL
- Subjects
- Aged, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Cryoglobulinemia genetics, Female, Hepatitis C, Chronic blood, Hepatitis C, Chronic genetics, Humans, Immunoglobulin kappa-Chains blood, Immunoglobulin lambda-Chains blood, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Receptor, Notch4 genetics, Recurrence, Sustained Virologic Response, Translocation, Genetic, Vasculitis genetics, Antiviral Agents therapeutic use, Cryoglobulinemia blood, Hepatitis C, Chronic drug therapy, Vasculitis blood
- Abstract
Background and Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome., Approach and Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively)., Conclusions: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.) more...
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- 2021
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18. Notch4 signaling limits regulatory T-cell-mediated tissue repair and promotes severe lung inflammation in viral infections.
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Harb H, Benamar M, Lai PS, Contini P, Griffith JW, Crestani E, Schmitz-Abe K, Chen Q, Fong J, Marri L, Filaci G, Del Zotto G, Pishesha N, Kolifrath S, Broggi A, Ghosh S, Gelmez MY, Oktelik FB, Cetin EA, Kiykim A, Kose M, Wang Z, Cui Y, Yu XG, Li JZ, Berra L, Stephen-Victor E, Charbonnier LM, Zanoni I, Ploegh H, Deniz G, De Palma R, and Chatila TA more...
- Subjects
- Amphiregulin pharmacology, Animals, Biomarkers, Cytokines metabolism, Disease Models, Animal, Disease Susceptibility, Humans, Immunohistochemistry, Immunomodulation drug effects, Inflammation Mediators metabolism, Influenza A virus physiology, Lung immunology, Lung metabolism, Lung pathology, Lung virology, Mice, Mice, Transgenic, Pneumonia, Viral pathology, Receptor, Notch4 antagonists & inhibitors, Receptor, Notch4 genetics, Severity of Illness Index, Host-Pathogen Interactions immunology, Immunity, Cellular, Pneumonia, Viral etiology, Pneumonia, Viral metabolism, Receptor, Notch4 metabolism, Signal Transduction, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism
- Abstract
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections., Competing Interests: Declaration of interests T.A.C., H.H., M.B., P.S.L., P.C., and R.D.P. are inventors on provisional patent application US 63/038,186 titled “Methods and Compositions for treating coronavirus infectious disease.” H.H. and T.A.C. are co-founders of and hold equity in Alcea Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...
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- 2021
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19. NOTCH Single Nucleotide Polymorphisms in the Predisposition of Breast and Colorectal Cancers in Saudi Patients.
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Alanazi IO, Shaik JP, Parine NR, Al Naeem A, Azzam NA, Almadi MA, Aljebreen AM, Alharbi O, Alanazi MS, and Khan Z
- Subjects
- Breast Neoplasms epidemiology, Breast Neoplasms genetics, Case-Control Studies, Colorectal Neoplasms epidemiology, Colorectal Neoplasms genetics, Female, Follow-Up Studies, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Saudi Arabia epidemiology, Biomarkers, Tumor genetics, Breast Neoplasms pathology, Colorectal Neoplasms pathology, Receptor, Notch1 genetics, Receptor, Notch2 genetics, Receptor, Notch3 genetics, Receptor, Notch4 genetics
- Abstract
Breast cancer (BC) is a heterogeneous disease and is one of the most common malignancy affecting women worldwide while colorectal cancer (CRC) is estimated to be the third common cancer and second leading cause of cancer related death globally. Both BC and CRC involve multiple genetic and epigenetic alterations in genes belonging to various signaling pathways including NOTCH that has been implicated in the development of these cancers. We investigated four single nucleotide polymorphisms, each in genes encoding NOTCH1-4 receptors for their role in susceptibility to breast and colorectal cancers in Saudi population. In this case-control study, TaqMan genotypic analysis of rs3124591 in NOTCH1 and rs3820041 in NOTCH4 did not exhibit association with breast as well as colorectal cancers. However, a strong association of rs11249433 which is in close proximity to NOTCH2 was observed with breast cancer susceptibility especially with those having an early onset of the disease. Interestingly, the rs1043994 located in NOTCH3 showed gender preference and was found to be significantly associated with colorectal cancers in males. Validation of these findings in bigger populations of different ethnicities may prove beneficial in identifying rs11249433 and rs1043994 as genetic screening markers for early detection of breast and colorectal carcinomas, respectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alanazi, Shaik, Parine, Al Naeem, Azzam, Almadi, Aljebreen, Alharbi, Alanazi and Khan.) more...
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- 2021
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20. Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma.
- Author
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Fukusumi T, Guo TW, Ren S, Haft S, Liu C, Sakai A, Ando M, Saito Y, Sadat S, and Califano JA
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Datasets as Topic, Feedback, Physiological, Gene Expression Regulation, Neoplastic, Humans, Mice, Receptor, Notch4 metabolism, Signal Transduction genetics, Spheroids, Cellular, Squamous Cell Carcinoma of Head and Neck pathology, Up-Regulation, Xenograft Model Antitumor Assays, Basic Helix-Loop-Helix Transcription Factors genetics, Cell Cycle Proteins genetics, Epithelial-Mesenchymal Transition genetics, Receptor, Notch4 genetics, SOXB1 Transcription Factors metabolism, Squamous Cell Carcinoma of Head and Neck genetics
- Abstract
Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites. more...
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- 2021
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21. Notch family members follow stringent requirements for intracellular domain dimerization at sequence-paired sites.
- Author
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Crow JJ and Albig AR
- Subjects
- Animals, Base Sequence, HEK293 Cells, Humans, Mice, Promoter Regions, Genetic, Protein Binding, Protein Domains, Protein Multimerization, Receptor, Notch2 chemistry, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Receptor, Notch3 chemistry, Receptor, Notch3 genetics, Receptor, Notch3 metabolism, Receptor, Notch4 chemistry, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Receptors, Notch genetics, Signal Transduction, Transcriptional Activation, Basic Helix-Loop-Helix Transcription Factors genetics, Mutagenesis, Receptors, Notch chemistry, Receptors, Notch metabolism
- Abstract
Notch signaling is essential for multicellular life, regulating core functions such as cellular identity, differentiation, and fate. These processes require highly sensitive systems to avoid going awry, and one such regulatory mechanism is through Notch intracellular domain dimerization. Select Notch target genes contain sequence-paired sites (SPS); motifs in which two Notch transcriptional activation complexes can bind and interact through Notch's ankyrin domain, resulting in enhanced transcriptional activation. This mechanism has been mostly studied through Notch1, and to date, the abilities of the other Notch family members have been left unexplored. Through the utilization of minimalized, SPS-driven luciferase assays, we were able to test the functional capacity of Notch dimers. Here we show that the Notch 2 and 3 NICDs also exhibit dimerization-induced signaling, following the same stringent requirements as seen with Notch1. Furthermore, our data suggested that Notch4 may also exhibit dimerization-induced signaling, although the amino acids required for Notch4 NICD dimerization appear to be different than those required for Notch 1, 2, and 3 NICD dimerization. Interestingly, we identified a mechanical difference between canonical and cryptic SPSs, leading to differences in their dimerization-induced regulation. Finally, we profiled the Notch family members' SPS gap distance preferences and found that they all prefer a 16-nucleotide gap, with little room for variation. In summary, this work highlights the potent and highly specific nature of Notch dimerization and refines the scope of this regulatory function., Competing Interests: The authors have declared that no competing interests exist. more...
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- 2020
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22. Methylation status of CpG sites in the NOTCH4 promoter region regulates NOTCH4 expression in patients with tetralogy of Fallot.
- Author
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Zhu Y, Ye M, Xu H, Gu R, Ma X, Chen M, Li X, Sheng W, and Huang G
- Subjects
- Adolescent, Case-Control Studies, Child, Child, Preschool, CpG Islands, Female, Humans, Infant, Infant, Newborn, Male, Promoter Regions, Genetic, Proto-Oncogene Protein c-ets-1 metabolism, Sequence Analysis, DNA, Tetralogy of Fallot metabolism, DNA Methylation, Down-Regulation, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Tetralogy of Fallot genetics
- Abstract
Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD). Although a lower methylation level of whole genome has been demonstrated in TOF patients, little is known regarding the DNA methylation changes in specific gene and its associations with TOF development. NOTCH4 is a mediator of the Notch signalling pathway that plays an important role in normal cardiac development. However, the role of epigenetic regulation of the NOTCH4 gene in the pathogenesis of TOF remains unclear. Considering the NOTCH4 low mutation frequency and reduced expression in the TOF patients, we hypothesized that abnormal DNA methylation change of NOTCH4 gene may influence its expression and responsible for TOF development. In this study, we measured the promoter methylation status of NOTCH4 and was measured and its regulation mechanism was explored, which may be related to TOF disease. Additionally, the promoter methylation statuses of NOTCH4 was measured in order to further understand epigenetic mechanisms that may serve a role in the development of TOF. Immunohistochemical analysis was used to examine NOTCH4 expression in right ventricular outflow tract myocardial tissues in patients with TOF. Compared with healthy controls, patients with TOF displayed significantly reduced in NOTCH4 expression (P=0.0055). Moreover, bisulphite sequencing suggested that the methylation levels of CpG site 2 in the NOTCH4 promoter was significantly higher in the patients than in the controls (P=0.0459). NOTCH4 expression was negatively associated with CpG site 2 methylation levels (r=‑0.51; P=0.01). ETS1 transcription factor can serve as transcriptional activators by binding to specific DNA sequences of target genes, such as DLL4 and NOTCH4, which serves an important role in normal heart development. Dual‑luciferase reporter and electrophoretic mobility shift assays indicated that the ETS1 transcription factor could bind to the NOTCH4 promoter region. However, binding of ETS1 to the NOTCH4 promoter was abrogated by methylation at the putative ETS1 binding sites. These findings suggested that decreased NOTCH4 expression in patients with TOF may be associated with hypermethylation of CpG site 2 in the NOTCH4 promoter region, due to impaired binding of ETS1. more...
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- 2020
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23. DLL1- and DLL4-Mediated Notch Signaling Is Essential for Adult Pancreatic Islet Homeostasis.
- Author
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Rubey M, Chhabra NF, Gradinger D, Sanz-Moreno A, Lickert H, Przemeck GKH, and Hrabě de Angelis M
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adult, Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Calcium-Binding Proteins genetics, Gene Expression Regulation physiology, Glucagon blood, Glucagon-Secreting Cells pathology, Glucagon-Secreting Cells physiology, Glucose genetics, Glucose metabolism, Humans, Mice, Mice, Transgenic, Receptor, Notch3 genetics, Receptor, Notch4 genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Transcription Factor HES-1 genetics, Transcription Factor HES-1 metabolism, Adaptor Proteins, Signal Transducing metabolism, Calcium-Binding Proteins metabolism, Insulin metabolism, Pancreas metabolism, Receptor, Notch3 metabolism, Receptor, Notch4 metabolism
- Abstract
Genes of the Notch signaling pathway are expressed in different cell types and organs at different time points during embryonic development and adulthood. The Notch ligand Delta-like 1 (DLL1) controls the decision between endocrine and exocrine fates of multipotent progenitors in the developing pancreas, and loss of Dll1 leads to premature endocrine differentiation. However, the role of Delta-Notch signaling in adult tissue homeostasis is not well understood. Here, we describe the spatial expression pattern of Notch pathway components in adult murine pancreatic islets and show that DLL1 and DLL4 are specifically expressed in β-cells, whereas JAGGED1 is expressed in α-cells. We show that mice lacking both DLL1 and DLL4 in adult β-cells display improved glucose tolerance, increased glucose-stimulated insulin secretion, and hyperglucagonemia. In contrast, overexpression of the intracellular domain of DLL1 in adult murine pancreatic β-cells results in impaired glucose tolerance and reduced insulin secretion, both in vitro and in vivo. These results suggest that Notch ligands play specific roles in the adult pancreas and highlight a novel function of the Delta/Notch pathway in β-cell insulin secretion., (© 2020 by the American Diabetes Association.) more...
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- 2020
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24. NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.
- Author
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Bertucci F, Rypens C, Finetti P, Guille A, Adélaïde J, Monneur A, Carbuccia N, Garnier S, Dirix P, Gonçalves A, Vermeulen P, Debeb BG, Wang X, Dirix L, Ueno NT, Viens P, Cristofanilli M, Chaffanet M, Birnbaum D, and Van Laere S more...
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Breast Neoplasms mortality, Breast Neoplasms pathology, Comparative Genomic Hybridization, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 6 genetics, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Inflammatory Breast Neoplasms mortality, Inflammatory Breast Neoplasms pathology, Middle Aged, Mutation, Neoplasm Staging, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Receptors, Estrogen genetics, Receptors, Estrogen metabolism, Signal Transduction, Young Adult, BRCA2 Protein genetics, Breast Neoplasms genetics, DNA Repair genetics, Inflammatory Breast Neoplasms genetics, Receptor, Notch4 genetics
- Abstract
Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.) more...
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- 2020
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25. A Notch4 missense mutation is associated with susceptibility to tuberculosis in Chinese population.
- Author
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Zhang J, Jiao L, Bai H, Wu Q, Wu T, Liu T, Hu X, Song J, and Ying B
- Subjects
- Adult, Animals, Asian People genetics, Case-Control Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Mutation, Missense, Receptor, Notch4 genetics, Tuberculosis genetics
- Abstract
Background: The infection process of tuberculosis is related to the interactions between Mycobacterium tuberculosis (MTB) and the host immune system. Polymorphisms in genes involved in the host immune system are related to susceptibility to tuberculosis. The Notch signalling pathway regulates innate and adaptive immunity. Notch4 is a member of the Notch receptor family and may be a negative regulator of Mtb-induced inflammation. However, little is known about the association between Notch4 genetic polymorphisms and susceptibility to tuberculosis; therefore, we explored the association between Notch4 variants and susceptibility to tuberculosis in China., Materials and Methods: A total of 900 tuberculosis patients and 1534 healthy people serving as controls were enrolled consecutively at West China Hospital between January 2014 and February 2016 Twelve selected SNPs (rs2071277, rs2071285, rs206016, rs438475, rs2256594, rs429853, rs422951, rs415929, rs915895, rs443198, rs3830041 and rs375244) were genotyped by a custom-by-design 2 48-plex SNP scan TM kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between the two groups, while the SNP-SNP interactions were analysed by Multifactor Dimensionality Reduction (MDR) software. The odds ratio (OR) with a corresponding 95% confidence interval (CI) was calculated., Results: The G allele rs2071277 of Notch4 was associated with a decreased risk for tuberculosis (OR 0.844; 95% CI 0.748-0.954, p = .006). The G allele rs422951 of Notch4 was associated with a decreased risk for tuberculosis (OR 0.818; 95% CI 0.703-0.950, p = .008). These findings were consistent with the results from both the dominant model and additive model. The allele, genotype and genetic model frequencies for the other SNPs were similar in the two groups (all P > .05). One haplotype (GTG) consisting of rs2071277, rs2071285 and rs206016 was associated with tuberculosis risk (p = .011)., Conclusion: Ours is the first study implies that the G allele variants of rs2071277 and rs422951 in Notch4 influence susceptibility to tuberculosis in a Chinese population, suggesting that Notch signalling is involved in the pathogenesis of tuberculosis. More studies with functional verification will refine our understanding of the role of Notch signalling and provide novel avenues for therapeutic intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2019. Published by Elsevier B.V.) more...
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- 2020
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26. Association of GWAS-supported noncoding area loci rs404860, rs3117098, and rs7775228 with asthma in Chinese Zhuang population.
- Author
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Liang SQ, Deng JM, Wei X, Chen ZR, Yang ML, Qin HJ, Zhang JQ, and He ZY
- Subjects
- Adult, Alleles, Asian People genetics, Case-Control Studies, China ethnology, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Asthma genetics, Butyrophilins genetics, HLA-DQ Antigens genetics, Polymorphism, Single Nucleotide, Receptor, Notch4 genetics
- Abstract
Background: Asthma is a complicated and polygenic inheritance disease, and its prevalence increases worldwide. Recent genome-wide association studies (GWASs) identified a significant association of single nucleotide polymorphism with asthma in the Japanese population. This study aimed to examine the association of GWAS-supported noncoding area loci, namely rs404860, rs3117098, and rs7775228, with asthma in Chinese Zhuang population., Methods: A case-control study involving 223 individuals, comprising 123 patients with asthma and 100 healthy controls, was conducted. Genotypes were determined by polymerase chain reaction (PCR)/ligase detection reaction assay. The association between gene polymorphisms and asthma risk was calculated by logistic regression analysis using different genetic models through comparisons of alleles (A vs a), homozygote genotypes (AA vs aa), heterozygote genotypes (Aa vs aa), dominant models (AA+Aa vs aa), and recessive models (AA vs. Aa+aa)., Results: The distribution of the genotype frequency of rs3117098 was statistically different between the case and control groups. For rs3117098, significant associations were observed through comparisons of alleles (OR: 1.832, 95% CI: 1.048-3.204, P = .034) and dominant models (OR: 2.065, 95% CI: 1.001-4.260, P = .050). The statistical analysis showed no significant difference for loci rs404860 and rs7775228 between patients with asthma and controls., Conclusion: rs3117098 may be the risk factor for asthma in Chinese Zhuang population., (© 2019 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals, Inc.) more...
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- 2020
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27. NOTCH4 maintains quiescent mesenchymal-like breast cancer stem cells via transcriptionally activating SLUG and GAS1 in triple-negative breast cancer.
- Author
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Zhou L, Wang D, Sheng D, Xu J, Chen W, Qin Y, Du R, Yang X, He X, Xie N, Liu S, and Zhang L
- Subjects
- Animals, Cell Cycle Checkpoints, Cell Cycle Proteins genetics, Cell Line, Tumor, Cell Proliferation, Epithelial-Mesenchymal Transition, Female, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Gene Knockdown Techniques, Humans, MCF-7 Cells, Mesenchymal Stem Cells metabolism, Mice, Prognosis, Receptor, Notch4 genetics, Snail Family Transcription Factors genetics, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms pathology, Cell Cycle Proteins metabolism, Neoplastic Stem Cells metabolism, Receptor, Notch4 metabolism, Snail Family Transcription Factors metabolism, Triple Negative Breast Neoplasms metabolism
- Abstract
Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24
- CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).) more...- Published
- 2020
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28. All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia.
- Author
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Nguyen CH, Bauer K, Hackl H, Schlerka A, Koller E, Hladik A, Stoiber D, Zuber J, Staber PB, Hoelbl-Kovacic A, Purton LE, Grebien F, and Wieser R
- Subjects
- Animals, Apoptosis drug effects, Carcinogenesis drug effects, Cell Proliferation drug effects, Disease Models, Animal, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Myeloid, Acute pathology, Mice, Myeloid Cells drug effects, Neoplastic Stem Cells metabolism, Leukemia, Myeloid, Acute genetics, MDS1 and EVI1 Complex Locus Protein genetics, Receptor, Notch4 genetics, Tretinoin metabolism
- Abstract
Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1
high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML. more...- Published
- 2019
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29. Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway.
- Author
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Lv H, Nan Z, Jiang P, Wang Z, Song M, Ding H, Liu D, Zhao G, Zheng Y, and Hu Y
- Subjects
- Adult, Animals, Blotting, Western, Cell Differentiation genetics, Cell Differentiation physiology, Female, Genotyping Techniques, Humans, Intracellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Mice, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Receptor, Notch4 genetics, Signal Transduction, Smad7 Protein genetics, Vascular Endothelial Growth Factor A genetics, Young Adult, Intracellular Signaling Peptides and Proteins metabolism, Membrane Proteins metabolism, Receptor, Notch4 metabolism, Smad7 Protein metabolism, Stromal Cells metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Endometrial fibrosis is the main pathological feature of Asherman's syndrome (AS), which is the leading cause of uterine infertility. Much is known about the expression of VEGF165 in luminal/glandular epithelial cells and stromal cells of the endometrium in normal menstrual cycles; however, less is known about the role and mechanism of VEGF165 in endometrial fibrosis. Herein, we report that VEGF165 is a key regulator in endometrial stromal cells to inhibit α-SMA and collagen 1 expression. Compared to human control subjects, patients with AS exhibited decreased VEGF165 expression in the endometrium along with increased fibrotic marker expression and collagen production. A fibrotic phenotype was shown in both mice with conditional VEGF reduction and VEGF165-deleted endometrial stromal cells. Exogenous VEGF165 could suppress TGFβ1-induced α-SMA and collagen 1 expression in human primary endometrial stromal cells. However, this beneficial effect was hindered when the expression of smad7 or Notch4 was inhibited or when Notch signaling was blocked, suggesting that smad7 and Notch4 are essential downstream molecules for VEGFA functioning. Overall, our results uncover a clinical targeting strategy for VEGF165 to inhibit pro-fibrotic differentiation of stromal cells by inducing DLL4/Notch4/smad7, which paves the way for AS treatment. more...
- Published
- 2019
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- View/download PDF
30. Associations of Multiple NOTCH4 Exonic Variants with Systemic Sclerosis.
- Author
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Zhou X, Li H, Guo S, Wang J, Shi C, Espitia M, Guo X, Wang Q, Liu M, Assassi S, Reveille JD, and Mayes MD
- Subjects
- Alleles, Asian People genetics, Autoantibodies genetics, Follow-Up Studies, Genetic Predisposition to Disease genetics, Genotype, High-Throughput Nucleotide Sequencing, Histocompatibility Antigens Class II genetics, Humans, Logistic Models, Polymorphism, Single Nucleotide genetics, Scleroderma, Systemic blood, Scleroderma, Systemic ethnology, Tandem Repeat Sequences genetics, White People genetics, Exons genetics, Receptor, Notch4 genetics, Scleroderma, Systemic genetics
- Abstract
Objective: Findings from previous genome-wide association studies indicated an association of the NOTCH4 gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of NOTCH4 in SSc., Methods: All exons of NOTCH4 were sequenced and analyzed in a total of 1006 patients with SSc and 1004 controls of US white ancestry with the Ion Torrent system. Identified SSc-associated variants were confirmed with Sanger sequencing, and then examined in a Chinese Han cohort consisting of 576 patients with SSc and 574 controls. The NOTCH4 variants were analyzed for association with SSc as a whole and with SSc clinical and autoantibody subtypes with and without the influence of specific HLA-class II alleles that had been previously identified as major genetic factors in SSc., Results: A total of 12 SSc-associated and SSc subtype-associated exonic variants of NOTCH4 were identified in the US cohort. Three of them are nonsynonymous single-nucleotide polymorphisms and 1 is a CTG tandem repeat that encodes for a poly-leucine, all of which are located in the NOTCH4 extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA-class II alleles indicated an independent association of the NOTCH4 variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of NOTCH4 to SSc and its subtypes., Conclusion: Multiple NOTCH4 exonic variants were associated with SSc and/or SSc subtypes. Several of these variants encode nonsynonymous sequence changes occurring in the NECD, which implicates a potentially functional effect of NOTCH4 . more...
- Published
- 2019
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31. Evaluation of the correlation of vasculogenic mimicry, Notch4, DLL4, and KAI1/CD82 in the prediction of metastasis and prognosis in non-small cell lung cancer.
- Author
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Wang Y, Yang R, Wang X, Ci H, Zhou L, Zhu B, Wu S, and Wang D
- Subjects
- Adaptor Proteins, Signal Transducing, Adult, Aged, Biomarkers, Tumor analysis, Calcium-Binding Proteins, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Lung Neoplasms secondary, Lymphatic Metastasis genetics, Male, Middle Aged, Multivariate Analysis, Neoplasm Grading, Neoplasm Staging, Prognosis, Survival Rate, Carcinoma, Non-Small-Cell Lung genetics, Intercellular Signaling Peptides and Proteins genetics, Kangai-1 Protein genetics, Lung Neoplasms genetics, Molecular Mimicry genetics, Receptor, Notch4 genetics
- Abstract
Vasculogenic mimicry (VM) is a new blood supply style in tumors and has long been treated as a useful factor in malignant tumor metastasis and prognosis. Notch4 (a marker of Notch signaling pathway receptors), DLL4 (a marker of Notch signaling pathway ligands) and KAI1/CD82 (a suppressor gene of tumor metastasis) are all effective predictive factors for tumor metastasis. In this study, we analyzed correlations among VM, Notch4, DLL4, and KAI1/CD82 in non-small cell lung cancer (NSCLC), and their respective associations with patients' clinicopathological parameters and survival rate in NSCLC.Positive rates of VM, Notch4, DLL4, and KAI1/CD82 in 189 whole NSCLC specimens were detected by histochemical and immunohistochemical staining. Moreover, patients' clinicopathological information was also collected.Positive rates of VM, Notch4, and DLL4 were significantly higher, and levels of KAI1/CD82 were significantly lower in NSCLC than in normal lung tissues. Positive rates of VM, Notch4, and DLL4 were positively associated with tumor size, lymph node metastasis (LNM), distant metastasis (DM) and tumor-node-metastasis (TNM) stage, and inversely with patients, overall survival (OS) time and positive rate of DLL4 were positively associated with tumor grade. Levels of KAI1/CD82 were negatively associated with tumor size, LNM, DM, and TNM stage. The KAI1/CD82+ subgroup had significantly longer OS time than did the KAI1/CD82- subgroup. In multivariate analysis, high VM, Notch4, DLL4 levels, tumor size, LNM, DM, TNM stage, and low KAI1/CD82 levels were potential to be independent prognostic factors for overall survival time (OST) in NSCLC patients.VM and the expression of Notch4, DLL4, and KAI1/CD82 represent promising markers for tumor metastasis and prognosis, and maybe potential therapeutic targets for NSCLC. more...
- Published
- 2018
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32. Increased expression of miR-1179 inhibits breast cancer cell metastasis by modulating Notch signaling pathway and correlates with favorable prognosis.
- Author
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Li WJ, Xie XX, Bai J, Wang C, Zhao L, and Jiang DQ
- Subjects
- Breast Neoplasms genetics, Breast Neoplasms mortality, Breast Neoplasms pathology, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, MicroRNAs genetics, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Receptors, Notch genetics, Signal Transduction, Transcription Factor HES-1 genetics, Transcription Factor HES-1 metabolism, Up-Regulation, Breast Neoplasms metabolism, Cell Movement, MicroRNAs metabolism, Receptors, Notch metabolism
- Abstract
Objective: MicroRNAs (miRNAs) play a key role in the regulation of gene expression. In this study, we aimed to identify the clinical values of miR-1179 and to investigate the potential molecular mechanisms in breast cancer (BC)., Materials and Methods: RT-PCR was used to detect the expression levels of miR-1179 in both BC tissues and cell lines. We analyzed the association between the miR-1179 levels and clinicopathological factors and patient prognosis. The proliferation ability of miR-1179 on BC cells was assessed by MTT and colony formation assay. The role of miR-1179 in BC cells migration and invasion was measured by transwell assays. Western blot analysis was used to quantify the expression of the molecular biomarkers of the Notch signaling pathway., Results: Our results showed that miR-1179 expression was frequently downregulated in BC tissues and cell lines. Clinicopathologic analysis revealed that low miR-1179 expression is correlated with lymph node metastasis, advanced clinical stage and shorter overall survival. Multivariable Cox proportional hazards regression analysis suggested that increased miR-1179 expression was an independent prognostic factor of overall survival in BC patients. Gain-of-function assay indicated that the overexpression of miR-1179 significantly suppressed BC cells proliferation, migration and invasion. Mechanistically, miR-1179 up-regulation inhibited the expression of Notch 1, Notch 4 and Hes1, indicating that miR-1179 could suppress the activation of the Notch signaling pathway., Conclusions: We showed that miR-1179 was a tumor suppressor that may serve as a novel potential prognostic biomarker or molecular therapeutic target for BC. more...
- Published
- 2018
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33. Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy.
- Author
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Chettimada S, Lorenz DR, Misra V, Dillon ST, Reeves RK, Manickam C, Morgello S, Kirk GD, Mehta SH, and Gabuzda D
- Subjects
- Antigens, CD genetics, Antigens, CD immunology, Antiretroviral Therapy, Highly Active, Biomarkers metabolism, Case-Control Studies, Catalase genetics, Catalase immunology, Chromatography, High Pressure Liquid, Computational Biology methods, Cystine immunology, Cystine metabolism, Exosomes genetics, Exosomes metabolism, Fatty Acids, Unsaturated immunology, Fatty Acids, Unsaturated metabolism, HIV drug effects, HIV immunology, HIV pathogenicity, HIV Infections genetics, HIV Infections virology, HLA Antigens genetics, HLA Antigens immunology, Humans, Immunity, Innate, Interferon Regulatory Factors genetics, Interferon Regulatory Factors immunology, Metabolome genetics, Oxidative Stress, Peroxiredoxins genetics, Peroxiredoxins immunology, Proteome genetics, Receptor, Notch4 genetics, Receptor, Notch4 immunology, THP-1 Cells, Tandem Mass Spectrometry, Anti-HIV Agents therapeutic use, Exosomes immunology, HIV Infections drug therapy, HIV Infections immunology, Metabolome immunology, Proteome immunology
- Abstract
Exosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes were characterized by electron microscopy, nanoparticle tracking, immunoblotting, and LC-MS/MS proteomics. Plasma exosomes were increased in HIV-positive subjects compared to controls, and correlated with increased oxidative stress markers (cystine, oxidized cys-gly) and decreased PUFA (DHA, EPA, DPA). Untargeted proteomics detected markers of exosomes (CD9, CD63, CD81), immune activation (CD14, CRP, HLA-A, HLA-B), oxidative stress (CAT, PRDX1, PRDX2, TXN), and Notch4 in plasma exosomes. Exosomal Notch4 was increased in HIV-positive subjects versus controls and correlated with immune activation markers. Treatment of THP-1 monocytic cells with patient-derived exosomes induced expression of genes related to interferon responses and immune activation. These results suggest that exosomes in ART-treated HIV patients carry proteins related to immune activation and oxidative stress, have immunomodulatory effects on myeloid cells, and may have pro-inflammatory and redox effects during pathogenesis. more...
- Published
- 2018
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34. The NOTCH4 - HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma.
- Author
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Fukusumi T, Guo TW, Sakai A, Ando M, Ren S, Haft S, Liu C, Amornphimoltham P, Gutkind JS, and Califano JA
- Subjects
- Basic Helix-Loop-Helix Transcription Factors genetics, Cell Cycle drug effects, Cell Cycle genetics, Cell Cycle Proteins genetics, Cell Line, Tumor, Cisplatin pharmacology, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Receptor, Notch4 genetics, Squamous Cell Carcinoma of Head and Neck genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Cycle Proteins metabolism, Epithelial-Mesenchymal Transition genetics, Receptor, Notch4 metabolism, Signal Transduction, Squamous Cell Carcinoma of Head and Neck metabolism, Squamous Cell Carcinoma of Head and Neck pathology
- Abstract
Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood. Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4 , we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1 , and epithelial-mesenchymal transition (EMT)-related genes using the TCGA data set and in vitro assays. Results: HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1 , and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration. Conclusions: In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619-33. ©2017 AACR ., (©2017 American Association for Cancer Research.) more...
- Published
- 2018
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35. Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion.
- Author
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Billiard F, Karaliota S, Wang B, Stellas D, Serafimidis I, Manousopoulou A, Koutmani Y, Ninou E, Golubov J, DaNave A, Tsakanikas P, Xin Y, Zhang W, Sleeman M, Yancopoulos GD, Murphy AJ, Garbis SD, Karalis K, and Skokos D more...
- Subjects
- Animals, Cell Differentiation, Mice, Mice, Inbred NOD, Signal Transduction, Insulin Secretion genetics, Receptor, Notch4 genetics
- Abstract
Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2018
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36. Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation.
- Author
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Li Y, Jin C, Bai H, Gao Y, Sun S, Chen L, Qin L, Liu PP, Cheng L, and Wang QF
- Subjects
- CRISPR-Cas Systems, Cell Line, Cell Proliferation, Core Binding Factor Alpha 2 Subunit metabolism, Humans, Induced Pluripotent Stem Cells metabolism, Megakaryocytes metabolism, Point Mutation, Receptor, Notch4 metabolism, Signal Transduction, Core Binding Factor Alpha 2 Subunit genetics, Gene Expression Regulation, Developmental, Induced Pluripotent Stem Cells cytology, Megakaryocytes cytology, Receptor, Notch4 genetics, Thrombopoiesis
- Abstract
Megakaryocytes (MKs) in adult marrow produce platelets that play important roles in blood coagulation and hemostasis. Monoallelic mutations of the master transcription factor gene RUNX1 lead to familial platelet disorder (FPD) characterized by defective MK and platelet development. However, the molecular mechanisms of FPD remain unclear. Previously, we generated human induced pluripotent stem cells (iPSCs) from patients with FPD containing a RUNX1 nonsense mutation. Production of MKs from the FPD-iPSCs was reduced, and targeted correction of the RUNX1 mutation restored MK production. In this study, we used isogenic pairs of FPD-iPSCs and the MK differentiation system to identify RUNX1 target genes. Using integrative genomic analysis of hematopoietic progenitor cells generated from FPD-iPSCs, and mutation-corrected isogenic controls, we identified 2 gene sets the transcription of which is either up- or downregulated by RUNX1 in mutation-corrected iPSCs. Notably, NOTCH4 expression was negatively controlled by RUNX1 via a novel regulatory DNA element within the locus, and we examined its involvement in MK generation. Specific inactivation of NOTCH4 by an improved CRISPR-Cas9 system in human iPSCs enhanced megakaryopoiesis. Moreover, small molecules known to inhibit Notch signaling promoted MK generation from both normal human iPSCs and postnatal CD34
+ hematopoietic stem and progenitor cells. Our study newly identified NOTCH4 as a RUNX1 target gene and revealed a previously unappreciated role of NOTCH4 signaling in promoting human megakaryopoiesis. Our work suggests that human iPSCs with monogenic mutations have the potential to serve as an invaluable resource for discovery of novel druggable targets. more...- Published
- 2018
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37. The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis.
- Author
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Raafat A, Bargo S, McCurdy D, and Callahan R
- Subjects
- Animals, Ankyrin Repeat, Cell Line, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic pathology, Epithelial Cells drug effects, Epithelial Cells metabolism, Epithelial Cells pathology, Female, I-kappa B Kinase antagonists & inhibitors, I-kappa B Kinase metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein genetics, Mammary Glands, Animal drug effects, Mammary Glands, Animal pathology, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental pathology, Mice, Knockout, Receptor, Notch4 genetics, Signal Transduction, Cell Transformation, Neoplastic metabolism, Immunoglobulin J Recombination Signal Sequence-Binding Protein deficiency, Mammary Glands, Animal metabolism, Mammary Neoplasms, Experimental metabolism, NF-kappa B metabolism, Receptor, Notch4 metabolism
- Abstract
Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice. Thus, Notch-induced mammary tumor development is Rbpj-independent. Here, we show that Int3 activates NF-κB in HC11 cells in absence of Rbpj through an association with the IKK signalosome. Int3 induced the canonical NF-κB activity and P50 phosphorylation in HC11 cells without altering the NF-κB2 pathway. The minimal domain within the Int3 protein required to activate NF-κB consists of the CDC10/Ankyrin (ANK) repeats domain. Treatment of WAP-Int3 tumor bearing mice with an IKK inhibitor resulted in tumor regression. In a soft agar assay, treatment of HC11-Int3 cells with P50-siRNA caused a significant decrease in colony formation. In addition, Wap-Int3/P50 knockout mice did not develop mammary tumors. This data indicates that the activation of NF-κB canonical signaling by Notch-4/Int3 is ANK repeats dependent, Rbpj-independent, and is mediated by IKK activation and P50 phosphorylation causing mammary tumorigenesis. more...
- Published
- 2017
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38. Protective effect of Shouwu Yizhi decoction against vascular dementia by promoting angiogenesis.
- Author
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Yang XN, Li CS, Chen C, Tang XY, Cheng GQ, and Li X
- Subjects
- Alpinia, Animals, Dementia, Vascular genetics, Dementia, Vascular metabolism, Dementia, Vascular psychology, Humans, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Memory drug effects, Plant Extracts, Rats, Rats, Wistar, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Angiogenesis Inducing Agents administration & dosage, Dementia, Vascular drug therapy, Drugs, Chinese Herbal administration & dosage, Neuroprotective Agents administration & dosage
- Abstract
Shouwu is a traditional Chinese medicine (TCM) with neuroprotective effect. Shouwu Yizhi decoction (SYD) was designed based on TCM theory. However, little is known about the roles of SYD in Vascular dementia (VaD). The present study aimed to evaluate the potential effects of SYD on the vascular cognitive impairment and explore the underlying mechanism by establishing focal cerebral ischemia/reperfusion (I/R) rat model to induce VaD. SYD administration (54 mg·kg
-1 ) for 40 days obviously improved the vascular cognitive impairment in the middle cerebral artery occlusion (MCAO) rats as evidenced by the declined neurological deficit score and shortened escape latency via neurological deficit assessment and Morris water maze test. Moreover, SYD decreased neuron damage-induced cell death and ameliorated the ultrastructure of endothelial cells in the MCAO rats, thereby alleviating VaD. Mechanistically, SYD caused increases in the expression of vascular endothelial growth factor (VEGF), CD34 and CD31, compared with the MCAO rats in coronal hippocampus. Simultaneously, the expression level of miR-210 was elevated significantly after SYD administration, compared with the vehicle rats (P < 0.01). The expression of Notch 4 at both mRNA and protein levels was upregulated remarkably along with the notably downregulated DLL4 expression under SYD administration compared with the vehicle rats (P < 0.05). Overall, the above results indicated that SYD promoted angiogenesis by upregulating VEGF-induced miR210 expression to activate Notch pathway, and further alleviated neuron damage and ameliorated the ultrastructure of endothelial cells in the MCAO rats, ultimately enhancing the cognition and memory of MCAO rats. Therefore, our findings preliminarily identified the effect and the mechanism of action for SYD on VaD in rats. SYD could be a potential candidate in treatment of VaD., (Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.) more...- Published
- 2017
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39. Notch4 inhibition suppresses invasion and vasculogenic mimicry formation of hepatocellular carcinoma cells.
- Author
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Cheng R, Cai XR, Ke K, and Chen YL
- Subjects
- Animals, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Cell Line, Tumor, Cell Movement drug effects, Down-Regulation, Epithelial-Mesenchymal Transition drug effects, Humans, Liver Neoplasms genetics, Liver Neoplasms metabolism, Matrix Metalloproteinases genetics, Matrix Metalloproteinases metabolism, Mice, Neoplasm Invasiveness, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, RNA, Small Interfering pharmacology, Receptor, Notch4 genetics, Xenograft Model Antitumor Assays, Carcinoma, Hepatocellular therapy, Liver Neoplasms therapy, Neovascularization, Pathologic therapy, RNA, Small Interfering administration & dosage, Receptor, Notch4 antagonists & inhibitors
- Abstract
Vasculogenic mimicry (VM) is a process by which aggressive tumor cells generate non-endothelial cell-lined channels in malignant tumors including hepatocellular carcinoma (HCC). It has provided new insights into tumor behavior and has surfaced as a potential target for drug therapy. The molecular events underlying the process of VM formation are still poorly understood. In this study, we attempted to elucidate the relationship between Notch4 and VM formation in HCC. An effective siRNA lentiviral vector targeting Notch4 was constructed and transfected into Bel7402, a HCC cell line. VM networks were observed with a microscope in a 3 dimensional cell culture system. Cell migration and invasion were evaluated using wound healing and transwell assays. Matrix metalloproteinases (MMPs) activity was detected by gelatin zymography. Furthermore, the role of Notch4 inhibition in Bel7402 cells in vivo was examined in subcutaneous xenograft tumor model of mice. The results showed that downregulation of Notch4 destroyed VM network formation and inhibited migration and invasion of tumor cells in vitro (P<0.05). In vivo, tumor growth was also inhibited in subcutaneous xenograft model (P<0.05). The potential mechanisms might be related with down-regulation of MT1-MMP, MMP-2, MMP-9 expression and inhibition of the activation of MMP2 and MMP9. These results indicated that Notch4 may play an important role in VM formation and tumor invasion in HCC. Related molecular pathways may be used as novel therapeutic targets for HCC antiangiogenesis therapy. more...
- Published
- 2017
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40. Olfactory Ensheathing Cells Inhibit Gliosis in Retinal Degeneration by Downregulation of the Müller Cell Notch Signaling Pathway.
- Author
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Xie J, Huo S, Li Y, Dai J, Xu H, and Yin ZQ
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cells, Cultured, Gliosis metabolism, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 3 genetics, Matrix Metalloproteinase 3 metabolism, Rats, Receptor, Notch3 genetics, Receptor, Notch3 metabolism, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Receptors, Notch genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Retinitis Pigmentosa metabolism, Retinitis Pigmentosa therapy, Signal Transduction physiology, Transcription Factor HES-1 genetics, Transcription Factor HES-1 metabolism, Down-Regulation, Ependymoglial Cells metabolism, Gliosis therapy, Olfactory Bulb cytology, Receptors, Notch metabolism, Signal Transduction genetics
- Abstract
Retinal regeneration and self-repair, whether in response to injury or degenerative disease, are severely impeded by glial scar formation by Müller cells (specialized retinal macroglia). We have previously demonstrated that the activation of Müller cells and gliosis in the degenerative retina are significantly suppressed by the subretinal transplantation of a mixture of olfactory ensheathing cells (OECs) and olfactory nerve fibroblasts. However, the underlying molecular mechanism has remained elusive. Here we transplanted purified rat OECs into the subretinal space of pigmented Royal College of Surgeons (RCS) rats, a classic rodent model of retinal degeneration. Using behavioral testing and electroretinography, we confirmed that the grafted OECs preserved the visual function of rats for 8 weeks, relative to vehicle controls (phosphate-buffered saline). Histological evaluation of outer nuclear layer thickness and composition demonstrated that more photoreceptors and ON-bipolar cells were preserved in the retinas of OEC-treated RCS rats than in controls. The grafted OECs migrated into the outer plexiform layer, inner nuclear layer, and inner plexiform layer. They interacted directly with Müller cells in the retina of RCS rats, in three distinct patterns, and secreted matrix metalloproteinases 2 and 3. Previous studies have demonstrated that rat OECs express delta-like ligand (DLL), while Müller cells express Notch3, the receptor for DLL. Here we found that the grafted OECs significantly decreased the expression, by retinal cells, of Notch signaling pathway components (including Notch3, Notch4, DLL1, DLL4, Jagged1, Hes1, and Hes5) 2 weeks after the cell transplantation and that this effect persisted for a further 2 weeks. Based on these findings, we suggest that transplanted OECs inhibit the activation of Müller cells and the associated gliosis, at least partly through suppression of the Notch pathway. more...
- Published
- 2017
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41. Prognostic roles of Notch receptor mRNA expression in human ovarian cancer.
- Author
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Chen C, Wang X, Huang S, Wang L, Han L, and Yu S
- Subjects
- Biomarkers, Tumor genetics, Disease-Free Survival, Female, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Mutation, Neoplasm Grading, Prognosis, Receptor, Notch1 genetics, Receptor, Notch2 genetics, Receptor, Notch3 genetics, Receptor, Notch4 genetics, Signal Transduction, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Receptors, Notch genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Aberrant activation of Notch signaling pathway has been correlated with high grade ovarian carcinoma and carcinogenesis. However, the predictive and prognostic values of Notch signaling pathway in ovarian cancer patients remains unclear. We utilize "The Kaplan-Meier plotter" (KM plotter) background database to access the prognostic values including overall survival (OS), progression-free survival (PFS), as well as post-progression survival (PPS) of four Notch receptor mRNA expression in ovarian cancer patients. Notch1 mRNA high expression was not correlated with OS, PFS and PPS for all ovarian cancer patients, but significantly correlated with poor PFS in TP53 wild type and favorite PFS in TP53 mutation type ovarian cancer patients. Notch2 mRNA high expression was significantly correlated with poor PFS for all ovarian cancer patients, especially in grade II patients. Notch3 mRNA high expression was significantly correlated with favorite PFS for all ovarian cancer patients. Notch4 mRNA high expression was significantly correlated with favorite OS, but not PFS and PPS for all ovarian cancer patients. The results strongly support that there are distinct prognostic values of four Notch receptor mRNA expression in ovarian cancer patients. more...
- Published
- 2017
- Full Text
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42. NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation.
- Author
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Delev D, Pavlova A, Grote A, Boström A, Höllig A, Schramm J, Fimmers R, Oldenburg J, and Simon M
- Subjects
- Adolescent, Adult, Aged, Case-Control Studies, Child, Female, Humans, Male, Middle Aged, Young Adult, Epilepsy genetics, Genetic Predisposition to Disease genetics, Intracranial Arteriovenous Malformations genetics, Intracranial Hemorrhages genetics, Polymorphism, Genetic genetics, Receptor, Notch4 genetics
- Abstract
OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs. METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation. RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor-like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis. CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease. more...
- Published
- 2017
- Full Text
- View/download PDF
43. Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study.
- Author
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Cardinale CJ, Li D, Tian L, Connolly JJ, March ME, Hou C, Wang F, Snyder J, Kim CE, Chiavacci RM, Sleiman PM, Burnham JM, and Hakonarson H
- Subjects
- Alleles, Child, Chromosomes, Human, Pair 6 genetics, Computational Biology, Female, Genetic Predisposition to Disease, Grandparents, Heterozygote, Humans, Male, Pedigree, Penetrance, Protein Domains genetics, Sequence Analysis, DNA, Exome genetics, Genes, Dominant genetics, Mutation, Missense, Receptor, Notch4 genetics, Scleroderma, Systemic genetics
- Abstract
Background: Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/scleroderma and a family history of SSc in a grandfather and maternal aunt., Methods: We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus., Results: Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c.4245G > A:p.Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 × 10
-5 by the data of the Exome Aggregation Consortium., Conclusion: This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc. more...- Published
- 2016
- Full Text
- View/download PDF
44. Regulation of Notch-mediated transcription by a bovine herpesvirus 1 encoded protein (ORF2) that is expressed in latently infected sensory neurons.
- Author
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Liu Y and Jones C
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Cell Line, Tumor, Core Binding Factors genetics, Core Binding Factors metabolism, DNA genetics, DNA metabolism, Gene Expression Regulation, Herpesvirus 1, Bovine, Mice, Neurons metabolism, Plasmids chemistry, Plasmids metabolism, Promoter Regions, Genetic, Protein Binding, Receptor, Notch1 metabolism, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Receptor, Notch3 genetics, Receptor, Notch3 metabolism, Receptor, Notch4 genetics, Receptor, Notch4 metabolism, Signal Transduction, Transfection, Viral Proteins chemistry, Viral Proteins metabolism, Host-Pathogen Interactions, Neurons virology, Open Reading Frames, Receptor, Notch1 genetics, Viral Proteins genetics, Virus Activation, Virus Latency
- Abstract
Bovine herpesvirus 1 (BoHV-1) is an Alphaherpesvirinae subfamily member that establishes life-long latency in sensory neurons. The latency-related RNA (LR-RNA) is abundantly expressed during latency. An LR mutant virus containing stop codons at the amino-terminus of open reading frame (ORF)2 does not reactivate from latency and replicates less efficiently in tonsils and trigeminal ganglia. ORF2 inhibits apoptosis, interacts with Notch family members, and interferes with Notch-dependent transcription suggesting ORF2 expression enhances survival of infected neurons. The Notch signaling pathway is crucial for neuronal differentiation and survival suggesting that interactions between ORF2 and Notch family members regulate certain aspects of latency. Consequently, for this study, we compared whether ORF2 interfered with the four mammalian Notch family members. ORF2 consistently interfered with Notch1-3-mediated transactivation of three cellular promoters. Conversely, Notch4-mediated transcription was not consistently inhibited by ORF2. Electrophoretic shift mobility assays using four copies of a consensus-DNA binding site for Notch/CSL (core binding factor (CBF)-1, Suppressor of Hairless, Lag-2) as a probe revealed ORF2 interfered with Notch1 and 3 interactions with a CSL family member bound to DNA. Additional studies demonstrated ORF2 enhances neurite sprouting in mouse neuroblastoma cells that express Notch1-3, but not Notch4. Collectively, these studies indicate that ORF2 inhibits Notch-mediated transcription and signaling by interfering with Notch interacting with CSL bound to DNA. more...
- Published
- 2016
- Full Text
- View/download PDF
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