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Fu L, Gu X, Lou N, Li J, Xue C. Current research of the Notch pathway in hepatocellular carcinoma. Eur J Med Res 2025; 30:402. [PMID: 40394648 PMCID: PMC12090635 DOI: 10.1186/s40001-025-02626-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 04/22/2025] [Indexed: 05/22/2025] Open
Abstract
Notch signaling is a widely preserved communication pathway that supports essential cellular functions by allowing adjacent cells to interact. The Notch signaling pathway consists of Notch ligands (DSL proteins), Notch receptors, DNA-binding proteins, and downstream target genes. Hepatocellular carcinoma (HCC) represents the predominant cause of cancer-related deaths globally and poses a significant threat to human health. For highly malignant HCC, current treatment options, including chemotherapy, radiotherapy, immunotherapy, targeted therapies, and surgical procedures, often have poor prognoses. Therefore, there is a need to explore additional therapeutic strategies. Many studies have found that abnormal activation of the Notch signaling pathway contributes to tumor initiation and progression by promoting HCC proliferation, metastasis, stem cell-like properties, and drug resistance. In this research, we reveal the composition and activation mechanisms of the Notch signaling pathway, as well as the molecular mechanism underlying its aberrant activation in HCC. Furthermore, we summarize recent advances in targeting Notch signaling for the treatment of HCC. This review aims to highlight the promising potential of investigating the Notch pathway as a therapeutic target in HCC.
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Affiliation(s)
- Leiya Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China
| | - Xinyu Gu
- Department of Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Na Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China.
| | - Chen Xue
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Erqi District, Zhengzhou, 450052, Henan, China.
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Di Donna MG, Colona VL, Bagnato MR, Bonomi CG, Tirrito L, Marchionni E, Motta C, Sangiuolo FC, Martorana A. NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients. Neurol Sci 2025; 46:1637-1646. [PMID: 39652165 DOI: 10.1007/s10072-024-07908-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/25/2024] [Indexed: 03/19/2025]
Abstract
INTRODUCTION The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. RESULTS The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers -Cerebrospinal fluid (CSF) analysis negative for Alzheimer's Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). DISCUSSION AND CONCLUSION The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.
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Affiliation(s)
- M G Di Donna
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy.
- Stroke Unit, Ospedale F. Spaziani, Via A. Fabi 5, 03100, Frosinone, Italy.
| | - V L Colona
- Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Movement Analysis and Robotics Laboratory (MARlab), Research Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - M R Bagnato
- Stroke Unit, Ospedale F. Spaziani, Via A. Fabi 5, 03100, Frosinone, Italy
- Stroke Unit, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - C G Bonomi
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - L Tirrito
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - E Marchionni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - C Motta
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - F C Sangiuolo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
| | - A Martorana
- UOSD Centro Demenze, University of Rome Tor Vergata, Viale Oxford 81, 00133, Rome, Italy
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Dilawar M, Yu X, Jin Y, Yang J, Lin S, Liao J, Dai Q, Zhang X, Nisar MF, Chen G. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. FASEB J 2025; 39:e70417. [PMID: 39985304 DOI: 10.1096/fj.202402545r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/18/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well-established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1-4), and four intracellular domains (NICD1-4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β-catenin, BMP, TGF-β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in-depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch-regulating drugs for clinical use.
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Affiliation(s)
- Muhammad Dilawar
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xuan Yu
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Yuanyuan Jin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Jing Yang
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Sisi Lin
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Junguang Liao
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qi Dai
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Xingen Zhang
- Department of Orthopedics, Jiaxing Key Laboratory for Minimally Invasive Surgery in Orthopaedics & Skeletal Regenerative Medicine, Zhejiang Rongjun Hospital, Jiaxing, China
| | - Muhammad Farrukh Nisar
- Department of Physiology & Biochemistry, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
- Ministry of Education and Jiangxi Key Laboratory of Crop Physiology, Ecology and Genetic Breeding, Jiangxi Agricultural University, Nanchang, China
| | - Guiqian Chen
- Department of Biopharmaceutics, Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Science and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
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Chen D, Liu X, Wang H, Merks RM, Baker DA. A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization. PLoS Comput Biol 2025; 21:e1012825. [PMID: 39932958 PMCID: PMC11841921 DOI: 10.1371/journal.pcbi.1012825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/20/2025] [Accepted: 01/25/2025] [Indexed: 02/13/2025] Open
Abstract
The ubiquitous Notch receptor signalling network is essential for tissue growth and maintenance. Operationally, receptor activity is regulated by two principal, counterposed mechanisms: intercellular Notch transactivation triggered by interactions between receptors and ligands expressed in neighbouring cells; intracellular cis inhibition mediated by ligands binding to receptors expressed in the same cell. Moreover, different Notch receptor/ligand combinations are known to elicit distinct molecular and cellular responses, and together, these phenomena determine the strength, the duration and the specificity of Notch receptor signalling. To date, it has been assumed that these processes involve discrete ligand homomers and not heteromeric complexes composed of more than one ligand species. In this study, we explore the molecular basis of the opposing actions of the Notch ligands, DLL4 and JAG1, which control angiogenic sprouting. Through a combination of experimental approaches and mathematical modelling, we provide evidence that two mechanisms could underpin this process: 1) DLL4 rather than JAG1 induces efficient Notch1 receptor transactivation; 2) JAG1 directly blocks DLL4-dependent cis-inhibition of Notch signalling through the formation of a JAG1/DLL4 complex. We propose a new model of Notch signalling that recapitulates the formation of tip and stalk cells, which is necessary for sprouting angiogenesis.
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Affiliation(s)
- Daipeng Chen
- School of Mathematics and Statistics, Xi’an Jiaotong University, Xi’an, China
- Mathematical Institute, Leiden University, Leiden, The Netherlands
| | - Xinxin Liu
- Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
| | - Haijiang Wang
- Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
- Department of General Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Roeland M.H. Merks
- Mathematical Institute, Leiden University, Leiden, The Netherlands
- Institute of Biology Leiden, Leiden University, Leiden, The Netherlands
| | - David A. Baker
- Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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Famta P, Shah S, Dey B, Kumar KC, Bagasariya D, Vambhurkar G, Pandey G, Sharma A, Srinivasarao DA, Kumar R, Guru SK, Raghuvanshi RS, Srivastava S. Despicable role of epithelial-mesenchymal transition in breast cancer metastasis: Exhibiting de novo restorative regimens. CANCER PATHOGENESIS AND THERAPY 2025; 3:30-47. [PMID: 39872366 PMCID: PMC11764040 DOI: 10.1016/j.cpt.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/03/2024] [Accepted: 01/10/2024] [Indexed: 01/30/2025]
Abstract
Breast cancer (BC) is the most prevalent cancer in women globally. Anti-cancer advancements have enabled the killing of BC cells through various therapies; however, cancer relapse is still a major limitation and decreases patient survival and quality of life. Epithelial-to-mesenchymal transition (EMT) is responsible for tumor relapse in several cancers. This highly regulated event causes phenotypic, genetic, and epigenetic changes in the tumor microenvironment (TME). This review summarizes the recent advancements regarding EMT using de-differentiation and partial EMT theories. We extensively review the mechanistic pathways, TME components, and various anti-cancer adjuvant and neo-adjuvant therapies responsible for triggering EMT in BC tumors. Information regarding essential clinical studies and trials is also discussed. Furthermore, we also highlight the recent strategies targeting various EMT pathways. This review provides a holistic picture of BC biology, molecular pathways, and recent advances in therapeutic strategies.
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Affiliation(s)
- Paras Famta
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Saurabh Shah
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Biswajit Dey
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Kondasingh Charan Kumar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Deepkumar Bagasariya
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Ganesh Vambhurkar
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Giriraj Pandey
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Anamika Sharma
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Dadi A. Srinivasarao
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rahul Kumar
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Santosh Kumar Guru
- Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | | | - Saurabh Srivastava
- Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
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Singh V, Singh R, Kushwaha R. Exploring novel protein biomarkers for early-stage diagnosis and prognosis of T-acute lymphoblastic leukemia (T-ALL). Hematol Transfus Cell Ther 2024; 46 Suppl 6:S93-S111. [PMID: 38584071 PMCID: PMC11726097 DOI: 10.1016/j.htct.2024.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 02/12/2024] [Indexed: 04/09/2024] Open
Abstract
BACKGROUND Efficient classification of T-acute lymphoblastic leukemia (T-ALL) involves considering various factors, such as age, white blood cell count, and chromosomal alterations. However, studying protein markers are crucial to improving T-ALL patients' diagnosis and treatment. A study analyzing the expression of proteomes was conducted to identify promising early-stage biomarkers for T-ALL patients METHODS: Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the blood proteins of both patients and healthy individuals to identify new biomarkers for T-ALL. The findings were validated by RT-PCR, ELISA and computational analysis RESULTS: The study identified 1467 proteins in the blood, of which nine were upregulated and 35 were downregulated by more than 2-fold. T-ALL patients showed a significant increase in specific disease-related proteins, such as eleven-nineteen lysine-rich leukemia protein, triggering receptor expressed on myeloid cells 1, cisplatin resistance-associated-overexpressed protein, X-ray radiation resistance-associated protein 1, tumor necrosis factor receptor superfamily member 10D, protein S100-A8, and copine-4, by more than 3-fold CONCLUSION: The findings of this study provide a valuable protein map of leukemic cells and identify potential biomarkers for leukemic aggressiveness. However, further studies using larger T-ALL patient samples must confirm these preliminary results.
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Affiliation(s)
- Vivek Singh
- King George's Medical University, Lucknow, UP, India,.
| | - Ranjana Singh
- King George's Medical University, Lucknow, UP, India,.
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Haque M, Shyanti RK, Mishra MK. Targeted therapy approaches for epithelial-mesenchymal transition in triple negative breast cancer. Front Oncol 2024; 14:1431418. [PMID: 39450256 PMCID: PMC11499239 DOI: 10.3389/fonc.2024.1431418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is distinguished by negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making it an aggressive subtype of breast cancer and contributes to 15-20% of the total incidence. TNBC is a diverse disease with various genetic variations and molecular subtypes. The tumor microenvironment involves multiple cells, including immune cells, fibroblast cells, extracellular matrix (ECM), and blood vessels that constantly interact with tumor cells and influence each other. The ECM undergoes significant structural changes, leading to induced cell proliferation, migration, adhesion, invasion, and epithelial-to-mesenchymal transition (EMT). The involvement of EMT in the occurrence and development of tumors through invasion and metastasis in TNBC has been a matter of concern. Therefore, EMT markers could be prognostic predictors and potential therapeutic targets in TNBC. Chemotherapy has been one of the primary options for treating patients with TNBC, but its efficacy against TNBC is still limited. Targeted therapy is a critical emerging option with enhanced efficacy and less adverse effects on patients. Various targeted therapy approaches have been developed based on the specific molecules and the signaling pathways involved in TNBC. These include inhibitors of signaling pathways such as TGF-β, Wnt/β-catenin, Notch, TNF-α/NF-κB and EGFR, as well as immune checkpoint inhibitors, such as pembrolizumab, 2laparib, and talazoparib have been widely explored. This article reviews recent developments in EMT in TNBC invasion and metastasis and potential targeted therapy strategies.
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Affiliation(s)
| | | | - Manoj K. Mishra
- Cancer Research Center, Department of Biological Sciences, Alabama State
University, Montgomery, AL, United States
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Pujar AA, Barua A, Dey PS, Singh D, Roy U, Jolly MK, Hatzikirou H. Microenvironmental entropy dynamics analysis reveals novel insights into Notch-Delta-Jagged decision-making mechanism. iScience 2024; 27:110569. [PMID: 39318535 PMCID: PMC11420447 DOI: 10.1016/j.isci.2024.110569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/31/2024] [Accepted: 07/19/2024] [Indexed: 09/26/2024] Open
Abstract
Notch-Delta-Jagged (NDJ) signaling among neighboring cells contributes crucially to spatiotemporal pattern formation and developmental decision-making. Despite numerous detailed mathematical models, their high-dimensionality parametric space limits analytical treatment, especially regarding local microenvironmental fluctuations. Using the low-dimensional dynamics of the recently postulated least microenvironmental uncertainty principle (LEUP) framework, we showcase how the LEUP formalism recapitulates a noisy NDJ spatial patterning. Our LEUP simulations show that local phenotypic entropy increases for lateral inhibition but decreases for lateral induction. This distinction allows us to identify a critical parameter that captures the transition from a Notch-Delta-driven lateral inhibition to a Notch-Jagged-driven lateral induction phenomenon and suggests random phenotypic patterning in the case of lack of dominance of either Notch-Delta or Notch-Jagged signaling. Our results enable an analytical treatment to map the high-dimensional dynamics of NDJ signaling on tissue-level patterning and can possibly be generalized to decode operating principles of collective cellular decision-making.
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Affiliation(s)
- Aditi Ajith Pujar
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
- Undergraduate Program, Indian Institute of Science, Bangalore 560012, India
| | - Arnab Barua
- Tata Institute of Fundamental Research, Hyderabad 500046, India
| | - Partha Sarathi Dey
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Divyoj Singh
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
- Undergraduate Program, Indian Institute of Science, Bangalore 560012, India
| | - Ushasi Roy
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore 560012, India
| | - Haralampos Hatzikirou
- Mathematics Department, Khalifa University, P.O. Box: 127788, Abu Dhabi, UAE
- Technische Univesität Dresden, Center for Information Services and High Performance Computing, Nöthnitzer Straße 46, P.O. Box: 01062, Dresden, Germany
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Foran G, Hallam RD, Megaly M, Turgambayeva A, Antfolk D, Li Y, Luca VC, Necakov A. Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping. Sci Rep 2024; 14:21912. [PMID: 39300145 PMCID: PMC11413390 DOI: 10.1038/s41598-024-71634-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/29/2024] [Indexed: 09/22/2024] Open
Abstract
The Notch receptor is a pleiotropic signaling protein that translates intercellular ligand interactions into changes in gene expression via the nuclear localization of the Notch intracellular Domain (NICD). Using a combination of immunohistochemistry, RNA in situ, Optogenetics and super-resolution live imaging of transcription in human cells, we show that the N1ICD can form condensates that positively facilitate Notch target gene expression. We determined that N1ICD undergoes Phase Separation Coupled Percolation (PSCP) into transcriptional condensates, which recruit, enrich, and encapsulate a broad set of core transcriptional proteins. We show that the capacity for condensation is due to the intrinsically disordered transcriptional activation domain of the N1ICD. In addition, the formation of such transcriptional condensates acts to promote Notch-mediated super enhancer-looping and concomitant activation of the MYC protooncogene expression. Overall, we introduce a novel mechanism of Notch1 activity in which discrete changes in nuclear N1ICD abundance are translated into the assembly of transcriptional condensates that facilitate gene expression by enriching essential transcriptional machineries at target genomic loci.
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Affiliation(s)
- Gregory Foran
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada
| | - Ryan Douglas Hallam
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada
| | - Marvel Megaly
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada
| | - Anel Turgambayeva
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada
| | - Daniel Antfolk
- Department of Immunology, Moffitt Cancer Centre, Tampa, FL, USA
| | - Yifeng Li
- Department of Computer Science, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada
| | - Vincent C Luca
- Department of Immunology, Moffitt Cancer Centre, Tampa, FL, USA
| | - Aleksandar Necakov
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON, L2S 3A1, Canada.
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Dabdoub S, Greenlee A, Abboud G, Brengartner L, Zuiker E, Gorr MW, Wold LE, Kumar PS, Cray J. Acute exposure to electronic cigarette components alters mRNA expression of pre-osteoblasts. FASEB J 2024; 38:e70017. [PMID: 39213037 PMCID: PMC11371384 DOI: 10.1096/fj.202302014rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 08/01/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
The use of traditional nicotine delivery products such as tobacco has long been linked to detrimental health effects. However, little work to date has focused on the emerging market of aerosolized nicotine delivery known as electronic nicotine delivery systems (ENDS) or electronic cigarettes, and their potential for new effects on human health. Challenges studying these devices include heterogeneity in the formulation of the common components of most available ENDS, including nicotine and a carrier (commonly composed of propylene glycol and vegetable glycerin, or PG/VG). In the present study, we report on experiments interrogating the effects of major identified components in e-cigarettes. Specifically, the potential concomitant effects of nicotine and common carrier ingredients in commercial "vape" products are explored in vitro to inform the potential health effects on the craniofacial skeleton through novel vectors as compared to traditional tobacco products. MC3T3-E1 murine pre-osteoblast cells were cultured in vitro with clinically relevant liquid concentrations of nicotine, propylene glycol (PG), vegetable glycerin (VG), Nicotine+PG/VG, and the vape liquid of a commercial product (Juul). Cells were treated acutely for 24 h and RNA-Seq was utilized to determine segregating alteration in mRNA signaling. Influential gene targets identified with sparse partial least squares discriminant analysis (sPLS-DA) implemented in mixOmics were assessed using the PANTHER Classification system for molecular functions, biological processes, cellular components, and pathways of effect. Additional endpoint functional analyses were used to confirm cell cycle changes. The initial excitatory concentration (EC50) studied defined a target concentration of carrier PG/VG liquid that altered the cell cycle of the calvarial cells. Initial sPLS-DA analysis demonstrated the segregation of nicotine and non-nicotine exposures utilized in our in vitro modeling. Pathway analysis suggests a strong influence of nicotine exposures on cellular processes including metabolic processes and response to stimuli including autophagic flux. Further interrogation of the individual treatment conditions demonstrated segregation by treatment modality (Control, Nicotine, Carrier (PG+VG), Nicotine+PG/VG) along three dimensions best characterized by: latent variable 1 (PLSDA-1) showing strong segregation based on nicotine influence on cellular processes associated with cellular adhesion to collagen, osteoblast differentiation, and calcium binding and metabolism; latent variable 2 (PLSDA-2) showing strong segregation of influence based on PG+VG and Control influence on cell migration, survival, and cycle regulation; and latent variable 3 (PLSDA-3) showing strong segregation based on Nicotine and Control exposure influence on cell activity and growth and developmental processes. Further, gene co-expression network analysis implicates targets of the major pathway genes associated with bone growth and development, particularly craniofacial (FGF, Notch, TGFβ, WNT) and analysis of active subnetwork pathways found these additionally overrepresented in the Juul exposure relative to Nicotine+PG/VG. Finally, experimentation confirmed alterations in cell count, and increased evidence of cell stress (markers of autophagy), but no alteration in apoptosis. These data suggest concomitant treatment with Nicotine+PG/VG drives alterations in pre-osteoblast cell cycle signaling, specifically transcriptomic targets related to cell cycle and potentially cell stress. Although we suspected cell stress and well as cytotoxic effects of Nicotine+PG/VG, no great influence on apoptotic factors was observed. Further RNA-Seq analysis allowed for the direct interrogation of molecular targets of major pathways involved in bone and craniofacial development, each demonstrating segregation (altered signaling) due to e-cigarette-type exposure. These data have implications directed toward ENDS formulation as synergistic effects of Nicotine+PG/VG are evidenced here. Thus, future research will continue to interrogate how varied formulation of Nicotine+PG/VG affects overall cell functions in multiple vital systems.
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Affiliation(s)
- Shareef Dabdoub
- Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa, Iowa City, Iowa 52242, USA
- Department of Periodontics, College of Dentistry, University of Iowa, Iowa City, Iowa 52242, USA
| | - Ashley Greenlee
- Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - George Abboud
- Undergraduate Biomedical Sciences Major, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - Lexie Brengartner
- Undergraduate Biomedical Sciences Major, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - Eryn Zuiker
- Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - Matthew W. Gorr
- Division of Cardiac Surgery, Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - Loren E. Wold
- Division of Cardiac Surgery, Department of Surgery, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
| | - Purnima S. Kumar
- Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan
| | - James Cray
- Department of Biomedical Education and Anatomy, College of Medicine, The Ohio State University, Columbus, Ohio, 43210, USA
- Divisions of Biosciences and Orthodontics, College of Dentistry, The Ohio State University, Columbus, Ohio, 43210, USA
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11
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Foran G, Hallam RD, Megaly M, Turgambayeva A, Antfolk D, Li Y, Luca VC, Necakov A. Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.17.533124. [PMID: 39131356 PMCID: PMC11312450 DOI: 10.1101/2023.03.17.533124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
The Notch receptor is a pleiotropic signaling protein that translates intercellular ligand interactions into changes in gene expression via the nuclear localization of the Notch intracellular Domain (NICD). Using a combination of immunohistochemistry, RNA in situ, Optogenetics and super-resolution live imaging of transcription in human cells, we show that the N1ICD can form condensates that positively facilitate Notch target gene expression. We determined that N1ICD undergoes Phase Separation Coupled Percolation (PSCP) into transcriptional condensates, which recruit, enrich, and encapsulate a broad set of core transcriptional proteins. We show that the capacity for condensation is due to the intrinsically disordered transcriptional activation domain of the N1ICD. In addition, the formation of such transcriptional condensates acts to promote Notch-mediated super enhancer-looping and concomitant activation of the MYC protooncogene expression. Overall, we introduce a novel mechanism of Notch1 activity in which discrete changes in nuclear N1ICD abundance are translated into the assembly of transcriptional condensates that facilitate gene expression by enriching essential transcriptional machineries at target genomic loci.
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Affiliation(s)
- Gregory Foran
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
| | - Ryan Douglas Hallam
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
| | - Marvel Megaly
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
| | - Anel Turgambayeva
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
| | - Daniel Antfolk
- Department of Immunology, Moffitt Cancer Centre, Tampa, FL, USA
| | - Yifeng Li
- Department of Computer Science, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
| | - Vincent C. Luca
- Department of Immunology, Moffitt Cancer Centre, Tampa, FL, USA
| | - Aleksandar Necakov
- Department of Biological Sciences, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S 3A1
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12
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Wang S, Gu S, Chen J, Yuan Z, Liang P, Cui H. Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy. Biomolecules 2024; 14:480. [PMID: 38672496 PMCID: PMC11048644 DOI: 10.3390/biom14040480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of glioma and the most common primary tumor of the central nervous system. Despite significant advances in clinical management strategies and diagnostic techniques for GBM in recent years, it remains a fatal disease. The current standard of care includes surgery, radiation, and chemotherapy, but the five-year survival rate for patients is less than 5%. The search for a more precise diagnosis and earlier intervention remains a critical and urgent challenge in clinical practice. The Notch signaling pathway is a critical signaling system that has been extensively studied in the malignant progression of glioblastoma. This highly conserved signaling cascade is central to a variety of biological processes, including growth, proliferation, self-renewal, migration, apoptosis, and metabolism. In GBM, accumulating data suggest that the Notch signaling pathway is hyperactive and contributes to GBM initiation, progression, and treatment resistance. This review summarizes the biological functions and molecular mechanisms of the Notch signaling pathway in GBM, as well as some clinical advances targeting the Notch signaling pathway in cancer and glioblastoma, highlighting its potential as a focus for novel therapeutic strategies.
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Affiliation(s)
- Shenghao Wang
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China;
| | - Sikuan Gu
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Junfan Chen
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Zhiqiang Yuan
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
| | - Ping Liang
- Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China;
- State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; (S.G.); (J.C.); (Z.Y.)
- Department of Neurosurgery, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
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13
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Genaro K, Luo ZD. Pathophysiological roles of thrombospondin-4 in disease development. Semin Cell Dev Biol 2024; 155:66-73. [PMID: 37391348 PMCID: PMC10753034 DOI: 10.1016/j.semcdb.2023.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 06/21/2023] [Indexed: 07/02/2023]
Abstract
Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its interactions with numerous extracellular matrix components, proteins and signaling molecules that enable its modulation to various physiological and pathological processes. Characterization of TSP-4 expression under development and pathogenesis of disorders has yielded important insights into mechanisms underlying the unique role of TSP-4 in mediating various processes including cell-cell, cell-extracellular matrix interactions, cell migration, proliferation, tissue remodeling, angiogenesis, and synaptogenesis. Maladaptation of these processes in response to pathological insults and stress can accelerate the development of disorders including skeletal dysplasia, osteoporosis, degenerative joint disease, cardiovascular diseases, tumor progression/metastasis and neurological disorders. Overall, the diverse functions of TSP-4 suggest that it may be a potential marker or therapeutic target for prognosis, diagnosis, and treatment of various pathological conditions upon further investigations. This review article highlights recent findings on the role of TSP-4 in both physiological and pathological conditions with a focus on what sets it apart from other TSPs.
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Affiliation(s)
- Karina Genaro
- Department of Anesthesiology & Perioperative Care, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
| | - Z David Luo
- Department of Anesthesiology & Perioperative Care, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
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14
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Paniri A, Hosseini MM, Amjadi-Moheb F, Tabaripour R, Soleimani E, Langroudi MP, Zafari P, Akhavan-Niaki H. The epigenetics orchestra of Notch signaling: a symphony for cancer therapy. Epigenomics 2023; 15:1337-1358. [PMID: 38112013 DOI: 10.2217/epi-2023-0270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2023] Open
Abstract
The aberrant regulation of the Notch signaling pathway, which is a fundamental developmental pathway, has been implicated in a wide range of human cancers. The Notch pathway can be activated by both canonical and noncanonical Notch ligands, and its role can switch between acting as an oncogene or a tumor suppressor depending on the context. Epigenetic modifications have the potential to modulate Notch and its ligands, thereby influencing Notch signal transduction. Consequently, the utilization of epigenetic regulatory mechanisms may present novel therapeutic opportunities for both single and combined therapeutics targeted at the Notch signaling pathway. This review offers insights into the mechanisms governing the regulation of Notch signaling and explores their therapeutic potential.
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Affiliation(s)
- Alireza Paniri
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
- Zoonoses Research Center, Pasteur Institute of Iran, 4619332976, Amol, Iran
| | | | - Fatemeh Amjadi-Moheb
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
| | - Reza Tabaripour
- Department of Cellular and Molecular Biology, Babol Branch, Islamic Azad University, Babol, 4747137381, Iran
| | - Elnaz Soleimani
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
| | | | - Parisa Zafari
- Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, 4691786953, Iran
| | - Haleh Akhavan-Niaki
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, 4717647745,Iran
- Zoonoses Research Center, Pasteur Institute of Iran, 4619332976, Amol, Iran
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15
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Golden CS, Williams S, Serrano MA. Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1. Birth Defects Res 2023; 115:1809-1824. [PMID: 37158694 PMCID: PMC10845236 DOI: 10.1002/bdr2.2183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/03/2023] [Accepted: 04/14/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Kabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the KMT2D gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase-independent roles in KS1 clinical manifestations. METHODS This scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic KMT2D variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches. RESULTS Our review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase-dependent and -independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development. CONCLUSION We discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.
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Affiliation(s)
- Carly S Golden
- Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine, Boston University, Boston, Massachusetts, USA
| | - Saylor Williams
- Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine, Boston University, Boston, Massachusetts, USA
| | - Maria A Serrano
- Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine, Boston University, Boston, Massachusetts, USA
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16
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Szymanowicz O, Korczowska-Łącka I, Słowikowski B, Wiszniewska M, Piotrowska A, Goutor U, Jagodziński PP, Kozubski W, Dorszewska J. Headache and NOTCH3 Gene Variants in Patients with CADASIL. Neurol Int 2023; 15:1238-1252. [PMID: 37873835 PMCID: PMC10594416 DOI: 10.3390/neurolint15040078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/28/2023] [Accepted: 10/05/2023] [Indexed: 10/25/2023] Open
Abstract
Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vascular disease characterized by recurrent strokes, cognitive impairment, psychiatric symptoms, apathy, and migraine. Approximately 40% of patients with CADASIL experience migraine with aura (MA). In addition to MA, CADASIL patients are described in the literature as having migraine without aura (MO) and other types of headaches. Mutations in the NOTCH3 gene cause CADASIL. This study investigated NOTCH3 genetic variants in CADASIL patients and their potential association with headache types. Genetic tests were performed on 30 patients with CADASIL (20 women aged 43.6 ± 11.5 and 10 men aged 39.6 ± 15.8). PCR-HRM and sequencing methods were used in the genetic study. We described three variants as pathogenic/likely pathogenic (p.Tyr189Cys, p.Arg153Cys, p.Cys144Arg) and two benign variants (p.Ala202=, p.Thr101=) in the NOTCH3 gene and also presented the NOTCH3 gene variant (chr19:15192258 G>T), which has not been previously described in the literature. Patients with pathogenic/likely pathogenic variants had similar headache courses. People with benign variants showed a more diverse clinical picture. It seems that different NOTCH3 variants may contribute to the differential presentation of a CADASIL headache, highlighting the diagnostic and prognostic value of headache characteristics in this disease.
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Affiliation(s)
- Oliwia Szymanowicz
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (O.S.); (I.K.-Ł.); (U.G.)
| | - Izabela Korczowska-Łącka
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (O.S.); (I.K.-Ł.); (U.G.)
| | - Bartosz Słowikowski
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (B.S.); (P.P.J.)
| | - Małgorzata Wiszniewska
- Faculty of Health Care, Stanislaw Staszic University of Applied Sciences in Pila, 64-920 Pila, Poland;
- Department of Neurology, Specialistic Hospital in Pila, 64-920 Pila, Poland
| | - Ada Piotrowska
- Chair and Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.P.); (W.K.)
| | - Ulyana Goutor
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (O.S.); (I.K.-Ł.); (U.G.)
| | - Paweł P. Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (B.S.); (P.P.J.)
| | - Wojciech Kozubski
- Chair and Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (A.P.); (W.K.)
| | - Jolanta Dorszewska
- Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (O.S.); (I.K.-Ł.); (U.G.)
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17
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Kaimari S, Kamalakar A, Goudy SL. Biomedical engineering approaches for the delivery of JAGGED1 as a potential tissue regenerative therapy. Front Bioeng Biotechnol 2023; 11:1217211. [PMID: 37781534 PMCID: PMC10534981 DOI: 10.3389/fbioe.2023.1217211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 08/31/2023] [Indexed: 10/03/2023] Open
Abstract
JAG1 is a ligand that activates the NOTCH signaling pathway which plays a crucial role in determining cell fate behavior through cell-to-cell signaling. JAG1-NOTCH signaling is required for mesenchymal stem cell (MSC) differentiation into cardiomyocytes and cranial neural crest (CNC) cells differentiation into osteoblasts, making it a regenerative candidate for clinical therapy to treat craniofacial bone loss and myocardial infarction. However, delivery of soluble JAG1 has been found to inhibit NOTCH signaling due to the requirement of JAG1 presentation in a bound form. For JAG1-NOTCH signaling to occur, JAG1 must be immobilized within a scaffold and the correct orientation between the NOTCH receptor and JAG1 must be achieved. The lack of clinically translatable JAG1 delivery methods has driven the exploration of alternative immobilization approaches. This review discusses the role of JAG1 in disease, the clinical role of JAG1 as a treatment, and summarizes current approaches for JAG1 delivery. An in-depth review was conducted on literature that used both in vivo and in vitro delivery models and observed the canonical versus non-canonical NOTCH pathway activated by JAG1. Studies were then compared and evaluated based on delivery success, functional outcomes, and translatability. Delivering JAG1 to harness its ability to control cell fate has the potential to serve as a therapeutic for many diseases.
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Affiliation(s)
- Sundus Kaimari
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Archana Kamalakar
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
| | - Steven L. Goudy
- Department of Pediatric Otolaryngology, Emory University, Atlanta, GA, United States
- Department of Pediatric Otolaryngology, Children’s Healthcare of Atlanta, Atlanta, GA, United States
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18
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Chen D, Forghany Z, Liu X, Wang H, Merks RMH, Baker DA. A new model of Notch signalling: Control of Notch receptor cis-inhibition via Notch ligand dimers. PLoS Comput Biol 2023; 19:e1010169. [PMID: 36668673 PMCID: PMC9891537 DOI: 10.1371/journal.pcbi.1010169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 02/01/2023] [Accepted: 12/30/2022] [Indexed: 01/22/2023] Open
Abstract
All tissue development and replenishment relies upon the breaking of symmetries leading to the morphological and operational differentiation of progenitor cells into more specialized cells. One of the main engines driving this process is the Notch signal transduction pathway, a ubiquitous signalling system found in the vast majority of metazoan cell types characterized to date. Broadly speaking, Notch receptor activity is governed by a balance between two processes: 1) intercellular Notch transactivation triggered via interactions between receptors and ligands expressed in neighbouring cells; 2) intracellular cis inhibition caused by ligands binding to receptors within the same cell. Additionally, recent reports have also unveiled evidence of cis activation. Whilst context-dependent Notch receptor clustering has been hypothesized, to date, Notch signalling has been assumed to involve an interplay between receptor and ligand monomers. In this study, we demonstrate biochemically, through a mutational analysis of DLL4, both in vitro and in tissue culture cells, that Notch ligands can efficiently self-associate. We found that the membrane proximal EGF-like repeat of DLL4 was necessary and sufficient to promote oligomerization/dimerization. Mechanistically, our experimental evidence supports the view that DLL4 ligand dimerization is specifically required for cis-inhibition of Notch receptor activity. To further substantiate these findings, we have adapted and extended existing ordinary differential equation-based models of Notch signalling to take account of the ligand dimerization-dependent cis-inhibition reported here. Our new model faithfully recapitulates our experimental data and improves predictions based upon published data. Collectively, our work favours a model in which net output following Notch receptor/ligand binding results from ligand monomer-driven Notch receptor transactivation (and cis activation) counterposed by ligand dimer-mediated cis-inhibition.
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Affiliation(s)
- Daipeng Chen
- School of Mathematics and Statistics, Xi’an Jiaotong University, Xi’an, China
- Mathematical Institute, Leiden University, Leiden, The Netherlands
| | - Zary Forghany
- Leiden University Medical Center (LUMC), Department of Cell & Chemical Biology, Leiden, The Netherlands
| | - Xinxin Liu
- Leiden University Medical Center (LUMC), Department of Cell & Chemical Biology, Leiden, The Netherlands
| | - Haijiang Wang
- Leiden University Medical Center (LUMC), Department of Cell & Chemical Biology, Leiden, The Netherlands
- Department of General Surgery, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Roeland M. H. Merks
- Mathematical Institute, Leiden University, Leiden, The Netherlands
- Institute of Biology Leiden, Leiden University, Leiden, The Netherlands
- * E-mail: (RMHM); (DAB)
| | - David A. Baker
- Leiden University Medical Center (LUMC), Department of Cell & Chemical Biology, Leiden, The Netherlands
- * E-mail: (RMHM); (DAB)
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19
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Casili G, Lanza M, Filippone A, Caffo M, Paterniti I, Campolo M, Colarossi L, Sciacca D, Lombardo SP, Cuzzocrea S, Esposito E. Overview on Common Genes Involved in the Onset of Glioma and on the Role of Migraine as Risk Factor: Predictive Biomarkers or Therapeutic Targets? J Pers Med 2022; 12:jpm12121969. [PMID: 36556190 PMCID: PMC9786313 DOI: 10.3390/jpm12121969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/22/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
Gliomas are relatively rare but fatal cancers, and there has been insufficient research to specifically evaluate the role of headache as a risk factor. Nowadays, gliomas are difficult to cure due to the infiltrative nature and the absence of specific adjuvant therapies. Until now, mutations in hundreds of genes have been identified in gliomas and most relevant discoveries showed specific genes alterations related to migraine as potential risk factors for brain tumor onset. Prognostic biomarkers are required at the time of diagnosis to better adapt therapies for cancer patients. In this review, we aimed to highlight the significant modulation of CLOCK, BMLA1 and NOTCH genes in glioma onset and development, praising these genes to be good as potentially attractive therapeutic markers for brain tumors. A improved knowledge regarding the role of these genes in triggering or modulating glioma maybe the key to early diagnosing brain tumor onset in patients affected by a simple headache. In addition, investigating on these genes we can suggest potential therapeutic targets for treating brain tumors. These considerations open up the possibility of personalized treatments that can target each brain tumor's specific genetic abnormality.
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Affiliation(s)
- Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Marika Lanza
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Alessia Filippone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Maria Caffo
- Unit of Neurosurgery, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98122 Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Lorenzo Colarossi
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Catania, Italy
| | - Dorotea Sciacca
- Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Catania, Italy
| | | | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98122 Messina, Italy
- Correspondence:
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van Asten JGM, Ristori T, Nolan DR, Lally C, Baaijens FPT, Sahlgren CM, Loerakker S. Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension. J Mech Behav Biomed Mater 2022; 133:105325. [PMID: 35839633 PMCID: PMC7613661 DOI: 10.1016/j.jmbbm.2022.105325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/03/2022] [Accepted: 06/18/2022] [Indexed: 11/29/2022]
Abstract
Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.
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Affiliation(s)
- Jordy G M van Asten
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Tommaso Ristori
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - David R Nolan
- School of Engineering and Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
| | - Caitríona Lally
- School of Engineering and Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
| | - Frank P T Baaijens
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands
| | - Cecilia M Sahlgren
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands; Faculty of Science and Engineering, Biosciences, Åbo Akademi, Turku, Finland
| | - Sandra Loerakker
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, the Netherlands.
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21
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Fu Z, Zhu G, Luo C, Chen Z, Dou Z, Chen Y, Zhong C, Su S, Liu F. Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment. Front Oncol 2022; 12:971462. [PMID: 36033448 PMCID: PMC9413079 DOI: 10.3389/fonc.2022.971462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 07/25/2022] [Indexed: 11/24/2022] Open
Abstract
Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.
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Affiliation(s)
- Zaixiang Fu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ganggui Zhu
- Department of Neurosurgery, Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chao Luo
- Department of Neurosurgery, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Zihang Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhangqi Dou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yike Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chen Zhong
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Su
- Department of Neurosurgery, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, China
| | - Fuyi Liu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Fuyi Liu,
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22
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Fedorova O, Parfenyev S, Daks A, Shuvalov O, Barlev NA. The Role of PTEN in Epithelial–Mesenchymal Transition. Cancers (Basel) 2022; 14:cancers14153786. [PMID: 35954450 PMCID: PMC9367281 DOI: 10.3390/cancers14153786] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/31/2022] [Accepted: 08/02/2022] [Indexed: 11/23/2022] Open
Abstract
Simple Summary The PTEN phosphatase is a ubiquitously expressed tumor suppressor, which inhibits the PI3K/AKT pathway in the cell. The PI3K/AKT pathway is considered to be one of the main signaling pathways that drives the proliferation of cancer cells. Furthermore, the same pathway controls the epithelial–mesenchymal transition (EMT). EMT is an evolutionarily conserved developmental program, which, upon aberrant reactivation, is also involved in the formation of cancer metastases. Importantly, metastasis is the leading cause of cancer-associated deaths. In this review, we discuss the literature data that highlight the role of PTEN in EMT. Based on this knowledge, we speculate about new possible strategies for cancer treatment. Abstract Phosphatase and Tensin Homolog deleted on Chromosome 10 (PTEN) is one of the critical tumor suppressor genes and the main negative regulator of the PI3K pathway. PTEN is frequently found to be inactivated, either partially or fully, in various malignancies. The PI3K/AKT pathway is considered to be one of the main signaling cues that drives the proliferation of cells. Perhaps it is not surprising, then, that this pathway is hyperactivated in highly proliferative tumors. Importantly, the PI3K/AKT pathway also coordinates the epithelial–mesenchymal transition (EMT), which is pivotal for the initiation of metastases and hence is regarded as an attractive target for the treatment of metastatic cancer. It was shown that PTEN suppresses EMT, although the exact mechanism of this effect is still not fully understood. This review is an attempt to systematize the published information on the role of PTEN in the development of malignant tumors, with a main focus on the regulation of the PI3K/AKT pathway in EMT.
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Huang H, Wang X, Guo AN, Li W, Duan RH, Fang JH, Yin B, Li DD. De novo brain arteriovenous malformation formation and development: A case report. World J Clin Cases 2022; 10:6277-6282. [PMID: 35949829 PMCID: PMC9254196 DOI: 10.12998/wjcc.v10.i18.6277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/01/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Brain arteriovenous malformation (AVM), an aberrant vascular development during the intrauterine period, is traditionally considered a congenital disease. Sporadic reports of cases of de novo AVM formation in children and adults have challenged the traditional view of its congenital origin.
CASE SUMMARY In this report, we have presented the case of a child with a de novo brain AVM. Magnetic resonance imaging and magnetic resonance angiography of the brain showed no AVM at the age of 5 years and 2 mo. Brain AVM was first detected in this child at the age of 7 years and 4 mo. The brain AVM was significantly advanced, and hemorrhage was seen for the first time at the age of 12 years and 8 mo. There was further progression in the AVM, and hemorrhage occurred again at the age of 13 years and 5 mo. Genetic analysis of this patient revealed a mutation in the NOTCH2 (p.Asp473Val) gene.
CONCLUSION In short, our case has once again confirmed the view that brain AVM is an acquired disease and is the result of the interaction of genes, environment, and molecules.
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Affiliation(s)
- Huan Huang
- Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xue Wang
- Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - An-Na Guo
- Department of Radiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Wei Li
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Ren-Hua Duan
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Jun-Hao Fang
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Bo Yin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Dan-Dong Li
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Patterson LL, Velayutham TS, Byerly CD, Bui DC, Patel J, Veljkovic V, Paessler S, McBride JW. Ehrlichia SLiM Ligand Mimetic Activates Notch Signaling in Human Monocytes. mBio 2022; 13:e0007622. [PMID: 35357214 PMCID: PMC9040721 DOI: 10.1128/mbio.00076-22] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/14/2022] [Indexed: 12/15/2022] Open
Abstract
Ehrlichia chaffeensis evades innate host defenses by reprogramming the mononuclear phagocyte through mechanisms that involve the exploitation of multiple evolutionarily conserved cellular signaling pathways, including Notch. This immune evasion strategy is directed in part by tandem repeat protein (TRP) effectors. Specifically, the TRP120 effector activates and regulates Notch signaling through interactions with the Notch receptor and the negative regulator, F-Box and WD repeat domain-containing 7 (FBW7). However, the specific molecular interactions and motifs required for E. chaffeensis TRP120-Notch receptor interaction and activation have not been defined. To investigate the molecular basis of TRP120 Notch activation, we compared TRP120 with endogenous canonical/noncanonical Notch ligands and identified a short region of sequence homology within the tandem repeat (TR) domain. TRP120 was predicted to share biological function with Notch ligands, and a function-associated sequence in the TR domain was identified. To investigate TRP120-Notch receptor interactions, colocalization between TRP120 and endogenous Notch-1 was observed. Moreover, direct interactions between full-length TRP120, the TRP120 TR domain containing the putative Notch ligand sequence, and the Notch receptor LBR were demonstrated. To molecularly define the TRP120 Notch activation motif, peptide mapping was used to identify an 11-amino acid short linear motif (SLiM) located within the TRP120 TR that activated Notch signaling and downstream gene expression. Peptide mutants of the Notch SLiM or anti-Notch SLiM antibody reduced or eliminated Notch activation and NICD nuclear translocation. This investigation reveals a novel molecularly defined pathogen encoded Notch SLiM mimetic that activates Notch signaling consistent with endogenous ligands. IMPORTANCE E. chaffeensis infects and replicates in mononuclear phagocytes, but how it evades innate immune defenses of this indispensable primary innate immune cell is not well understood. This investigation revealed the molecular details of a ligand mimicry cellular reprogramming strategy that involved a short linear motif (SLiM), which enabled E. chaffeensis to exploit host cell signaling to establish and maintain infection. E. chaffeensis TRP120 is a moonlighting effector that has been associated with cellular activation and other functions, including ubiquitin ligase activity. Herein, we identified and demonstrated that a SLiM present within each tandem repeat of TRP120 activated Notch signaling. Notch is an evolutionarily conserved signaling pathway responsible for many cell functions, including cell fate, development, and innate immunity. This study is significant because it revealed the first molecularly defined pathogen encoded SLiM that appears to have evolved de novo to mimic endogenous Notch ligands. Understanding Notch activation during E. chaffeensis infection provides a model to study pathogen exploitation of signaling pathways and will be useful in developing molecularly targeted countermeasures for inhibiting infection by a multitude of disease-causing pathogens that exploit cell signaling through molecular mimicry.
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Affiliation(s)
- LaNisha L. Patterson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | | | - Caitlan D. Byerly
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Duc Cuong Bui
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Jignesh Patel
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | | | - Slobodan Paessler
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Jere W. McBride
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, USA
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA
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Relationship between the Chromosome Structural Dynamics and Gene Expression—A Chicken and Egg Dilemma? Microorganisms 2022; 10:microorganisms10050846. [PMID: 35630292 PMCID: PMC9144111 DOI: 10.3390/microorganisms10050846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/14/2022] [Indexed: 02/06/2023] Open
Abstract
Prokaryotic transcription was extensively studied over the last half-century. A great deal of data has been accumulated regarding the control of gene expression by transcription factors regulating their target genes by binding at specific DNA sites. However, there is a significant gap between the mechanistic description of transcriptional control obtained from in vitro biochemical studies and the complexity of transcriptional regulation in the context of the living cell. Indeed, recent studies provide ample evidence for additional levels of complexity pertaining to the regulation of transcription in vivo, such as, for example, the role of the subcellular localization and spatial organization of different molecular components involved in the transcriptional control and, especially, the role of chromosome configurational dynamics. The question as to how the chromosome is dynamically reorganized under the changing environmental conditions and how this reorganization is related to gene expression is still far from being clear. In this article, we focus on the relationships between the chromosome structural dynamics and modulation of gene expression during bacterial adaptation. We argue that spatial organization of the bacterial chromosome is of central importance in the adaptation of gene expression to changing environmental conditions and vice versa, that gene expression affects chromosome dynamics.
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Aramini B, Masciale V, Grisendi G, Bertolini F, Maur M, Guaitoli G, Chrystel I, Morandi U, Stella F, Dominici M, Haider KH. Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence. Cancers (Basel) 2022; 14:cancers14040976. [PMID: 35205721 PMCID: PMC8869911 DOI: 10.3390/cancers14040976] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 01/27/2023] Open
Abstract
Simple Summary Cancer is one of the most debated problems all over the world. Cancer stem cells are considered responsible of tumor initiation, metastasis, drug resistance, and recurrence. This subpopulation of cells has been found into the tumor bulk and showed the capacity to self-renew, differentiate, up to generate a new tumor. In the last decades, several studies have been set on the molecular mechanisms behind their specific characteristics as the Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling, transcription factors, etc. The most powerful part of CSCs is represented by the niches as “promoter” of their self-renewal and “protector” from the common oncological treatment as chemotherapy and radiotherapy. In our review article we highlighted the primary mechanisms involved in CSC tumorigenesis for the setting of further targets to control the metastatic process. Abstract Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
- Correspondence:
| | - Valentina Masciale
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Federica Bertolini
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Michela Maur
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Giorgia Guaitoli
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Isca Chrystel
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
| | - Uliano Morandi
- Thoracic Surgery Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (V.M.); (U.M.)
| | - Franco Stella
- Division of Thoracic Surgery, Department of Experimental Diagnostic and Specialty Medicine–DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni-L. Pierantoni Hospital, 47121 Forlì, Italy;
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy; (G.G.); (F.B.); (M.M.); (G.G.); (I.C.); (M.D.)
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Buyuk B, Jin S, Ye K. Epithelial-to-Mesenchymal Transition Signaling Pathways Responsible for Breast Cancer Metastasis. Cell Mol Bioeng 2022; 15:1-13. [PMID: 35096183 PMCID: PMC8761190 DOI: 10.1007/s12195-021-00694-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
Breast carcinoma is highly metastatic and invasive. Tumor metastasis is a convoluted and multistep process involving tumor cell disseminating from their primary site and migrating to the secondary organ. Epithelial-mesenchymal transition (EMT) is one of the crucial steps that initiate cell progression, invasion, and metastasis. During EMT, epithelial cells alter their molecular features and acquire a mesenchymal phenotype. The regulation of EMT is centered by several signaling pathways, including primary mediators TGF-β, Notch, Wnt, TNF-α, Hedgehog, and RTKs. It is also affected by hypoxia and microRNAs (miRNAs). All these pathways are the convergence on the transcriptional factors such as Snail, Slug, Twist, and ZEB1/2. In addition, a line of evidence suggested that EMT and cancer stem like cells (CSCs) are associated. EMT associated cancer stem cells display mesenchymal phenotypes and resist to chemotherapy or targeted therapy. In this review, we highlighted recent discoveries in these signaling pathways and their regulation in breast cancer metastasis and invasion. While the clinical relevance of EMT and breast cancers remains controversial, we speculated a convergent signaling network pivotal to elucidating the transition of epithelial to mesenchymal phenotypes and onset of metastasis of breast cancer cells.
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Affiliation(s)
- Busra Buyuk
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Sha Jin
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Kaiming Ye
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
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28
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Sotomska M, Liefke R, Ferrante F, Schwederski H, Oswald F, Borggrefe T. SUMOylated non-canonical polycomb PRC1.6 complex as a prerequisite for recruitment of transcription factor RBPJ. Epigenetics Chromatin 2021; 14:38. [PMID: 34332624 PMCID: PMC8325870 DOI: 10.1186/s13072-021-00412-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 07/19/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Notch signaling controls cell fate decisions in many contexts during development and adult stem cell homeostasis and, when dysregulated, leads to carcinogenesis. The central transcription factor RBPJ assembles the Notch coactivator complex in the presence of Notch signaling, and represses Notch target gene expression in its absence. RESULTS We identified L3MBTL2 and additional members of the non-canonical polycomb repressive PRC1.6 complex in DNA-bound RBPJ associated complexes and demonstrate that L3MBTL2 directly interacts with RBPJ. Depletion of RBPJ does not affect occupancy of PRC1.6 components at Notch target genes. Conversely, absence of L3MBTL2 reduces RBPJ occupancy at enhancers of Notch target genes. Since L3MBTL2 and additional members of the PRC1.6 are known to be SUMOylated, we investigated whether RBPJ uses SUMO-moieties as contact points. Indeed, we found that RBPJ binds to SUMO2/3 and that this interaction depends on a defined SUMO-interaction motif. Furthermore, we show that pharmacological inhibition of SUMOylation reduces RBPJ occupancy at Notch target genes. CONCLUSIONS We propose that the PRC1.6 complex and its conjugated SUMO-modifications provide a favorable environment for binding of RBPJ to Notch target genes.
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Affiliation(s)
- Małgorzata Sotomska
- Institute of Biochemistry, Justus-Liebig University of Giessen, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Robert Liefke
- Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Hans-Meerwein Strasse 2, 35043, Marburg, Germany.,Department of Hematology, Oncology and Immunology, University Hospital Marburg and Philipps University of Marburg, Baldingerstrasse, 35043, Marburg, Germany
| | - Francesca Ferrante
- Institute of Biochemistry, Justus-Liebig University of Giessen, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Heiko Schwederski
- Center for Internal Medicine, Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Franz Oswald
- Center for Internal Medicine, Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Tilman Borggrefe
- Institute of Biochemistry, Justus-Liebig University of Giessen, Friedrichstrasse 24, 35392, Giessen, Germany.
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Young KZ, Cartee NMP, Lee SJ, Keep SG, Ivanova MI, Wang MM. Electrophilic and Drug-Induced Stimulation of NOTCH3 N-terminal Fragment Oligomerization in Cerebrovascular Pathology. Transl Stroke Res 2021; 12:1081-1092. [PMID: 33939102 DOI: 10.1007/s12975-021-00908-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 12/24/2022]
Abstract
Small vessel disease is a prevalent age-related condition linked to increased risk of dementia and stroke. We investigate the most commonly inherited form, CADASIL, caused by cysteine-involving mutations in NOTCH3. Recent studies highlight accumulation of NOTCH3 N-terminal fragmentation product (NTF) in disease. In vitro, NTF is capable of both spontaneous and catecholamine-enhanced cysteine-mediated oligomerization. Despite well-characterized genetic influence on CADASIL, environmental effects, including medication usage, on disease remain unclear. We studied effects of assorted electrophilic compounds and drugs on NTF oligomerization by SDS-PAGE and dynamic light scattering. We then examined direct proton pump inhibitor-NTF binding with antibodies designed against proton pump inhibitor-labeled proteins and mass spectrometry. Finally, we used monoclonal NTF antibodies with Proximity Ligation Assay to identify NTF oligomers in 3 CADASIL and 2 age-matched control brains. We identified enhancement of NTF oligomerization by two electrophilic cysteine-modifying compounds, N-ethylmaleimide and iodoacetamide, and an electrophilic compound capable of oxidizing cysteines, ferric chloride. Electrophilic clinical drugs (fenoldopam, omeprazole, tenatoprazole, lansoprazole, and rabeprazole) also promoted oligomerization, and we identified direct omeprazole-NTF and tenatoprazole-NTF complexes. Additionally, we provide novel evidence of NTF multimers in human CADASIL brains. A broad array of electrophilic chemicals, including clinically relevant drugs, influences oligomerization of a pathological CADASIL protein, providing mechanistic insight into disease protein oligomerization. We posit that environmental influences, which may include usage of electrophilic drugs, may affect CADASIL presentations.
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Affiliation(s)
- K Z Young
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA
- Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109-5622, USA
| | - N M P Cartee
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA
| | - S J Lee
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA
| | - S G Keep
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA
| | - M I Ivanova
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA
- Biophysics Program, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Michael M Wang
- Department of Neurology, University of Michigan, 7725 Medical Science Building II Box 5622, 1137 Catherine St., Ann Arbor, MI, 48109-5622, USA.
- Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109-5622, USA.
- Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA.
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Li HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol 2021; 147:1569-1585. [PMID: 33864521 DOI: 10.1007/s00432-021-03604-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression. METHODS PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched. RESULTS The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors. CONCLUSION This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs.
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Affiliation(s)
- Hong-Li Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Qian-Yu Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Min-Jie Jin
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chao-Fan Lu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Zhao-Yang Mu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wei-Yi Xu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China.
| | - Yan Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China. .,Zhengzhou University, Henan Institute of Advanced Technology, Zhengzhou, 450001, China.
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Drug Development in Neuroendocrine Tumors: What Is on the Horizon? Curr Treat Options Oncol 2021; 22:43. [PMID: 33786683 DOI: 10.1007/s11864-021-00834-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2021] [Indexed: 02/08/2023]
Abstract
OPINION STATEMENT Neuroendocrine neoplasms (NENs) constitute a heterogenous group of malignancies. Translational research into NEN cell biology is the cornerstone for drug development strategies in this field. Somatostatin receptor type 2 (SSTR2) expression is the hallmark of well-differentiated neuroendocrine tumors (NETs). Somatostatin analogs and peptide receptor radionuclide therapy (PRRT) form the basis of anti-SSTR2 treatment onto new combination strategies, antibody-drug conjugates and bispecific antibodies. Classical pathways involved in NET development (PI3K-Akt-mTOR and antiangiogenics) are reviewed but new potential targets for NET treatment will be explored. Epigenetic drugs have shown clinical activity in monotherapy and preclinical combination strategies are more than attractive. Immunotherapy has shown opposite results in different NEN settings. Although the NOTCH pathway has been targeted with disappointing results, new strategies are being developed. Finally, after years of solid preclinical evidence on different genetically engineered oncolytic viruses, clinical trials for refractory NET patients are now ongoing.
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Relevance of Notch Signaling for Bone Metabolism and Regeneration. Int J Mol Sci 2021; 22:ijms22031325. [PMID: 33572704 PMCID: PMC7865281 DOI: 10.3390/ijms22031325] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/24/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023] Open
Abstract
Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.
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Ting KK, Coleman P, Zhao Y, Vadas MA, Gamble JR. The aging endothelium. VASCULAR BIOLOGY 2021; 3:R35-R47. [PMID: 33880430 PMCID: PMC8052565 DOI: 10.1530/vb-20-0013] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 01/12/2021] [Indexed: 01/10/2023]
Abstract
Cellular senescence is now recognized as one of the hallmarks of aging. Herein, we examine current findings on senescence of the vascular endothelium and its impacts on age-related vascular diseases. Endothelial senescence can result in systemic metabolic changes, implicating senescence in chronic diseases such as diabetes, obesity and atherosclerosis. Senolytics, drugs that eliminate senescent cells, afford new therapeutic strategies for control of these chronic diseases.
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Affiliation(s)
- Ka Ka Ting
- Centre for the Endothelium Vascular Biology Program Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Paul Coleman
- Centre for the Endothelium Vascular Biology Program Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Yang Zhao
- Centre for the Endothelium Vascular Biology Program Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Mathew A Vadas
- Centre for the Endothelium Vascular Biology Program Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Jennifer R Gamble
- Centre for the Endothelium Vascular Biology Program Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
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Young KZ, Xu G, Keep SG, Borjigin J, Wang MM. Overlapping Protein Accumulation Profiles of CADASIL and CAA: Is There a Common Mechanism Driving Cerebral Small-Vessel Disease? THE AMERICAN JOURNAL OF PATHOLOGY 2020; 191:1871-1887. [PMID: 33387456 DOI: 10.1016/j.ajpath.2020.11.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 11/04/2020] [Accepted: 11/24/2020] [Indexed: 12/19/2022]
Abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cerebral amyloid angiopathy (CAA) are two distinct vascular angiopathies that share several similarities in clinical presentation and vascular pathology. Given the clinical and pathologic overlap, the molecular overlap between CADASIL and CAA was explored. CADASIL and CAA protein profiles from recently published proteomics-based and immuno-based studies were compared to investigate the potential for shared disease mechanisms. A comparison of affected proteins in each disease highlighted 19 proteins that are regulated in both CADASIL and CAA. Functional analysis of the shared proteins predicts significant interaction between them and suggests that most enriched proteins play roles in extracellular matrix structure and remodeling. Proposed models to explain the observed enrichment of extracellular matrix proteins include both increased protein secretion and decreased protein turnover by sequestration of chaperones and proteases or formation of stable protein complexes. Single-cell RNA sequencing of vascular cells in mice suggested that the vast majority of the genes accounting for the overlapped proteins between CADASIL and CAA are expressed by fibroblasts. Thus, our current understanding of the molecular profiles of CADASIL and CAA appears to support potential for common mechanisms underlying the two disorders.
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Affiliation(s)
- Kelly Z Young
- Departments of Neurology, University of Michigan, Ann Arbor, Michigan; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Gang Xu
- Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Simon G Keep
- Departments of Neurology, University of Michigan, Ann Arbor, Michigan
| | - Jimo Borjigin
- Departments of Neurology, University of Michigan, Ann Arbor, Michigan; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Michael M Wang
- Departments of Neurology, University of Michigan, Ann Arbor, Michigan; Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Neurology Service, VA Ann Arbor Healthcare System, Ann Arbor, Michigan.
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Kaushal K, Ramakrishna S. Deubiquitinating Enzyme-Mediated Signaling Networks in Cancer Stem Cells. Cancers (Basel) 2020; 12:E3253. [PMID: 33158118 PMCID: PMC7694198 DOI: 10.3390/cancers12113253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/23/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs) have both the capacity for self-renewal and the potential to differentiate and contribute to multiple tumor properties, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Thus, CSCs are considered to be promising therapeutic targets for cancer therapy. The function of CSCs can be regulated by ubiquitination and deubiquitination of proteins related to the specific stemness of the cells executing various stem cell fate choices. To regulate the balance between ubiquitination and deubiquitination processes, the disassembly of ubiquitin chains from specific substrates by deubiquitinating enzymes (DUBs) is crucial. Several key developmental and signaling pathways have been shown to play essential roles in this regulation. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of CSCs. These signaling pathways have been experimentally shown to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. In this review, we focus on the DUBs involved in CSCs signaling pathways, which are vital in regulating their stem-cell fate determination.
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Affiliation(s)
- Kamini Kaushal
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Korea;
- College of Medicine, Hanyang University, Seoul 04763, Korea
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Tenascin-C Function in Glioma: Immunomodulation and Beyond. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1272:149-172. [PMID: 32845507 DOI: 10.1007/978-3-030-48457-6_9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
First identified in the 1980s, tenascin-C (TNC) is a multi-domain extracellular matrix glycoprotein abundantly expressed during the development of multicellular organisms. TNC level is undetectable in most adult tissues but rapidly and transiently induced by a handful of pro-inflammatory cytokines in a variety of pathological conditions including infection, inflammation, fibrosis, and wound healing. Persistent TNC expression is associated with chronic inflammation and many malignancies, including glioma. By interacting with its receptor integrin and a myriad of other binding partners, TNC elicits context- and cell type-dependent function to regulate cell adhesion, migration, proliferation, and angiogenesis. TNC operates as an endogenous activator of toll-like receptor 4 and promotes inflammatory response by inducing the expression of multiple pro-inflammatory factors in innate immune cells such as microglia and macrophages. In addition, TNC drives macrophage differentiation and polarization predominantly towards an M1-like phenotype. In contrast, TNC shows immunosuppressive function in T cells. In glioma, TNC is expressed by tumor cells and stromal cells; high expression of TNC is correlated with tumor progression and poor prognosis. Besides promoting glioma invasion and angiogenesis, TNC has been found to affect the morphology and function of tumor-associated microglia/macrophages in glioma. Clinically, TNC can serve as a biomarker for tumor progression; and TNC antibodies have been utilized as an adjuvant agent to deliver anti-tumor drugs to target glioma. A better mechanistic understanding of how TNC impacts innate and adaptive immunity during tumorigenesis and tumor progression will open new therapeutic avenues to treat brain tumors and other malignancies.
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Parekh PA, Garcia TX, Hofmann MC. Regulation of GDNF expression in Sertoli cells. Reproduction 2020; 157:R95-R107. [PMID: 30620720 DOI: 10.1530/rep-18-0239] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 01/08/2019] [Indexed: 12/15/2022]
Abstract
Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is maintained by the interplay of several signaling pathways and growth factors. These factors are secreted by Sertoli cells located within the seminiferous epithelium, and by interstitial cells residing between the seminiferous tubules. Sertoli cells and peritubular myoid cells produce glial cell line-derived neurotrophic factor (GDNF), which binds to the RET/GFRA1 receptor complex at the surface of undifferentiated spermatogonia. GDNF is known for its ability to drive SSC self-renewal and proliferation of their direct cell progeny. Even though the effects of GDNF are well studied, our understanding of the regulation its expression is still limited. The purpose of this review is to discuss how GDNF expression in Sertoli cells is modulated within the niche, and how these mechanisms impact germ cell homeostasis.
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Affiliation(s)
- Parag A Parekh
- Department of Endocrine Neoplasia, UT MD Anderson Cancer Center, Houston, Texas, USA
| | - Thomas X Garcia
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.,Department of Biological and Environmental Sciences, University of Houston-Clear Lake, Houston, Texas, USA
| | - Marie-Claude Hofmann
- Department of Endocrine Neoplasia, UT MD Anderson Cancer Center, Houston, Texas, USA
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Kanwal M, Smahel M, Olsen M, Smahelova J, Tachezy R. Aspartate β-hydroxylase as a target for cancer therapy. J Exp Clin Cancer Res 2020; 39:163. [PMID: 32811566 PMCID: PMC7433162 DOI: 10.1186/s13046-020-01669-w] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/06/2020] [Indexed: 12/24/2022] Open
Abstract
As metastasis is a major cause of death in cancer patients, new anti-metastatic strategies are needed to improve cancer therapy outcomes. Numerous pathways have been shown to contribute to migration and invasion of malignant tumors. Aspartate β-hydroxylase (ASPH) is a key player in the malignant transformation of solid tumors by enhancing cell proliferation, migration, and invasion. ASPH also promotes tumor growth by stimulation of angiogenesis and immunosuppression. These effects are mainly achieved via the activation of Notch and SRC signaling pathways. ASPH expression is upregulated by growth factors and hypoxia in different human tumors and its inactivation may have broad clinical impact. Therefore, small molecule inhibitors of ASPH enzymatic activity have been developed and their anti-metastatic effect confirmed in preclinical mouse models. ASPH can also be targeted by monoclonal antibodies and has also been used as a tumor-associated antigen to induce both cluster of differentiation (CD) 8+ and CD4+ T cells in mice. The PAN-301-1 vaccine against ASPH has already been tested in a phase 1 clinical trial in patients with prostate cancer. In summary, ASPH is a promising target for anti-tumor and anti-metastatic therapy based on inactivation of catalytic activity and/or immunotherapy.
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Affiliation(s)
- Madiha Kanwal
- Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
| | - Michal Smahel
- Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic.
| | - Mark Olsen
- Department of Pharmaceutical Sciences, College of Pharmacy - Glendale, Midwestern University, Glendale, AZ, USA
- Crenae Therapeutics, Phoenix, AZ, USA
| | - Jana Smahelova
- Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
| | - Ruth Tachezy
- Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic
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The oncogenic role of Jagged1/Notch signaling in cancer. Biomed Pharmacother 2020; 129:110416. [PMID: 32593969 DOI: 10.1016/j.biopha.2020.110416] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/14/2022] Open
Abstract
Aberrant activation of Notch signaling plays an oncogenic role in cancer development. Jagged1 (JAG1) is an important Notch ligand that triggers Notch signaling through cell-cell interactions. JAG1 overexpression has been reported in many different types of cancer and correlates with a poor clinical prognosis. JAG1/Notch signaling controls oncogenic processes in different cell types and cellular contexts. Furthermore, JAG1/Notch signaling cascades activate a number of oncogenic factors that regulate cellular functions such as proliferation, metastasis, drug-resistance, and angiogenesis. To suppress the severe toxicity of pan-Notch inhibitors, JAG1 is attracting increasing attention as a source of therapeutic targets for cancers. In this review, the oncogenic role of JAG1/Notch signaling in cancer is discussed, as well as implications of strategies to inhibit JAG1/Notch signaling activity.
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40
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Xiu MX, Liu YM, Kuang BH. The Role of DLLs in Cancer: A Novel Therapeutic Target. Onco Targets Ther 2020; 13:3881-3901. [PMID: 32440154 PMCID: PMC7213894 DOI: 10.2147/ott.s244860] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022] Open
Abstract
Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.
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Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Yuan-Meng Liu
- Medical School of Nanchang University, Nanchang, People's Republic of China
| | - Bo-Hai Kuang
- Medical School of Nanchang University, Nanchang, People's Republic of China
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41
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Ristori T, Stassen OMJA, Sahlgren CM, Loerakker S. Lateral induction limits the impact of cell connectivity on Notch signaling in arterial walls. INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING 2020; 36:e3323. [PMID: 32058657 PMCID: PMC7217017 DOI: 10.1002/cnm.3323] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 12/17/2019] [Accepted: 02/02/2020] [Indexed: 06/10/2023]
Abstract
It is well known that arteries grow and remodel in response to mechanical stimuli. Vascular smooth muscle cells are the main mediators of this process, as they can switch phenotype from contractile to synthetic, and vice-versa, based on the surrounding bio-chemo-mechanical stimuli. A correct regulation of this phenotypic switch is fundamental to obtain and maintain arterial homeostasis. Notch, a mechanosensitive signaling pathway, is one of the main regulators of the vascular smooth muscle cell phenotype. Therefore, understanding Notch dynamics is key to elucidate arterial growth, remodeling, and mechanobiology. We have recently developed a one-dimensional agent-based model to investigate Notch signaling in arteries. However, due to its one-dimensional formulation, the model cannot be adopted to study complex nonsymmetrical geometries and, importantly, it cannot capture the realistic "cell connectivity" in arteries, here defined as the number of cell neighbors. Notch functions via direct cell-cell contact; thus, the number of cell neighbors could be an essential feature of Notch dynamics. Here, we extended the agent-based model to a two-dimensional formulation, to investigate the effects of cell connectivity on Notch dynamics and cell phenotypes in arteries. The computational results, supported by a sensitivity analysis, indicate that cell connectivity has marginal effects when Notch dynamics is dominated by the process of lateral induction, which induces all cells to have a uniform phenotype. When lateral induction is weaker, cells exhibit a nonuniform phenotype distribution and the percentage of synthetic cells within an artery depends on the number of neighbors.
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Affiliation(s)
- Tommaso Ristori
- Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
- Faculty of Science and Engineering, BiosciencesÅbo Academi UniversityTurkuFinland
- Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhovenThe Netherlands
| | - Oscar M. J. A. Stassen
- Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
- Faculty of Science and Engineering, BiosciencesÅbo Academi UniversityTurkuFinland
| | - Cecilia M. Sahlgren
- Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
- Faculty of Science and Engineering, BiosciencesÅbo Academi UniversityTurkuFinland
- Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhovenThe Netherlands
| | - Sandra Loerakker
- Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands
- Institute for Complex Molecular SystemsEindhoven University of TechnologyEindhovenThe Netherlands
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Zhu Q, Shen Y, Chen X, He J, Liu J, Zu X. Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells. Onco Targets Ther 2020; 13:525-540. [PMID: 32021295 PMCID: PMC6970631 DOI: 10.2147/ott.s224465] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 11/07/2019] [Indexed: 12/24/2022] Open
Abstract
The poor survival and prognosis of individuals with cancer are often attributed to tumour relapse and metastasis, which may be due to the presence of cancer stem cells (CSCs). CSCs have the characteristics of self-renewal, differentiation potential, high carcinogenicity, and drug resistance. In addition, CSCs exhibit many characteristics similar to those of embryonic or tissue stem cells while displaying persistent abnormal activation of self-renewal pathways associated with development and tissue homeostasis, including the Wnt, Notch, Hedgehog (Hh), TGF-β, JAK/STAT3, and NF-κB pathways. Therefore, we can eliminate CSCs by targeting these self-renewal pathways to constrain stem cell replication, survival and differentiation. At the same time, we cannot neglect the ping-pong effect of the tumour microenvironment, which releases cytokines and promotes self-renewal pathways in CSCs. Recently, meaningful progress has been made in the study of inhibitors of self-renewal pathways in tumours. This review primarily summarizes several representative and novel agents targeting these self-renewal signalling pathways and the tumour microenvironment and that represent a promising strategy for treating refractory and recurrent cancer.
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Affiliation(s)
- Qingyun Zhu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yingying Shen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Xiguang Chen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Jun He
- Department of Spine Surgery, The Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Jianghua Liu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Xuyu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, People's Republic of China
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Cho SJ, Yun SM, Jo C, Jeong J, Park MH, Han C, Koh YH. Altered expression of Notch1 in Alzheimer's disease. PLoS One 2019; 14:e0224941. [PMID: 31770379 PMCID: PMC6879159 DOI: 10.1371/journal.pone.0224941] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/19/2019] [Indexed: 02/07/2023] Open
Abstract
Notch signaling is an evolutionarily conserved pathway that regulates cell-cell interactions through binding of Notch family receptors to their cognate ligands. Notch signaling has an essential role in vascular development and angiogenesis. Recent studies have reported that Notch may be implicated in Alzheimer's disease (AD) pathophysiology. We measured the levels of soluble Notch1 (sNotch1) in the plasma samples from 72 dementia patients (average age 75.1 y), 89 subjects with amnestic mild cognitive impairment (MCI) (average age 73.72 y), and 150 cognitively normal controls (average age 72.34 y). Plasma levels of sNotch1 were 25.27% lower in dementia patients as compared to healthy control subjects. However, the level of Notch1 protein was significantly increased in human brain microvascular endothelial cells (HBMECs) after amyloid-beta treatment. Also, Notch1 mRNA level was significantly increased in HBMECs and iPSC-derived neuronal cells from AD patient compared to normal control. These results indicate that altered expression of Notch1 might be associated with the risk of Alzheimer's disease.
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Affiliation(s)
- Sun-Jung Cho
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Sang-Moon Yun
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Chulman Jo
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Jihyun Jeong
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Moon Ho Park
- Departments of Neurology, Korea University Medical College, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Republic of Korea
| | - Changsu Han
- Departments of Psychiatry, Korea University Medical College, Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, Republic of Korea
| | - Young Ho Koh
- Division of Brain Diseases, Center for Biomedical Sciences, Korea National Institute of Health, 187 Osongsaengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea
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Varshney S, Wei HX, Batista F, Nauman M, Sundaram S, Siminovitch K, Tanwar A, Stanley P. A modifier in the 129S2/SvPasCrl genome is responsible for the viability of Notch1[12f/12f] mice. BMC DEVELOPMENTAL BIOLOGY 2019; 19:19. [PMID: 31590629 PMCID: PMC6781419 DOI: 10.1186/s12861-019-0199-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 09/06/2019] [Indexed: 12/27/2022]
Abstract
Background Mouse NOTCH1 carries a highly conserved O-fucose glycan at Thr466 in epidermal growth factor-like repeat 12 (EGF12) of the extracellular domain. O-Fucose at this site has been shown by X-ray crystallography to be recognized by both DLL4 and JAG1 Notch ligands. We previously showed that a Notch1 Thr466Ala mutant exhibits very little ligand-induced NOTCH1 signaling in a reporter assay, whereas a Thr466Ser mutation enables the transfer of O-fucose and reverts the NOTCH1 signaling defect. We subsequently generated a mutant mouse with the Thr466Ala mutation termed Notch1[12f](Notch1tm2Pst). Surprisingly, homozygous Notch1[12f/12f] mutants on a mixed background were viable and fertile. Results We now report that after backcrossing to C57BL/6 J mice for 11–15 generations, few homozygous Notch1[12f/12f] embryos were born. Timed mating showed that embryonic lethality occurred by embryonic day (E) ~E11.5, somewhat delayed compared to mice lacking Notch1 or Pofut1 (the O-fucosyltransferase that adds O-fucose to Notch receptors), which die at ~E9.5. The phenotype of C57BL/6 J Notch1[12f/12f] embryos was milder than mutants affected by loss of a canonical Notch pathway member, but disorganized vasculogenesis in the yolk sac, delayed somitogenesis and development were characteristic. In situ hybridization of Notch target genes Uncx4.1 and Dll3 or western blot analysis of NOTCH1 cleavage did not reveal significant differences at E9.5. However, qRT-PCR of head cDNA showed increased expression of Dll3, Uncx4.1 and Notch1 in E9.5 Notch1[12f/12f] embryos. Sequencing of cDNA from Notch1[12f/12f] embryo heads and Southern analysis showed that the Notch1[12f] locus was intact following backcrossing. We therefore looked for evidence of modifying gene(s) by crossing C57BL/6 J Notch1 [12f/+] mice to 129S2/SvPasCrl mice. Intercrosses of the F1 progeny gave viable F2 Notch1[12f/12f] mice. Conclusion We conclude that the 129S2/SvPasCrl genome contains a dominant modifying gene that rescues the functions of NOTCH1[12f] in signaling. Identification of the modifying gene has the potential to illuminate novel factor(s) that promote Notch signaling when an O-fucose glycan is absent from EGF12 of NOTCH1.
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Affiliation(s)
- Shweta Varshney
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA.,Present address: ETHOS Health Communications, Yardley, PA, 19067, USA
| | - Hua-Xing Wei
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA.,Present address: The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People's Republic of China
| | - Frank Batista
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA
| | - Mohd Nauman
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA
| | - Subha Sundaram
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA
| | - Katherine Siminovitch
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, CA, M5G 1X5, Canada
| | - Ankit Tanwar
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA
| | - Pamela Stanley
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA.
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Yuan Y, Duan R, Wu B, Huang W, Zhang X, Qu M, Liu T, Yu X. Gene expression profiles and bioinformatics analysis of insulin-like growth factor-1 promotion of osteogenic differentiation. Mol Genet Genomic Med 2019; 7:e00921. [PMID: 31419079 PMCID: PMC7082822 DOI: 10.1002/mgg3.921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/20/2019] [Accepted: 07/23/2019] [Indexed: 02/04/2023] Open
Abstract
Background Insulin‐like growth factor‐1 (IGF‐1) promotes osteoblast differentiation and mineralization. The objective of this study was to investigate the effects of IGF‐1 on proliferation, mineralization, alkaline phosphatase (ALP) synthesis, and gene expression of osteoblast differentiation in MC3T3‐E1 osteoblasts cells, and to explore gene expression profiling differential genes. Methods MC3T3‐E1 osteoblasts cells were cultured in medium with or without IGF‐1. The ALP assay was employed to determine the osteoblast mineralization, and Alizarin red S to stain for calcium deposits, which were the indicators of mature osteocytes. The living cell number was assessed by the Cell Counting Kit‐8 method. RNA‐seq analysis was applied to identify genes that were differentially expressed in with or without IGF‐1 as well as genes that varied between these two groups. The expression of osteogenic marker genes was determined by quantitative real‐time polymerase chain reaction (qRT‐PCR) and western blot analysis. Result The cell number of osteoblasts exposed to IGF‐1 at 200 μg/L significantly increased compared with the control group. The ALP activity in IGF‐1‐treated cells was higher than that in the control group. IGF‐1 can increase ALP synthesis in osteoblasts in vitro. RNA‐seq analysis showed that 677 triggered differentially expressed genes by IGF, of which 383 genes were downregulated and 294 genes were upregulated. Gene ontology (GO) analysis showed that IGF‐1 caused a significant change in gene expression patterns. Conclusions This result suggested that IGF‐1 could probably promote the synthesis of organic matrix and mineralize action of bone. Osteogenic‐related genes (DMP1, PHEX, SOST, BMP2, RUNX2, OPN, and OCN) were significantly upregulated both in GO analysis and in pathway analysis to perform qRT‐PCR. Western blot analysis demonstrated that the Notch pathway was highly upregulated in MC3T3‐E1 cells.
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Affiliation(s)
- Yashuai Yuan
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Ruimeng Duan
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Baolin Wu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Wei Huang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xiuzhi Zhang
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Mingjia Qu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Tao Liu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Xiaobing Yu
- Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
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Picocci S, Bizzoca A, Corsi P, Magrone T, Jirillo E, Gennarini G. Modulation of Nerve Cell Differentiation: Role of Polyphenols and of Contactin Family Components. Front Cell Dev Biol 2019; 7:119. [PMID: 31380366 PMCID: PMC6656924 DOI: 10.3389/fcell.2019.00119] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 06/12/2019] [Indexed: 12/18/2022] Open
Abstract
In this study the mechanisms are explored, which modulate expression and function of cell surface adhesive glycoproteins of the Immunoglobulin Supergene Family (IgSF), and in particular of its Contactin subset, during neuronal precursor developmental events. In this context, a specific topic concerns the significance of the expression profile of such molecules and their ability to modulate signaling pathways activated through nutraceuticals, in particular polyphenols, administration. Both in vitro and in vivo approaches are chosen. As for the former, by using as a model the human SH-SY5Y neuroblastoma line, the effects of grape seed polyphenols are evaluated on proliferation and commitment/differentiation events along the neuronal lineage. In SH-SY5Y cell cultures, polyphenols were found to counteract precursor proliferation while promoting their differentiation, as deduced by studying their developmental parameters through the expression of cell cycle and neuronal commitment/differentiation markers as well as by measuring neurite growth. In such cultures, Cyclin E expression and BrdU incorporation were downregulated, indicating reduced precursor proliferation while increased neuronal differentiation was inferred from upregulation of cell cycle exit (p27–Kip) and neuronal commitment (NeuN) markers as well as by measuring neurite length through morphometric analysis. The polyphenol effects on developmental parameters were also explored in vivo, in cerebellar cortex, by using as a model the TAG/F3 transgenic line, which undergoes delayed neural development as a consequence of Contactin1 adhesive glycoprotein upregulation and premature expression under control of the Contactin2 gene (Cntn-2) promoter. In this transgenic line, a Notch pathway activation is known to occur and polyphenol treatment was found to counteract such an effect, demonstrated through downregulation of the Hes-1 transcription factor. Polyphenols also downregulated the expression of adhesive glycoproteins of the Contactin family themselves, demonstrated for both Contactin1 and Contactin2, indicating the involvement of changes in the expression of the underlying genes in the observed phenotype. These data support the hypothesis that the complex control exerted by polyphenols on neural development involves modulation of expression and function of the genes encoding cell adhesion molecules of the Contactin family and of the associated signaling pathways, indicating potential mechanisms whereby such compounds may control neurogenesis.
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Affiliation(s)
- Sabrina Picocci
- Laboratories of Developmental Neurobiology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - Antonella Bizzoca
- Laboratories of Developmental Neurobiology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - Patrizia Corsi
- Laboratories of Developmental Neurobiology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - Thea Magrone
- Laboratories of Immunology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - Emilio Jirillo
- Laboratories of Immunology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
| | - Gianfranco Gennarini
- Laboratories of Developmental Neurobiology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Medical School, University of Bari Aldo Moro, Bari, Italy
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Sanna MD, Borgonetti V, Galeotti N. μ Opioid Receptor-Triggered Notch-1 Activation Contributes to Morphine Tolerance: Role of Neuron–Glia Communication. Mol Neurobiol 2019; 57:331-345. [DOI: 10.1007/s12035-019-01706-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 07/10/2019] [Indexed: 01/07/2023]
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Norum HM, Michelsen AE, Lekva T, Arora S, Otterdal K, Olsen MB, Kong XY, Gude E, Andreassen AK, Solbu D, Karason K, Dellgren G, Gullestad L, Aukrust P, Ueland T. Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression. Am J Transplant 2019; 19:1050-1060. [PMID: 30312541 DOI: 10.1111/ajt.15141] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/02/2018] [Accepted: 10/07/2018] [Indexed: 02/06/2023]
Abstract
Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.
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Affiliation(s)
- Hilde M Norum
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway.,Division of Emergencies and Critical Care, Department for Research and Development, Oslo University Hospital, Oslo, Norway
| | - Annika E Michelsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway
| | - Tove Lekva
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Satish Arora
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Center for Heart Failure Research, Medical Faculty, University of Oslo, Oslo, Norway
| | - Kari Otterdal
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Maria Belland Olsen
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Xiang Yi Kong
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway
| | - Einar Gude
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Arne K Andreassen
- Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Kristjan Karason
- Sahlgrenska University Hospital, Transplant Institute, Gothenburg, Sweden.,Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Göran Dellgren
- Sahlgrenska University Hospital, Transplant Institute, Gothenburg, Sweden.,Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.,Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lars Gullestad
- Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway.,Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway.,K.G. Jebsen TREC, University of Tromsø, Tromsø, Norway
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Bazzoni R, Bentivegna A. Role of Notch Signaling Pathway in Glioblastoma Pathogenesis. Cancers (Basel) 2019; 11:cancers11030292. [PMID: 30832246 PMCID: PMC6468848 DOI: 10.3390/cancers11030292] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 02/17/2019] [Accepted: 02/25/2019] [Indexed: 12/12/2022] Open
Abstract
Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1–4) and five ligands (Dll1-3–4, Jagged1–2) that mainly contribute to the development and maintenance of the central nervous system (CNS). Neural stem cells (NSCs) are the starting point for neurogenesis and other neurological functions, representing an essential aspect for the homeostasis of the CNS. Therefore, genetic and functional alterations to NSCs can lead to the development of brain tumors, including glioblastoma. Glioblastoma remains an incurable disease, and the reason for the failure of current therapies and tumor relapse is the presence of a small subpopulation of tumor cells known as glioma stem cells (GSCs), characterized by their stem cell-like properties and aggressive phenotype. Growing evidence reveals that Notch signaling is highly active in GSCs, where it suppresses differentiation and maintains stem-like properties, contributing to Glioblastoma tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to Glioblastoma and its possible implication as a target for new therapeutic approaches.
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Affiliation(s)
- Riccardo Bazzoni
- Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Pz.le Scuro 10, 37134 Verona, Italy.
- Program in Clinical and Experimental Biomedical Sciences, University of Verona, 37134 Verona, Italy.
- NeuroMi, Milan Center for Neuroscience, Department of Neurology and Neuroscience, San Gerardo Hospital, University of Milano-Bicocca, 20900 Monza, Italy.
| | - Angela Bentivegna
- NeuroMi, Milan Center for Neuroscience, Department of Neurology and Neuroscience, San Gerardo Hospital, University of Milano-Bicocca, 20900 Monza, Italy.
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy.
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Zhang X, Qiao B, Hu Z, Ni W, Guo S, Luo G, Zhang H, Ren H, Zou L, Wang P, Shui W. BMP9 Promotes the Extracellular Matrix of Nucleus Pulposus Cells via Inhibition of the Notch Signaling Pathway. DNA Cell Biol 2019; 38:358-366. [PMID: 30758228 DOI: 10.1089/dna.2018.4478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Intervertebral disk degeneration (IDD) is a common disease that is caused by degeneration of the nucleus pulposus (NP). One goal in the treatment of IDD is delaying or reversing the degeneration of NP via the transformation of exogenous genes. This study first investigated the role of BMP9 in the extracellular matrix (ECM) of nucleus pulposus cells (NPCs) and its mechanism. We found that BMP9 promotes the expression of ECM in NPCs, and the key molecules of Notch signaling, namely, NICD-1, hes and hey, and it was significantly altered in BMP9-transfected NPCs, which suggests that BMP9 may regulate the ECM via the Notch signaling pathway. We verified the expression of Notch ligands and receptors in NPCs infected with Ad-BMP9 and demonstrated a significant decrease in DLL1 and Notch1; then, NPCs were transfected with Ad-dnNotch1, Ad-Jagged1, and Ad-DLL1, and different multiple groups were established to further identify the ligands or receptors that affected ECM expression. The results demonstrated that Ad-dnNotch1, Jagged1 and DLL1 inhibited ECM expression, and dnNotch1 promoted expression. Therefore, we demonstrated that BMP9 promoted the expression of ECM in NPCs via inhibition of Notch1 and DLL1. This study provides a possible method for IDD treatment.
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Affiliation(s)
- Xiang Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Qiao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhenming Hu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weidong Ni
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuquan Guo
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Gang Luo
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hanxiang Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Honglei Ren
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lvetao Zou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Shui
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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