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Wang H, Zheng T, Xu D, Sun C, Huang D, Liu X. Targeting DLL3: Innovative Strategies for Tumor Treatment. Pharmaceutics 2025; 17:520. [PMID: 40284515 PMCID: PMC12030079 DOI: 10.3390/pharmaceutics17040520] [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: 03/10/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
Delta-like 3 (DLL3) is an oncogenic protein aberrantly expressed in several tumors, particularly in small-cell lung cancer. DLL3-targeted therapies have recently made significant progress, demonstrating promising preclinical and clinical efficacy. This review aims to explore the mechanisms, challenges, and future opportunities associated with therapies targeting DLL3 for cancer treatment. The biological characteristics of DLL3 and its role in the Notch signaling pathway are introduced first, delving into the role of DLL3 in tumorigenesis and cancer progression. Next, current therapeutic approaches targeting DLL3 are described, including antibody-drug conjugates, T cell engagers, chimeric antigen receptor T cells, and radiopharmaceutical therapy, highlighting their effectiveness and safety in clinical trials. Despite the promising prospects, difficulties remain in the use of DLL3 as a therapeutic target due to tumor heterogeneity, the development of resistance, potential adverse effects, and barriers to patient stratification. Therefore, the potential of combination therapies, the use of innovative drug delivery systems, and ongoing clinical trial advancements are also discussed. Finally, the potential of DLL3-targeted therapies is summarized, highlighting the importance of multidisciplinary research to guide the clinical application and optimization of this emerging treatment strategy. These approaches might provide new therapeutic options, potentially starting a new era in cancer treatment.
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Affiliation(s)
- Hui Wang
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (H.W.); (T.Z.); (D.X.); (C.S.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tong Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (H.W.); (T.Z.); (D.X.); (C.S.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Dan Xu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (H.W.); (T.Z.); (D.X.); (C.S.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (H.W.); (T.Z.); (D.X.); (C.S.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Daqing Huang
- School of Nuclear Science and Engineering, East China University of Technology, Nanchang 330013, China;
| | - Xiongxiong Liu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China; (H.W.); (T.Z.); (D.X.); (C.S.)
- Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou 730000, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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Junier MP, El-Habr EA. Emergence of the cell-matrix adhesion element ILK as a player in glioblastoma cell plasticity. Dev Cell 2024; 59:3189-3190. [PMID: 39689679 DOI: 10.1016/j.devcel.2024.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 12/19/2024]
Abstract
Glioblastoma cells exhibit remarkable plasticity, enabling them to adapt to environmental cues and transition through various developmental-like states with distinct properties. In this issue of Developmental Cell, Loftus et al. identify ILK as an intrinsic regulator of glioblastoma cell transitions between progenitor-like and mesenchymal/astrocyte-like states.
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Affiliation(s)
- Marie-Pierre Junier
- Sorbonne université, CNRS, INSERM, Institut de Biologie Paris Seine, F-75005 Paris, France.
| | - Elias A El-Habr
- Sorbonne université, CNRS, INSERM, Institut de Biologie Paris Seine, F-75005 Paris, France
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3
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Zheng Z, Liu J, Ma J, Kang R, Liu Z, Yu J. Advances in new targets for immunotherapy of small cell lung cancer. Thorac Cancer 2024; 15:3-14. [PMID: 38093497 PMCID: PMC10761621 DOI: 10.1111/1759-7714.15178] [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: 10/26/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 01/04/2024] Open
Abstract
Small cell lung cancer (SCLC) is one of the highly aggressive malignancies characterized by rapid growth and early metastasis, but treatment options are limited. For SCLC, carboplatin or cisplatin in combination with etoposide chemotherapy has been considered the only standard of care, but the standard first-line treatment only results in 10-month survival. The majority of patients relapse within a few weeks to months after treatment, despite the relatively sensitive response to chemotherapy. Over the past decade, immunotherapy has made significant progress in the treatment of SCLC patients. However, there have been limited improvements in survival rates for SCLC patients with the current immune checkpoint inhibitors PD-1/PD-L1 and CTLA-4. In the face of high recurrence rates, small beneficiary populations, and low survival benefits, the exploration of new targets for key molecules and signals in SCLC and the development of drugs with novel mechanisms may provide fresh hope for immunotherapy in SCLC. Therefore, the aim of this review was to explore four new targets, DLL3, TIGIT, LAG-3, and GD2, which may play a role in the immunotherapy of SCLC to find useful clues and strategies to improve the outcome for SCLC patients.
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Affiliation(s)
- Zitong Zheng
- Department of OncologyBinzhou Medical University HospitalBinzhouP.R. China
| | - Juanjuan Liu
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingP.R. China
| | - Junling Ma
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingP.R. China
| | - Runting Kang
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingP.R. China
| | - Zhen Liu
- Department of Graduate Work OfficeBinzhou Medical University HospitalBinzhouP.R. China
| | - Jiangyong Yu
- Center of Biotherapy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric MedicineChinese Academy of Medical SciencesBeijingP.R. China
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Turchi L, Sakakini N, Saviane G, Polo B, Saurty-Seerunghen MS, Gabut M, Gouillou CA, Guerlais V, Pasquier C, Vignais ML, Almairac F, Chneiweiss H, Junier MP, Burel-Vandenbos F, Virolle T. CELF2 Sustains a Proliferating/OLIG2+ Glioblastoma Cell Phenotype via the Epigenetic Repression of SOX3. Cancers (Basel) 2023; 15:5038. [PMID: 37894405 PMCID: PMC10605641 DOI: 10.3390/cancers15205038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/23/2023] [Accepted: 08/10/2023] [Indexed: 10/29/2023] Open
Abstract
Glioblastomas (GBs) are incurable brain tumors. The persistence of aggressive stem-like tumor cells after cytotoxic treatments compromises therapeutic efficacy, leading to GBM recurrence. Forcing the GBM cells to irreversibly abandon their aggressive stem-like phenotype may offer an alternative to conventional cytotoxic treatments. Here, we show that the RNA binding protein CELF2 is strongly expressed in mitotic and OLIG2-positive GBM cells, while it is downregulated in differentiated and non-mitotic cells by miR-199a-3p, exemplifying GBM intra-tumor heterogeneity. Using patient-derived cells and human GBM samples, we demonstrate that CELF2 plays a key role in maintaining the proliferative/OLIG2 cell phenotype with clonal and tumorigenic properties. Indeed, we show that CELF2 deficiency in patient-derived GSCs drastically reduced tumor growth in the brains of nude mice. We further show that CELF2 promotes TRIM28 and G9a expression, which drive a H3K9me3 epigenetic profile responsible for the silencing of the SOX3 gene. Thus, CELF2, which is positively correlated with OLIG2 and Ki67 expression in human GBM samples, is inversely correlated with SOX3 and miR-199a-3p. Accordingly, the invalidation of SOX3 in CELF2-deficient patient-derived cells rescued proliferation and OLIG2 expression. Finally, patients expressing SOX3 above the median level of expression tend to have a longer life expectancy. CELF2 is therefore a crucial target for the malignant potential of GBM and warrants attention when developing novel anticancer strategies.
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Affiliation(s)
- Laurent Turchi
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- DRCI, CHU de Nice, 06107 Nice, France
| | - Nathalie Sakakini
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Gaelle Saviane
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Béatrice Polo
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
| | - Mirca Saras Saurty-Seerunghen
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Mathieu Gabut
- Stemness in Gliomas Laboratory, Cancer Initiation and Tumoral Cell Identity (CITI) Department, INSERM 1052, CNRS 5286, Centre Léon Bérard, 69008 Lyon, France;
- Cancer Research Center of Lyon 1, Université Claude Bernard Lyon 1, 69100 Villeurbanne, France
| | | | - Vincent Guerlais
- CNRS, I3S, Université Côte d’Azur, 06560 Valbonne, France; (V.G.); (C.P.)
| | - Claude Pasquier
- CNRS, I3S, Université Côte d’Azur, 06560 Valbonne, France; (V.G.); (C.P.)
| | - Marie Luce Vignais
- CNRS, INSERM, Institut de Génomique Fonctionnelle, IGF, Université de Montpellier, 34090 Montpellier, France;
| | - Fabien Almairac
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
| | - Hervé Chneiweiss
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Marie-Pierre Junier
- CNRS UMR8246, INSERM U1130, Neuroscience Paris Seine-IBPS Laboratory, Team Glial Plasticity and NeuroOncology, Sorbonne Université, 75252 Paris, France; (M.S.S.-S.); (H.C.); (M.-P.J.)
| | - Fanny Burel-Vandenbos
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
- Service d’Anatomopathologie, Hôpital Pasteur, CHU de Nice, 06107 Nice, France
| | - Thierry Virolle
- CNRS, INSERM, Institut de Biologie Valrose, Team INSERM “Cancer Stem Cell Plasticity and Functional Intra-tumor Heterogeneity”, Université Côte D’Azur, 06107 Nice, France; (L.T.); (N.S.); (G.S.); (B.P.); (F.A.); (F.B.-V.)
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Xiang J, Gong W, Liu J, Zhang H, Li M, Wang R, Lv Y, Sun P. Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma. Front Genet 2023; 14:1098190. [PMID: 37274780 PMCID: PMC10233108 DOI: 10.3389/fgene.2023.1098190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 04/24/2023] [Indexed: 06/07/2023] Open
Abstract
Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth. Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample. Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group (p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control (p < 0.0001) and in metastasis than in primary lesion (p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.
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Affiliation(s)
- Jinyu Xiang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Wenjing Gong
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Jiannan Liu
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Huijuan Zhang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ming Li
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Rujian Wang
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Yaodong Lv
- Departments of Neurology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
| | - Ping Sun
- Departments of Oncology, Yantai Yuhuangding Hospital, Shandong University, Yantai, Shandong, China
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Elshaer SS, Abulsoud AI, Fathi D, Abdelmaksoud NM, Zaki MB, El-Mahdy HA, Ismail A, Elsakka EGE, Abd-Elmawla MA, Abulsoud LA, Doghish AS. miRNAs role in glioblastoma pathogenesis and targeted therapy: Signaling pathways interplay. Pathol Res Pract 2023; 246:154511. [PMID: 37178618 DOI: 10.1016/j.prp.2023.154511] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 04/28/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
High mortality and morbidity rates and variable clinical behavior are hallmarks of glioblastoma (GBM), the most common and aggressive primary malignant brain tumor. Patients with GBM often have a dismal outlook, even after undergoing surgery, postoperative radiation, and chemotherapy, which has fueled the search for specific targets to provide new insights into the development of contemporary therapies. The ability of microRNAs (miRNAs/miRs) to posttranscriptionally regulate the expression of various genes and silence many target genes involved in cell proliferation, cell cycle, apoptosis, invasion, angiogenesis, stem cell behavior and chemo- and radiotherapy resistance makes them promising candidates as prognostic biomarkers and therapeutic targets or factors to advance GBM therapeutics. Hence, this review is like a crash course in GBM and how miRNAs related to GBM. Here, we will outline the miRNAs whose role in the development of GBM has been established by recent in vitro or in vivo research. Moreover, we will provide a summary of the state of knowledge regarding oncomiRs and tumor suppressor (TS) miRNAs in relation to GBM with an emphasis on their potential applications as prognostic biomarkers and therapeutic targets.
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Affiliation(s)
- Shereen Saeid Elshaer
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt; Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Doaa Fathi
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Mai A Abd-Elmawla
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Logyna A Abulsoud
- Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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7
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Rajabi A, Kayedi M, Rahimi S, Dashti F, Mirazimi SMA, Homayoonfal M, Mahdian SMA, Hamblin MR, Tamtaji OR, Afrasiabi A, Jafari A, Mirzaei H. Non-coding RNAs and glioma: Focus on cancer stem cells. Mol Ther Oncolytics 2022; 27:100-123. [PMID: 36321132 PMCID: PMC9593299 DOI: 10.1016/j.omto.2022.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Glioblastoma and gliomas can have a wide range of histopathologic subtypes. These heterogeneous histologic phenotypes originate from tumor cells with the distinct functions of tumorigenesis and self-renewal, called glioma stem cells (GSCs). GSCs are characterized based on multi-layered epigenetic mechanisms, which control the expression of many genes. This epigenetic regulatory mechanism is often based on functional non-coding RNAs (ncRNAs). ncRNAs have become increasingly important in the pathogenesis of human cancer and work as oncogenes or tumor suppressors to regulate carcinogenesis and progression. These RNAs by being involved in chromatin remodeling and modification, transcriptional regulation, and alternative splicing of pre-mRNA, as well as mRNA stability and protein translation, play a key role in tumor development and progression. Numerous studies have been performed to try to understand the dysregulation pattern of these ncRNAs in tumors and cancer stem cells (CSCs), which show robust differentiation and self-regeneration capacity. This review provides recent findings on the role of ncRNAs in glioma development and progression, particularly their effects on CSCs, thus accelerating the clinical implementation of ncRNAs as promising tumor biomarkers and therapeutic targets.
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Affiliation(s)
- Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehrdad Kayedi
- Department of Radiology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shiva Rahimi
- School of Medicine,Fasa University of Medical Sciences, Fasa, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mina Homayoonfal
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Amin Mahdian
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Omid Reza Tamtaji
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Afrasiabi
- Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ameneh Jafari
- Advanced Therapy Medicinal Product (ATMP) Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Guo W, Qiao T, Li T. The role of stem cells in small-cell lung cancer: evidence from chemoresistance to immunotherapy. Semin Cancer Biol 2022; 87:160-169. [PMID: 36371027 DOI: 10.1016/j.semcancer.2022.11.006] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 11/03/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer, accounting for approximately 15% among all lung cancers. Despite the ability of chemotherapy, the first-line treatment for SCLC, to rapidly shrink tumors, nearly all patients experience recurrence and metastasis within a few months. Cancer stem cells (CSCs) are a small population of tumor cells responsible for tumorigenesis, metastasis, and recurrence after treatment, which play a crucial role in chemoresistance by promoting DNA repair and expression of drug resistance-associated proteins. Thus, targeting CSCs has been successful in certain malignancies. Tumor therapy has entered the era of immunotherapy and numerous preclinical trials have demonstrated the effectiveness of immunotherapeutic approaches targeting CSCs, such as tumor vaccines and chimeric antigen receptor (CAR) T cell, and the feasibility of combining them with chemotherapy. Therefore, a deeper understanding of the interaction between CSCs and immune system is essential to facilitate the advances of new immunotherapies approaches targeting CSCs as well as combination with standard drugs such as chemotherapy. This narrative review summarizes the mechanisms of chemoresistance of CSCs in SCLC and the latest advances in targeted therapies. Thereafter, we discuss the effects of CSCs on tumor immune microenvironment in SCLC and corresponding immunotherapeutic approaches. Eventually, we propose that the combination of immunotherapy targeting CSCs with standard drugs is a promising direction for SCLC therapies.
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Affiliation(s)
- Wenwen Guo
- Department of Pathology, Xianyang Central Hospital, Xianyang 712000, China
| | - Tianyun Qiao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Tian Li
- School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China.
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9
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Sengupta S, Mondal M, Prasasvi KR, Mukherjee A, Magod P, Urbach S, Friedmann-Morvinski D, Marin P, Somasundaram K. Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth. eLife 2022; 11:78972. [PMID: 35642785 PMCID: PMC9259034 DOI: 10.7554/elife.78972] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/29/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.
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Affiliation(s)
- Shreoshi Sengupta
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Mainak Mondal
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Kaval Reddy Prasasvi
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Arani Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Prerna Magod
- School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
| | - Serge Urbach
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Philippe Marin
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
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10
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Integrated Gene Expression and Methylation Analyses Identify DLL3 as a Biomarker for Prognosis of Malignant Glioma. J Mol Neurosci 2021; 71:1622-1635. [PMID: 33713320 DOI: 10.1007/s12031-021-01817-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 02/15/2021] [Indexed: 12/21/2022]
Abstract
Glioma is one of the most common neurological malignancies worldwide. Delta-like ligand 3 (DLL3), an inhibitory ligand-driven activation of the Notch pathway, has been shown to be significantly associated with overall survival in patients with glioma. Therefore, the purpose of this study was to determine whether DLL3 as a biomarker in glioma is associated with patients' clinicopathological features and prognosis. We identified differences in transcriptome and promoter methylation in the Chinese Glioma Genome Atlas (CGGA) in patients with malignant glioma with shorter (less than 1 year) and longer (greater than 3 years) survival time. Further analysis of The Cancer Genome Atlas (TCGA) revealed that four genes (DLL3, TSPAN15, RTN1, PAK7) are highly associated with patient prognosis and play an indispensable role in evolution. We chose the expression level of DLL3 in glioma patients for our study. Patients were divided into groups with low and high expression of DLL3 according to the cutoff values obtained, and Kaplan-Meier and Cox analysis were used to examine the correlation between DLL3 gene expression and patient survival. We then performed a gene set enrichment analysis (GSEA) to identify significantly enriched signaling pathways. Our results confirmed that the overall survival of patients with low DLL3 expression was significantly shorter than that of patients with high DLL3 expression. GSEA showed that the signaling pathways of the immune process and immune response, among others, were enhanced with the DLL3 low-expression phenotype. Collectively, our findings signify that DLL3 is a potent prognostic factor for glioma, which can provide a viable approach for glioma prognostic assessment and valuable insights for anti-tumor immune-targeted therapies.
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11
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Hajj GNM, Nunes PBC, Roffe M. Genome-wide translation patterns in gliomas: An integrative view. Cell Signal 2020; 79:109883. [PMID: 33321181 DOI: 10.1016/j.cellsig.2020.109883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/01/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023]
Abstract
Gliomas are the most frequent tumors of the central nervous system (CNS) and include the highly malignant glioblastoma (GBM). Characteristically, gliomas have translational control deregulation related to overactivation of signaling pathways such as PI3K/AKT/mTORC1 and Ras/ERK1/2. Thus, mRNA translation appears to play a dominant role in glioma gene expression patterns. The, analysis of genome-wide translated transcripts, together known as the translatome, may reveal important information for understanding gene expression patterns in gliomas. This review provides a brief overview of translational control mechanisms altered in gliomas with a focus on the current knowledge related to the translatomes of glioma cells and murine glioma models. We present an integrative meta-analysis of selected glioma translatome data with the aim of identifying recurrent patterns of gene expression preferentially regulated at the level of translation and obtaining clues regarding the pathological significance of these alterations. Re-analysis of several translatome datasets was performed to compare the translatomes of glioma models with those of their non-tumor counterparts and to document glioma cell responses to radiotherapy and MNK modulation. The role of recurrently altered genes in the context of translational control and tumorigenesis are discussed.
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Affiliation(s)
- Glaucia Noeli Maroso Hajj
- International Research Institute, A.C.Camargo Cancer Center, Rua Taguá, 440, São Paulo ZIP Code: 01508-010, Brazil; National Institute of Oncogenomics and Innovation, Brazil.
| | - Paula Borzino Cordeiro Nunes
- International Research Institute, A.C.Camargo Cancer Center, Rua Taguá, 440, São Paulo ZIP Code: 01508-010, Brazil
| | - Martin Roffe
- International Research Institute, A.C.Camargo Cancer Center, Rua Taguá, 440, São Paulo ZIP Code: 01508-010, Brazil; National Institute of Oncogenomics and Innovation, Brazil.
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12
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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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13
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Almairac F, Turchi L, Sakakini N, Debruyne DN, Elkeurti S, Gjernes E, Polo B, Bianchini L, Fontaine D, Paquis P, Chneiweiss H, Junier MP, Verrando P, Burel-Vandenbos F, Virolle T. ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a "Toggle Switch" of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells. Cancer Res 2020; 80:3236-3250. [PMID: 32366479 DOI: 10.1158/0008-5472.can-19-0855] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 01/27/2020] [Accepted: 04/29/2020] [Indexed: 11/16/2022]
Abstract
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells. SIGNIFICANCE: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.See related commentary by Koncar and Agnihotri, p. 3195.
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Affiliation(s)
- Fabien Almairac
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France.,Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, France
| | - Laurent Turchi
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France.,DRCI, CHU de Nice, France
| | - Nathalie Sakakini
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France
| | | | - Sarah Elkeurti
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France
| | - Elisabet Gjernes
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France
| | - Beatrice Polo
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France
| | - Laurence Bianchini
- Laboratory of Solid Tumor Genetics, Université Côte d'Azur (UCA), CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
| | - Denys Fontaine
- Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, France
| | - Philippe Paquis
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France.,Service de Neurochirurgie, Hôpital Pasteur, CHU de Nice, France
| | - Herve Chneiweiss
- CNRS UMR8246 Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France.,Inserm U1130, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France.,Sorbonne University, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France
| | - Marie-Pierre Junier
- CNRS UMR8246 Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France.,Inserm U1130, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France.,Sorbonne University, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris, France
| | - Patrick Verrando
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France
| | - Fanny Burel-Vandenbos
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France.,Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, France
| | - Thierry Virolle
- Université Côte D'Azur, CNRS, INSERM, Institut de Biologie Valrose, Nice, France.
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14
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Satheesh NJ, Samuel SM, Büsselberg D. Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells. Biomolecules 2020; 10:biom10010079. [PMID: 31947879 PMCID: PMC7022456 DOI: 10.3390/biom10010079] [Citation(s) in RCA: 20] [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: 11/25/2019] [Revised: 12/24/2019] [Accepted: 12/26/2019] [Indexed: 12/13/2022] Open
Abstract
Cancer remains one of the most feared and dreaded diseases in this era of modern medicine, claiming the lives of many, and affecting the quality of life of several others around the globe despite major advances in the diagnosis, treatment, palliative care and the immense resources invested into cancer research. While research in cancer has largely focused on the neoplasm/tumor and the cancerous cells that make up the tumor, more recently, the existence, proliferation, differentiation, migration and invasion of cancer stem cells (CSCs) and the role that CSCs play in tumor initiation, progression, metastasis, drug resistance and relapse/recurrence of the disease has gained widespread interest in cancer research. Although the conventional therapeutic approaches such as surgery, chemotherapy and radiation therapy are effective cancer treatments, very often these treatment modalities fail to target the CSCs, which then later become the source of disease recurrence. A majority of the anti-cancer agents target rapidly dividing cancer cells and normal cells and hence, have side effects that are not expected. Targeting CSCs remains a challenge due to their deviant nature with a low proliferation rate and increased drug resistance mechanism. Ascorbic acid/Vitamin C (Vit.C), a potent antioxidant, is a cofactor for several biosynthetic and gene regulatory enzymes and a vital contributor to immune defense of the body, and was found to be deficient in patients with advanced stages of cancer. Vit.C has gained importance in the treatment of cancer due to its ability to modulate the redox status of the cell and influence epigenetic modifications and significant roles in HIF1α signaling. Studies have reported that intravenous administration of Vit.C at pharmacological doses selectively kills tumor cells and targets CSCs when administered along with chemotherapeutic drugs. In the current article, we provide an in-depth review of how Vit.C plays an important role in targeting CSCs and its possible use as an adjuvant, neoadjuvant or co-treatment in the treatment of cancers.
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15
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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16
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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: 114] [Impact Index Per Article: 19.0] [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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17
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Yan D, Hao C, Xiao-Feng L, Yu-Chen L, Yu-Bin F, Lei Z. Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma. J Cell Physiol 2018; 234:158-170. [PMID: 30076599 DOI: 10.1002/jcp.26775] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 04/27/2018] [Indexed: 02/06/2023]
Abstract
Glioma is the most aggressive primary brain tumor and is notorious for resistance to chemoradiotherapy. Although its associated mechanisms are still not completely understood, Notch signaling, an evolutionarily conserved pathway, appears to be the key processes involved. Nevertheless, its mechanisms are sophisticated, due to a variety of targets and signal pathways, especially microRNA. MicroRNAs, which are small noncoding regulatory RNA molecules, have been proposed as one of the key mechanisms in glioma pathogenesis. Among the known glioma associated microRNA, microRNA-129, microRNA-34 family, and microRNA-326 have been shown to influence the progress of glioma through Notch signaling. Evidence also indicates that recurrence is due to development or persistence of the glioma stem-like cells and active angiogenesis, which are tightly regulated by a variety of factors, including Notch signaling. In this review, we summarize the recent progress regarding the functional roles of Notch signaling in glioma, including Notch ligand, microRNA, intracellular crosstalk, glioma stem-like cells and active angiogenesis and explore their clinical implications as diagnostic or prognostic biomarkers and molecular therapeutic targets for glioma.
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Affiliation(s)
- Du Yan
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Chen Hao
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Li Xiao-Feng
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Lu Yu-Chen
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Feng Yu-Bin
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
| | - Zhang Lei
- Department of Basic and Clinical Pharmacology, School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Hefei, China.,Anhui Institute of Innovative Drugs, Hefei, China
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18
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Hombach-Klonisch S, Mehrpour M, Shojaei S, Harlos C, Pitz M, Hamai A, Siemianowicz K, Likus W, Wiechec E, Toyota BD, Hoshyar R, Seyfoori A, Sepehri Z, Ande SR, Khadem F, Akbari M, Gorman AM, Samali A, Klonisch T, Ghavami S. Glioblastoma and chemoresistance to alkylating agents: Involvement of apoptosis, autophagy, and unfolded protein response. Pharmacol Ther 2018; 184:13-41. [DOI: 10.1016/j.pharmthera.2017.10.017] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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19
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Zhao M, Li L, Zhou J, Cui X, Tian Q, Jin Y, Zhu Y. MiR-2861 Behaves as a Biomarker of Lung Cancer Stem Cells and Regulates the HDAC5-ERK System Genes. Cell Reprogram 2018; 20:99-106. [PMID: 29620443 DOI: 10.1089/cell.2017.0045] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence, and drug resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. Lung cancer stem cells (LCSCs) were closely related to the occurrence and development of lung cancer. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSC differentiation model was established through introducing serum into the medium of H460 spheres. miR-2861 expression was significantly higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs, and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861. The role of HDAC5 in the regulation of LCSC differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSC differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy.
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Affiliation(s)
- Mengya Zhao
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China .,2 College of Life Sciences, Shanghai University , Shanghai, China
| | - Lin Li
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China
| | - Jundong Zhou
- 3 Department of Radio Oncology, Affiliated Suzhou Hospital, Nanjing Medical University , Suzhou, China
| | - Xueyuan Cui
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China .,2 College of Life Sciences, Shanghai University , Shanghai, China
| | - Qingmei Tian
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China .,4 School of Pharmacy, Xi'an Jiaotong University , Xi'an, China
| | - Yaqing Jin
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China .,5 University of Chinese Academy of Sciences , Beijing, China
| | - Yimin Zhu
- 1 CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics , Chinese Academy of Sciences, Suzhou, China
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20
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Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness. Acta Neuropathol 2018; 135:267-283. [PMID: 29149419 PMCID: PMC5773658 DOI: 10.1007/s00401-017-1783-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 10/25/2017] [Accepted: 10/25/2017] [Indexed: 12/20/2022]
Abstract
Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients’ glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients’ tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.
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21
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Virolle T. [Cancer stem cells in glioblastoma]. Bull Cancer 2017; 104:1075-1079. [PMID: 29153545 DOI: 10.1016/j.bulcan.2017.10.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 10/19/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Thierry Virolle
- Université Côte-d'Azur, institut de biologie Valrose (iBV), Inserm, CNRS, 06108 Nice cedex 2, France.
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22
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Ahir BK, Ozer H, Engelhard HH, Lakka SS. MicroRNAs in glioblastoma pathogenesis and therapy: A comprehensive review. Crit Rev Oncol Hematol 2017; 120:22-33. [PMID: 29198335 DOI: 10.1016/j.critrevonc.2017.10.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 09/05/2017] [Accepted: 10/04/2017] [Indexed: 01/17/2023] Open
Abstract
Glioblastoma (GBM), also known as grade IV astrocytoma, is the most aggressive primary intracranial tumor of the adult brain. MicroRNAs (miRNAs), a class of small non-coding RNA species, have critical functions across various biological processes. A great deal of progress has been made recently in dissecting miRNA pathways associated with the pathogenesis of GBM. miRNA expression signatures called gene signatures also characterize and contribute to the phenotypic diversity of GBM subclasses through their ability to regulate developmental growth and differentiation. miRNA molecules have been identified as diagnostic and prognostic biomarkers for patient stratification and may also serve as therapeutic targets and agents. This review summarizes: (i) the current understanding of the roles of miRNAs in the pathogenesis of GBM, (ii) the potential use of miRNAs in GBM diagnosis and glioma grading, (iii) further prospects of developing miRNAs as novel biomarkers and therapeutic targets for GBM, and (iv) important practical considerations when considering miRNA therapy for GBM patients.
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Affiliation(s)
- Bhavesh K Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Howard Ozer
- Section of Hematology and Oncology, Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Herbert H Engelhard
- Department of Neurosurgery, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Sajani S Lakka
- Section of Hematology and Oncology, Department of Medicine, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA.
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23
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Debruyne DN, Turchi L, Burel-Vandenbos F, Fareh M, Almairac F, Virolle V, Figarella-Branger D, Baeza-Kallee N, Lagadec P, Kubiniek V, Paquis P, Fontaine D, Junier MP, Chneiweiss H, Virolle T. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene 2017; 37:241-254. [PMID: 28925399 DOI: 10.1038/onc.2017.323] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/20/2017] [Accepted: 07/28/2017] [Indexed: 12/21/2022]
Abstract
Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.
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Affiliation(s)
- D N Debruyne
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France
| | - L Turchi
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France.,Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, France
| | - F Burel-Vandenbos
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France.,Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, France
| | - M Fareh
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France
| | - F Almairac
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France.,Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, France
| | - V Virolle
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France
| | - D Figarella-Branger
- Aix Marseille Université, Faculté de Médecine de la Timone, Marseille, France.,CRO2, INSERM UMR 911, Marseille Cedex, France.,Departement de Pathology, CHU de la Timone, Marseille Cedex 5, France
| | - N Baeza-Kallee
- Aix Marseille Université, Faculté de Médecine de la Timone, Marseille, France.,CRO2, INSERM UMR 911, Marseille Cedex, France
| | - P Lagadec
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France
| | - V Kubiniek
- Laboratory of Solid Tumors Genetics, University Hospital of Nice, France
| | - P Paquis
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France.,Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, France
| | - D Fontaine
- Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, France
| | - M-P Junier
- CNRS UMR8246 Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris France.,Inserm U1130, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris France.,University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine - IBPS; Team Glial, Plasticity; 7 quai Saint-Bernard Paris France
| | - H Chneiweiss
- CNRS UMR8246 Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris France.,Inserm U1130, Neuroscience Paris Seine - IBPS; Team Glial Plasticity; 7 quai Saint-Bernard, Paris France.,University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine - IBPS; Team Glial, Plasticity; 7 quai Saint-Bernard Paris France
| | - T Virolle
- Université Côte d'Azur, Nice, France.,CNRS, UMR7277, Nice, France.,Inserm, U1091, Nice, France
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24
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Sarkar S, Mirzaei R, Zemp FJ, Wei W, Senger DL, Robbins SM, Yong VW. Activation of NOTCH Signaling by Tenascin-C Promotes Growth of Human Brain Tumor-Initiating Cells. Cancer Res 2017; 77:3231-3243. [PMID: 28416488 DOI: 10.1158/0008-5472.can-16-2171] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 02/10/2017] [Accepted: 04/10/2017] [Indexed: 01/08/2023]
Abstract
Oncogenic signaling by NOTCH is elevated in brain tumor-initiating cells (BTIC) in malignant glioma, but the mechanism of its activation is unknown. Here we provide evidence that tenascin-C (TNC), an extracellular matrix protein prominent in malignant glioma, increases NOTCH activity in BTIC to promote their growth. We demonstrate the proximal localization of TNC and BTIC in human glioblastoma specimens and in orthotopic murine xenografts of human BTIC implanted intracranially. In tissue culture, TNC was superior amongst several extracellular matrix proteins in enhancing the sphere-forming capacity of glioma patient-derived BTIC. Exogenously applied or autocrine TNC increased BTIC growth through an α2β1 integrin-mediated mechanism that elevated NOTCH ligand Jagged1 (JAG1). Microarray analyses and confirmatory PCR and Western analyses in BTIC determined that NOTCH signaling components including JAG1, ADAMTS15, and NICD1/2 were elevated in BITC after TNC exposure. Inhibition of γ-secretase and metalloproteinase proteolysis in the NOTCH pathway, or silencing of α2β1 integrin or JAG1, reduced the proliferative effect of TNC on BTIC. Collectively, our findings identified TNC as a pivotal initiator of elevated NOTCH signaling in BTIC and define the establishment of a TN-α2β1-JAG1-NOTCH signaling axis as a candidate therapeutic target in glioma patients. Cancer Res; 77(12); 3231-43. ©2017 AACR.
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Affiliation(s)
- Susobhan Sarkar
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Reza Mirzaei
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.,Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
| | - Franz J Zemp
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Wu Wei
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Donna L Senger
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - Stephen M Robbins
- Department of Oncology, University of Calgary, Calgary, Alberta, Canada.,Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. .,Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
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25
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Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth. Cell Death Dis 2017; 8:e2713. [PMID: 28358371 PMCID: PMC5386523 DOI: 10.1038/cddis.2017.117] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 01/31/2017] [Accepted: 02/22/2017] [Indexed: 12/15/2022]
Abstract
Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.
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26
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He Z, Wang Y, Huang G, Wang Q, Zhao D, Chen L. The lncRNA UCA1 interacts with miR-182 to modulate glioma proliferation and migration by targeting iASPP. Arch Biochem Biophys 2017; 623-624:1-8. [PMID: 28137422 DOI: 10.1016/j.abb.2017.01.013] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/17/2017] [Accepted: 01/25/2017] [Indexed: 01/03/2023]
Abstract
Long non-coding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) has been reported to be involved in the development and progression of many types of tumors including breast cancer, gastric cancer, and bladder cancer. However, the exact effects and molecular mechanisms of UCA1 in glioma progression remain unclear up to now. In this study, we firstly found that UCA1 was upregulated in glioma tumor samples and negatively correlated with survival time. Then, we investigated the role of UCA1 in human glioma cell lines. Our results showed that upregulation of lncRNA-UCA1 in glioma tissues and cell lines could promote glioma cell proliferation and migration through interaction with miR-182, and knockdown of UCA1 inhibited the proliferation and migration of human glioma cell. In addition, miR-182 dependent inhibitor of apoptosis-stimulating protein of p53 (iASPP) was required in the regulation of UCA1 induced glioma cell proliferation. Taken together, UCA1 might promote proliferation and migration of glioma, to regulate the tumor growth and metastasis via miR-182 dependent iASPP regulation. Therefore, lncRNA-UCA1 could be regarded as a therapeutic target in human glioma.
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Affiliation(s)
- Zongze He
- Department of Neurosurgery, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China
| | - Yujue Wang
- Department of Neurosurgery, Kai Luan General Hospital, Tangshan City, Hebei Province 063000, China
| | - Guangfu Huang
- Department of Neurosurgery, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China
| | - Qi Wang
- Department of Neurosurgery, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China
| | - Dongdong Zhao
- Department of Neurosurgery, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China.
| | - Longyi Chen
- Department of Neurosurgery, Hospital of University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, Sichuan Province 610072, China.
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27
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28
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Jungk C, Mock A, Exner J, Geisenberger C, Warta R, Capper D, Abdollahi A, Friauf S, Lahrmann B, Grabe N, Beckhove P, von Deimling A, Unterberg A, Herold-Mende C. Spatial transcriptome analysis reveals Notch pathway-associated prognostic markers in IDH1 wild-type glioblastoma involving the subventricular zone. BMC Med 2016; 14:170. [PMID: 27782828 PMCID: PMC5080721 DOI: 10.1186/s12916-016-0710-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 10/01/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The spatial relationship of glioblastoma (GBM) to the subventricular zone (SVZ) is associated with inferior patient survival. However, the underlying molecular phenotype is largely unknown. We interrogated an SVZ-dependent transcriptome and potential location-specific prognostic markers. METHODS mRNA microarray data of a discovery set (n = 36 GBMs) were analyzed for SVZ-dependent gene expression and process networks using the MetaCore™ workflow. Differential gene expression was confirmed by qPCR in a validation set of 142 IDH1 wild-type GBMs that was also used for survival analysis. RESULTS Microarray analysis revealed a transcriptome distinctive of SVZ+ GBM that was enriched for genes associated with Notch signaling. No overlap was found to The Cancer Genome Atlas's molecular subtypes. Independent validation of SVZ-dependent expression confirmed four genes with simultaneous prognostic impact: overexpression of HES4 (p = 0.034; HR 1.55) and DLL3 (p = 0.017; HR 1.61) predicted inferior, and overexpression of NTRK2 (p = 0.049; HR 0.66) and PIR (p = 0.025; HR 0.62) superior overall survival (OS). Additionally, overexpression of DLL3 was predictive of shorter progression-free survival (PFS) (p = 0.043; HR 1.64). Multivariate analysis revealed overexpression of HES4 to be independently associated with inferior OS (p = 0.033; HR 2.03), and overexpression of DLL3 with inferior PFS (p = 0.046; HR 1.65). CONCLUSIONS We identified four genes with SVZ-dependent expression and prognostic significance, among those HES4 and DLL3 as part of Notch signaling, suggesting further evaluation of location-tailored targeted therapies.
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Affiliation(s)
- Christine Jungk
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
| | - Andreas Mock
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Janina Exner
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Christoph Geisenberger
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Rolf Warta
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - David Capper
- Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Amir Abdollahi
- Department of Radiation Oncology, Heidelberg University Hospital; Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sara Friauf
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Bernd Lahrmann
- Hamamatsu Tissue and Imaging Analysis Center, University of Heidelberg, Heidelberg, Germany
| | - Niels Grabe
- Hamamatsu Tissue and Imaging Analysis Center, University of Heidelberg, Heidelberg, Germany
| | - Philipp Beckhove
- Division of Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Regensburg Center for Interventional Immunology (RCI), University Hospital, Regensburg, Germany
| | - Andreas von Deimling
- Department of Neuropathology, Heidelberg University Hospital; CCU Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas Unterberg
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Christel Herold-Mende
- Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
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29
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Shea A, Harish V, Afzal Z, Chijioke J, Kedir H, Dusmatova S, Roy A, Ramalinga M, Harris B, Blancato J, Verma M, Kumar D. MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics. Cancer Med 2016; 5:1917-46. [PMID: 27282910 PMCID: PMC4971921 DOI: 10.1002/cam4.775] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 04/05/2016] [Accepted: 04/14/2016] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA-based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA-based therapies could provide a critical step forward in cancer treatment.
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Affiliation(s)
- Amanda Shea
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | | | - Zainab Afzal
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Juliet Chijioke
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Habib Kedir
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Shahnoza Dusmatova
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Arpita Roy
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Malathi Ramalinga
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
| | - Brent Harris
- Department of Neurology and PathologyGeorgetown UniversityWashingtonDistrict of Columbia20057
| | - Jan Blancato
- Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonDistrict of Columbia20057
| | - Mukesh Verma
- Division of Cancer Control and Population SciencesNational Cancer Institute (NCI)National Institutes of Health (NIH)RockvilleMaryland20850
| | - Deepak Kumar
- Division of Science and MathematicsCancer Research LaboratoryUniversity of the District of ColumbiaWashingtonDistrict of Columbia20008
- Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonDistrict of Columbia20057
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30
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Sakakini N, Turchi L, Bergon A, Holota H, Rekima S, Lopez F, Paquis P, Almairac F, Fontaine D, Baeza-Kallee N, Van Obberghen-Schilling E, Junier MP, Chneiweiss H, Figarella-Branger D, Burel-Vandenbos F, Imbert J, Virolle T. A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells. J Biol Chem 2016; 291:10684-99. [PMID: 27002148 DOI: 10.1074/jbc.m116.720698] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Indexed: 01/06/2023] Open
Abstract
Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.
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Affiliation(s)
- Nathalie Sakakini
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Laurent Turchi
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France
| | - Aurélie Bergon
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Hélène Holota
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Samah Rekima
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France
| | - Fabrice Lopez
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France
| | - Philipe Paquis
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Fabien Almairac
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Denys Fontaine
- the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Nathalie Baeza-Kallee
- Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France
| | | | - Marie-Pierre Junier
- CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France
| | - Hervé Chneiweiss
- CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France
| | - Dominique Figarella-Branger
- Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France, the Departement de Pathology, CHU de la Timone, 13385 Marseille Cedex 5, France
| | - Fanny Burel-Vandenbos
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice 06107, France
| | - Jean Imbert
- INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France,
| | - Thierry Virolle
- From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France,
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31
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Garg M. Emerging role of microRNAs in cancer stem cells: Implications in cancer therapy. World J Stem Cells 2015; 7:1078-1089. [PMID: 26435768 PMCID: PMC4591786 DOI: 10.4252/wjsc.v7.i8.1078] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 06/27/2015] [Accepted: 08/20/2015] [Indexed: 02/06/2023] Open
Abstract
A small subset of cancer cells that act as tumor initiating cells or cancer stem cells (CSCs) maintain self-renewal and growth promoting capabilities of cancer and are responsible for drug/treatment resistance, tumor recurrence and metastasis. Due to their potential clinical importance, many researchers have put their efforts over decades to unravel the molecular mechanisms that regulate CSCs functions. MicroRNAs (miRNAs) which are 21-23 nucleotide long, endogenous non-coding RNAs, regulate gene expression through gene silencing at post-transcriptional level by binding to the 3'-untranslated regions or the open reading frames of target genes, thereby result in target mRNA degradation or its translational repression and serve important role in several cellular, physiological and developmental processes. Aberrant miRNAs expression and their implication in CSCs regulation by controlling asymmetric cell division, drug/treatment resistance and metastasis make miRNAs a tool of great therapeutic potential against cancer. Recent advancements on the biological complexities of CSCs, modulation in CSCs properties by miRNA network and development of miRNA based treatment strategies specifically targeting the CSCs as an attractive therapeutic targets for clinical application are being critically analysed.
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Affiliation(s)
- Minal Garg
- Minal Garg, Department of Biochemistry, University of Lucknow, Lucknow 226007, India
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32
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Sun JJ, Wang ZY, Li LS, Yu HY, Xu YS, Wu HB, Luo Y, Liu B, Zheng M, Mao JL, Lou XH. Prevention against diffuse spinal cord astrocytoma: can the Notch pathway be a novel treatment target? Neural Regen Res 2015; 10:244-51. [PMID: 25883623 PMCID: PMC4392672 DOI: 10.4103/1673-5374.152378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/04/2014] [Indexed: 11/25/2022] Open
Abstract
This study was designed to investigate whether the Notch pathway is involved in the development of diffuse spinal cord astrocytomas. BALB/c nude mice received injections of CD133+ and CD133− cell suspensions prepared using human recurrent diffuse spinal cord astrocytoma tissue through administration into the right parietal lobe. After 7–11 weeks, magnetic resonance imaging was performed weekly. Xenografts were observed on the surfaces of the brains of mice receiving the CD133+ cell suspension, and Notch-immunopositive expression was observed in the xenografts. By contrast, no xenografts appeared in the identical position on the surfaces of the brains of mice receiving the CD133− cell suspension, and Notch-immunopositive expression was hardly detected either. Hematoxylin-eosin staining and immunohistochemical staining revealed xenografts on the convex surfaces of the brains of mice that underwent CD133+ astrocytoma transplantation. Some sporadic astroglioma cells showed pseudopodium-like structures, which extended into the cerebral white matter. However, it should be emphasized that the subcortex xenograft with Notch-immunopositive expression was found in the fourth mouse received injection of CD133− astrocytoma cells. However, these findings suggest that the Notch pathway plays an important role in the formation of astrocytomas, and can be considered a novel treatment target for diffuse spinal cord astrocytoma.
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Affiliation(s)
- Jian-Jun Sun
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Zhen-Yu Wang
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Ling-Song Li
- China Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing, China
| | - Hai-Yan Yu
- Clinical Stem Cell Center, Peking University Third Hospital, Peking University, Beijing, China
| | - Yong-Sheng Xu
- Clinical Stem Cell Center, Peking University Third Hospital, Peking University, Beijing, China ; Clinical Laboratory of Tissue & Cell Research Center, Department of Biotech Treatment, Logistics College of Chinese People's Armed Police Force, Tianjin, China
| | - Hai-Bo Wu
- Department of Neuroradiology, Peking University Third Hospital, Peking University, Beijing, China
| | - Yi Luo
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Bin Liu
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Mei Zheng
- Department of Neurology, Peking University Third Hospital, Peking University, Beijing, China
| | - Jin-Long Mao
- Neurosurgical Department, Peking Union Medical College Hospital, Beijing, China
| | - Xiao-Hui Lou
- Department of Neurosurgery, Rui'an People's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, China
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Rostama B, Peterson SM, Vary CPH, Liaw L. Notch signal integration in the vasculature during remodeling. Vascul Pharmacol 2014; 63:97-104. [PMID: 25464152 PMCID: PMC4304902 DOI: 10.1016/j.vph.2014.10.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 10/06/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023]
Abstract
Notch signaling plays many important roles in homeostasis and remodeling in the vessel wall, and serves a critical role in the communication between endothelial cells and smooth muscle cells. Within blood vessels, Notch signaling integrates with multiple pathways by mechanisms including direct protein–protein interaction, cooperative or synergistic regulation of signal cascades, and co-regulation of transcriptional targets. After establishment of the mature blood vessel, the spectrum and intensity of Notch signaling change during phases of active remodeling or disease progression. These changes can be mediated by regulation via microRNAs and protein stability or signaling, and corresponding changes in complementary signaling pathways. Notch also affects endothelial cells on a system level by regulating key metabolic components. This review will outline the most recent findings of Notch activity in blood vessels, with a focus on how Notch signals integrate with other molecular signaling pathways controlling vascular phenotype.
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Affiliation(s)
- Bahman Rostama
- Center for Molecular Medicine, Maine Medical Center Research Institute, USA
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Matchett KB, Lappin TR. Concise Reviews: Cancer Stem Cells: From Concept to Cure. Stem Cells 2014; 32:2563-70. [DOI: 10.1002/stem.1798] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 07/14/2014] [Indexed: 12/17/2022]
Affiliation(s)
- K. B. Matchett
- Centre for Cancer Research and Cell Biology; Queen's University Belfast; Belfast United Kingdom
| | - T. R. Lappin
- Centre for Cancer Research and Cell Biology; Queen's University Belfast; Belfast United Kingdom
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Abstract
PURPOSE OF REVIEW Recent advances in the role of cancer stem cells (CSCs) in glioblastoma will be reviewed. RECENT FINDINGS In the decade since the description of brain tumor CSCs, the potential significance of these cells in tumor growth, therapeutic resistance, and spread has become evident. Most recently, the interplay between CSCs, tumor genetics, and the microenvironment has offered potential nodes of fragility under therapeutic development. The CSC phenotype is informed by specific receptor signaling, and study of the regulation of stem cell genes by transcription factors and microRNAs has identified a number of new targets amenable to treatment. Like normal stem cells, CSCs display specific epigenetic landscapes and metabolic profiles. SUMMARY Brain cancers activate core stem cell regulatory pathways to empower self-renewal, maintenance of an organ system (albeit an aberrant one), and survival under stress that collectively permits tumor growth, therapeutic resistance, invasion, and angiogenesis. These properties have implicated CSCs as contributors in GBM progression and recurrence, spurring a search for anti-CSC therapies that do not disrupt normal stem cell maintenance. The last year has witnessed a rapid evolution in the understanding of CSC biology to inform preclinical targeting.
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Abstract
PURPOSE OF REVIEW Recent advances in the role of cancer stem cells (CSCs) in glioblastoma will be reviewed. RECENT FINDINGS In the decade since the description of brain tumor CSCs, the potential significance of these cells in tumor growth, therapeutic resistance, and spread has become evident. Most recently, the interplay between CSCs, tumor genetics, and the microenvironment has offered potential nodes of fragility under therapeutic development. The CSC phenotype is informed by specific receptor signaling, and study of the regulation of stem cell genes by transcription factors and microRNAs has identified a number of new targets amenable to treatment. Like normal stem cells, CSCs display specific epigenetic landscapes and metabolic profiles. SUMMARY Brain cancers activate core stem cell regulatory pathways to empower self-renewal, maintenance of an organ system (albeit an aberrant one), and survival under stress that collectively permits tumor growth, therapeutic resistance, invasion, and angiogenesis. These properties have implicated CSCs as contributors in GBM progression and recurrence, spurring a search for anti-CSC therapies that do not disrupt normal stem cell maintenance. The last year has witnessed a rapid evolution in the understanding of CSC biology to inform preclinical targeting.
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Song Y, Wang P, Zhao W, Yao Y, Liu X, Ma J, Xue Y, Liu Y. MiR-18a regulates the proliferation, migration and invasion of human glioblastoma cell by targeting neogenin. Exp Cell Res 2014; 324:54-64. [PMID: 24657544 DOI: 10.1016/j.yexcr.2014.03.009] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 03/05/2014] [Accepted: 03/10/2014] [Indexed: 01/22/2023]
Abstract
MiR-17-92 cluster has recently been reported as an oncogene in some tumors. However, the association of miR-18a, an important member of this cluster, with glioblastoma remains unknown. Therefore, this study aims to investigate the expression of miR-18a in glioblastoma and its role in biological behavior of U87 and U251 human glioblastoma cell lines. Quantitative RT-PCR results showed that miR-18a was highly expressed in glioblastoma tissues and U87 and U251 cell lines compared with that in human brain tissues and primary normal human astrocytes, and the expression levels were increased along with the rising pathological grades of glioblastoma. Neogenin was identified as the target gene of miR-18a by dual-luciferase reporter assays. RT-PCR and western blot results showed that its expression levels were decreased along with the rising pathological grades of glioblastoma. Inhibition of miR-18a expression was established by transfecting exogenous miR-18a inhibitor into U87 and U251 cells, and its effects on the biological behavior of glioblastoma cells were studied using CCK-8 assay, transwell assay and flow cytometry. Inhibition of miR-18a expression in U87 and U251 cells significantly up-regulated neogenin, and dramatically suppressed the abilities of cell proliferation, migration and invasion, induced cell cycle arrest and promoted cellular apoptosis. Collectively, these results suggest that miR-18a may regulate biological behavior of human glioblastoma cells by targeting neogenin, and miR-18a can serve as a potential target in the treatment of glioblastoma.
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Affiliation(s)
- Yichen Song
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People׳s Republic of China.
| | - Ping Wang
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People׳s Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People׳s Republic of China.
| | - Wei Zhao
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People׳s Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People׳s Republic of China.
| | - Yilong Yao
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People׳s Republic of China.
| | - Xiaobai Liu
- The 96th Class, 7-year Program, China Medical University, Shenyang, Liaoning Province 110001, People׳s Republic of China.
| | - Jun Ma
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People׳s Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People׳s Republic of China.
| | - Yixue Xue
- Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People׳s Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People׳s Republic of China.
| | - Yunhui Liu
- Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People׳s Republic of China.
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Brain tumor stem cells: Molecular characteristics and their impact on therapy. Mol Aspects Med 2013; 39:82-101. [PMID: 23831316 DOI: 10.1016/j.mam.2013.06.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 06/14/2013] [Indexed: 01/05/2023]
Abstract
Glioblastoma (GBM) is the most prevalent primary brain tumor and ranks among the most lethal of human cancers with conventional therapy offering only palliation. Great strides have been made in understanding brain cancer genetics and modeling these tumors with new targeted therapies being tested, but these advances have not translated into substantially improved patient outcomes. Multiple chemotherapeutic agents, including temozolomide, the first-line treatment for glioblastoma, have been developed to kill cancer cells. However, the response to temozolomide in GBM is modest. Radiation is also moderately effective but this approach is plagued by limitations due to collateral radiation damage to healthy brain tissue and development of radioresistance. Therapeutic resistance is attributed at least in part to a cell population within the tumor that possesses stem-like characteristics and tumor propagating capabilities, referred to as cancer stem cells. Within GBM, the intratumoral heterogeneity is derived from a combination of regional genetic variance and a cellular hierarchy often regulated by distinct cancer stem cell niches, most notably perivascular and hypoxic regions. With the recent emergence as a key player in tumor biology, cancer stem cells have symbiotic relationships with the tumor microenvironment, oncogenic signaling pathways, and epigenetic modifications. The origins of cancer stem cells and their contributions to brain tumor growth and therapeutic resistance are under active investigation with novel anti-cancer stem cell therapies offering potential new hope for this lethal disease.
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