1
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Liu Y, Dong X, Wu B, Cheng Z, Zhang J, Wang J. Promising Pharmacological Interventions for Posterior Capsule Opacification: A Review. GLOBAL CHALLENGES (HOBOKEN, NJ) 2024; 8:2400181. [PMID: 39679290 PMCID: PMC11637782 DOI: 10.1002/gch2.202400181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/18/2024] [Indexed: 12/17/2024]
Abstract
Phacoemulsification combined with intraocular lens implantation is the primary treatment for cataract. Although this treatment strategy benefits patients with cataracts, posterior capsule opacification (PCO) remains a common complication that impairs vision and affects treatment outcomes. The pathogenesis of PCO is associated with the proliferation, migration, and fibrogenesis activity of residual lens epithelial cells, with epithelial-mesenchymal transition (EMT) serving as a key mechanism underlying the condition. Transforming growth factor-beta 2 (TGF-β2) is a major promotor of EMT, thereby driving PCO development. Most studies have shown that drugs and miRNAs mitigate EMT by inhibiting, clearing, or eliminating LECs. In addition, targeting EMT-related signaling pathways in TGF-β2-stimulated LECs has garnered attention as a research focus. This review highlights potential treatments for PCO and details the mechanisms by which drugs and miRNAs counter EMT.
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Affiliation(s)
- Yuxuan Liu
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
| | - Xiaoming Dong
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
| | - Bin Wu
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
| | - Zhigang Cheng
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Chaoyang Aier Eye HospitalChaoyangLiaoning Province122000China
| | - Jinsong Zhang
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
| | - Jing Wang
- AIER Cataract InstituteShenyangLiaoning Province110000China
- Shenyang Aier Ophthalmology Institute of Precision MedicineShenyangLiaoning Province110000China
- Liaoning Aier Eye HospitalShenyangLiaoning Province110000China
- Shenyang Aier Excellent Eye HospitalShenyangLiaoning Province110000China
- Aier Academy of OphthalmologyCentral South UniversityNo. 188, Furong South Road, Tianxin DistrictChangshaHunan410004P. R. China
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2
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Jang JJ, Kang D, Lee YS, Lee YS. The Versatile Roles of nc886, a Fascinating and Peculiar Regulatory Non-Coding RNA, in Cancer. Int J Mol Sci 2024; 25:10825. [PMID: 39409154 PMCID: PMC11476670 DOI: 10.3390/ijms251910825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
This review concerns nc886, a 101-nucleotide non-coding RNA (ncRNA). Because nc886 is transcribed by RNA polymerase III (Pol III) and contains a CpG island in its promoter region, its expression is regulated by several transcription factors and the DNA methylation status. These features drive nc886 expression in two opposing directions during tumorigenesis. The known function of nc886 is to bind to and modulate the activity of target proteins such as PKR, Dicer, and OAS1. By being differentially expressed during tumorigenesis and interacting with these proteins, nc886 plays a role in tumor surveillance, promotes or suppresses tumorigenesis, and influences the efficacy of cancer therapy. The multiple roles of nc886 have been well-documented in the literature. In this review, we have summarized this literature and critically discussed the roles and mechanisms of action of nc886 in various cancers.
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Affiliation(s)
- Jiyoung Joan Jang
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
- Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea;
| | - Dongmin Kang
- Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul 03760, Republic of Korea;
| | - Yeon-Su Lee
- Division of Rare Cancer, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea;
| | - Yong Sun Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of Korea;
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3
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Zhao Y, Wang G, Wei Z, Li D, Morshedi M. RETRACTED ARTICLE: Wnt, notch signaling and exercise: what are their functions? Hum Cell 2024; 37:1612. [PMID: 38386243 DOI: 10.1007/s13577-024-01036-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 01/18/2024] [Indexed: 02/23/2024]
Affiliation(s)
- Yijie Zhao
- Ministry of Public Sports, Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Guangjun Wang
- Ministry of Public Sports, Hebei North University, Zhangjiakou, 075000, Hebei, China.
| | - Zhifeng Wei
- The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, Hebei, China
| | - Duo Li
- The First Affiliated Hospital of Hebei North University, Zhangjiakou, 075000, Hebei, China
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4
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Li Y, Ma A, Wang Y, Guo Q, Wang C, Fu H, Liu B, Ma Q. Enhancer-driven gene regulatory networks inference from single-cell RNA-seq and ATAC-seq data. Brief Bioinform 2024; 25:bbae369. [PMID: 39082647 PMCID: PMC11289686 DOI: 10.1093/bib/bbae369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/19/2024] [Accepted: 07/15/2024] [Indexed: 08/03/2024] Open
Abstract
Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks (eGRNs) is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner forest problem model, a hybrid biclustering pipeline, and submodular optimization to infer eGRNs from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF-enhancer linkage prediction, and enhancer-gene relation discovery. Application of STREAM to an Alzheimer's disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer-gene relations associated with pseudotime, as well as key TF-enhancer-gene relations and TF cooperation underlying tumor cells.
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Affiliation(s)
- Yang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Anjun Ma
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
| | - Yizhong Wang
- School of Mathematics, Shandong University, Jinan, Shandong 250100, China
| | - Qi Guo
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Cankun Wang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Hongjun Fu
- Department of Neuroscience, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Bingqiang Liu
- School of Mathematics, Shandong University, Jinan, Shandong 250100, China
| | - Qin Ma
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, United States
- Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
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5
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Ku SY, Wang Y, Garcia MM, Yamada Y, Mizuno K, Long MD, Rosario S, Chinnam M, Al Assaad M, Puca L, Kim MJ, Bakht MK, Venkadakrishnan VB, Robinson BD, Acosta AM, Wadosky KM, Mosquera JM, Goodrich DW, Beltran H. Notch signaling suppresses neuroendocrine differentiation and alters the immune microenvironment in advanced prostate cancer. J Clin Invest 2024; 134:e175217. [PMID: 39024561 PMCID: PMC11364388 DOI: 10.1172/jci175217] [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: 08/28/2023] [Accepted: 07/10/2024] [Indexed: 07/20/2024] Open
Abstract
Notch signaling can have either an oncogenic or tumor-suppressive function in cancer depending on the cancer type and cellular context. While Notch can be oncogenic in early prostate cancer, we identified significant downregulation of the Notch pathway during prostate cancer progression from adenocarcinoma to neuroendocrine (NE) prostate cancer, where it functions as a tumor suppressor. Activation of Notch in NE and Rb1/Trp53-deficient prostate cancer models led to phenotypic conversion toward a more indolent, non-NE state with glandular features and expression of luminal lineage markers. This was accompanied by upregulation of MHC and type I IFN and immune cell infiltration. Overall, these data support Notch signaling as a suppressor of NE differentiation in advanced prostate cancer and provide insights into how Notch signaling influences lineage plasticity and the tumor microenvironment (TME).
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Affiliation(s)
- Sheng-Yu Ku
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | - Maria Mica Garcia
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Yasutaka Yamada
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kei Mizuno
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Mark D. Long
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Spencer Rosario
- Department of Pharmacology and Therapeutics and
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | | | | | - Loredana Puca
- Department of Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Min Jin Kim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Martin K. Bakht
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | | | | | - Andrés M. Acosta
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | | | | | - David W. Goodrich
- Department of Pharmacology and Therapeutics and
- Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Himisha Beltran
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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6
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Agarwal S, Parija M, Naik S, Kumari P, Mishra SK, Adhya AK, Kashaw SK, Dixit A. Dysregulated gene subnetworks in breast invasive carcinoma reveal novel tumor suppressor genes. Sci Rep 2024; 14:15691. [PMID: 38977697 PMCID: PMC11231308 DOI: 10.1038/s41598-024-59953-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 04/17/2024] [Indexed: 07/10/2024] Open
Abstract
Breast invasive carcinoma (BRCA) is the most malignant and leading cause of death in women. Global efforts are ongoing for improvement in early detection, prevention, and treatment. In this milieu, a comprehensive analysis of RNA-sequencing data of 1097 BRCA samples and 114 normal adjacent tissues is done to identify dysregulated genes in major molecular classes of BRCA in various clinical stages. Significantly enriched pathways in distinct molecular classes of BRCA have been identified. Pathways such as interferon signaling, tryptophan degradation, granulocyte adhesion & diapedesis, and catecholamine biosynthesis were found to be significantly enriched in Estrogen/Progesterone Receptor positive/Human Epidermal Growth Factor Receptor 2 negative, pathways such as RAR activation, adipogenesis, the role of JAK1/2 in interferon signaling, TGF-β and STAT3 signaling intricated in Estrogen/Progesterone Receptor negative/Human Epidermal Growth Factor Receptor 2 positive and pathways as IL-1/IL-8, TNFR1/TNFR2, TWEAK, and relaxin signaling were found in triple-negative breast cancer. The dysregulated genes were clustered based on their mutation frequency which revealed nine mutated clusters, some of which were well characterized in cancer while others were less characterized. Each cluster was analyzed in detail which led to the identification of NLGN3, MAML2, TTN, SYNE1, ANK2 as candidate genes in BRCA. They are central hubs in the protein-protein-interaction network, indicating their important regulatory roles. Experimentally, the Real-Time Quantitative Reverse Transcription PCR and western blot confirmed our computational predictions in cell lines. Further, immunohistochemistry corroborated the results in ~ 100 tissue samples. We could experimentally show that the NLGN3 & ANK2 have tumor-suppressor roles in BRCA as shown by cell viability assay, transwell migration, colony forming and wound healing assay. The cell viability and migration was found to be significantly reduced in MCF7 and MDA-MB-231 cell lines in which the selected genes were over-expressed as compared to control cell lines. The wound healing assay also demonstrated a significant decrease in wound closure at 12 h and 24 h time intervals in MCF7 & MDA-MB-231 cells. These findings established the tumor suppressor roles of NLGN3 & ANK2 in BRCA. This will have important ramifications for the therapeutics discovery against BRCA.
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Affiliation(s)
- Shivangi Agarwal
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, 470003, India
| | - Monalisa Parija
- Institute of Life Sciences, Nalco Square, Bhubanesawar, 751023, Odisha, India
| | - Sanoj Naik
- Institute of Life Sciences, Nalco Square, Bhubanesawar, 751023, Odisha, India
| | - Pratima Kumari
- Institute of Life Sciences, Nalco Square, Bhubanesawar, 751023, Odisha, India
| | - Sandip K Mishra
- Institute of Life Sciences, Nalco Square, Bhubanesawar, 751023, Odisha, India
| | - Amit K Adhya
- All India Institute of Medical Sciences, Bhubanesawar, 751019, India
| | - Sushil K Kashaw
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, 470003, India
| | - Anshuman Dixit
- Institute of Life Sciences, Nalco Square, Bhubanesawar, 751023, Odisha, India.
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7
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Diaz JEL, Barcessat V, Bahamon C, Hecht C, Das TK, Cagan RL. Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer. Dis Model Mech 2024; 17:dmm050191. [PMID: 38721669 PMCID: PMC11247506 DOI: 10.1242/dmm.050191] [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: 03/14/2023] [Accepted: 04/30/2024] [Indexed: 07/04/2024] Open
Abstract
Accounting for 10-20% of breast cancer cases, triple-negative breast cancer (TNBC) is associated with a disproportionate number of breast cancer deaths. One challenge in studying TNBC is its genomic profile: with the exception of TP53 loss, most breast cancer tumors are characterized by a high number of copy number alterations (CNAs), making modeling the disease in whole animals challenging. We computationally analyzed 186 CNA regions previously identified in breast cancer tumors to rank genes within each region by likelihood of acting as a tumor driver. We then used a Drosophila p53-Myc TNBC model to identify 48 genes as functional drivers. To demonstrate the utility of this functional database, we established six 3-hit models; altering candidate genes led to increased aspects of transformation as well as resistance to the chemotherapeutic drug fluorouracil. Our work provides a functional database of CNA-associated TNBC drivers, and a template for an integrated computational/whole-animal approach to identify functional drivers of transformation and drug resistance within CNAs in other tumor types.
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Affiliation(s)
- Jennifer E L Diaz
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Internal Medicine, UCLA David Geffen School of Medicine, CA 90095, USA
| | - Vanessa Barcessat
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Christian Bahamon
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Chana Hecht
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tirtha K Das
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ross L Cagan
- Department of Cell, Development, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- School of Cancer Sciences and Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow G61 1BD, UK
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8
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Zhu R, Shirley CM, Chu SH, Li L, Nguyen BH, Seo J, Wu M, Seale T, Duffield AS, Staudt LM, Levis M, Hu Y, Small D. Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition. Leukemia 2024; 38:1581-1591. [PMID: 38811818 DOI: 10.1038/s41375-024-02292-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 05/31/2024]
Abstract
Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations.
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MESH Headings
- Humans
- fms-Like Tyrosine Kinase 3/genetics
- fms-Like Tyrosine Kinase 3/antagonists & inhibitors
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Animals
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Mice
- Receptor, Notch4/genetics
- Xenograft Model Antitumor Assays
- Mutation
- Cell Line, Tumor
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Signal Transduction/drug effects
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Affiliation(s)
- Ruiqi Zhu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Courtney M Shirley
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - S Haihua Chu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Beam Therapeutics, Cambridge, MA, USA
| | - Li Li
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Bao H Nguyen
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jaesung Seo
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Min Wu
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tessa Seale
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Amy S Duffield
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Louis M Staudt
- Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mark Levis
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yu Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Donald Small
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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9
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Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther 2024; 9:128. [PMID: 38797752 PMCID: PMC11128457 DOI: 10.1038/s41392-024-01828-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/31/2024] [Accepted: 04/15/2024] [Indexed: 05/29/2024] Open
Abstract
Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
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Affiliation(s)
- Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Shuwen Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Jinzhi Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yaqi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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10
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Schiroli G, Kartha V, Duarte FM, Kristiansen TA, Mayerhofer C, Shrestha R, Earl A, Hu Y, Tay T, Rhee C, Buenrostro JD, Scadden DT. Cell of origin epigenetic priming determines susceptibility to Tet2 mutation. Nat Commun 2024; 15:4325. [PMID: 38773071 PMCID: PMC11109152 DOI: 10.1038/s41467-024-48508-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 04/30/2024] [Indexed: 05/23/2024] Open
Abstract
Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
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Affiliation(s)
- Giulia Schiroli
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Vinay Kartha
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Fabiana M Duarte
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Trine A Kristiansen
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Christina Mayerhofer
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Rojesh Shrestha
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Andrew Earl
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Yan Hu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Tristan Tay
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Catherine Rhee
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Jason D Buenrostro
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
- Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
| | - David T Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
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11
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Bhartiya D, Raouf S, Pansare K, Tripathi A, Tripathi A. Initiation of Cancer: The Journey From Mutations in Somatic Cells to Epigenetic Changes in Tissue-resident VSELs. Stem Cell Rev Rep 2024; 20:857-880. [PMID: 38457060 DOI: 10.1007/s12015-024-10694-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2024] [Indexed: 03/09/2024]
Abstract
Multiple theories exist to explain cancer initiation, although a consensus on this is crucial for developing effective therapies. 'Somatic mutation theory' suggests that mutations in somatic cells during DNA repair initiates cancer but this concept has several attached paradoxes. Research efforts to identify quiescent cancer stem cells (CSCs) that survive therapy and result in metastasis and recurrence have remained futile. In solid cancers, CSCs are suggested to appear during epithelial-mesenchymal transition by the dedifferentiation and reprogramming of epithelial cells. Pluripotent and quiescent very small embryonic-like stem cells (VSELs) exist in multiple tissues but remain elusive owing to their small size and scarce nature. VSELs are developmentally connected to primordial germ cells, undergo rare, asymmetrical cell divisions and are responsible for the regular turnover of cells to maintain tissue homeostasis throughout life. VSELs are directly vulnerable to extrinsic endocrine insults because they express gonadal and gonadotropin hormone receptors. VSELs undergo epigenetic changes due to endocrine insults and transform into CSCs. CSCs exhibit genomic instability and develop mutations due to errors during DNA replication while undergoing excessive proliferation and clonal expansion to form spheroids. Thus tissue-resident VSELs offer a connection between extrinsic insults and variations in cancer incidence reported in various body tissues. To conclude, cancer is indeed a stem cell disease with mutations occurring as a consequence. In addition to immunotherapy, targeting mutations, and Lgr5 + organoids for developing new therapeutics, targeting CSCs (epigenetically altered VSELs) by improving their niche and epigenetic status could serve as a promising strategy to treat cancer.
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Affiliation(s)
- Deepa Bhartiya
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, 400013, Mumbai, India.
| | | | - Kshama Pansare
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, 400013, Mumbai, India
| | - Anish Tripathi
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, 400013, Mumbai, India
| | - Ashish Tripathi
- Epigeneres Biotech Pvt Ltd, Todi Mill Compound, Senapati Bapat Marg, Lower Parel, 400013, Mumbai, India
- 23Ikigai Pte Ltd, 30 Cecil Street, #21-08 Prudentsial Tower, Singapore, 049712, Singapore
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12
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Qin L, Qiu M, Lin Q, Jiang B, Zhan S, Wei X, Wei J, Liu Y, Wen Q, Chen P, Jiang Y, Zhou Z, Liang X, Cao J, Gong Y, Wei Y, Wei X, Yu H. Association between novel genetic variants of Notch signaling pathway genes and survival of hepatitis B virus-related hepatocellular carcinoma. Cancer Med 2024; 13:e7040. [PMID: 38562021 PMCID: PMC10985410 DOI: 10.1002/cam4.7040] [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: 09/16/2023] [Revised: 10/22/2023] [Accepted: 02/08/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Although the Notch pathway plays an important role in formation and progression of hepatocellular carcinoma (HCC), few studies have reported the associations between functional genetic variants and the survival of hepatitis B virus (HBV)-related HCC. METHODS In the present study, we performed multivariable Cox proportional hazard regression analysis to evaluate associations between 36,101 SNPs in 264 Notch pathway-related genes and overall survival (OS) of 866 patients with HBV-related HCC. RESULTS It was found that three independent SNPs (NEURL1B rs4868192, CNTN1 rs444927 and FCER2 rs1990975) were significantly associated with the HBV-related HCC OS. The number of protective genotypes (NPGs) were significantly associated with better survival in a dose-response manner (ptrend <0.001). Compared with the model with sole clinical factors, the addition of protective genotypes to the predict models significantly increased the AUC, i.e., from 72.72% to 75.13% (p = 0.002) and from 72.04% to 74.76 (p = 0.004) for 3-year and 5-year OS, respectively. The expression quantitative trait loci (eQTL) analysis further revealed that the rs4868192 C allele was associated with lower mRNA expression levels of NEURL1B in the whole blood (p = 1.71 × 10-3), while the rs1990975 T allele was correlated with higher mRNA expression levels of FCER2 in the whole blood and normal liver tissues (p = 3.51 × 10-5 and 0.033, respectively). CONCLUSIONS Three potentially functional SNPs of NEURL1B, CNTN1 and FCER2 may serve as potential prognostic biomarkers for HBV-related HCC.
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Affiliation(s)
- Liming Qin
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
- Department of Epidemiology and Health Statistics, School of Public HealthGuangxi Medical UniversityNanningChina
| | - Moqin Qiu
- Department of Respiratory OncologyGuangxi Medical University Cancer HospitalNanningChina
| | - Qiuling Lin
- Department of Clinical ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Binbin Jiang
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Shicheng Zhan
- Department of Epidemiology and Health Statistics, School of Public HealthGuangxi Medical UniversityNanningChina
| | - Xueyan Wei
- Department of Epidemiology and Health Statistics, School of Public HealthGuangxi Medical UniversityNanningChina
| | - Junjie Wei
- Department of Epidemiology and Health Statistics, School of Public HealthGuangxi Medical UniversityNanningChina
| | - Yingchun Liu
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Qiuping Wen
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Peiqin Chen
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Yanji Jiang
- Department of Scientific ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Zihan Zhou
- Department of Cancer Prevention and ControlGuangxi Medical University Cancer HospitalNanningChina
| | - Xiumei Liang
- Department of Disease Process ManagementGuangxi Medical University Cancer HospitalNanningChina
| | - Ji Cao
- Department of Cancer Prevention and ControlGuangxi Medical University Cancer HospitalNanningChina
| | - Yizhen Gong
- Department of Clinical ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Yuying Wei
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Xiaoxia Wei
- Department of Clinical ResearchGuangxi Medical University Cancer HospitalNanningChina
| | - Hongping Yu
- Department of Experimental ResearchGuangxi Medical University Cancer HospitalNanningChina
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University), Ministry of EducationNanningChina
- Key Cultivated Laboratory of Cancer Molecular Medicine of Guangxi Health CommissionGuangxi Medical University Cancer HospitalNanningChina
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13
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Ramsey KM, Barrick D. Unraveling paralog-specific Notch signaling through thermodynamics of ternary complex formation and transcriptional activation of chimeric receptors. Protein Sci 2024; 33:e4947. [PMID: 38511488 PMCID: PMC10962485 DOI: 10.1002/pro.4947] [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: 10/25/2023] [Revised: 02/07/2024] [Accepted: 02/11/2024] [Indexed: 03/22/2024]
Abstract
Notch signaling in humans is mediated by four paralogous receptors that share conserved architectures and possess overlapping, yet non-redundant functions. The receptors share a canonical activation pathway wherein upon extracellular ligand binding, the Notch intracellular domain (NICD) is cleaved from the membrane and translocates to the nucleus where its N-terminal RBP-j-associated molecule (RAM) region and ankyrin repeat (ANK) domain bind transcription factor CSL and recruit co-activator Mastermind-like-1 (MAML1) to activate transcription. However, different paralogs can lead to distinct outcomes. To better understand paralog-specific differences in Notch signaling, we performed a thermodynamic analysis of the Notch transcriptional activation complexes for all four Notch paralogs using isothermal titration calorimetry. Using chimeric constructs, we find that the RAM region is the primary determinant of stability of binary RAMANK:CSL complexes, and that the ANK regions are largely the determinants of MAML1 binding to pre-formed RAMANK:CSL complexes. Free energies of these binding reactions (ΔGRA and ΔGMAML) vary among the four Notch paralogs, although variations for Notch2, 3, and 4 offset in the free energy of the ternary complex (ΔGTC, where ΔGTC = ΔGRA + ΔGMAML). To probe how these affinity differences affect Notch signaling, we performed transcriptional activation assays with the paralogous and chimeric NICDs, and analyzed the results with an independent multiplicative model that quantifies contributions of the paralogous RAM, ANK, and C-terminal regions (CTR) to activation. This analysis shows that transcription activation correlates with ΔGTC, but that activation is further modified by CTR identity in a paralog-specific way.
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Affiliation(s)
- Kristen M. Ramsey
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Doug Barrick
- T.C. Jenkins Department of BiophysicsJohns Hopkins UniversityBaltimoreMarylandUSA
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14
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Chang LY, Lee MZ, Wu Y, Lee WK, Ma CL, Chang JM, Chen CW, Huang TC, Lee CH, Lee JC, Tseng YY, Lin CY. Gene set correlation enrichment analysis for interpreting and annotating gene expression profiles. Nucleic Acids Res 2024; 52:e17. [PMID: 38096046 PMCID: PMC10853793 DOI: 10.1093/nar/gkad1187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 11/17/2023] [Accepted: 11/29/2023] [Indexed: 02/10/2024] Open
Abstract
Pathway analysis, including nontopology-based (non-TB) and topology-based (TB) methods, is widely used to interpret the biological phenomena underlying differences in expression data between two phenotypes. By considering dependencies and interactions between genes, TB methods usually perform better than non-TB methods in identifying pathways that include closely relevant or directly causative genes for a given phenotype. However, most TB methods may be limited by incomplete pathway data used as the reference network or by difficulties in selecting appropriate reference networks for different research topics. Here, we propose a gene set correlation enrichment analysis method, Gscore, based on an expression dataset-derived coexpression network to examine whether a differentially expressed gene (DEG) list (or each of its DEGs) is associated with a known gene set. Gscore is better able to identify target pathways in 89 human disease expression datasets than eight other state-of-the-art methods and offers insight into how disease-wide and pathway-wide associations reflect clinical outcomes. When applied to RNA-seq data from COVID-19-related cells and patient samples, Gscore provided a means for studying how DEGs are implicated in COVID-19-related pathways. In summary, Gscore offers a powerful analytical approach for annotating individual DEGs, DEG lists, and genome-wide expression profiles based on existing biological knowledge.
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Affiliation(s)
- Lan-Yun Chang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Meng-Zhan Lee
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yujia Wu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Wen-Kai Lee
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Chia-Liang Ma
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Jun-Mao Chang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Ciao-Wen Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Tzu-Chun Huang
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Chia-Hwa Lee
- School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, New Taipei City 235, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, New Taipei City 235, Taiwan
| | - Jih-Chin Lee
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 110, Taiwan
| | - Yu-Yao Tseng
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei 104, Taiwan
| | - Chun-Yu Lin
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Institute of Data Science and Engineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
- School of Dentistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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15
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Hussan SS, Ali MS, Fatima M, Altaf M, Sadaf S. Epigenetically dysregulated NOTCH-Delta-HES signaling cascade can serve as a subtype classifier for acute lymphoblastic leukemia. Ann Hematol 2024; 103:511-523. [PMID: 37922005 DOI: 10.1007/s00277-023-05515-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 10/15/2023] [Indexed: 11/05/2023]
Abstract
The NOTCH-Delta-HES signaling cascade is regarded as a double-edged sword owing to its dual tumor-suppressor and oncogenic roles, in different cellular environments. In the T-cells, it supports leukemogenesis by promoting differentiation while in B-cells, it controls leukemogenesis by inhibiting early differentiation/inducing growth arrest in the lead to apoptosis. The present study was undertaken to assess if this bi-faceted behavior of NOTCH family can be exploited as a diagnostic biomarker or subtype classifier of acute lymphoblastic leukemia (ALL). In this pursuit, expression of seven NOTCH cascade genes was analyzed in bone marrow (BM) biopsy and blood plasma (BP) of pediatric ALL patients using quantitative PCR (qPCR). Further, promoter DNA methylation status of the differentially expressed genes (DEGs) was assessed by methylation-specific qMSP and validated through bisulphite amplicon sequencing. Whereas hypermethylation of JAG1, DLL1, and HES-2, HES-4, and HES-5 was observed in all patients, NOTCH3 was found hypermethylated specifically in Pre-B ALL cases while DLL4 in Pre-T ALL cases. Aberrant DNA methylation strongly correlated with downregulated gene expression, which restored at complete remission stage as observed in "follow-up/post-treatment" subjects. The subtype-specific ROC curve analysis and Kaplan-Meier survival analysis predicted a clinically applicable diagnostic and prognostic potential of the panel. Moreover, the logistic regression model (Pre-B vs Pre-T ALL) was found to be the best-fitted model (McFadden's R2 = 0.28, F1 measure = 0.99). Whether analyzed in BM-aspirates or blood plasma, the NOTCH epigenetic signatures displayed comparable results (p < 0.001), advocating the potential of NOTCH-Delta-HES cascade, as a subtype classifier, in minimally invasive diagnosis of ALL.
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Affiliation(s)
- Syeda Saliah Hussan
- Biopharmaceuticals and Biomarkers Discovery Lab., School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 54590, Pakistan
| | - Muhammad Shrafat Ali
- Biopharmaceuticals and Biomarkers Discovery Lab., School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 54590, Pakistan
| | - Mishal Fatima
- Biopharmaceuticals and Biomarkers Discovery Lab., School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 54590, Pakistan
| | - Memoona Altaf
- Biopharmaceuticals and Biomarkers Discovery Lab., School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 54590, Pakistan
| | - Saima Sadaf
- Biopharmaceuticals and Biomarkers Discovery Lab., School of Biochemistry and Biotechnology, University of the Punjab, Lahore, 54590, Pakistan.
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16
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Ghosh A, Mitra AK. Metastasis and cancer associated fibroblasts: taking it up a NOTCH. Front Cell Dev Biol 2024; 11:1277076. [PMID: 38269089 PMCID: PMC10806909 DOI: 10.3389/fcell.2023.1277076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.
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Affiliation(s)
- Argha Ghosh
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
| | - Anirban K. Mitra
- Indiana University School of Medicine-Bloomington, Bloomington, IN, United States
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN, United States
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
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17
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Suzuki S, Saito S, Narushima Y, Kodani S, Kagaya N, Suenaga H, Shin-Ya K, Arai MA. Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation. J Antibiot (Tokyo) 2024; 77:30-38. [PMID: 37938761 DOI: 10.1038/s41429-023-00673-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/18/2023] [Accepted: 10/24/2023] [Indexed: 11/09/2023]
Abstract
We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F (1) and G (2), and cyclopiazonic acid (CPA) (3) as Notch activators. Pulicatin F (1) and (±)-pulicatin G were synthesized and their activities were evaluated. Notch activation of CPA (3) was investigated using Western blot and RT-PCR. CPA (3) increased protein level of HES1 and mRNA expression of HES1. Also, the expression of FMS-like tyrosine kinase 3 (FLT3), which was known to inhibit apoptosis, was also inhibited by CPA (3) addition. The Notch activation by CPA (3) and cytotoxicity against HL-60 were clearly canceled by addition of FK506, which is an inhibitor of calcineurin (CaN). In addition, it was revealed that CPA (3) induced apoptosis in HL-60 cells.
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Affiliation(s)
- Shiina Suzuki
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Shun Saito
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Yuki Narushima
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Shunta Kodani
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan
| | - Noritaka Kagaya
- Technology Research Association for Next Generation Natural Products Chemistry, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Hikaru Suenaga
- National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Kazuo Shin-Ya
- National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Midori A Arai
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan.
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18
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Ajmeera D, Ajumeera R. Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance. Genes Dis 2024; 11:148-175. [PMID: 37588226 PMCID: PMC10425757 DOI: 10.1016/j.gendis.2022.12.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 11/21/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023] Open
Abstract
Chemotherapy is an effortless and frequently used approach in cancer therapy. However, in most cases, it can only prolong life expectancy and does not guarantee a complete cure. Furthermore, chemotherapy is associated with severe adverse effects, one of the major complications of effective cancer therapy. In addition, newly published research outputs show that cancer stem cells are involved in cancer disease progression, drug resistance, metastasis, and recurrence and that they are functional in the trans-differentiation capacity of cancer stem cells to cancer cells in response to treatments. Novel strategies are therefore required for better management of cancer therapy. The prime approach would be to synthesize and develop novel drugs that need extensive resources, time, and endurance to be brought into therapeutic use. The subsequent approach would be to screen the anti-cancer activity of available non-cancerous drugs. This concept of repurposing non-cancer drugs as an alternative to current cancer therapy has become popular in recent years because using existing anticancer drugs has several adverse effects. Micronutrients have also been investigated for cancer therapy due to their significant anti-cancer effects with negligible or no side effects and availability in food sources. In this paper, we discuss an ideal hypothesis for screening available non-cancerous drugs with anticancer activity, with a focus on cancer stem cells and their clinical application for cancer treatment. Further, drug repurposing and the combination of micronutrients that can target both cancers and cancer stem cells may result in a better therapeutic approach leading to maximum tumor growth control.
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Affiliation(s)
- Divya Ajmeera
- Cell Biology Department, ICMR-National Institute of Nutrition (NIN), Hyderabad, Telangana 500007, India
| | - Rajanna Ajumeera
- Cell Biology Department, ICMR-National Institute of Nutrition (NIN), Hyderabad, Telangana 500007, India
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19
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Wang CW, Clémot M, Hashimoto T, Diaz JA, Goins LM, Goldstein AS, Nagaraj R, Banerjee U. A conserved mechanism for JNK-mediated loss of Notch function in advanced prostate cancer. Sci Signal 2023; 16:eabo5213. [PMID: 37934809 PMCID: PMC10802904 DOI: 10.1126/scisignal.abo5213] [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: 02/08/2022] [Accepted: 10/19/2023] [Indexed: 11/09/2023]
Abstract
Dysregulated Notch signaling is a common feature of cancer; however, its effects on tumor initiation and progression are highly variable, with Notch having either oncogenic or tumor-suppressive functions in various cancers. To better understand the mechanisms that regulate Notch function in cancer, we studied Notch signaling in a Drosophila tumor model, prostate cancer-derived cell lines, and tissue samples from patients with advanced prostate cancer. We demonstrated that increased activity of the Src-JNK pathway in tumors inactivated Notch signaling because of JNK pathway-mediated inhibition of the expression of the gene encoding the Notch S2 cleavage protease, Kuzbanian, which is critical for Notch activity. Consequently, inactive Notch accumulated in cells, where it was unable to transcribe genes encoding its target proteins, many of which have tumor-suppressive activities. These findings suggest that Src-JNK activity in tumors predicts Notch activity status and that suppressing Src-JNK signaling could restore Notch function in tumors, offering opportunities for diagnosis and targeted therapies for a subset of patients with advanced prostate cancer.
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Affiliation(s)
- Cheng-Wei Wang
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Marie Clémot
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Takao Hashimoto
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Johnny A. Diaz
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Lauren M. Goins
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Andrew S. Goldstein
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
- Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute; University of California, Los Angeles, Los Angeles, CA, USA
| | - Raghavendra Nagaraj
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
| | - Utpal Banerjee
- Department of Molecular, Cell and Developmental Biology; University of California, Los Angeles, Los Angeles, CA, USA
- Department of Biological Chemistry; University of California, Los Angeles, Los Angeles, CA, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
- Molecular Biology Institute; University of California, Los Angeles, Los Angeles, CA, USA
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20
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Scicchitano S, Faniello MC, Mesuraca M. Zinc Finger 521 Modulates the Nrf2-Notch Signaling Pathway in Human Ovarian Carcinoma. Int J Mol Sci 2023; 24:14755. [PMID: 37834202 PMCID: PMC10572470 DOI: 10.3390/ijms241914755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/21/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
The human zinc finger protein 521 (ZNF521) is a co-transcriptional factor with multiple recognized regulatory functions in a range of normal, cancer and stem cell compartments. ZNF521 regulates proliferation, progression and CSC (cancer stem cell) compartments in human ovarian cancer (hOC), which is a very aggressive and late-diagnosed female tumor. Two other important regulators of hOC are the NRF2 and NOTCH signaling pathways. In the present paper, the mRNA and protein levels of ZNF521 were correlated with those of the NRF2-NOTCH signaling components in two different hOC cell lines and in a public dataset of 381 hOC patients. The data show that high levels of ZNF521 significantly increase NRF2-NOTCH signaling expression; conversely, the silencing of ZNF521 impairs NRF2-NOTCH signaling. This experimental work shows that, in hOC, different levels of ZNF521 modulate the NRF2-NOTCH signaling pathway and also influences hOC CSC properties.
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Affiliation(s)
- Stefania Scicchitano
- Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy;
| | - Maria Concetta Faniello
- Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy;
| | - Maria Mesuraca
- Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
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21
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Sugiura K, Masuike Y, Suzuki K, Shin AE, Sakai N, Matsubara H, Otsuka M, Sims PA, Lengner CJ, Rustgi AK. LIN28B promotes cell invasion and colorectal cancer metastasis via CLDN1 and NOTCH3. JCI Insight 2023; 8:e167310. [PMID: 37318881 PMCID: PMC10443801 DOI: 10.1172/jci.insight.167310] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 06/13/2023] [Indexed: 06/17/2023] Open
Abstract
The RNA-binding protein LIN28B is overexpressed in over 30% of patients with colorectal cancer (CRC) and is associated with poor prognosis. In the present study, we unraveled a potentially novel mechanism by which LIN28B regulates colonic epithelial cell-cell junctions and CRC metastasis. Using human CRC cells (DLD-1, Caco-2, and LoVo) with either knockdown or overexpression of LIN28B, we identified claudin 1 (CLDN1) tight junction protein as a direct downstream target and effector of LIN28B. RNA immunoprecipitation revealed that LIN28B directly binds to and posttranscriptionally regulates CLDN1 mRNA. Furthermore, using in vitro assays and a potentially novel murine model of metastatic CRC, we show that LIN28B-mediated CLDN1 expression enhances collective invasion, cell migration, and metastatic liver tumor formation. Bulk RNA sequencing of the metastatic liver tumors identified NOTCH3 as a downstream effector of the LIN28B/CLDN1 axis. Additionally, genetic and pharmacologic manipulation of NOTCH3 signaling revealed that NOTCH3 was necessary for invasion and metastatic liver tumor formation. In summary, our results suggest that LIN28B promotes invasion and liver metastasis of CRC by posttranscriptionally regulating CLDN1 and activating NOTCH3 signaling. This discovery offers a promising new therapeutic option for metastatic CRC to the liver, an area where therapeutic advancements have been relatively scarce.
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Affiliation(s)
- Kensuke Sugiura
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Yasunori Masuike
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Kensuke Suzuki
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
- Department of General Surgery and
| | - Alice E. Shin
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | | | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | | | - Peter A. Sims
- Department of Systems Biology and Department of Biochemistry & Molecular Biophysics, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Christopher J. Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Anil K. Rustgi
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
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22
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Marchioni A, Tonelli R, Samarelli AV, Cappiello GF, Andreani A, Tabbì L, Livrieri F, Bosi A, Nori O, Mattioli F, Bruzzi G, Marchioni D, Clini E. Molecular Biology and Therapeutic Targets of Primitive Tracheal Tumors: Focus on Tumors Derived by Salivary Glands and Squamous Cell Carcinoma. Int J Mol Sci 2023; 24:11370. [PMID: 37511133 PMCID: PMC10379311 DOI: 10.3390/ijms241411370] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Primary tracheal tumors are rare, constituting approximately 0.1-0.4% of malignant diseases. Squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) account for about two-thirds of these tumors. Despite most primary tracheal cancers being eligible for surgery and/or radiotherapy, unresectable, recurrent and metastatic tumors may require systemic treatments. Unfortunately, the poor response to available chemotherapy as well as the lack of other real therapeutic alternatives affects the quality of life and outcome of patients suffering from more advanced disease. In this condition, target therapy against driver mutations could constitute an alternative to chemotherapy, and may help in disease control. The past two decades have seen extraordinary progress in developing novel target treatment options, shifting the treatment paradigm for several cancers such as lung cancer. The improvement of knowledge regarding the genetic and biological alterations, of major primary tracheal tumors, has opened up new treatment perspectives, suggesting the possible role of biological targeted therapies for the treatment of these rare tumors. The purpose of this review is to outline the state of knowledge regarding the molecular biology, and the preliminary data on target treatments of the main primary tracheal tumors, focusing on salivary-gland-derived cancers and squamous cell carcinoma.
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Affiliation(s)
- Alessandro Marchioni
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Roberto Tonelli
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41121 Modena, Italy
| | - Anna Valeria Samarelli
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41121 Modena, Italy
| | - Gaia Francesca Cappiello
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Alessandro Andreani
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Luca Tabbì
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Francesco Livrieri
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Annamaria Bosi
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | - Ottavia Nori
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
| | | | - Giulia Bruzzi
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
- Otolaryngology Unit, University Hospital of Modena, 41121 Modena, Italy
| | - Daniele Marchioni
- Otolaryngology Unit, University Hospital of Modena, 41121 Modena, Italy
| | - Enrico Clini
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University of Modena Reggio Emilia, University Hospital of Modena, 41121 Modena, Italy
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23
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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24
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Deshotels L, Safa FM, Saba NS. NOTCH Signaling in Mantle Cell Lymphoma: Biological and Clinical Implications. Int J Mol Sci 2023; 24:10280. [PMID: 37373427 DOI: 10.3390/ijms241210280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Despite major progress in mantle cell lymphoma (MCL) therapeutics, MCL remains a deadly disease with a median survival not exceeding four years. No single driver genetic lesion has been described to solely give rise to MCL. The hallmark translocation t(11;14)(q13;q32) requires additional genetic alterations for the malignant transformation. A short list of recurrently mutated genes including ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1, NOTCH2, and TRAF2 recently emerged as contributors to the pathogenesis of MCL. Notably, NOTCH1 and NOTCH2 were found to be mutated in multiple B cell lymphomas, including 5-10% of MCL, with most of these mutations occurring within the PEST domain of the protein. The NOTCH genes play a critical role in the early and late phases of normal B cell differentiation. In MCL, mutations in the PEST domain stabilize NOTCH proteins, rendering them resistant to degradation, which subsequently results in the upregulation of genes involved in angiogenesis, cell cycle progression, and cell migration and adhesion. At the clinical level, mutated NOTCH genes are associated with aggressive features in MCL, such as the blastoid and pleomorphic variants, a shorter response to treatment, and inferior survival. In this article, we explore in detail the role of NOTCH signaling in MCL biology and the ongoing efforts toward targeted therapeutic interventions.
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Affiliation(s)
- Leigh Deshotels
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Firas M Safa
- Service d'hématologie, Centre Hospitalier du Mans, 72037 Le Mans, France
| | - Nakhle S Saba
- Section of Hematology and Medical Oncology, Deming Department of Medicine, Tulane University, New Orleans, LA 70112, USA
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25
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Ahmad W, Panicker NG, Akhlaq S, Gull B, Baby J, Khader TA, Rizvi TA, Mustafa F. Global Down-regulation of Gene Expression Induced by Mouse Mammary Tumor Virus (MMTV) in Normal Mammary Epithelial Cells. Viruses 2023; 15:v15051110. [PMID: 37243196 DOI: 10.3390/v15051110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Mouse mammary tumor virus (MMTV) is a betaretrovirus that causes breast cancer in mice. The mouse mammary epithelial cells are the most permissive cells for MMTV, expressing the highest levels of virus upon infection and being the ones later transformed by the virus due to repeated rounds of infection/superinfection and integration, leading eventually to mammary tumors. The aim of this study was to identify genes and molecular pathways dysregulated by MMTV expression in mammary epithelial cells. Towards this end, mRNAseq was performed on normal mouse mammary epithelial cells stably expressing MMTV, and expression of host genes was analyzed compared with cells in its absence. The identified differentially expressed genes (DEGs) were grouped on the basis of gene ontology and relevant molecular pathways. Bioinformatics analysis identified 12 hub genes, of which 4 were up-regulated (Angp2, Ccl2, Icam, and Myc) and 8 were down-regulated (Acta2, Cd34, Col1a1, Col1a2, Cxcl12, Eln, Igf1, and Itgam) upon MMTV expression. Further screening of these DEGs showed their involvement in many diseases, especially in breast cancer progression when compared with available data. Gene Set Enrichment Analysis (GSEA) identified 31 molecular pathways dysregulated upon MMTV expression, amongst which the PI3-AKT-mTOR was observed to be the central pathway down-regulated by MMTV. Many of the DEGs and 6 of the 12 hub genes identified in this study showed expression profile similar to that observed in the PyMT mouse model of breast cancer, especially during tumor progression. Interestingly, a global down-regulation of gene expression was observed, where nearly 74% of the DEGs in HC11 cells were repressed by MMTV expression, an observation similar to what was observed in the PyMT mouse model during tumor progression, from hyperplasia to adenoma to early and late carcinomas. Comparison of our results with the Wnt1 mouse model revealed further insights into how MMTV expression could lead to activation of the Wnt1 pathway independent of insertional mutagenesis. Thus, the key pathways, DEGs, and hub genes identified in this study can provide important clues to elucidate the molecular mechanisms involved in MMTV replication, escape from cellular anti-viral response, and potential to cause cell transformation. These data also validate the use of the MMTV-infected HC11 cells as an important model to study early transcriptional changes that could lead to mammary cell transformation.
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Affiliation(s)
- Waqar Ahmad
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Neena G Panicker
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Shaima Akhlaq
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Bushra Gull
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Jasmin Baby
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Thanumol A Khader
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
| | - Tahir A Rizvi
- Department of Microbiology and Immunology, College of Medicine and Health Sciences (CMHS), UAE University, Al Ain 15551, United Arab Emirates
- Zayed Center for Health Sciences (ZCHS), UAE University, Al Ain 15551, United Arab Emirates
- ASPIRE Research Institute in Precision Medicine, Abu Dhabi, UAE University, Al Ain 15551, United Arab Emirates
| | - Farah Mustafa
- Department of Biochemistry & Molecular Biology, College of Medicine and Health Sciences (CMHS), United Arab Emirates (UAE) University, Al Ain 15551, United Arab Emirates
- Zayed Center for Health Sciences (ZCHS), UAE University, Al Ain 15551, United Arab Emirates
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26
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Chatterjee D, Rahman MM, Saha AK, Siam MKS, Sharif Shohan MU. Transcriptomic analysis of esophageal cancer reveals hub genes and networks involved in cancer progression. Comput Biol Med 2023; 159:106944. [PMID: 37075603 DOI: 10.1016/j.compbiomed.2023.106944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 04/09/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023]
Abstract
Esophageal carcinoma (ESCA) has a 5-year survival rate of fewer than 20%. The study aimed to identify new predictive biomarkers for ESCA through transcriptomics meta-analysis to address the problems of ineffective cancer therapy, lack of efficient diagnostic tools, and costly screening and contribute to developing more efficient cancer screening and treatments by identifying new marker genes. Nine GEO datasets of three kinds of esophageal carcinoma were analyzed, and 20 differentially expressed genes were detected in carcinogenic pathways. Network analysis revealed four hub genes, namely RAR Related Orphan Receptor A (RORA), lysine acetyltransferase 2B (KAT2B), Cell Division Cycle 25B (CDC25B), and Epithelial Cell Transforming 2 (ECT2). Overexpression of RORA, KAT2B, and ECT2 was identified with a bad prognosis. These hub genes modulate immune cell infiltration. These hub genes modulate immune cell infiltration. Although this research needs lab confirmation, we found interesting biomarkers in ESCA that may aid in diagnosis and treatment.
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Affiliation(s)
- Dipankor Chatterjee
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Md Mostafijur Rahman
- Department of Microbiology, Jashore University of Science and Technology, Bangladesh
| | - Anik Kumar Saha
- Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research, Dhaka, Bangladesh
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27
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Alotaibi G, Alharthi S, Basu B, Ash D, Dutta S, Singh S, Prajapati BG, Bhattacharya S, Chidrawar VR, Chitme H. Nano-Gels: Recent Advancement in Fabrication Methods for Mitigation of Skin Cancer. Gels 2023; 9:gels9040331. [PMID: 37102943 PMCID: PMC10137892 DOI: 10.3390/gels9040331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/08/2023] [Accepted: 04/10/2023] [Indexed: 04/28/2023] Open
Abstract
In the 21st century, melanoma and non-melanoma skin cancers have become an epidemic outbreak worldwide. Therefore, the exploration of all potential preventative and therapeutic measures based on either physical or bio-chemical mechanisms is essential via understanding precise pathophysiological pathways (Mitogen-activated protein kinase, Phosphatidylinositol 3-kinase Pathway, and Notch signaling pathway) and other aspects of such skin malignancies. Nano-gel, a three-dimensional polymeric cross-linked porous hydrogel having a diameter of 20-200 nm, possesses dual properties of both hydrogel and nanoparticle. The capacity of high drug entrapment efficiency with greater thermodynamic stability, remarkable solubilization potential, and swelling behavior of nano-gel becomes a promising candidate as a targeted drug delivery system in the treatment of skin cancer. Nano-gel can be either synthetically or architectonically modified for responding to either internal or external stimuli, including radiation, ultrasound, enzyme, magnetic, pH, temperature, and oxidation-reduction to achieve controlled release of pharmaceuticals and several bio-active molecules such as proteins, peptides, genes via amplifying drug aggregation in the active targeted tissue and reducing adverse pharmacological effects. Several drugs, such as anti-neoplastic biomolecules having short biological half-lives and prompt enzyme degradability capacity, must be appropriate for administration employing either chemically bridged or physically constructed nano-gel frameworks. The comprehensive review summarizes the advancement in the preparation and characterization methods of targeted nano-gel with enhanced pharmacological potential and preserved intracellular safety limits for the mitigation of skin malignancies with a special emphasize on skin cancer inducing pathophysiological pathways and prospective research opportunities for skin malignancy targeted nano-gels.
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Affiliation(s)
- Ghallab Alotaibi
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Al-Dawadmi Campus, Al-Dawadmi 11961, Saudi Arabia
| | - Sitah Alharthi
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Al-Dawadmi Campus, Al-Dawadmi 11961, Saudi Arabia
| | - Biswajit Basu
- Department of Pharmaceutical Technology, Global College of Pharmaceutical Technology, Krishnagar 741102, West Bengal, India
| | - Dipanjana Ash
- Department of Pharmaceutics, BCDA College of Pharmacy & Technology, Kolkata 700127, West Bengal, India
| | - Swarnali Dutta
- Department of Pharmacology, Birla Institute of Technology, Ranchi 835215, Jharkhand, India
| | - Sudarshan Singh
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Bhupendra G Prajapati
- S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana 384012, Gujarat, India
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy and Technology Management, SVKM's NMIMS Deemed-to-Be University, Shirpur 425405, Maharashtra, India
| | - Vijay R Chidrawar
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Ananthapuramu 515721, Andhra Pradesh, India
| | - Havagiray Chitme
- Faculty of Pharmacy, DIT University, Dehradun 248009, Uttarakhand, India
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28
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Agrawal-Singh S, Bagri J, Giotopoulos G, Azazi DMA, Horton SJ, Lopez CK, Anand S, Bach AS, Stedham F, Antrobus R, Houghton JW, Vassiliou GS, Sasca D, Yun H, Whetton AD, Huntly BJP. HOXA9 forms a repressive complex with nuclear matrix-associated protein SAFB to maintain acute myeloid leukemia. Blood 2023; 141:1737-1754. [PMID: 36577137 PMCID: PMC10113176 DOI: 10.1182/blood.2022016528] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 11/07/2022] [Accepted: 11/28/2022] [Indexed: 12/29/2022] Open
Abstract
HOXA9 is commonly upregulated in acute myeloid leukemia (AML), in which it confers a poor prognosis. Characterizing the protein interactome of endogenous HOXA9 in human AML, we identified a chromatin complex of HOXA9 with the nuclear matrix attachment protein SAFB. SAFB perturbation phenocopied HOXA9 knockout to decrease AML proliferation, increase differentiation and apoptosis in vitro, and prolong survival in vivo. Integrated genomic, transcriptomic, and proteomic analyses further demonstrated that the HOXA9-SAFB (H9SB)-chromatin complex associates with nucleosome remodeling and histone deacetylase (NuRD) and HP1γ to repress the expression of factors associated with differentiation and apoptosis, including NOTCH1, CEBPδ, S100A8, and CDKN1A. Chemical or genetic perturbation of NuRD and HP1γ-associated catalytic activity also triggered differentiation, apoptosis, and the induction of these tumor-suppressive genes. Importantly, this mechanism is operative in other HOXA9-dependent AML genotypes. This mechanistic insight demonstrates the active HOXA9-dependent differentiation block as a potent mechanism of disease maintenance in AML that may be amenable to therapeutic intervention by targeting the H9SB interface and/or NuRD and HP1γ activity.
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Affiliation(s)
- Shuchi Agrawal-Singh
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Jaana Bagri
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - George Giotopoulos
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Dhoyazan M A Azazi
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Sarah J Horton
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Cecile K Lopez
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Shubha Anand
- Cancer Molecular Diagnostics Laboratory, Cancer Research UK Cambridge Centre, Cambridge, United Kingdom
| | - Anne-Sophie Bach
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Frances Stedham
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Robin Antrobus
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Jack W Houghton
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - George S Vassiliou
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Daniel Sasca
- Department of Hematology, Oncology and Pneumology, University Medical Center Mainz, Mainz, Germany
| | - Haiyang Yun
- Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Anthony D Whetton
- School of Veterinary Medicine, School of Biosciences and Medicine, University of Surrey, Guildford, Surrey, United Kingdom
| | - Brian J P Huntly
- Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
- Department of Haematology, University of Cambridge, Cambridge, United Kingdom
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
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29
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Zhu N, Yang R, Wang X, Yuan L, Li X, Wei F, Zhang L. The Hippo signaling pathway: from multiple signals to the hallmarks of cancers. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 36942989 DOI: 10.3724/abbs.2023035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023] Open
Abstract
Evolutionarily conserved, the Hippo signaling pathway is critical in regulating organ size and tissue homeostasis. The activity of this pathway is tightly regulated under normal circumstances, since its physical function is precisely maintained to control the rate of cell proliferation. Failure of maintenance leads to a variety of tumors. Our understanding of the mechanism of Hippo dysregulation and tumorigenesis is becoming increasingly precise, relying on the emergence of upstream inhibitor or activator and the connection linking Hippo target genes, mutations, and related signaling pathways with phenotypes. In this review, we summarize recent reports on the signaling network of the Hippo pathway in tumorigenesis and progression by exploring its critical mechanisms in cancer biology and potential targeting in cancer therapy.
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Affiliation(s)
- Ning Zhu
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ruizeng Yang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaodong Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Liang Yuan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Xiaoyu Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Fang Wei
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Lei Zhang
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
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30
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Zhang Z, Lu YX, Liu F, Sang L, Shi C, Xie S, Bian W, Yang JC, Yang Z, Qu L, Chen SY, Li J, Yang L, Yan Q, Wang W, Fu P, Shao J, Li X, Lin A. lncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1. Proc Natl Acad Sci U S A 2023; 120:e2206694120. [PMID: 36795754 PMCID: PMC9974429 DOI: 10.1073/pnas.2206694120] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 01/12/2023] [Indexed: 02/17/2023] Open
Abstract
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.
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Affiliation(s)
- Zhen Zhang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang310058, China
| | - Yun-xin Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong510060, China
| | - Fangzhou Liu
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang310058, China
| | - Lingjie Sang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Chengyu Shi
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Shaofang Xie
- Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang310024, China
| | - Weixiang Bian
- Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang310024, China
| | - Jie-cheng Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Zuozhen Yang
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Lei Qu
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Shi-yi Chen
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Jun Li
- Department of Pathology School of Medicine, The First Affiliated Hospital Zhejiang University, Hangzhou, Zhejiang310003, China
| | - Lu Yang
- Department of Radiotherapy, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, School of Medicine South China University of Technology, Guangzhou510080, China
| | - Qingfeng Yan
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Wenqi Wang
- Department of Developmental and Cell Biology, University of California, Irvine, CA92697
| | - Peifen Fu
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang310003, China
| | - Jianzhong Shao
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
| | - Xu Li
- Key Laboratory of Structural Biology of Zhejiang Province, Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang310024, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang310058, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang310058, China
- Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Zhejiang310058, China
- Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang310003, China
- International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang322000, China
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31
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Blöchl C, Wang D, Mayboroda OA, Lageveen-Kammeijer GSM, Wuhrer M. Transcriptionally imprinted glycomic signatures of acute myeloid leukemia. Cell Biosci 2023; 13:31. [PMID: 36788594 PMCID: PMC9926860 DOI: 10.1186/s13578-023-00981-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/03/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous disease that has been suffering from stagnant survival curves for decades. In the endeavor toward improved diagnosis and treatment, cellular glycosylation has emerged as an interesting focus area in AML. While mechanistic insights are still limited, aberrant glycosylation may affect intracellular signaling pathways of AML blasts, their interactions within the microenvironment, and even promote chemoresistance. Here, we performed a meta-omics study to portray the glycomic landscape of AML, thereby screening for potential subtypes and responsible glyco-regulatory networks. RESULTS Initially, by integrating comprehensive N-, O-, and glycosphingolipid (GSL)-glycomics of AML cell lines with transcriptomics from public databases, we were able to pinpoint specific glycosyltransferases (GSTs) and upstream transcription factors (TFs) associated with glycan phenotypes. Intriguingly, subtypes M5 and M6, as classified by the French-American-British (FAB) system, emerged with distinct glycomic features such as high (sialyl) Lewisx/a ((s)Lex/a) and high sialylation, respectively. Exploration of transcriptomics datasets of primary AML cells further substantiated and expanded our findings from cell lines as we observed similar gene expression patterns and regulatory networks that were identified to be involved in shaping AML glycan signatures. CONCLUSIONS Taken together, our data suggest transcriptionally imprinted glycomic signatures of AML, reflecting their differentiation status and FAB classification. This study expands our insights into the emerging field of AML glycosylation and paves the way for studies of FAB class-associated glycan repertoires of AML blasts and their functional implications.
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Affiliation(s)
- Constantin Blöchl
- grid.10419.3d0000000089452978Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Di Wang
- grid.10419.3d0000000089452978Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Oleg A. Mayboroda
- grid.10419.3d0000000089452978Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Guinevere S. M. Lageveen-Kammeijer
- grid.10419.3d0000000089452978Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
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32
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Notch Signaling in Acute Inflammation and Sepsis. Int J Mol Sci 2023; 24:ijms24043458. [PMID: 36834869 PMCID: PMC9967996 DOI: 10.3390/ijms24043458] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Notch signaling, a highly conserved pathway in mammals, is crucial for differentiation and homeostasis of immune cells. Besides, this pathway is also directly involved in the transmission of immune signals. Notch signaling per se does not have a clear pro- or anti-inflammatory effect, but rather its impact is highly dependent on the immune cell type and the cellular environment, modulating several inflammatory conditions including sepsis, and therefore significantly impacts the course of disease. In this review, we will discuss the contribution of Notch signaling on the clinical picture of systemic inflammatory diseases, especially sepsis. Specifically, we will review its role during immune cell development and its contribution to the modulation of organ-specific immune responses. Finally, we will evaluate to what extent manipulation of the Notch signaling pathway could be a future therapeutic strategy.
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33
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Lv Y, Du Y, Li K, Ma X, Wang J, Du T, Ma Y, Teng Y, Tang W, Ma R, Wu J, Wu J, Feng J. The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy. Cell Commun Signal 2023; 21:16. [PMID: 36691066 PMCID: PMC9869543 DOI: 10.1186/s12964-022-01031-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/25/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Aggressive B-cell non-Hodgkin's lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. METHODS We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. RESULTS CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. CONCLUSIONS CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL. Video Abstract.
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Affiliation(s)
- Yan Lv
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Yuxin Du
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China.
| | - Kening Li
- Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China
| | - Xiao Ma
- Department of General Surgery, The Affiliated Zhongda Hospital of Southeast University, 87 Dingjiaqiao, Nanjing, 210009, Jiangsu Province, China
| | - Juan Wang
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Tongde Du
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Yuxin Ma
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Yue Teng
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Weiyan Tang
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Rong Ma
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Jianqiu Wu
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Jianzhong Wu
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China
| | - Jifeng Feng
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, 42 Baiziting, Nanjing, 210009, Jiangsu Province, China.
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Ye S, Wang C, Xu Z, Lin H, Wan X, Yu Y, Adhicary S, Zhang JZ, Zhou Y, Liu C, Alonzo M, Bi J, Ramirez-Navarro A, Deschenes I, Ma Q, Garg V, Wu JC, Zhao MT. Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency. Circ Res 2023; 132:187-204. [PMID: 36583388 PMCID: PMC9852089 DOI: 10.1161/circresaha.122.321398] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND NOTCH1 pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left heart syndrome, where the left ventricle is underdeveloped. It is unknown how NOTCH1 regulates human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which NOTCH1 pathogenic variants lead to ventricular hypoplasia in hypoplastic left heart syndrome remain elusive. METHODS CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 genome editing was utilized to delete NOTCH1 in human induced pluripotent stem cells. Cardiac differentiation was carried out by sequential modulation of WNT signaling, and NOTCH1 knockout and wild-type differentiating cells were collected at day 0, 2, 5, 10, 14, and 30 for single-cell RNA-seq. RESULTS Human NOTCH1 knockout induced pluripotent stem cells are able to generate functional cardiomyocytes and endothelial cells, suggesting that NOTCH1 is not required for mesoderm differentiation and cardiovascular development in vitro. However, disruption of NOTCH1 blocks human ventricular-like cardiomyocyte differentiation but promotes atrial-like cardiomyocyte generation through shortening the action potential duration. NOTCH1 deficiency leads to defective proliferation of early human cardiomyocytes, and transcriptomic analysis indicates that pathways involved in cell cycle progression and mitosis are downregulated in NOTCH1 knockout cardiomyocytes. Single-cell transcriptomic analysis reveals abnormal cell lineage determination of cardiac mesoderm, which is manifested by the biased differentiation toward epicardial and second heart field progenitors at the expense of first heart field progenitors in NOTCH1 knockout cell populations. CONCLUSIONS NOTCH1 is essential for human ventricular-like cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm and modulating cell cycle progression. Because first heart field progenitors primarily contribute to the left ventricle, we speculate that pathogenic NOTCH1 variants lead to biased differentiation of first heart field progenitors, blocked ventricular-like cardiomyocyte differentiation, and defective cardiomyocyte proliferation, which collaboratively contribute to left ventricular hypoplasia in hypoplastic left heart syndrome.
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Affiliation(s)
- Shiqiao Ye
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Cankun Wang
- Department of Biomedical Informatics (C.W., Q.M.), The Ohio State University College of Medicine, Columbus, OH
| | - Zhaohui Xu
- Department of Pediatrics (Z.X., V.G., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH.,Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (Z.X.)
| | - Hui Lin
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Xiaoping Wan
- Department of Physiology and Cell Biology (X.W., A.R.-N., I.D., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH
| | - Yang Yu
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Subhodip Adhicary
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Joe Z. Zhang
- Stanford Cardiovascular Institute (J.Z.Z., Y.Z., C.L., J.C.W.), Stanford University School of Medicine, Stanford, CA.,Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, China (J.Z.Z.)
| | - Yang Zhou
- Stanford Cardiovascular Institute (J.Z.Z., Y.Z., C.L., J.C.W.), Stanford University School of Medicine, Stanford, CA
| | - Chun Liu
- Stanford Cardiovascular Institute (J.Z.Z., Y.Z., C.L., J.C.W.), Stanford University School of Medicine, Stanford, CA
| | - Matthew Alonzo
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Jianli Bi
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.)
| | - Angelina Ramirez-Navarro
- Department of Physiology and Cell Biology (X.W., A.R.-N., I.D., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH
| | - Isabelle Deschenes
- Department of Physiology and Cell Biology (X.W., A.R.-N., I.D., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH
| | - Qin Ma
- Department of Biomedical Informatics (C.W., Q.M.), The Ohio State University College of Medicine, Columbus, OH
| | - Vidu Garg
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,Department of Pediatrics (Z.X., V.G., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH
| | - Joseph C. Wu
- Stanford Cardiovascular Institute (J.Z.Z., Y.Z., C.L., J.C.W.), Stanford University School of Medicine, Stanford, CA.,Division of Cardiovascular Medicine, Department of Medicine (J.C.W.), Stanford University School of Medicine, Stanford, CA.,Department of Radiology (J.C.W.), Stanford University School of Medicine, Stanford, CA
| | - Ming-Tao Zhao
- Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH (S.Y., H.L., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,The Heart Center, Nationwide Children’s Hospital, Columbus, OH (S.Y., Y.Y., S.A., M.A., J.B., V.G., M.-T.Z.).,Department of Pediatrics (Z.X., V.G., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH.,Department of Physiology and Cell Biology (X.W., A.R.-N., I.D., M.-T.Z.), The Ohio State University College of Medicine, Columbus, OH
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Hino C, Xu Y, Xiao J, Baylink DJ, Reeves ME, Cao H. The potential role of the thymus in immunotherapies for acute myeloid leukemia. Front Immunol 2023; 14:1102517. [PMID: 36814919 PMCID: PMC9940763 DOI: 10.3389/fimmu.2023.1102517] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/20/2023] [Indexed: 02/09/2023] Open
Abstract
Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease's progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).
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Affiliation(s)
- Christopher Hino
- Department of Internal Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Yi Xu
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
| | - Jeffrey Xiao
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - David J Baylink
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Mark E Reeves
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
| | - Huynh Cao
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
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36
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Cheke RS, Bagwe P, Bhange S, Kharkar PS. Biologicals and small molecules as target-specific cancer chemotherapeutic agents. MEDICINAL CHEMISTRY OF CHEMOTHERAPEUTIC AGENTS 2023:615-646. [DOI: 10.1016/b978-0-323-90575-6.00018-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Activities and binding partners of E3 ubiquitin ligase DTX3L and its roles in cancer. Biochem Soc Trans 2022; 50:1683-1692. [DOI: 10.1042/bst20220501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/27/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022]
Abstract
Ubiquitination is a protein post-translational modification that affects protein localisation, stability and interactions. E3 ubiquitin ligases regulate the final step of the ubiquitination reaction by recognising target proteins and mediating the ubiquitin transfer from an E2 enzyme. DTX3L is a multi-domain E3 ubiquitin ligase in which the N-terminus mediates protein oligomerisation, a middle D3 domain mediates the interaction with PARP9, a RING domain responsible for recognising E2 ∼ Ub and a DTC domain has the dual activity of ADP-ribosylating ubiquitin and mediating ubiquitination. The activity of DTX3L is known to be modulated by at least two different factors: the concentration of NAD+, which dictates if the enzyme acts as a ligase or as an ADP-ribosyltransferase, and its binding partners, which affect DTX3L activity through yet unknown mechanisms. In light of recent findings it is possible that DTX3L could ubiquitinate ADP-ribose attached to proteins. Different DTX3L–protein complexes have been found to be part of multiple signalling pathways through which they promote the adhesion, proliferation, migration and chemoresistance of e.g. lymphoma, glioma, melanoma, and prostate cancer. In this review, we have covered the literature available for the molecular functions of DTX3L especially in the context of cancer biology, different pathways it regulates and how these relate to its function as an oncoprotein.
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The oncogenic JAG1 intracellular domain is a transcriptional cofactor that acts in concert with DDX17/SMAD3/TGIF2. Cell Rep 2022; 41:111626. [DOI: 10.1016/j.celrep.2022.111626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 09/19/2022] [Accepted: 10/18/2022] [Indexed: 11/23/2022] Open
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Vriend J, Thanasupawat T, Sinha N, Klonisch T. Ubiquitin Proteasome Gene Signatures in Ependymoma Molecular Subtypes. Int J Mol Sci 2022; 23:ijms232012330. [PMID: 36293188 PMCID: PMC9604155 DOI: 10.3390/ijms232012330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes UBE2C, UBE2S, and UBE2I was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase HDAC4 and the F-box cullin ring ligase adaptor FBX031. Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome Pathways associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.
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Affiliation(s)
- Jerry Vriend
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Correspondence: ; Tel.: +1-204-789-3732
| | - Thatchawan Thanasupawat
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Namita Sinha
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
| | - Thomas Klonisch
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
- Department of Medical Microbiology and Infectious Diseases, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
- CancerCare Manitoba, Winnipeg, MB R3E 0J9, Canada
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Non-classical Notch signaling by MDA-MB-231 breast cancer cell-derived small extracellular vesicles promotes malignancy in poorly invasive MCF-7 cells. Cancer Gene Ther 2022; 29:1056-1069. [PMID: 35022518 DOI: 10.1038/s41417-021-00411-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 10/23/2021] [Accepted: 11/18/2021] [Indexed: 11/08/2022]
Abstract
Aberrant Notch signaling is implicated in breast cancer progression, and recent studies have demonstrated links between the Notch pathway components Notch1 and Notch1 intracellular domain (N1ICD) with poor clinical outcomes. Growing evidence suggests that Notch signaling can be regulated by small extracellular vesicles (SEVs). Here, we used breast cancer cell models to examine whether SEVs are involved in functional Notch signaling. We found that Notch components are packaged into MDA-MB-231- and MCF-7-derived SEVs, although higher levels of N1ICD were detected in SEVs from the more aggressive MDA-MB-231 cell line than from poorly invasive MCF-7 cells. SEV-Notch components were functional, as SEVs cargo from MDA-MB-231 cells induced the expression of Notch target genes in MCF-7 cells and triggered a more invasive and proliferative phenotype concomitant with the acquisition of mesenchymal features. Neutralization of the N1ICD cargo in MDA-MB-231-derived SEVs significantly reduced their potential to enhance the aggressiveness of MCF-7 cells in vitro and in a xenograft model. Overall, our results indicate that a SEV-mediated non-classical pathway of Notch signal transduction in breast cancer models bypasses the need for classical ligand-receptor interactions, which may have important implications in cancer.
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Anti-Jagged-1 immunotherapy in cancer. Adv Med Sci 2022; 67:196-202. [PMID: 35421813 DOI: 10.1016/j.advms.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 01/25/2022] [Accepted: 04/02/2022] [Indexed: 02/06/2023]
Abstract
Notch signaling is a highly conserved pathway and it plays an essential role in regulating cellular proliferation, differentiation, and apoptosis. The human Notch family includes four receptors, Notch 1-4, and five ligands, delta-like ligand 1 (DLL1), delta-like ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2). It is widely known, that Notch signaling components are often mutated and have deregulated expression in many types of cancer and other diseases. Thus, various therapeutic approaches targeting receptors and ligands of the Notch pathway are being investigated. Human JAG1 is closely related to tumor biology among the Notch ligands, and recent studies have shown potential for monoclonal antibodies targeting JAG1 in cancer therapy. Therefore, this review focuses on current reports on the significance of JAG1 directed cancer treatment, emphasizing immunotherapy.
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Kozlov AP. Mammalian tumor-like organs. 2. Mammalian adipose has many tumor features and obesity is a tumor-like process. Infect Agent Cancer 2022; 17:15. [PMID: 35395810 PMCID: PMC8994355 DOI: 10.1186/s13027-022-00423-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 03/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND In previous publications, the author developed the theory of carcino-evo-devo, which predicts that evolutionarily novel organs should recapitulate some features of tumors in their development. MAIN TEXT Mammalian adipose is currently recognized as a multi-depot metabolic and endocrine organ consisting of several adipose tissues. Although lipid-storing cells and proteins are ancient, the adipose organ as a whole is evolutionarily novel to mammals. The adipose expansion has remarkable similarities with the growth of solid tumors. These similarities are the following: (1) The capability to unlimited expansion; (2) Reversible plasticity; (3) Induction of angiogenesis; (4) Chronic inflammation; (5) Remodeling and disfunction; (6) Systemic influence on the organism; (7) Hormone production; (8) Production of miRNAs that influence other tissues; (9) Immunosuppression; (10) DNA damage and resistance to apoptosis; (11) Destructive infiltration in other organs and tissues. These similarities include the majority of "hallmarks of cancer". In addition, lipomas are the most frequent soft tissue tumors, and similar drugs may be used for the treatment of obesity and cancer by preventing infiltration. This raises the possibility that obesity, at least in part, may represent an oncological problem. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors. Indeed, using a transgenic inducible zebrafish tumor model, we described many genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with the adipose organ. They are also involved in tumor development in humans. CONCLUSION If the hypothesis of the evolutionary origin of the adipose organ from the ancestral hereditary tumor is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, NOTCH1, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.
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Affiliation(s)
- A P Kozlov
- Vavilov Institute of General Genetics, Russian Academy of Sciences, 3, Gubkina Street, Moscow, Russia, 117971.
- Peter the Great St. Petersburg Polytechnic University, 29, Polytekhnicheskaya Street, St. Petersburg, Russia, 195251.
- The Biomedical Center, 8, Viborgskaya Street, St. Petersburg, Russia, 194044.
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Cheng H, Kuang S, Tan L, Sun S. Circ_0001955 plays a carcinogenic role in breast cancer via positively regulating GLUT1 via decoying miR-1299. Thorac Cancer 2022; 13:913-924. [PMID: 35174654 PMCID: PMC8977153 DOI: 10.1111/1759-7714.14310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Breast cancer is widespread in females. The role of circular RNA (circRNA) in breast cancer has aroused much attention. However, the function of several circRNAs remain unclear. The aim of our study was to determine the role of circ_0001955 in breast cancer. METHODS Quantitative real-time PCR (qPCR) and western blot was employed for expression analysis of circ_0001955, miR-1299 and glucose transporter 1 (GLUT1). Cell functions including proliferation, apoptosis, migration, invasion and angiogenesis, were assessed using EdU, flow cytometry, transwell and tube formation assays. Glycolysis metabolism was assessed according to glucose consumption, lactate production and ATP content. Dual-luciferase reporter assay and RIP assay were utilized to validate the binding between miR-1299 and circ_0001955 or GLUT1. The effects of circ_0001955 in vivo were observed by animal study. RESULTS Upregulation of circ_0001955 was detected in breast cancer. Knockdown of circ_0001955 inhibited breast cancer cell proliferation, migration, invasion, angiogenesis and glycolysis. MiR-1299 was a target of circ_0001955, and its repression reversed the effects of circ_0001955 knockdown. Moreover, circ_0001955 targeted miR-1299 to positively regulate GLUT1 expression. GLUT1 overexpression reversed the effects of miR-1299 enrichment. GLUT1 knockdown was verified to block tumor growth in vivo. CONCLUSIONS Circ_0001955 was found to promote breast cancer malignant development via targeting of the miR-1299/GLUT1 pathway, which contributes to our understanding of the pathogenesis of breast cancer.
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Affiliation(s)
- Hong Cheng
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan City, Hubei, China
| | - Sijie Kuang
- Department of Breast Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi City, Hubei Province, China
| | - Lingzhen Tan
- Department of Breast Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi City, Hubei Province, China
| | - Shengrong Sun
- Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan City, Hubei, China
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Yu L, Li W. Abnormal activation of notch 1 signaling causes apoptosis resistance in cervical cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:11-19. [PMID: 35145579 PMCID: PMC8822208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 08/23/2020] [Indexed: 06/14/2023]
Abstract
Notch1 signaling pathway is an evolutionarily conserved and crucial regulator to determine cell fate and differentiation. Notch1 is often over expressed in several cancers, which plays an essential for cancer cell proliferation, survival, invasion and metastasis. The oncogenic function of Notch1 signaling in cervical cancer progression is not well-characterized. In the present study, we showed that Notch1 is significantly enhanced in cervical cancer tissues. Similarly, the relative mRNA and expression of Notch1 protein are significantly upregulated in cervical cancer cell lines such as HeLa and SiHa. Further, we have performed RNAi for NOTCH1 depletion to determine its specific role in cervical cancer progression. Flow cytometry analysis revealed that NOTCH1 depletion leads to activation of apoptotic cell death in cervical cancer. Further, the NOTCH1 depleted cells showed increased sensitivity towards DNA-targeting drugs and therefore cell viability was reduced efficiently. Altogether, our findings suggest that Notch1 overexpression in cervical cancer cells was involved in tumorigenesis and apoptosis resistance of cervical cancer.
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Affiliation(s)
- Lu Yu
- Department of Obstetrics and Gynaecology, People's Hospital of China Three Gorges University Yichang 443000, Hubei, China
| | - Wei Li
- Department of Obstetrics and Gynaecology, People's Hospital of China Three Gorges University Yichang 443000, Hubei, China
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Xu XY, Choi HS, Park SY, Kim JK, Seo KH, Kim H, Kim YJ. Hibiscus syriacus L. cultivated in callus culture exerts cytotoxicity in colorectal cancer via Notch signaling-mediated cholesterol biosynthesis suppression. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 95:153870. [PMID: 34896899 DOI: 10.1016/j.phymed.2021.153870] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/25/2021] [Accepted: 11/27/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND In our previous study, Hibiscus syriacus leaf tissue was successfully cultivated in an optimized callus culture system, and subsequently extracted with 70% ethanol to prepare H. syriacus callus extract (HCE). The previous study suggested that the callus culture is useful method for obtaining the anti-inflammatory ingredients from H. syriacus. PURPOSE In the present study, we aimed to investigate the effect of HCE on the colorectal cancer (CRC) and its underlying mechanism of action using HT-29 cells and thymus-deficient mice bearing HT-29 xenografts. METHODS The cytotoxicity of HCE was investigated by MTT and colonies formation. The underling mechanism by which HCE regulates specific proteins in HT-29 cells was evaluated by the proteomic analysis. These putative proteins were validated using qRT-PCR and immunoblotting analyses. Subsequently, oral administration of HCE for 15 days further evaluating the anti-tumor activity by mRNA and protein expressions levels and tumor histopathology. RESULTS Results of cell viability and colony formation assays revealed a significant cytotoxic effect of HCE at doses below 100 μg/ml against HT-29 cells, but not against normal cells. Through differential protein expression analysis, signaling pathways underlying anti-CRC activity were predicted in HCE-treated HT-29 cells: Notch signaling, cholesterol biosynthesis, and AMPK signaling pathways. qRT-PCR and immunoblotting analyses indicated that the cytotoxic effect of HCE against HT-29 cells might be associated with the suppression of Notch signaling, which positively contributes to cholesterol biosynthesis. To our knowledge, this can be presented as the first study to demonstrate the detailed relationship between Notch signaling and cholesterol-AMPK signaling. Our in vivo result further corroborated the in vitro finding that 100 and 200 mg/kg HCE for 15 days exerts its anti-cancer effect via Notch signaling-mediated suppression of cholesterol synthesis without systemic toxicity. CONCLUSION Our findings can serve as a starting point for developing the novel anti-CRC agent using HCE, as a targeted medicine acting on regulating Notch signaling and cholesterol synthesis.
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Affiliation(s)
- Xing Yue Xu
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Gyeonggi, Republic of Korea
| | - Han Sol Choi
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Gyeonggi, Republic of Korea
| | | | - Jin-Kyu Kim
- Biocenter, Gyeonggido Business and Science Accelerator, Suwon 16229, Republic of Korea
| | - Kwang Hoon Seo
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Gyeonggi, Republic of Korea
| | - Hoon Kim
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Gyeonggi, Republic of Korea.
| | - Yeon-Ju Kim
- Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin 17104, Gyeonggi, Republic of Korea.
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Yang SA, Salazar JL, Li-Kroeger D, Yamamoto S. Functional Studies of Genetic Variants Associated with Human Diseases in Notch Signaling-Related Genes Using Drosophila. Methods Mol Biol 2022; 2472:235-276. [PMID: 35674905 PMCID: PMC9396741 DOI: 10.1007/978-1-0716-2201-8_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Rare variants in the many genes related to Notch signaling cause diverse Mendelian diseases that affect myriad organ systems. In addition, genome- and exome-wide association studies have linked common and rare variants in Notch-related genes to common diseases and phenotypic traits. Moreover, somatic mutations in these genes have been observed in many types of cancer, some of which are classified as oncogenic and others as tumor suppressive. While functional characterization of some of these variants has been performed through experimental studies, the number of "variants of unknown significance" identified in patients with diverse conditions keeps increasing as high-throughput sequencing technologies become more commonly used in the clinic. Furthermore, as disease gene discovery efforts identify rare variants in human genes that have yet to be linked to a disease, the demand for functional characterization of variants in these "genes of unknown significance" continues to increase. In this chapter, we describe a workflow to functionally characterize a rare variant in a Notch signaling related gene that was found to be associated with late-onset Alzheimer's disease. This pipeline involves informatic analysis of the variant of interest using diverse human and model organism databases, followed by in vivo experiments in the fruit fly Drosophila melanogaster. The protocol described here can be used to study variants that affect amino acids that are not conserved between human and fly. By "humanizing" the almondex gene in Drosophila with mutant alleles and heterologous genomic rescue constructs, a missense variant in TM2D3 (TM2 Domain Containing 3) was shown to be functionally damaging. This, and similar approaches, greatly facilitate functional interpretations of genetic variants in the human genome and propel personalized medicine.
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Affiliation(s)
- Sheng-An Yang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Jose L Salazar
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - David Li-Kroeger
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
| | - Shinya Yamamoto
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
- Development, Disease Models and Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX, USA.
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Isik S, Gunden G, Gunduz E, Akay OM, Aslan A, Ozen H, Cilingir O, Erzurumluoglu Gokalp E, Kocagil S, Artan S, Gulbas Z, Durak Aras B. An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3. Cytogenet Genome Res 2021; 161:479-487. [PMID: 34915466 DOI: 10.1159/000520242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/15/2021] [Indexed: 11/19/2022] Open
Abstract
Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.
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Affiliation(s)
- Sevgi Isik
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Gulcin Gunden
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Eren Gunduz
- Department of Hematology, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Olga Meltem Akay
- Department of Hematology, Faculty of Medicine, University of Koc, Istanbul, Turkey
| | - Abdulvahap Aslan
- Department of Hematology, Private Umit Hospital, Eskisehir, Turkey
| | - Hulya Ozen
- Department of Biostatistics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Oguz Cilingir
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Ebru Erzurumluoglu Gokalp
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Sinem Kocagil
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Sevilhan Artan
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
| | - Zafer Gulbas
- Department of Hematology, Anadolu Medical Center, İzmit, Turkey
| | - Beyhan Durak Aras
- Department of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey.,Translational Medicine Research and Clinical Center, University of Eskisehir Osmangazi, Eskisehir, Turkey
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Siddharth S, Parida S, Muniraj N, Hercules S, Lim D, Nagalingam A, Wang C, Gyorffy B, Daniel JM, Sharma D. Concomitant activation of GLI1 and Notch1 contributes to racial disparity of human triple negative breast cancer progression. eLife 2021; 10:70729. [PMID: 34889737 PMCID: PMC8664295 DOI: 10.7554/elife.70729] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 11/19/2021] [Indexed: 01/16/2023] Open
Abstract
Mortality from triple negative breast cancer (TNBC) is significantly higher in African American (AA) women compared to White American (WA) women emphasizing ethnicity as a major risk factor; however, the molecular determinants that drive aggressive progression of AA-TNBC remain elusive. Here, we demonstrate for the first time that AA-TNBC cells are inherently aggressive, exhibiting elevated growth, migration, and cancer stem-like phenotype compared to WA-TNBC cells. Meta-analysis of RNA-sequencing data of multiple AA- and WA-TNBC cell lines shows enrichment of GLI1 and Notch1 pathways in AA-TNBC cells. Enrichment of GLI1 and Notch1 pathway genes was observed in AA-TNBC. In line with this observation, analysis of TCGA dataset reveals a positive correlation between GLI1 and Notch1 in AA-TNBC and a negative correlation in WA-TNBC. Increased nuclear localization and interaction between GLI1 and Notch1 is observed in AA-TNBC cells. Of importance, inhibition of GLI1 and Notch1 synergistically improves the efficacy of chemotherapy in AA-TNBC cells. Combined treatment of AA-TNBC-derived tumors with GANT61, DAPT, and doxorubicin/carboplatin results in significant tumor regression, and tumor-dissociated cells show mitigated migration, invasion, mammosphere formation, and CD44+/CD24- population. Indeed, secondary tumors derived from triple-therapy-treated AA-TNBC tumors show diminished stem-like phenotype. Finally, we show that TNBC tumors from AA women express significantly higher level of GLI1 and Notch1 expression in comparison to TNBC tumors from WA women. This work sheds light on the racial disparity in TNBC, implicates the GLI1 and Notch1 axis as its functional mediators, and proposes a triple-combination therapy that can prove beneficial for AA-TNBC.
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Affiliation(s)
- Sumit Siddharth
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Sheetal Parida
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Nethaji Muniraj
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Shawn Hercules
- Department of Biology, MacMaster University, Hamilton, Canada
| | - David Lim
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Arumugam Nagalingam
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Chenguang Wang
- Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
| | - Balazs Gyorffy
- MTA TTK Momentum Cancer Biomarker Research Group, Budapest, Hungary.,Semmelweis University, Department of Bioinformatics and 2nd Dept. of Pediatrics, Budapest, Hungary
| | - Juliet M Daniel
- Department of Biology, MacMaster University, Hamilton, Canada
| | - Dipali Sharma
- Dept. of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, United States
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Makita Y, Saito S, Tsuchiya A, Ishibashi M, Arai MA. Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity. J Nat Med 2021; 76:234-243. [PMID: 34779991 DOI: 10.1007/s11418-021-01584-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/02/2021] [Indexed: 11/25/2022]
Abstract
Notch signaling plays crucial roles in cell differentiation and proliferation, but aberrant activation of this signaling results in tumorigenesis and cancer progression. Notch signaling is thus a promising drug target for oncotherapy, and the development of Notch signaling inhibitors is eagerly awaited. Notch inhibitory activity-guided fractionation of a Spilanthes acmella extract led to the identification of five sesquiterpene lactones: tagitinin A (1), 1β,2α-epoxytagitinin C (2), tagitinin C (3), orizabin (4), and 2α-hydroxytirotundin (5). 1β,2α-Epoxytagitinin C (2) exhibited Notch signaling inhibition, with an IC50 of 25.6 μM, and was further evaluated for its activity against HPB-ALL, a Notch-activated leukemia cell line. Compound 2 showed potent cytotoxicity against HPB-ALL (IC50 1.7 μM) and arrested the cell cycle at the G2/M phase, but did not induce apoptotic cell death. Notch inhibitory mechanism analysis suggested that compound 2 transcriptionally suppresses Notch1 mRNA. In addition, we found that oxidative stress induction is critical for Notch signaling inhibition and the cytotoxicity of compound 2. This is the first mechanism of small molecule Notch inhibition. Our results demonstrate that 1β,2α-epoxytagitinin C (2) is a potential anti-leukemia agent and further investigation of this compound is warranted.
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Affiliation(s)
- Yoshinori Makita
- Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.,Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Shun Saito
- Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan
| | - Anna Tsuchiya
- Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Masami Ishibashi
- Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan
| | - Midori A Arai
- Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan.
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Li G, Lei X, Zhang Y, Liu Z, Zhu K. LncRNA PPM1A-AS Regulate Tumor Development Through Multiple Signal Pathways in T-Cell Acute Lymphoblastic Leukemia. Front Oncol 2021; 11:761205. [PMID: 34746000 PMCID: PMC8567141 DOI: 10.3389/fonc.2021.761205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/29/2021] [Indexed: 01/17/2023] Open
Abstract
ALL (Acute lymphoblastic leukemia) is the most common pediatric malignancy and T-ALL (T-cell acute lymphoblastic leukemia) comprises about 15% cases. Compared with B-ALL (B-cell acute lymphoblastic leukemia), the prognosis of T-ALL is poorer, the chemotherapy is easier to fail and the relapse rate is higher. Previous studies mainly focused in Notch1-related long non-coding RNAs (lncRNAs) in T-ALL. Here, we intend to investigate lncRNAs involved in T-ALL covering different subtypes. The lncRNA PPM1A-AS was screened out for its significant up-regulation in 10 T-ALL samples of different subtypes than healthy human thymus extracts. Besides, the PPM1A-AS expression levels in 3 T-ALL cell lines are markedly higher than that in CD45+ T cells of healthy human. We further demonstrate that PPM1A-AS can promote cell proliferation and inhibit cell apoptosis in vitro and can influence T-ALL growth in vivo. Finally, we verified that PPM1A-AS can regulate core proteins, Notch4, STAT3 and Akt, of 3 important signaling pathways related to T-ALL. These results confirm that lncRNA PPM1A-AS can act as an oncogene in T-ALL and maybe a potential clinical target of patients resistant to current chemotherapy or relapsed cases.
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Affiliation(s)
- Guoli Li
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Xinyue Lei
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China
| | - Yingchi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zhe Liu
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University, Tianjin, China.,Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Tianjin, China
| | - Kegan Zhu
- Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China.,Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, Tianjin Medical University, Tianjin, China
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