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1
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England FJ, Bordeu I, Ng ME, Bang J, Kim B, Choi J, Cardoso EC, Koo BK, Simons BD, Lee JH. Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation. Cell Stem Cell 2025; 32:375-390.e9. [PMID: 39978341 DOI: 10.1016/j.stem.2025.01.011] [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: 03/26/2024] [Revised: 10/30/2024] [Accepted: 01/20/2025] [Indexed: 02/22/2025]
Abstract
Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.
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Affiliation(s)
- Frances J England
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Ignacio Bordeu
- Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Departamento de Física, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, Chile
| | - Minn-E Ng
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - JaeHak Bang
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Bumsoo Kim
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Jinwook Choi
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Erik C Cardoso
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Bon-Kyoung Koo
- Center for Genome Engineering, Institute for Basic Science, Daejeon 34126, Republic of Korea
| | - Benjamin D Simons
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge CB3 0WA, UK.
| | - Joo-Hyeon Lee
- Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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2
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Miret Durazo CI, Zachariah Saji S, Rawat A, Motiño Villanueva AL, Bhandari A, Nurjanah T, Ryali N, Zepeda Martínez IG, Cruz Santiago JA. Exploring Aspirin's Potential in Cancer Prevention: A Comprehensive Review of the Current Evidence. Cureus 2024; 16:e70005. [PMID: 39445288 PMCID: PMC11498354 DOI: 10.7759/cureus.70005] [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] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Aspirin, traditionally recognized for its analgesic, anti-inflammatory, antipyretic, and antiplatelet effects, has recently attracted attention for its potential role in cancer prevention. Initially studied for cardiovascular disease prevention, emerging evidence suggests that aspirin may reduce the risk of certain cancers, particularly colorectal cancer (CRC). This narrative review integrates findings from early studies, animal models, epidemiological data, and clinical trials to evaluate aspirin's efficacy as a chemopreventive agent. Aspirin's anticancer effects are primarily attributed to its cyclooxygenase (COX) enzyme inhibition, which decreases prostaglandin E2 (PGE2) levels and disrupts cancer-related signaling pathways. While epidemiological studies support an association between aspirin use and reduced cancer incidence and mortality, especially for CRC and potentially for breast (BC) and prostate cancers (PCa), the risk of adverse effects, such as gastrointestinal (GI) and intracranial bleeding, complicates its use and warrants careful consideration. The decision to use aspirin for cancer prevention should be individualized, balancing its therapeutic benefits against potential adverse effects. It also underscores the necessity for further research to refine dosage guidelines, assess long-term impacts, and explore additional biomarkers to guide personalized cancer prevention strategies.
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Affiliation(s)
| | | | - Akash Rawat
- Department of General Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, IND
| | | | - Amit Bhandari
- Internal Medicine, American University of the Caribbean School of Medicine, Cupecoy, SXM
| | - Tutut Nurjanah
- Department of General Medicine, Universitas Yarsi, Jakarta, IDN
| | - Niharika Ryali
- Department of General Medicine, Gandhi Medical College, Hyderabad, IND
| | | | - Josue A Cruz Santiago
- Department of General Medicine, Universidad Autónoma de Guadalajara, Guadalajara, MEX
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3
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Montalban-Bravo G, Thongon N, Rodriguez-Sevilla JJ, Ma F, Ganan-Gomez I, Yang H, Kim YJ, Adema V, Wildeman B, Tanaka T, Darbaniyan F, Al-Atrash G, Dwyer K, Loghavi S, Kanagal-Shamanna R, Song X, Zhang J, Takahashi K, Kantarjian H, Garcia-Manero G, Colla S. Targeting MCL1-driven anti-apoptotic pathways overcomes blast progression after hypomethylating agent failure in chronic myelomonocytic leukemia. Cell Rep Med 2024; 5:101585. [PMID: 38781960 PMCID: PMC11228590 DOI: 10.1016/j.xcrm.2024.101585] [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: 12/04/2022] [Revised: 11/27/2023] [Accepted: 04/30/2024] [Indexed: 05/25/2024]
Abstract
RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML.
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MESH Headings
- Leukemia, Myelomonocytic, Chronic/drug therapy
- Leukemia, Myelomonocytic, Chronic/pathology
- Leukemia, Myelomonocytic, Chronic/genetics
- Leukemia, Myelomonocytic, Chronic/metabolism
- Myeloid Cell Leukemia Sequence 1 Protein/metabolism
- Myeloid Cell Leukemia Sequence 1 Protein/genetics
- Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors
- Humans
- Apoptosis/drug effects
- Animals
- Mutation/genetics
- Mice
- Signal Transduction/drug effects
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/drug effects
- Disease Progression
- Sulfonamides/pharmacology
- Sulfonamides/therapeutic use
- NF-kappa B/metabolism
- DNA Methylation/drug effects
- DNA Methylation/genetics
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
- Blast Crisis/pathology
- Blast Crisis/drug therapy
- Blast Crisis/genetics
- Blast Crisis/metabolism
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Affiliation(s)
| | - Natthakan Thongon
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Feiyang Ma
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Irene Ganan-Gomez
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hui Yang
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yi June Kim
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vera Adema
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bethany Wildeman
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tomoyuki Tanaka
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Faezeh Darbaniyan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gheath Al-Atrash
- Department of Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karen Dwyer
- Department of Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sanam Loghavi
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rashmi Kanagal-Shamanna
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Koichi Takahashi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Simona Colla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Calmon MS, Lemos FFB, Silva Luz M, Rocha Pinheiro SL, de Oliveira Silva LG, Correa Santos GL, Rocha GR, Freire de Melo F. Immune pathway through endometriosis to ovarian cancer. World J Clin Oncol 2024; 15:496-522. [PMID: 38689629 PMCID: PMC11056862 DOI: 10.5306/wjco.v15.i4.496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/29/2024] [Accepted: 03/18/2024] [Indexed: 04/22/2024] Open
Abstract
Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.
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Affiliation(s)
- Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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5
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Chen Z, Giotti B, Kaluzova M, Vallcorba MP, Rawat K, Price G, Herting CJ, Pinero G, Cristea S, Ross JL, Ackley J, Maximov V, Szulzewsky F, Thomason W, Marquez-Ropero M, Angione A, Nichols N, Tsankova NM, Michor F, Shayakhmetov DM, Gutmann DH, Tsankov AM, Hambardzumyan D. A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression. J Clin Invest 2023; 133:e163802. [PMID: 37733448 PMCID: PMC10645395 DOI: 10.1172/jci163802] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/19/2023] [Indexed: 09/23/2023] Open
Abstract
Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1β, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1β could be considered as an effective therapy specifically for proneural GBM.
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Affiliation(s)
- Zhihong Chen
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Bruno Giotti
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Milota Kaluzova
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
- Department of Neurology, Rutgers University, New Brunswick, New Jersey, USA
| | - Montse Puigdelloses Vallcorba
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Kavita Rawat
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Gabrielle Price
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Cameron J. Herting
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
| | - Gonzalo Pinero
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Simona Cristea
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
| | - James L. Ross
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
- Emory University Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, Georgia, USA
| | - James Ackley
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
| | - Victor Maximov
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
| | - Frank Szulzewsky
- Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Wes Thomason
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Mar Marquez-Ropero
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Angelo Angione
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | | | - Nadejda M. Tsankova
- Department of Pathology and Molecular and Cell-Based Medicine, Mount Sinai Icahn School of Medicine, New York, New York, USA
| | - Franziska Michor
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
- The Ludwig Center at Harvard, Boston, Massachusetts, USA
- The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Dmitry M. Shayakhmetov
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
- Lowance Center for Human Immunology and Emory Vaccine Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA
| | - David H. Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Alexander M. Tsankov
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dolores Hambardzumyan
- Department of Oncological Sciences, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, New York, USA
- Department of Pediatrics, AFLAC Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Winship Cancer Institute, and
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
- Department of Neurosurgery and
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6
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Fard D, Giraudo E, Tamagnone L. Mind the (guidance) signals! Translational relevance of semaphorins, plexins, and neuropilins in pancreatic cancer. Trends Mol Med 2023; 29:817-829. [PMID: 37598000 DOI: 10.1016/j.molmed.2023.07.009] [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: 06/24/2023] [Revised: 07/19/2023] [Accepted: 07/19/2023] [Indexed: 08/21/2023]
Abstract
Pancreatic cancer is a major cause of demise worldwide. Although key associated genetic changes have been discovered, disease progression is sustained by pathogenic mechanisms that are poorly understood at the molecular level. In particular, the tissue microenvironment of pancreatic adenocarcinoma (PDAC) is usually characterized by high stromal content, scarce recruitment of immune cells, and the presence of neuronal fibers. Semaphorins and their receptors, plexins and neuropilins, comprise a wide family of regulatory signals that control neurons, endothelial and immune cells, embryo development, and normal tissue homeostasis, as well as the microenvironment of human tumors. We focus on the role of these molecular signals in pancreatic cancer progression, as revealed by experimental research and clinical studies, including novel approaches for cancer treatment.
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Affiliation(s)
- Damon Fard
- Università Cattolica del Sacro Cuore, Department of Life Sciences and Public Health, Rome, Italy
| | - Enrico Giraudo
- Department of Science and Drug Technology, University of Turin, Turin, Italy; Candiolo Cancer Institute, FPO IRCCS, Candiolo, Turin, Italy
| | - Luca Tamagnone
- Università Cattolica del Sacro Cuore, Department of Life Sciences and Public Health, Rome, Italy; Fondazione Policlinico Gemelli, IRCCS, Rome, Italy.
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7
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Sattarifard H, Safaei A, Khazeeva E, Rastegar M, Davie JR. Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states. Biochem Cell Biol 2023; 101:204-219. [PMID: 36812480 DOI: 10.1139/bcb-2022-0371] [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] [Indexed: 02/24/2023] Open
Abstract
The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB and CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host's innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.
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Affiliation(s)
- Hedieh Sattarifard
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, MB, Canada
| | - Akram Safaei
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, MB, Canada
| | - Enzhe Khazeeva
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, MB, Canada
| | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, MB, Canada
| | - James R Davie
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, MB, Canada
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8
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Cao M, Wang Y, Lu G, Qi H, Li P, Dai X, Lu J. Classical Angiogenic Signaling Pathways and Novel Anti-Angiogenic Strategies for Colorectal Cancer. Curr Issues Mol Biol 2022; 44:4447-4471. [PMID: 36286020 PMCID: PMC9601273 DOI: 10.3390/cimb44100305] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/17/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Although productive progress has been made in colorectal cancer (CRC) researchs, CRC is the second most frequent type of malignancy and the major cause of cancer-related death among gastrointestinal cancers. As angiogenesis constitutes an important point in the control of CRC progression and metastasis, understanding the key signaling pathways that regulate CRC angiogenesis is critical in elucidating ways to inhibit CRC. Herein, we comprehensively summarized the angiogenesis-related pathways of CRC, including vascular endothelial growth factor (VEGF), nuclear factor-kappa B (NF-κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), Wingless and int-1 (Wnt), and Notch signaling pathways. We divided the factors influencing the specific pathway into promoters and inhibitors. Among these, some drugs or natural compounds that have antiangiogenic effects were emphasized. Furthermore, the interactions of these pathways in angiogenesis were discussed. The current review provides a comprehensive overview of the key signaling pathways that are involved in the angiogenesis of CRC and contributes to the new anti-angiogenic strategies for CRC.
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Affiliation(s)
- Mengyuan Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yunmeng Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guige Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Haoran Qi
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Peiyu Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiaoshuo Dai
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Jing Lu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
- Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
- Correspondence:
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9
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Cáceres-Gutiérrez RE, Alfaro-Mora Y, Andonegui MA, Díaz-Chávez J, Herrera LA. The Influence of Oncogenic RAS on Chemotherapy and Radiotherapy Resistance Through DNA Repair Pathways. Front Cell Dev Biol 2022; 10:751367. [PMID: 35359456 PMCID: PMC8962660 DOI: 10.3389/fcell.2022.751367] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 02/15/2022] [Indexed: 11/27/2022] Open
Abstract
RAS oncogenes are chief tumorigenic drivers, and their mutation constitutes a universal predictor of poor outcome and treatment resistance. Despite more than 30 years of intensive research since the identification of the first RAS mutation, most attempts to therapeutically target RAS mutants have failed to reach the clinic. In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021. However, since Sotorasib targets the KRAS G12C mutant with high specificity, relatively few patients will benefit from this therapy. On the other hand, indirect approaches to inhibit the RAS pathway have revealed very intricate cascades involving feedback loops impossible to overcome with currently available therapies. Some of these mechanisms play different roles along the multistep carcinogenic process. For instance, although mutant RAS increases replicative, metabolic and oxidative stress, adaptive responses alleviate these conditions to preserve cellular survival and avoid the onset of oncogene-induced senescence during tumorigenesis. The resulting rewiring of cellular mechanisms involves the DNA damage response and pathways associated with oxidative stress, which are co-opted by cancer cells to promote survival, proliferation, and chemo- and radioresistance. Nonetheless, these systems become so crucial to cancer cells that they can be exploited as specific tumor vulnerabilities. Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.
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Affiliation(s)
- Rodrigo E. Cáceres-Gutiérrez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | - Yair Alfaro-Mora
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - Marco A. Andonegui
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
| | - José Díaz-Chávez
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
- *Correspondence: Luis A. Herrera, ; José Díaz-Chávez,
| | - Luis A. Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, Mexico City, Mexico
- Instituto Nacional de Medicina Genómica, Mexico City, Mexico
- *Correspondence: Luis A. Herrera, ; José Díaz-Chávez,
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10
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Zhang S, Pan C, Shang Q, Wang W, Hu T, Liu P, Chen S, Wang J, Fang Q. Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1. Eur J Pharmacol 2022; 917:174722. [PMID: 34953799 DOI: 10.1016/j.ejphar.2021.174722] [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: 06/11/2021] [Revised: 12/07/2021] [Accepted: 12/20/2021] [Indexed: 11/27/2022]
Abstract
Drug resistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). Finding specific molecules responsible for mediating drug resistance in AML contributes to the effective reversal of drug resistance. Recent studies have found that mitogen- and stress-activated protein kinase 1 (MSK1) is of great significance in the occurrence and development of tumors. In the current study, MSK1 was found highly expressed in drug-resistant AML patients. Heme oxygenase-1 (HO-1) has been previously validated to be associated with drug resistance in AML. Our study revealed a positive correlation between MSK1 and HO-1 in patient samples. In vitro experiments revealed that the sensitivity of AML cell lines THP-1 and U937 to cytarabine (Ara-C) significantly decreased after overexpression of MSK1. Meanwhile, downregulation of MSK1 by siRNA transfection or treatment of pharmacological inhibitor SB-747651A in AML cell lines and primary AML cells enhanced the sensitivity to Ara-C. Flow cytometry analysis showed that downregulation of MSK1 in AML cells accelerated apoptosis and arrested cell cycle progression in G0/G1 phase. However, the increased cell sensitivity induced by MSK1 downregulation was reversed by the induction of HO-1 inducer Hemin. Through further mechanism exploration, real-time PCR, immunofluorescence and Western blot analysis demonstrated that brahma related gene 1 (BRG1) was involved in the regulatory effect of MSK1 on HO-1. High expression of MSK1 could promote the resistance of AML through BRG1-mediated upregulation of HO-1. Downregulation of MSK1 enhanced the sensitivity of AML cells to Ara-C. Our findings provide novel ideas for developing effective anti-AML targets.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Cytarabine/pharmacology
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
- Heme Oxygenase-1/genetics
- Heme Oxygenase-1/metabolism
- Up-Regulation/drug effects
- Ribosomal Protein S6 Kinases, 90-kDa/metabolism
- Ribosomal Protein S6 Kinases, 90-kDa/genetics
- Apoptosis/drug effects
- Apoptosis/genetics
- Male
- Cell Line, Tumor
- Female
- U937 Cells
- Middle Aged
- THP-1 Cells
- Gene Expression Regulation, Leukemic/drug effects
- Adult
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Affiliation(s)
- Siyu Zhang
- College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China
| | - Chengyun Pan
- Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Qin Shang
- College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China
| | - Weili Wang
- Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Tianzhen Hu
- College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China
| | - Ping Liu
- Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Siyu Chen
- Department of Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, China
| | - Jishi Wang
- Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
| | - Qin Fang
- College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
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11
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Liu L, Gao H, Wen T, Gu T, Zhang S, Yuan Z. Tanshinone IIA attenuates AOM/DSS-induced colorectal tumorigenesis in mice via inhibition of intestinal inflammation. PHARMACEUTICAL BIOLOGY 2021; 59:89-96. [PMID: 33535870 PMCID: PMC8871617 DOI: 10.1080/13880209.2020.1865412] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
CONTEXT Tanshinone IIA is a natural extract derived from a Chinese medicinal herb with multiple bioactivities; however, whether and how tanshinone IIA protects against colorectal cancer (CRC) are uncertain. OBJECTIVE We investigated the potential beneficial effects of tanshinone IIA in a colitis-associated colorectal tumorigenesis mouse model and its underlying mechanisms. MATERIALS AND METHODS Male C57BL/6 mice were treated with azoxymethane (AOM) 10 mg/kg body weight and dextran sulphate sodium (2.5% DSS) to induce a colitis-associated cancer model. Tanshinone IIA (200 mg/kg body weight) was given to the mice intraperitoneally. After 12 weeks, all mice were sacrificed to measure tumour formation, intestinal permeability, neutrophil infiltration, and colonic inflammation. In addition, whether tanshinone IIA has inhibitory effects on neutrophil activation was determined through in vitro investigations. RESULTS We observed that tanshinone IIA significantly decreased tumour formation in AOM/DSS-treated mice compared to AOM/DSS-treated alone mice (0.266 ± 0.057 vs. 0.78 ± 0.153, p = 0.013). Tanshinone IIA also decreased intestinal permeability compared to that in AOM/DSS-treated alone mice (3.12 ± 0.369 vs. 5.06 ± 0.597, p = 0.034) and consequently reduced neutrophil infiltration of the colonic mucosa (53.25 ± 8.85 vs. 107.6 ± 13.09, p = 0.014) as well as intestinal inflammation in mice. Mechanistically, tanshinone IIA downregulated the NF-κB signalling pathway in the colonic tumours of AOM/DSS-treated mice. In vitro assays further validated that tanshinone IIA suppressed LPS-induced neutrophil activation. CONCLUSION These data suggest that tanshinone IIA alleviates colorectal tumorigenesis through inhibition of intestinal inflammation. Tanshinone IIA may have a therapeutic potential for CRC in clinical practice.
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Affiliation(s)
- Lijie Liu
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Hanjing Gao
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- Department of Radiation Oncology, Tianjin 4TH Centre Hospital, Tianjin, China
| | - Tao Wen
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Tao Gu
- Department of Oncology, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Shuang Zhang
- Department of Cardiology, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Zhiyong Yuan
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- CONTACT Zhiyong Yuan Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, West Huan-Hu Road, Hexi District, Tianjin300060, China
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12
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Ohta S, Tago K, Kuchimaru T, Funakoshi-Tago M, Horie H, Aoki-Ohmura C, Matsugi J, Yanagisawa K. The role of MerTK in promoting cell migration is enhanced by the oncogenic Ras/IL-33 signaling axis. FEBS J 2021; 289:1950-1967. [PMID: 34743410 DOI: 10.1111/febs.16271] [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: 04/29/2021] [Revised: 09/15/2021] [Accepted: 11/05/2021] [Indexed: 11/29/2022]
Abstract
Ras genes are frequently mutated in many cancer types; however, there are currently no conclusively effective anticancer drugs against Ras-induced cancer. Therefore, the downstream effectors of Ras signaling need to be identified for the development of promising novel therapeutic approaches. We previously reported that oncogenic Ras induced the expression of NF-HEV/IL-33, a member of the interleukin-1 family, and showed that intracellular IL-33 was required for oncogenic Ras-induced cellular transformation. In the present study, we demonstrated that the c-Mer proto-oncogene tyrosine kinase (MerTK), a receptor tyrosine kinase, played essential roles in oncogenic Ras/IL-33 signaling. The expression of MerTK was enhanced in transformed NIH-3T3 cells by the expression of oncogenic Ras, H-Ras (G12V), in an IL-33-dependent manner. In human colorectal cancer tissues, MerTK expression also correlated with IL-33 expression. The knockdown of IL-33 or MerTK effectively attenuated the migration of NIH-3T3 cells transformed by H-Ras (G12V) and A549, LoVo, and HCT116 cells harboring an oncogenic K-Ras mutation. Furthermore, the suppression of Ras-induced cell migration by the knockdown of IL-33 was rescued by the enforced expression of MerTK. The present results also revealed that MerTK was effectively phosphorylated in NIH-3T3 cells transformed by Ras (G12V). Ras signaling was essential for the tyrosine phosphorylation of MerTK, and the kinase activity of MerTK was indispensable for accelerating cell migration. Collectively, the present results reveal a novel role for MerTK in cancer malignancy, which may be utilized to develop novel therapeutic strategies that target Ras-transformed cells.
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Affiliation(s)
- Satoshi Ohta
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | - Kenji Tago
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | | | | | - Hisanaga Horie
- Department of Surgery, Jichi Medical University, Tochigi, Japan
| | | | - Jitsuhiro Matsugi
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | - Ken Yanagisawa
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
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13
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Tago K, Ohta S, Aoki-Ohmura C, Funakoshi-Tago M, Sashikawa M, Matsui T, Miyamoto Y, Wada T, Oshio T, Komine M, Matsugi J, Furukawa Y, Ohtsuki M, Yamauchi J, Yanagisawa K. K15 promoter-driven enforced expression of NKIRAS exhibits tumor suppressive activity against the development of DMBA/TPA-induced skin tumors. Sci Rep 2021; 11:20658. [PMID: 34667224 PMCID: PMC8526694 DOI: 10.1038/s41598-021-00200-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/01/2021] [Indexed: 12/17/2022] Open
Abstract
NKIRAS1 and NKIRAS2 (also called as κB-Ras) were identified as members of the atypical RAS family that suppress the transcription factor NF-κB. However, their function in carcinogenesis is still controversial. To clarify how NKIRAS acts on cellular transformation, we generated transgenic mice in which NKIRAS2 was forcibly expressed using a cytokeratin 15 (K15) promoter, which is mainly activated in follicle bulge cells. The ectopic expression of NKIRAS2 was mainly detected in follicle bulges of transgenic mice with NKIRAS2 but not in wild type mice. K15 promoter-driven expression of NKIRAS2 failed to affect the development of epidermis, which was evaluated using the expression of K10, K14, K15 and filaggrin. However, K15 promoter-driven expression of NKIRAS2 effectively suppressed the development of skin tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA). This observation suggested that NKIRAS seemed to function as a tumor suppressor in follicle bulges. However, in the case of oncogenic HRAS-driven cellular transformation of murine fibroblasts, knockdown of NKIRAS2 expression drastically suppressed HRAS-mutant-provoked cellular transformation, suggesting that NKIRAS2 was required for the cellular transformation of murine fibroblasts. Furthermore, moderate enforced expression of NKIRAS2 augmented oncogenic HRAS-provoked cellular transformation, whereas an excess NKIRAS2 expression converted its functional role into a tumor suppressive phenotype, suggesting that NKIRAS seemed to exhibit a biphasic bell-shaped enhancing effect on HRAS-mutant-provoked oncogenic activity. Taken together, the functional role of NKIRAS in carcinogenesis is most likely determined by not only cellular context but also its expression level.
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Affiliation(s)
- Kenji Tago
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.
| | - Satoshi Ohta
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Chihiro Aoki-Ohmura
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Megumi Funakoshi-Tago
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan
| | - Miho Sashikawa
- Department of Dermatology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Takeshi Matsui
- Laboratory for Evolutionary Cell Biology of the Skin, School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakura, Hachioji, Tokyo, 192-0982, Japan
| | - Yuki Miyamoto
- Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan
| | - Taeko Wada
- Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Tomoyuki Oshio
- Department of Dermatology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Mayumi Komine
- Department of Dermatology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Jitsuhiro Matsugi
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Yusuke Furukawa
- Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Mamitaro Ohtsuki
- Department of Dermatology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
| | - Junji Yamauchi
- Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan.,Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan
| | - Ken Yanagisawa
- Division of Structural Biochemistry, Department of Biochemistry, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
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14
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Lin X, Tago K, Okazaki N, So T, Takahashi K, Mashino T, Tamura H, Funakoshi-Tago M. The indole-hydantoin derivative exhibits anti-inflammatory activity by preventing the transactivation of NF-κB through the inhibition of NF-κB p65 phosphorylation at Ser276. Int Immunopharmacol 2021; 100:108092. [PMID: 34474272 DOI: 10.1016/j.intimp.2021.108092] [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: 04/21/2021] [Revised: 08/18/2021] [Accepted: 08/22/2021] [Indexed: 01/17/2023]
Abstract
Indole- and hydantoin-based derivatives both exhibit anti-inflammatory activity, suggesting that the structures of indole and hydantoin are functional for this activity. In the present study, we synthesized two types of indole-hydantoin derivatives, IH-1 (5-(1H-indole-3-ylmethylene) imidazolidine-2,4-dione) and IH-2 (5-(1H-indole-3-ylmethyl) imidazolidine-2,4-dione) and examined their effects on LPS-induced inflammatory responses in murine macrophage-like RAW264.7 cells. LPS-induced inflammatory responses were not affected by indole, hydantoin, or IH-2. In contrast, IH-1 significantly inhibited the LPS-induced production of nitric oxide (NO) and secretion of CCL2 and CXCL1 by suppressing the mRNA expression of inducible NO synthase (iNOS), CCL2, and CXCL1. IH-1 markedly inhibited the LPS-induced activation of NF-κB without affecting the degradation of IκBα or nuclear translocation of NF-κB. IH-1 markedly attenuated the transcriptional activity of NF-κB by suppressing the LPS-induced phosphorylation of the NF-κB p65 subunit at Ser276. Furthermore, IH-1 prevented the LPS-induced interaction of NF-κB p65 subunit with a transcriptional coactivator, cAMP response element-binding protein (CBP). Collectively, these results revealed the potential of the novel indole-hydantoin derivative, IH-1 as an anti-inflammatory drug.
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Affiliation(s)
- Xin Lin
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Kenji Tago
- Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
| | - Nozomi Okazaki
- Division of Bio-organic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Takanori So
- Division of Bio-organic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Kyoko Takahashi
- Division of Bio-organic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Tadahiko Mashino
- Division of Bio-organic and Medicinal Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Hiroomi Tamura
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
| | - Megumi Funakoshi-Tago
- Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
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15
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Wang S, Zheng Y, Yang F, Zhu L, Zhu XQ, Wang ZF, Wu XL, Zhou CH, Yan JY, Hu BY, Kong B, Fu DL, Bruns C, Zhao Y, Qin LX, Dong QZ. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives. Signal Transduct Target Ther 2021; 6:249. [PMID: 34219130 PMCID: PMC8255319 DOI: 10.1038/s41392-021-00659-4] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/27/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.
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Affiliation(s)
- Shun Wang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Feng Yang
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China
| | - Le Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Xiao-Qiang Zhu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhe-Fang Wang
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Xiao-Lin Wu
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Cheng-Hui Zhou
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Jia-Yan Yan
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bei-Yuan Hu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Bo Kong
- Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - De-Liang Fu
- Department of Pancreatic Surgery, Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China
| | - Christiane Bruns
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany
| | - Yue Zhao
- General, Visceral and Cancer Surgery, University Hospital of Cologne, Cologne, Germany.
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, China.
- Key laboratory of whole-period monitoring and precise intervention of digestive cancer, Shanghai Municipal Health Commission (SMHC), Shanghai, China.
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16
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Chen Y, Lei Y, Lin J, Huang Y, Zhang J, Chen K, Sun S, Lin X. The LINC01260 Functions as a Tumor Suppressor via the miR-562/CYLD/NF-κB Pathway in Non-Small Cell Lung Cancer. Onco Targets Ther 2020; 13:10707-10719. [PMID: 33116647 PMCID: PMC7585791 DOI: 10.2147/ott.s253730] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/11/2020] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Recently, long noncoding RNAs (lncRNAs) have been identified as novel and potential therapeutic targets in various cancer types. Nonetheless, the levels and biological effects of lncRNAs in non-small cell lung cancer (NSCLC) remain largely unknown. In this study, we aimed to identify the effects of lncRNA-LINC01260 throughout the progression of NSCLC and explore the underlying mechanism. METHODS Quantitative real-time PCR (qRT-PCR) and Western blot were performed to measure LINC01260, miR-562, and CYLD expression and protein levels. Luciferase reporter assay was employed to investigate the relationship between LINC01260 and miR-562, and miR-562 and CYLD, respectively. The viability and migration of cells were evaluated using CCK-8, colony formation, and transwell assays. The effects of LINC01260 were identified through tumorigenesis in vivo. ELISA was performed to detect the activity of NF-κB and p65 expression. RESULTS In NSCLC tissues and cell lines, LINC01260 expression was downregulated, which corresponded to a lower survival rate of patients with NSCLC. Knockdown of LINC01260 accelerated the proliferation, colony formation, and migration of NSCLC cells. Moreover, downregulation of LINC01260 inhibited apoptosis of NSCLC cells by regulating the expression of Bcl-2 and Bax proteins in vitro. In vivo, the downregulation of LINC01260 promoted tumor growth. miR-562 was identified as the target gene of LINC01260, which was upregulated in NSCLC tumors. Furthermore, CYLD was identified as the target gene of miR-562. The effects of LINC01260 were exerted by regulating CYLD via sponging miR-562. ELISA confirmed that the upregulation of CYLD inhibited NF-κB activity; however, the co-transfection of sh-LINC01260 partly reversed the inhibition. Additionally, CYLD reduced p65 expression; however, downregulation of LINC01260 slightly increased the expression level. CONCLUSION This study revealed a novel LINC01260/miR-562/CYLD/NF-κB pathway in the pathogenesis of NSCLC and suggested a potential therapeutic target for NSCLC.
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Affiliation(s)
- Yangming Chen
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
| | - Yujie Lei
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, The International Cooperation Key Laboratory of Regional Tumor in High Altitude Area, Kunming, Yunnan650106, People’s Republic of China
| | - Jianbin Lin
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
| | - Yunchao Huang
- Department of Thoracic Surgery I, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, The International Cooperation Key Laboratory of Regional Tumor in High Altitude Area, Kunming, Yunnan650106, People’s Republic of China
| | - Jiguang Zhang
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
| | - Kai Chen
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
| | - Shihui Sun
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
| | - Xing Lin
- Department of Thoracic Surgery, Shengli Clinical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian350001, People’s Republic of China
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