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Reid G, Williams M, Cheng YY, Sarun K, Winata P, Kirschner MB, Mugridge N, Weiss J, Molloy M, Brahmbhatt H, MacDiarmid J, van Zandwijk N. Therapeutic potential of synthetic microRNA mimics based on the miR-15/107 consensus sequence. Cancer Gene Ther 2025; 32:486-496. [PMID: 40121357 PMCID: PMC11976272 DOI: 10.1038/s41417-025-00885-w] [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: 09/15/2024] [Revised: 02/11/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
MicroRNA expression is frequently suppressed in cancer, and previously we demonstrated coordinate downregulation of multiple related microRNAs of the miR-15/107 group in malignant pleural mesothelioma (PM). From an alignment of the miR-15 family and the related miR-103/107, we derived a consensus sequence and used this to generate synthetic mimics. The synthetic mimics displayed tumour suppressor activity in PM cells in vitro, which was greater than that of a mimic based on the native miR-16 sequence. These mimics were also growth inhibitory in cells from non-small cell lung (NSCLC), prostate, breast and colorectal cancer, and sensitised all cell lines to the chemotherapeutic drug gemcitabine. The increased activity corresponded to enhanced inhibition of the expression of target genes and was associated with an increase in predicted binding to target sites, and proteomic analysis revealed a strong effect on proteins involved in RNA and DNA processes. Applying the novel consensus mimics to xenograft models of PM and NSCLC in vivo using EGFR-targeted nanocells loaded with mimic led to tumour growth inhibition. These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.
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Affiliation(s)
- Glen Reid
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia.
- School of Medicine, University of Sydney, Sydney, NSW, Australia.
- Department of Pathology, University of Otago, Dunedin, New Zealand.
| | - Marissa Williams
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- School of Medicine, University of Sydney, Sydney, NSW, Australia
| | - Yuen Yee Cheng
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- School of Medicine, University of Sydney, Sydney, NSW, Australia
- Institute for Biomedical Materials and Devices (IBMD), University of Technology Sydney, Sydney, Australia
| | - Kadir Sarun
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
| | - Patrick Winata
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
| | - Michaela B Kirschner
- Asbestos and Dust Diseases Research Institute (ADDRI), Sydney, NSW, Australia
- Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
| | | | | | - Mark Molloy
- The Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia
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Shah AU, Hemida MG. The dual actions of miRNA16a in restricting Bovine Coronavirus replication through downregulation of Furin and enhancing the host immune response. Sci Rep 2024; 14:29308. [PMID: 39592722 PMCID: PMC11599744 DOI: 10.1038/s41598-024-80708-4] [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: 08/13/2024] [Accepted: 11/21/2024] [Indexed: 11/28/2024] Open
Abstract
The roles of host cell miRNAs have not been well studied in the context of BCoV replication and immune regulation. This study aimed to identify miRNA candidates that regulate essential host genes involved in BCoV replication, tissue tropism, and immune regulation. To achieve these goals, we used two isolates of BCoV (enteric and respiratory) to infect bovine endothelial cells (BECs) and Madine Darby Bovine Kidney (MDBK) cells. We determined the miRNA expression profiles of these cells after BCoV infection. The expression of miRNA16a is differentially altered during BCoV infection. Our data show that miRNA16a is a significantly downregulated miRNA in both in vitro and ex vivo models. We confirmed the miRNA16aexpression profile by qRT-PCR. Overexpression of pre-miRNA16ain the BEC and the MDBK cell lines markedly inhibited BCoV infection, as determined by the viral genome copy numbers measured by qRT‒PCR, viral protein expression (S and N) measured by Western blot, and virus infectivity using a plaque assay. Our bioinformatic prediction showed that Furin is a potential target of miRNA16a. We compared the Furin protein expression level in pre-miRNA16a-transfected/BCoV-infected cells to that in pre-miRNA-scrambled-transfected cells. Our qRT-PCR and Western blot data revealed marked inhibition of Furin expression at the mRNA and protein levels, respectively. BCoV-S protein expression was markedly inhibited at both the mRNA and protein levels. To further confirm the impact of the downregulation of the Furin enzyme on the replication of BCoV, we transfected cells with specific Furin-siRNAs parallel to the scrambled siRNA. Marked inhibition of BCoV replication was observed in the Furin-siRNA-treated group. To further validate Furin as a novel target for miRNA16a, we cloned the 3'UTR of bovine Furin carrying the seed region of miRNA16a in the dual luciferase vector. Our data showed that luciferase activity in pre-miRNA16a-transfected cells decreased by more than 50% compared to cells transfected with the construct carrying the mutated Furin seed region. Our data confirmed that miRNA16ainhibits BCoV replication by targeting the host cell line Furin and the BCoV-S glycoprotein. It also enhances the host immune response, which contributes to the inhibition of viral replication. This is the first study to confirm that Furin is a valid target of miRNA16a. Our findings highlight the clinical applications of host miRNA16a as a potential miRNA-based vaccine/antiviral therapy.
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Affiliation(s)
- Abid Ullah Shah
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, 212 Roth Hall, 720 Northern Blvd., Brookville, NY, 11548, USA
| | - Maged Gomaa Hemida
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, 212 Roth Hall, 720 Northern Blvd., Brookville, NY, 11548, USA.
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Tsai HY, Wang JC, Hsu YJ, Lin CY, Huang PH, Tsai MC, Hsu CW, Yang SF, Tsai SH. miR-424/322 attenuates cardiac remodeling by modulating the nuclear factor-activated T-cell 3/furin pathway. Biomed J 2024:100818. [PMID: 39586376 DOI: 10.1016/j.bj.2024.100818] [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: 03/13/2024] [Revised: 11/07/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Cardiac remodeling is implicated in numerous physiologic and pathologic conditions, including scar formation, heart failure, and cardiac arrhythmias. Nuclear factor-activated T-cell cytoplasmic (NFATc) is a crucial transcription factor that regulates cardiac remodeling. MicroRNA (miR)-424/322 has pathophysiological roles in the cardiovascular and respiratory systems by modulating hypoxia and inflammatory pathways. The role of miR-424/322 in regulating cardiac remodeling is under investigation. We identified several cardiac hypertrophy and fibrosis-related molecules as putative targets of miR-424/322. We propose that miR-424/322 could have crucial roles in cardiac remodeling by modulating several key molecules for cardiac fibrosis and hypertrophy. METHODS Human cardiac fibroblasts (HCFs) and a myogenic cell line H9c2 cells were used for in vitro experiments. A murine model of angiotensin II (AngII)-induced cardiac remodeling was used to assess the roles of miR-322 on cardiac hypertrophy and fibrosis in vivo. Immunoblotting, immunofluorescence, real-time polymerase chain reaction and cell proliferation, Sirius Red, and dual-luciferase reporter assays were used to decipher the molecular mechanism. RESULTS We found that miR-322 knockout mice were susceptible to AngII-induced cardiac fibrosis and hypertrophy in vivo. Administration of miR-424/322 inhibitors aggravated AngII-induced overexpression of NFATc3, furin, natriuretic peptides and collagen 1A1 in H9c2 cells and HCFs. miR-424/322 mimics reversed the AngII-induced fibrosis, hypertrophy, and proliferation by targeting NFATc3 and furin in vitro. miR-424/322 could be transactivated by NFATc3. Exogenous miR-322 ameliorated AngII-induced hypertrophy and cardiac fibrosis in vivo. CONCLUSIONS The NFATc3/miR-424/322/furin axis is crucial for developing cardiac remodeling, and exogenous miR-322 mimics could have therapeutic potential in cardiac remodeling.
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Affiliation(s)
- Hsiao-Ya Tsai
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jen-Chun Wang
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Juei Hsu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Yuan Lin
- Department of Surgery, Division of Cardiovascular Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Po-Hsun Huang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Min-Chien Tsai
- Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan
| | - Chin-Wang Hsu
- Department of Emergency Medicine, School of Medicine, College of Medicine; Taipei Medical University, Taipei, Taiwan; Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Shang-Feng Yang
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan; Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan.
| | - Shih-Hung Tsai
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan; Taichung Armed Forces General Hospital, Taichung, Taiwan.
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Wu X, Tian Y, Zhang N, Ren Y, Zhang Z, Zhao Y, Guo Y, Gong Y, Zhang Y, Li D, Li H, Jiang R, Li G, Liu X, Kang X, Tian Y. The role of AdipoQ on proliferation, apoptosis, and hormone Secretion in chicken primary adenohypophysis cells. Poult Sci 2024; 103:104137. [PMID: 39142032 PMCID: PMC11379664 DOI: 10.1016/j.psj.2024.104137] [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: 04/01/2024] [Revised: 07/15/2024] [Accepted: 07/24/2024] [Indexed: 08/16/2024] Open
Abstract
Adiponectin (AdipoQ), an adipokine secreted by adipocytes, has been reported to exist widely in various cell types and tissues, including the adenohypophysis of chickens. However, the molecular mechanism by which AdipoQ regulates the function of chicken adenohypophysis remains elusive. In this study, we investigated the effects of AdipoQ on proliferation, apoptosis, secretion of related hormones (FSH, LH, TSH, GH, PRL and ACTH) and expression of related genes (FSHβ, LHβ, GnRHR, TSHβ, GH, PRL and ACTH) in primary adenohypophysis cells of chickens by using real-time fluorescent quantitative PCR (RT-qPCR), cell counting kit-8 (CCK-8), flow cytometry, enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) assays. Our results showed that AdipoQ promoted the proliferation of chicken primary adenohypophysis cells, up-regulated the mRNA expression of proliferation-related genes CDK1, PCNA, CCND1 and P21 (P < 0.05), as well as the increased protein expression of CDK1 and PCNA (P < 0.05). Furthermore, AdipoQ inhibited apoptosis of chicken primary adenohypophysis cells, resulting in down-regulation of pro-apoptotic genes Caspase3, Fas, and FasL mRNA expression, and decreased Caspase3 protein expression (P < 0.05). Moreover, there was an up-regulation of anti-apoptotic gene Bcl2 mRNA and protein expression (P < 0.05). Additionally, AdipoQ suppressed the secretion of FSH, LH, TSH, GH, PRL, and ACTH (P < 0.05), as well as the mRNA expression levels of related genes (P < 0.05). Treatment with AdipoRon (a synthetic substitute for AdipoQ) and co-treatment with RNA interference targeting AdipoQ receptors 1/2 (AdipoR1/2) had no effect on the secretion of FSH, LH, TSH, GH, PRL, and ACTH, as well as the mRNA expression levels of the related genes. This suggests that AdipoQ's regulation of hormone secretion and related gene expression is mediated by the AdipoR1/2 signaling axis. Importantly, we further demonstrated that the mechanism of AdipoQ on FSH, LH, TSH and GH secretion is realized through AMPK signaling pathway. In conclusion, we have revealed, for the first time the molecular mechanism by which AdipoQ regulates hormone secretion in chicken primary adenohypophysis cells.
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Affiliation(s)
- Xing Wu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yixiang Tian
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Na Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yangguang Ren
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Zihao Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yudian Zhao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yulong Guo
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yujie Gong
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yanhua Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Donghua Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Hong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Ruirui Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Guoxi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xiaojun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China.
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Christoforidou E, Moody L, Joilin G, Simoes FA, Gordon D, Talbot K, Hafezparast M. An ALS-associated mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner. Dis Model Mech 2024; 17:dmm050638. [PMID: 38721655 PMCID: PMC11152562 DOI: 10.1242/dmm.050638] [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: 11/30/2023] [Accepted: 04/29/2024] [Indexed: 05/30/2024] Open
Abstract
Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation originates from microglia. Furthermore, TDP-43 (encoded by TARDBP), involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of three candidate miRNAs, namely, miR-16-5p, miR-99a-5p and miR-191-5p, by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and identified their predicted targets, which primarily include genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia, which may in turn be a source of the miRNA dysregulation observed in the disease. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
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Affiliation(s)
- Eleni Christoforidou
- Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
| | - Libby Moody
- Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
| | - Greig Joilin
- Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
| | - Fabio A. Simoes
- Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
| | - David Gordon
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK
| | - Kevin Talbot
- Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK
| | - Majid Hafezparast
- Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
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ZENUNAJ G. The role of circulating miRNAs as predictive biomarkers for the neointimal hyperplasia after femoro-popliteal endovascular procedures for symptomatic peripheral arterial disease. ITALIAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY 2024; 30. [DOI: 10.23736/s1824-4777.23.01634-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
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Wheeler BD, Gagnon JD, Zhu WS, Muñoz-Sandoval P, Wong SK, Simeonov DS, Li Z, DeBarge R, Spitzer MH, Marson A, Ansel KM. The lncRNA Malat1 inhibits miR-15/16 to enhance cytotoxic T cell activation and memory cell formation. eLife 2023; 12:RP87900. [PMID: 38127070 PMCID: PMC10735224 DOI: 10.7554/elife.87900] [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] [Indexed: 12/23/2023] Open
Abstract
Proper activation of cytotoxic T cells via the T cell receptor and the costimulatory receptor CD28 is essential for adaptive immunity against viruses, intracellular bacteria, and cancers. Through biochemical analysis of RNA:protein interactions, we uncovered a non-coding RNA circuit regulating activation and differentiation of cytotoxic T cells composed of the long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and the microRNA family miR-15/16. miR-15/16 is a widely and highly expressed tumor suppressor miRNA family important for cell proliferation and survival. miR-15/16 play important roles in T cell responses to viral infection, including the regulation of antigen-specific T cell expansion and memory. Comparative Argonaute-2 high-throughput sequencing of crosslinking immunoprecipitation (AHC) combined with gene expression profiling in normal and miR-15/16-deficient mouse T cells revealed a large network of hundreds of direct miR-15/16 target mRNAs, many with functional relevance for T cell activation, survival and memory formation. Among these targets, Malat1 contained the largest absolute magnitude miR-15/16-dependent AHC peak. This binding site was among the strongest lncRNA:miRNA interactions detected in the T cell transcriptome. We used CRISPR targeting with homology directed repair to generate mice with a 5-nucleotide mutation in the miR-15/16-binding site in Malat1. This mutation interrupted Malat1:miR-15/16 interaction, and enhanced the repression of other miR-15/16 target genes, including CD28. Interrupting Malat1 interaction with miR-15/16 decreased cytotoxic T cell activation, including the expression of interleukin 2 (IL-2) and a broader CD28-responsive gene program. Accordingly, Malat1 mutation diminished memory cell persistence in mice following LCMV Armstrong and Listeria monocytogenes infection. This study marks a significant advance in the study of long non-coding RNAs in the immune system by ascribing cell-intrinsic, sequence-specific in vivo function to Malat1. These findings have implications for T cell-mediated autoimmune diseases, antiviral and anti-tumor immunity, as well as lung adenocarcinoma and other malignancies where Malat1 is overexpressed.
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Affiliation(s)
- Benjamin D Wheeler
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Sandler Asthma Basic Research Program, University of California, San FranciscoSan FranciscoUnited States
| | - John D Gagnon
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Sandler Asthma Basic Research Program, University of California, San FranciscoSan FranciscoUnited States
| | - Wandi S Zhu
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Sandler Asthma Basic Research Program, University of California, San FranciscoSan FranciscoUnited States
| | - Priscila Muñoz-Sandoval
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Sandler Asthma Basic Research Program, University of California, San FranciscoSan FranciscoUnited States
| | - Simon K Wong
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
| | - Dimitre S Simeonov
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
| | - Zhongmei Li
- Gladstone-UCSF Institute of Genomic ImmunologySan FranciscoUnited States
| | - Rachel DeBarge
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Gladstone-UCSF Institute of Genomic ImmunologySan FranciscoUnited States
- Department of Otolaryngology-Head and Neck Surgery, University of California San FranciscoSan FranciscoUnited States
| | - Matthew H Spitzer
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Gladstone-UCSF Institute of Genomic ImmunologySan FranciscoUnited States
- Department of Otolaryngology-Head and Neck Surgery, University of California San FranciscoSan FranciscoUnited States
- Parker Institute for Cancer Immunotherapy, San FranciscoSan FranciscoUnited States
- Chan Zuckerberg BiohubSan FranciscoUnited States
| | - Alexander Marson
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Gladstone-UCSF Institute of Genomic ImmunologySan FranciscoUnited States
- Department of Medicine, University of California San FranciscoLexingtonUnited States
| | - K Mark Ansel
- Department of Microbiology & Immunology, University of California San FranciscoSan FranciscoUnited States
- Sandler Asthma Basic Research Program, University of California, San FranciscoSan FranciscoUnited States
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Gupta S, Silveira DA, Mombach JCM, Hashimoto RF. The lncRNA DLX6-AS1/miR-16-5p axis regulates autophagy and apoptosis in non-small cell lung cancer: A Boolean model of cell death. Noncoding RNA Res 2023; 8:605-614. [PMID: 37767112 PMCID: PMC10520667 DOI: 10.1016/j.ncrna.2023.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/25/2023] [Accepted: 08/06/2023] [Indexed: 09/29/2023] Open
Abstract
Long non-coding RNA (lncRNA) distal-less homeobox 6 antisense RNA 1 (DLX6-AS1) is elevated in a variety of cancers, including non-small cell lung cancer (NSCLC) and cervical cancer. Although it was found that the microRNA-16-5p (miR-16), which is known to regulate autophagy and apoptosis, had been downregulated in similar cancers. Recent research has shown that in tumors with similar characteristics, DLX6-AS1 acts as a sponge for miR-16 expression. However, the cell death-related molecular mechanism of the DLX6-AS1/miR-16 axis has yet to be investigated. Therefore, we propose a dynamic Boolean model to investigate gene regulation in cell death processes via the DLX6-AS1/miR-16 axis. We found the finest concordance when we compared our model to many experimental investigations including gain-of-function genes in NSCLC and cervical cancer. A unique positive circuit involving BMI1/ATM/miR-16 is also something we predict. Our results suggest that this circuit is essential for regulating autophagy and apoptosis under stress signals. Thus, our Boolean network enables an evident cell-death process coupled with NSCLC and cervical cancer. Therefore, our results suggest that DLX6-AS1 targeting may boost miR-16 activity and thereby restrict tumor growth in these cancers by triggering autophagy and apoptosis.
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Affiliation(s)
- Shantanu Gupta
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua Do Matão 1010, São Paulo, SP, 05508-090, Brazil
| | - Daner A. Silveira
- Children's Cancer Institute, Porto Alegre, Rio Grande do Sul, Brazil
| | - José Carlos M. Mombach
- Departamento de Física, Universidade Federal de Santa Maria, Santa Maria, RS, 97105-900, Brazil
| | - Ronaldo F. Hashimoto
- Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua Do Matão 1010, São Paulo, SP, 05508-090, Brazil
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Asberger J, Berner K, Bicker A, Metz M, Jäger M, Weiß D, Kreutz C, Juhasz-Böss I, Mayer S, Ge I, Erbes T. In Vitro microRNA Expression Profile Alterations under CDK4/6 Therapy in Breast Cancer. Biomedicines 2023; 11:2705. [PMID: 37893081 PMCID: PMC10604872 DOI: 10.3390/biomedicines11102705] [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: 07/25/2023] [Revised: 09/16/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Breast cancer is the most common type of cancer worldwide. Cyclin-dependent kinase inhibition is one of the backbones of metastatic breast cancer therapy. However, there are a significant number of therapy failures. This study evaluates the biomarker potential of microRNAs for the prediction of a therapy response under cyclin-dependent kinase inhibition. METHODS This study comprises the analysis of intracellular and extracellular microRNA-expression-level alterations of 56 microRNAs under palbociclib mono as well as combination therapy with letrozole. Breast cancer cell lines BT-474, MCF-7 and HS-578T were analyzed using qPCR. RESULTS A palbociclib-induced microRNA signature could be detected intracellularly as well as extracellularly. Intracellular miR-10a, miR-15b, miR-21, miR-23a and miR-23c were constantly regulated in all three cell lines, whereas let-7b, let-7d, miR-15a, miR-17, miR-18a, miR-20a, miR-191 and miR301a_3p were regulated only in hormone-receptor-positive cells. Extracellular miR-100, miR-10b and miR-182 were constantly regulated across all cell lines, whereas miR-17 was regulated only in hormone-receptor-positive cells. CONCLUSIONS Because they are secreted and significantly upregulated in the microenvironment of tumor cells, miRs-100, -10b and -182 are promising circulating biomarkers that can be used to predict or detect therapy responses under CDK inhibition. MiR-10a, miR-15b, miR-21, miR-23a and miR-23c are potential tissue-based biomarkers.
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Affiliation(s)
- Jasmin Asberger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Kai Berner
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Bicker
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynecology, St. Josefs-Hospital Wiesbaden, 65189 Wiesbaden, Germany
| | - Marius Metz
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Markus Jäger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daniela Weiß
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Clemens Kreutz
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, 79104 Freiburg, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Sebastian Mayer
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Hospital Krumbach, 86381 Krumbach, Germany
| | - Isabell Ge
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynaecology, University Hospital of Basel, 4056 Basel, Switzerland
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Diako Mannheim, 68135 Mannheim, Germany
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10
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Nurcan Yüksel T, Bozgeyik E, Bozgeyik İ. The Role and Antagonistic Effects of miR-16-5p in the Regulation of ADP-Ribosylation Factor-Like Tumor Suppressor Gene 1 in Lung Cancer Cells. Eurasian J Med 2023; 55:204-207. [PMID: 37909191 PMCID: PMC10724712 DOI: 10.5152/eurasianjmed.2023.23073] [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: 03/08/2023] [Accepted: 04/28/2023] [Indexed: 11/02/2023] Open
Abstract
OBJECTIVE ADP-ribosylation factor-like tumor suppressor gene 1 is a member of the Ras superfamily of small guanosine triphosphatases that are known to be involved in multiple regulatory pathways in the multistage development of human cancers. Also, ADP-ribosylation factor-like tumor suppressor gene 1 expression levels have been reported to be dramatically lower in both cancer cell lines and tumor tissues compared to controls. Accordingly, defects in the regulation of the ADP-ribosylation factor-like tumor suppressor gene 1 gene seems have key tumor suppressive effects in the formation and development of human cancers including lung cancer. Moreover, microRNAs regulating the expression of ADP-ribosylation factor-like tumor suppressor gene 1 have not been described previously. Accordingly, the present study aimed to reveal the influence of miR-16-5p on the regulation of ADP-ribosylation factor-like tumor suppressor gene 1 gene. MATERIALS AND METHODS A549 lung adenocarcinoma cells were used. For the overexpression and silencing experiments of miR-16-5p synthetic microRNA mimics and inhibitors were used, respectively. Gene expression analyses were achieved with the help of quantitative real-time polymerase chain reaction. RESULTS MiR-16-5p was identified to be predictive target of ADP-ribosylation factor-like tumor suppressor gene 1 and directly targets the expression of ADP-ribosylation factor-like tumor suppressor gene 1 as revealed by the overexpression and silencing experiments. Specifically, it was found that miR-16-5p-overexpressed A549 cells showed a decrease in ADP-ribosylation factor-like tumor suppressor gene 1 gene expression, whereas miR16-5p-suppressed cells showed an increase in expression. These findings possibly suggest that miR-16-5p is the direct regulatory microRNA that posttranscriptionally regulates the expression of ADP-ribosylation factor-like tumor suppressor gene 1. CONCLUSION Collectively, miR-16-5p seems to be a key regulatory molecule involved in the posttranscriptional regulation of the ADP-ribosylation factor-like tumor suppressor gene 1, and it might be responsible for the downregulation of this gene in lung cancer.
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Affiliation(s)
- Tuğba Nurcan Yüksel
- Department of Pharmacology, Tekirdağ Namik Kemal University Faculty of Medicine, Tekirdağ, Turkey
| | - Esra Bozgeyik
- Department of Medical Services and Techniques, Adiyaman University Vocational School of Health Sciences, Adiyaman, Turkey
| | - İbrahim Bozgeyik
- Department of Medical Biology, Adiyaman University Faculty of Medicine, Adiyaman, Turkey
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11
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Abd-Elmawla MA, Abdel Mageed SS, Al-Noshokaty TM, Elballal MS, Abulsoud AI, Elshaer SS, El-Husseiny AA, Fathi D, Midan HM, Rizk NI, Elrebehy MA, Sayed GA, Tabaa MME, Salman A, Mohammed OA, Ashraf A, Khidr EG, Khaled R, El-Dakroury WA, Helal GK, Moustafa YM, Doghish AS. Melodic maestros: Unraveling the role of miRNAs in the diagnosis, progression, and drug resistance of malignant pleural mesothelioma. Pathol Res Pract 2023; 250:154817. [PMID: 37713736 DOI: 10.1016/j.prp.2023.154817] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/03/2023] [Accepted: 09/09/2023] [Indexed: 09/17/2023]
Abstract
Malignant pleural mesothelioma (MPM) is a highly lethal form of pleural cancer characterized by a scarcity of effective therapeutic interventions, resulting in unfavorable prognoses for afflicted individuals. Besides, many patients experience substantial consequences from being diagnosed in advanced stages. The available diagnostic, prognostic, and therapeutic options for MPM are restricted in scope. MicroRNAs (miRNAs) are a subset of small, noncoding RNA molecules that exert significant regulatory influence over several cellular processes within cell biology. A wide range of miRNAs have atypical expression patterns in cancer, serving specific functions as either tumor suppressors or oncomiRs. This review aims to collate, epitomize, and analyze the latest scholarly investigations on miRNAs that are believed to be implicated in the dysregulation leading to MPM. miRNAs are also discussed concerning their potential clinical usefulness as diagnostic and prognostic biomarkers for MPM. The future holds promising prospects for enhancing diagnostic, prognostic, and therapeutic modalities for MPM, with miRNAs emerging as a potential trigger for such advancements.
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Affiliation(s)
- Mai A Abd-Elmawla
- Biochemistry, Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Manar Mohammed El Tabaa
- Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City 32897, Menoufia, Egypt
| | - Aya Salman
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Alaa Ashraf
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt
| | - Reem Khaled
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Gouda Kamel Helal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo 11231, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Yasser M Moustafa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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12
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Gorbea C, Elhakiem A, Cazalla D. Shaping the host cell environment with viral noncoding RNAs. Semin Cell Dev Biol 2023; 146:20-30. [PMID: 36581481 PMCID: PMC10101873 DOI: 10.1016/j.semcdb.2022.12.008] [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: 08/29/2022] [Revised: 12/24/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022]
Abstract
Just like the cells they infect viruses express different classes of noncoding RNAs (ncRNAs). Viral ncRNAs come in all shapes and forms, and they usually associate with cellular proteins that are important for their functions. Viral ncRNAs have diverse functions, but they all contribute to the viral control of the cellular environment. Viruses utilize ncRNAs to regulate viral replication, to decide whether they should remain latent or reactivate, to evade the host immune responses, or to promote cellular transformation. In this review we describe the diverse functions played by different classes of ncRNAs expressed by adenoviruses and herpesviruses, how they contribute to the viral infection, and how their study led to insights into RNA-based mechanisms at play in host cells.
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Affiliation(s)
- Carlos Gorbea
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Abdalla Elhakiem
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
| | - Demián Cazalla
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
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13
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Otsuka K, Nishiyama H, Kuriki D, Kawada N, Ochiya T. Connecting the dots in the associations between diet, obesity, cancer, and microRNAs. Semin Cancer Biol 2023; 93:52-69. [PMID: 37156343 DOI: 10.1016/j.semcancer.2023.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
The prevalence of obesity has reached pandemic levels worldwide, leading to a lower quality of life and higher health costs. Obesity is a major risk factor for noncommunicable diseases, including cancer, although obesity is one of the major preventable causes of cancer. Lifestyle factors, such as dietary quality and patterns, are also closely related to the onset and development of obesity and cancer. However, the mechanisms underlying the complex association between diet, obesity, and cancer remain unclear. In the past few decades, microRNAs (miRNAs), a class of small non-coding RNAs, have been demonstrated to play critical roles in biological processes such as cell differentiation, proliferation, and metabolism, highlighting their importance in disease development and suppression and as therapeutic targets. miRNA expression levels can be modulated by diet and are involved in cancer and obesity-related diseases. Circulating miRNAs can also mediate cell-to-cell communications. These multiple aspects of miRNAs present challenges in understanding and integrating their mechanism of action. Here, we introduce a general consideration of the associations between diet, obesity, and cancer and review the current knowledge of the molecular functions of miRNA in each context. A comprehensive understanding of the interplay between diet, obesity, and cancer could be valuable for the development of effective preventive and therapeutic strategies in future.
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Affiliation(s)
- Kurataka Otsuka
- Tokyo NODAI Research Institure, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan; R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan; Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan; Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiroshi Nishiyama
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Daisuke Kuriki
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Naoki Kawada
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan
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14
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Wheeler BD, Gagnon JD, Zhu WS, Muñoz-Sandoval P, Wong SK, Simeonov DR, Li Z, Debarge R, Spitzer MH, Marson A, Ansel KM. The lncRNA Malat1 Inhibits miR-15/16 to Enhance Cytotoxic T Cell Activation and Memory Cell Formation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.14.536843. [PMID: 37547023 PMCID: PMC10401941 DOI: 10.1101/2023.04.14.536843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
Proper activation of cytotoxic T cells via the T cell receptor and the costimulatory receptor CD28 is essential for adaptive immunity against viruses, many intracellular bacteria and cancers. Through biochemical analysis of RNA:protein interactions, we uncovered a non-coding RNA circuit regulating activation and differentiation of cytotoxic T cells composed of the long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and the microRNA family miR-15/16. miR-15/16 is a widely and highly expressed tumor suppressor miRNA family important for cell proliferation and survival. miR-15/16 also play important roles in T cell responses to viral infection, including the regulation of antigen-specific T cell expansion and T cell memory. Comparative Argonaute-2 high throughput sequencing of crosslinking immunoprecipitation (Ago2 HITS-CLIP, or AHC) combined with gene expression profiling in normal and miR-15/16-deficient T cells revealed a large network of several hundred direct miR-15/16 target mRNAs, many with functional relevance for T cell activation, survival and memory formation. Among these targets, the long non-coding RNA Malat1 contained the largest absolute magnitude miR-15/16-dependent AHC peak in T cells. This binding site was also among the strongest lncRNA:miRNA interactions detected in the T cell transcriptome. We used CRISPR targeting with homology directed repair to generate mice with a 5-nucleotide mutation in the miR-15/16 binding site in Malat1. This mutation interrupted Malat1:miR-15/16 interaction, and enhanced the repression of other miR-15/16 target genes, including CD28. Interrupting Malat1 interaction with miR-15/16 decreased cytotoxic T cell activation, including the expression of IL-2 and a broader CD28-responsive gene program. Accordingly, Malat1 mutation diminished memory cell persistence following LCMV Armstrong and Listeria monocytogenes infection. This study marks a significant advance in the study of long noncoding RNAs in the immune system by ascribing cell-intrinsic, sequence-specific in vivo function to Malat1. These findings have implications for T cell-mediated autoimmune diseases, antiviral and anti-tumor immunity, as well as lung adenocarcinoma and other malignancies where Malat1 is overexpressed.
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Affiliation(s)
- Benjamin D Wheeler
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Program, University of California, San Francisco, San Francisco, CA, USA
| | - John D Gagnon
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Program, University of California, San Francisco, San Francisco, CA, USA
| | - Wandi S Zhu
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Program, University of California, San Francisco, San Francisco, CA, USA
| | - Priscila Muñoz-Sandoval
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Program, University of California, San Francisco, San Francisco, CA, USA
| | - Simon K Wong
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Dimitre R Simeonov
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
| | - Zhongmei Li
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Rachel Debarge
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Matthew H Spitzer
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
- Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129
- Chan Zuckerberg Biohub, San Francisco, CA 94158
| | - Alexander Marson
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
- Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA
| | - K Mark Ansel
- Department of Microbiology & Immunology, University of California San Francisco, San Francisco, CA 94143, USA
- Sandler Asthma Basic Research Program, University of California, San Francisco, San Francisco, CA, USA
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15
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Firouzjaei AA, Sharifi K, Khazaei M, Mohammadi-Yeganeh S, Aghaee-Bakhtiari SH. Screening and introduction of key cell cycle microRNAs deregulated in colorectal cancer by integrated bioinformatics analysis. Chem Biol Drug Des 2023; 102:137-152. [PMID: 37081586 DOI: 10.1111/cbdd.14242] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 03/05/2023] [Accepted: 04/03/2023] [Indexed: 04/22/2023]
Abstract
Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. Impaired cell cycle regulation leads to many cancers and is also approved in CRC. Therefore, cell cycle regulation is a critical therapeutic target for CRC. Furthermore, miRNAs have been discovered as regulators in a variety of cancer-related pathways. This study is designed to investigate how miRNAs and mRNAs interact to regulate the cell cycle in CRC patients. Utilizing the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Expression Omnibus (GEO), and Therapeutic Target Database (TTD), cell cycle-associated genes were identified and evaluated. Seven of the 22 differentially expressed genes (DEGs) implicated in the cell cycle in three GSEs (GSE24514, GSE10950, and GSE74604) were identified as potential therapeutic targets. Then, using PyRx software, we performed docking proteins with selected drugs. The results demonstrated that these drugs are appropriate molecules for targeting cell cycle DEGs. Tarbase, miRTarbase, miRDIP, and miRCancer databases were used to find miRNAs that target the indicated genes. The ability of these six miRNAs to impact the cell cycle in colorectal cancer may be concluded. These miRNAs were found to be downregulated in SW480 cells when compared to the normal tissue. Our data imply that a precise selection of bioinformatics tools can facilitate the identification of miRNAs that impact mRNA translation at different stages of the cell cycle. The candidates can be investigated more as targets for cell cycle arrest in cancers.
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Affiliation(s)
- Ali Ahmadizad Firouzjaei
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kazem Sharifi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samira Mohammadi-Yeganeh
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hamid Aghaee-Bakhtiari
- Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Hu Q, Huang T. Regulation of the Cell Cycle by ncRNAs Affects the Efficiency of CDK4/6 Inhibition. Int J Mol Sci 2023; 24:ijms24108939. [PMID: 37240281 DOI: 10.3390/ijms24108939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.
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Affiliation(s)
- Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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17
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Zanjirband M, Rahgozar S, Aberuyi N. miR-16-5p enhances sensitivity to RG7388 through targeting PPM1D expression (WIP1) in Childhood Acute Lymphoblastic Leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2023; 6:242-256. [PMID: 37457129 PMCID: PMC10344722 DOI: 10.20517/cdr.2022.113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 03/02/2023] [Accepted: 04/28/2023] [Indexed: 07/18/2023]
Abstract
Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.
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Affiliation(s)
- Maryam Zanjirband
- Correspondence to: Dr. Soheila Rahgozar, Dr. Maryam Zanjirband, Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Avenue, Isfahan 15100, Iran. E-mail: ;
| | - Soheila Rahgozar
- Correspondence to: Dr. Soheila Rahgozar, Dr. Maryam Zanjirband, Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Avenue, Isfahan 15100, Iran. E-mail: ;
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Bhatia A, Upadhyay AK, Sharma S. miRNAs are now starring in "No Time to Die: Overcoming the chemoresistance in cancer". IUBMB Life 2023; 75:238-256. [PMID: 35678612 DOI: 10.1002/iub.2652] [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: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 12/24/2022]
Abstract
Cancer is a leading cause of death globally, with about 19.3 million new cases reported each year. Current therapies for cancer management include-chemotherapy, radiotherapy, and surgery. However, they are loaded with side effects and tend to cause toxicity in the patient's body posttreatment, ultimately hindering the response towards the treatment building up resistance. This is where noncoding RNAs such as miRNAs help provide us with a helping hand for taming the chemoresistance and providing potential holistic cancer management. MicroRNAs are promising targets for anticancer therapy as they perform critical regulatory roles in various signaling cascades related to cell proliferation, apoptosis, migration, and invasion. Combining miRNAs and anticancer drugs and devising a combination therapy has managed cancer well in various independent studies. This review aims to provide insights into how miRNAs play a mechanistic role in cancer development and progression and regulate drug resistance in various types of cancers. Furthermore, next-generation novel therapies using miRNAs in combination with anticancer treatments in multiple cancers have been put forth and how they improve the efficacy of the treatments. Exemplary studies currently in the preclinical and clinical models have been summarized. Ultimately, we briefly talk through the challenges that come forward with it and minimize them.
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Affiliation(s)
- Anmol Bhatia
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Atul Kumar Upadhyay
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
| | - Siddharth Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, India
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19
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Rahman MM, Nakanishi R, Tsukada F, Takashima S, Wakihara Y, Kamatari YO, Shimizu K, Okada A, Inoshima Y. Identification of Suitable Internal Control miRNAs in Bovine Milk Small Extracellular Vesicles for Normalization in Quantitative Real-Time Polymerase Chain Reaction. MEMBRANES 2023; 13:185. [PMID: 36837688 PMCID: PMC9961204 DOI: 10.3390/membranes13020185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/17/2023] [Accepted: 01/31/2023] [Indexed: 06/18/2023]
Abstract
This study aimed to identify a suitable RNA extraction kit and stable internal control microRNA (miRNA) in bovine milk small extracellular vesicles (sEVs) for a quantitative polymerase chain reaction (qPCR) analysis. Two RNA extraction kits, miRNeasy Micro Kit, and Maxwell RSC miRNA Tissue Kit, were compared and evaluated using bovine milk sEVs via qPCR analysis. Five miRNAs, bta-miR-29a, bta-miR-200a, bta-miR-26b, hsa-miR-27b-3p, and hsa-miR-30b-5p, were selected by microarray analyses, and their cycle threshold (Ct) values were further evaluated mathematically using geNorm, NormFinder, BestKeeper, and ∆Ct algorithms. The results revealed that both the miRNeasy Micro Kit and Maxwell RSC miRNA Tissue Kit are useful for the efficient recovery of RNA from bovine milk sEVs. According to the final stability ranking analyzed by RefFinder, hsa-miR-27b-3p and bta-miR-29a can be used as suitable internal control miRNAs in bovine milk sEVs. The study also indicated that using a suitable internal control miRNA may improve the reliability and accuracy of the qPCR analysis for normalization in bovine milk sEVs. To the best of our knowledge, this is the first study to uncover the suitable internal control miRNAs in bovine milk sEVs.
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Affiliation(s)
- Md. Matiur Rahman
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
- Department of Medicine, Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Ryoka Nakanishi
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
| | - Fumi Tsukada
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
| | - Shigeo Takashima
- Division of Genomics Research, Life Science Research Center, Gifu University, Gifu 501-1193, Japan
- Institute for Glyco-Core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan
| | - Yoshiko Wakihara
- Division of Genomics Research, Life Science Research Center, Gifu University, Gifu 501-1193, Japan
| | - Yuji O. Kamatari
- Institute for Glyco-Core Research (iGCORE), Gifu University, Gifu 501-1193, Japan
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan
- Division of Instrumental Analysis, Life Science Research Center, Gifu University, Gifu 501-1193, Japan
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Gifu University, Gifu 501-1193, Japan
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), Gifu 501-1193, Japan
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan
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20
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Scalon MC, Martins CS, Ferreira GG, Schlemmer F, Titze de Almeida R, Paludo GR. miR-20a is upregulated in serum from domestic feline with PKD1 mutation. PLoS One 2022; 17:e0279337. [PMID: 36538546 PMCID: PMC9767353 DOI: 10.1371/journal.pone.0279337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Polycystic kidney disease (PKD), also known as autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous condition characterized by cysts in renal parenchyma. It is the most prevalent inherited disease of domestic cats. MicroRNAs (miRNAs or ncRNA) are short, noncoding, single-stranded RNAs that may induce PKD cytogenesis by affecting numerous targets genes as well as by directly regulating PKD gene expression. We compared the relative expression profile of miR-20a, -192, -365, -15b-5p, and -16-5p from plasma and serum samples of nine domestic cats with PKD1 mutation, detected by polymerase chain reaction (PCR), and a control group (n = 10). Blood samples from cats with PKD1 mutation provide similar concentrations of microRNAs either from plasma or serum. Serum miR-20a is upregulated in PKD group with p < 0.005; Roc curve analysis showed an AUC of 90,1% with a cut-off value sensitivity of 77.8% and specificity of 100%. This data provides important information regarding renal miRNA expression in peripheral blood sampling.
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Affiliation(s)
- Marcela Correa Scalon
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Christine Souza Martins
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Gabriel Ginani Ferreira
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Franciele Schlemmer
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Ricardo Titze de Almeida
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Giane Regina Paludo
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
- * E-mail:
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21
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Duman E, Özmen Ö, Kul S. Oar-miR-16b and oar-miR-27a: negatively correlated with milk yield and milk protein in sheep. Anim Biotechnol 2022; 33:1466-1479. [PMID: 33840373 DOI: 10.1080/10495398.2021.1908317] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The characterization of miRNAs from sheep milk and their effect on milk yield and composition in sheep are remain unclear. Therefore, the aim of this study was to determine the expression pattern of several important miRNAs, which are associated with lactation in the sheep milk between high and low lactating-yield ewe groups. In addition to experimentally obtained miRNA expression results, the miRNA target genes were determined by bioinformatics analysis to identify biological pathways involved. miRNAs found to differ significantly in the expression level between the groups were oar-miR-181a, oar-miR-23a, oar-miR-27a, oar-miR-16b and oar-miR-374. Also, oar-miR-27a was shown negative correlation with milk protein and lactose contents while oar-miR-16b was shown negative correlation with milk yield in the high milk yield group. The highest connected hub genes for miR-27a target genes were determined as MAPK14 and PPARG. Also, six genes (HSPA4L, DNAJA2, ATP6V1B2, PPP2R1A, PPP2R1B, and PRKAR2A) were detected as hub genes for miR-16b. In this study, the relationship between expression profiles of several important miRNAs in sheep milk and milk yield and milk composition were investigated for the first time in high and low lactating yield groups.
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Affiliation(s)
- Esra Duman
- Department of Veterinary Medicine and Laboratory, Tokat Gaziosmanpaşa University, Artova Vocational School, Tokat, Turkey
| | - Özge Özmen
- Faculty of Veterinary Medicine, Department of Genetics, Ankara University, Ankara, Turkey
| | - Selim Kul
- Faculty of Veterinary Medicine, Department of Animal Breeding, Fırat University, Elazig, Turkey
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22
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Quéméner AM, Bachelot L, Aubry M, Avner S, Leclerc D, Salbert G, Cabillic F, Decaudin D, Mari B, Mouriaux F, Galibert MD, Gilot D. Non-canonical miRNA-RNA base-pairing impedes tumor suppressor activity of miR-16. Life Sci Alliance 2022; 5:5/12/e202201643. [PMID: 36202613 PMCID: PMC9553902 DOI: 10.26508/lsa.202201643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/24/2022] Open
Abstract
In uveal melanoma tumors, the RNA decay activity of the tumor suppressor miR-16 is impaired by sponge RNAs. These RNAs defined a powerful signature to predict overall survival. Uveal melanoma (UM), the most common primary intraocular tumor in adults, has been extensively characterized by omics technologies during the last 5 yr. Despite the discovery of gene signatures, the molecular actors driving cancer aggressiveness are not fully understood, and UM is still associated with very poor overall survival (OS) at the metastatic stage. By defining the miR-16 interactome, we revealed that miR-16 mainly interacts via non-canonical base-pairing to a subset of RNAs, promoting their expression levels. Consequently, the canonical miR-16 activity, involved in the RNA decay of oncogenes, such as cyclin D3, is impaired. This non-canonical base-pairing can explain both the derepression of miR-16 targets and the promotion of oncogene expression observed in patients with poor OS in two cohorts. miR-16 activity, assessment using our RNA signature, discriminates the patient’s OS as effectively as current methods. To the best of our knowledge, this is the first time that a predictive signature has been composed of genes belonging to the same mechanism (miR-16) in UM. Altogether, our results strongly suggest that UM is a miR-16 disease.
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Affiliation(s)
- Anaïs M Quéméner
- University of Rennes, Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR) - UMR 6290, Rennes, France
| | - Laura Bachelot
- University of Rennes, Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR) - UMR 6290, Rennes, France
| | - Marc Aubry
- INSERM U1242, University of Rennes, Rennes, France
| | - Stéphane Avner
- SPARTE, University of Rennes, CNRS, IGDR - UMR 6290, Rennes, France
| | - Delphine Leclerc
- INSERM U1242, University of Rennes, Rennes, France.,Service d'Ophtalmologie, CHU de Rennes, Rennes, France
| | - Gilles Salbert
- SPARTE, University of Rennes, CNRS, IGDR - UMR 6290, Rennes, France
| | - Florian Cabillic
- NSERM U1241, Université Rennes, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Rennes, France.,Laboratoire de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
| | - Didier Decaudin
- Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.,Curie, Department of Medical Oncology, PSL Research University, Paris, France
| | - Bernard Mari
- Fédération Hospitalo Universitaire-OncoAge, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, Valbonne, France
| | - Frédéric Mouriaux
- INSERM U1242, University of Rennes, Rennes, France.,Service d'Ophtalmologie, CHU de Rennes, Rennes, France
| | - Marie-Dominique Galibert
- University of Rennes, Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR) - UMR 6290, Rennes, France.,CHU Rennes, Service de Génétique Moléculaire et Génomique, Rennes, France
| | - David Gilot
- University of Rennes, Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR) - UMR 6290, Rennes, France .,INSERM U1242, University of Rennes, Rennes, France
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23
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Ingelson-Filpula WA, Cheng H, Eaton L, Pamenter ME, Storey KB. Small RNA sequencing in hypoxic naked mole-rat hearts suggests microRNA regulation of RNA- and translation-related processes. FEBS Lett 2022; 596:2821-2833. [PMID: 36120811 DOI: 10.1002/1873-3468.14499] [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: 08/25/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/09/2022]
Abstract
The naked mole-rat (Heterocephalus glaber) regularly endures intermittent periods of hypoxia in its burrows, surviving in part due to metabolic rate depression (MRD)-a strategy of conserving cellular resources by downregulating nonessential gene expression and reorganizing cellular processes. MicroRNA (miRNA) are short, noncoding RNAs already implicated for their roles in numerous models of extreme environmental stress; given their rapid, reversible nature, they are ideal for implementing MRD. We performed small RNA sequencing on cardiac tissue from normoxic vs. 24 h hypoxic naked mole-rats, and used bioinformatics to predict eighteen miRNAs which may be differentially regulated during hypoxia. Gene Ontology and KEGG pathway mapping further suggest these miRNAs play roles in largely translation-related functions, including RNA processing and catabolism.
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Affiliation(s)
- W Aline Ingelson-Filpula
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
| | - Hang Cheng
- Biology Department, University of Ottawa, Marie-Curie Pvt, Ottawa, Ontario, K1N 9A7, Canada
| | - Liam Eaton
- Biology Department, University of Ottawa, Marie-Curie Pvt, Ottawa, Ontario, K1N 9A7, Canada
| | - Matthew E Pamenter
- Biology Department, University of Ottawa, Marie-Curie Pvt, Ottawa, Ontario, K1N 9A7, Canada.,Brain and Mind Research Institute, University of Ottawa, Ottawa, Ontario, Canada
| | - Kenneth B Storey
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, K1S 5B6, Canada
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24
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Cho JG, Kim SW, Lee A, Jeong HN, Yun E, Choi J, Jeong SJ, Chang W, Oh S, Yoo KH, Lee JB, Yoon S, Lee MS, Park JH, Jung MH, Kim SW, Kim KH, Suh DS, Choi KU, Choi J, Kim J, Kwon BS. MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer. MOLECULAR THERAPY - NUCLEIC ACIDS 2022; 29:803-822. [PMID: 36159587 PMCID: PMC9463562 DOI: 10.1016/j.omtn.2022.08.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 08/17/2022] [Indexed: 01/22/2023]
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25
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Rahnama N, Jahangir M, Alesaeid S, Kahrizi MS, Adili A, Mohammed RN, Aslaminabad R, Akbari M, Özgönül AM. Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives. Pathol Res Pract 2022; 236:153982. [PMID: 35779293 DOI: 10.1016/j.prp.2022.153982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.
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Affiliation(s)
- Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Samira Alesaeid
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, FL, USA; Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Sciences, Cihan University of Sulaimaniya, Kurdistan Region, Iraq; College of Veterinary Medicine, University of Sulaimani, Sulaimaniyah, Iraq
| | - Ramin Aslaminabad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Mert Özgönül
- Department of Biochemistry, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey.
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26
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Burgos CF, Cikutovic R, Alarcón M. MicroRNA expression in male infertility. Reprod Fertil Dev 2022; 34:805-818. [PMID: 35760398 DOI: 10.1071/rd21131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 05/25/2022] [Indexed: 11/23/2022] Open
Abstract
Male infertility is a multifactorial disorder that involves different physiopathological mechanisms and multiple genes. In this sense, we analyse the role of miRNAs in this pathology. Gene expression analysis can provide relevant information to detect biomarkers, signalling pathways, pathologic mechanisms, and potential therapeutic targets for the disease. In this review, we describe four miRNA microarrays related to patients who present infertility diseases, including azoospermia, asthenozoospermia, and oligoasthenozoospermic. We selected 13 miRNAs with altered expressions in testis tissue (hsa-miR-122-5p, hsa-miR-145-5p, hsa-miR-16-5p, hsa-miR-193a-3p, hsa-miR-19a-3p, hsa-miR-23a-3p, hsa-miR-30b-5p, hsa-miR-34b-5p, hsa-miR-34c-5p, hsa-miR-374b-5p, hsa-miR-449a, hsa-miR-574-3p and hsa-miR-92a-3p), and systematically examine the mechanisms of four relevant miRNAs (hsa-miR-16-5p, hsa-miR-19a-3p, hsa-miR-92a-3p and hsa-miR-30b-5p) which we found that regulated a large number of proteins. An interaction network was generated, and its connections allowed us to identify signalling pathways and interactions between proteins associated with male infertility. In this way, we confirm that the most affected and relevant pathway is the PI3K-Akt signalling.
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Affiliation(s)
- C F Burgos
- Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, Concepcion, Chile
| | - R Cikutovic
- Universidad de Talca, Talca, 360000 Maule, Chile
| | - M Alarcón
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile
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27
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Biggar Y, Ingelson-Filpula WA, Storey KB. Pro- and anti-apoptotic microRNAs are differentially regulated during estivation in Xenopus laevis. Gene 2022; 819:146236. [PMID: 35114277 DOI: 10.1016/j.gene.2022.146236] [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: 08/10/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 11/17/2022]
Abstract
Xenopus laevis, the African clawed frog, undergoes seasonal estivation to survive periods of drought when its lake-bed habitats dry up. The frog can lose ∼30% of its total body water, leading to conditions of impaired blood flow and ischemia which risk cellular survival under these harsh conditions. MicroRNAs are short, noncoding, single-stranded RNAs 21-24 nt long that have been widely implicated in hypometabolic responses, and serve functions including apoptosis survival. The levels of three pro-apoptotic and four anti-apoptotic miRNAs were measured in liver and skeletal muscle of estivating X. laevis, and bioinformatic analysis was performed to verify potential mRNA targets of these miRNAs. Members of pro-apoptotic miRNAs miR-15a, miR-16, and miR-101 showed upregulation as a result of dehydration stress, while anti-apoptotic miRNAs miR-19b, miR-21, miR-92a, and miR-155 showed differential regulation between the two tissues. Together, these miRNAs act in a more diverse fashion than arbitrarily pro- or anti-apoptotic, and encompass functions ranging from the inhibition of cell proliferation through cell cycle arrest to the prevention of skeletal muscle atrophy.
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Affiliation(s)
- Yulia Biggar
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada
| | - W Aline Ingelson-Filpula
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada
| | - Kenneth B Storey
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
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28
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Lagunas-Martínez A, Madrid-Marina V, Gómez-Cerón C, Deas J, Peralta-Zaragoza O. The Autophagy Process in Cervical Carcinogenesis: Role of Non-Coding-RNAs, Molecular Mechanisms, and Therapeutic Targets. Cells 2022; 11:cells11081323. [PMID: 35456001 PMCID: PMC9028856 DOI: 10.3390/cells11081323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 02/01/2023] Open
Abstract
Autophagy is a highly conserved multistep lysosomal degradation process in which cellular components are localized to autophagosomes, which subsequently fuse with lysosomes to degrade the sequestered contents. Autophagy serves to maintain cellular homeostasis. There is a close relationship between autophagy and tumor progression, which provides opportunities for the development of anticancer therapeutics that target the autophagy pathway. In this review, we analyze the effects of human papillomavirus (HPV) E5, E6, and E7 oncoproteins on autophagy processes in cervical cancer development. Inhibition of the expression or the activity of E5, E6, and E7 can induce autophagy in cells expressing HPV oncogenes. Thus, E5, E6, and E7 oncoproteins target autophagy during HPV-associated carcinogenesis. Furthermore, noncoding RNA (ncRNA) expression profiling in cervical cancer has allowed the identification of autophagy-related ncRNAs associated with HPV. Autophagy-related genes are essential drivers of autophagy and are regulated by ncRNAs. We review the existing evidence regarding the role of autophagy-related proteins, the function of HPV E5, E6, and E7 oncoproteins, and the effects of noncoding RNA on autophagy regulation in the setting of cervical carcinogenesis. By characterizing the mechanisms behind the dysregulation of these critical factors and their impact on host cell autophagy, we advance understanding of the relationship between autophagy and progression from HPV infection to cervical cancer, and highlight pathways that can be targeted in preventive and therapeutic strategies against cervical cancer.
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Affiliation(s)
- Alfredo Lagunas-Martínez
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Av. Universidad No. 655, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca 62100, Morelos, Mexico; (A.L.-M.); (V.M.-M.); (J.D.)
| | - Vicente Madrid-Marina
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Av. Universidad No. 655, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca 62100, Morelos, Mexico; (A.L.-M.); (V.M.-M.); (J.D.)
| | - Claudia Gómez-Cerón
- Research Center in Population Health, Department of Cancer Epidemiology, National Institute of Public Health, Av. Universidad No. 655, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca 62100, Morelos, Mexico;
| | - Jessica Deas
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Av. Universidad No. 655, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca 62100, Morelos, Mexico; (A.L.-M.); (V.M.-M.); (J.D.)
| | - Oscar Peralta-Zaragoza
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Av. Universidad No. 655, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca 62100, Morelos, Mexico; (A.L.-M.); (V.M.-M.); (J.D.)
- Correspondence: ; Tel.: +52-777-3293000
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29
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Sequence Requirements for miR-424-5p Regulating and Function in Cancers. Int J Mol Sci 2022; 23:ijms23074037. [PMID: 35409396 PMCID: PMC8999618 DOI: 10.3390/ijms23074037] [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: 03/14/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 12/13/2022] Open
Abstract
MiRNAs (microRNAs) are the most abundant family of small noncoding RNAs in mammalian cells. Increasing evidence shows that miRNAs are crucial regulators of individual development and cell homeostasis by controlling various biological processes. Therefore, miRNA dysfunction can lead to human diseases, especially in cancers with high morbidity and mortality worldwide. MiRNAs play different roles in these processes. In recent years, studies have found that miR-424-5p is closely related to the occurrence, development, prognosis and treatment of tumors. This review discusses how miR-424-5p plays a role in different kinds of cancers from different stages of tumors, including its roles in (i) promoting or inhibiting tumorigenesis, (ii) regulating tumor development in the tumor microenvironment and (iii) participating in cancer chemotherapy. This review provides a deep discussion of the latest findings on miR-424-5p and its importance in cancer, as well as a mechanistic analysis of the role of miR-424-5p in various tissues through target gene verification and pathway analysis.
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30
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Rajabi F, Mozdarani H. Expression level of miR-155, miR-15a and miR-19a in peripheral blood of ductal carcinoma breast cancer patients: Possible bioindicators for cellular inherent radiosensitivity. Exp Mol Pathol 2022; 126:104758. [PMID: 35337805 DOI: 10.1016/j.yexmp.2022.104758] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 01/12/2022] [Accepted: 03/19/2022] [Indexed: 11/29/2022]
Abstract
Examination of cellular radiosensitivity (RS) helps prevent the adverse side-effects of Radiotherapy in exposed patients. We aim to study whether miRNA-155 (miR-155), miR-19a and miR-15a can predict inherent RS according to cellular RS in breast cancer (BC) patients. This study was done on the blood samples of 40 invasive ductal carcinoma (IDC) BC patients and 15 healthy women. G2 assay was performed to evaluate cellular RS. To study the expression level of these miRNAs in blood, qRT-PCR was used. The sensitivity and specificity of the studied miRNAs were assessed by the receiver operating characteristic (ROC) curve. The yield of spontaneous (SY) and radiation-induced (RIY) chromatid breaks (CBs) was significantly different between control and patient groups (p < 0.0001). A cut-off value was specified to make distinct the patients with cellular RS to those without. Expression of miR-15a was significantly downregulated (p < 0.0001) in BC patients. However, miR-19a showed upregulation in the blood of BC patients. It was also found the expression level of miR-155 and miR-19a were significantly associated with frequency of CBs (FCB) (p < 0.05). ROC curve analysis manifested that the miR-15a and miR-19a differentiate BC patients and healthy women with 0.91 and 0.68 yielding an area under the ROC curve, respectively. miR-155 and miR-19a discriminate between BC patients with and without cellular RS with area under the ROC curve 0.98 and 0.68. Our findings uncovered miR-155 and miR-19a could be applied as a bioindicator to predict cellular radiosensitivity of BC patients.
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Affiliation(s)
- Fatemeh Rajabi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Mozdarani
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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Gupta S, Silveira DA, Hashimoto RF, Mombach JCM. A Boolean Model of the Proliferative Role of the lncRNA XIST in Non-Small Cell Lung Cancer Cells. BIOLOGY 2022; 11:biology11040480. [PMID: 35453680 PMCID: PMC9024590 DOI: 10.3390/biology11040480] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/12/2022] [Accepted: 03/13/2022] [Indexed: 12/15/2022]
Abstract
The long non-coding RNA X inactivate-specific transcript (lncRNA XIST) has been verified as an oncogenic gene in non-small cell lung cancer (NSCLC) whose regulatory role is largely unknown. The important tumor suppressors, microRNAs: miR-449a and miR-16 are regulated by lncRNA XIST in NSCLC, these miRNAs share numerous common targets and experimental evidence suggests that they synergistically regulate the cell-fate regulation of NSCLC. LncRNA XIST is known to sponge miR-449a and miR-34a, however, the regulatory network connecting all these non-coding RNAs is still unknown. Here we propose a Boolean regulatory network for the G1/S cell cycle checkpoint in NSCLC contemplating the involvement of these non-coding RNAs. Model verification was conducted by comparison with experimental knowledge from NSCLC showing good agreement. The results suggest that miR-449a regulates miR-16 and p21 activity by targeting HDAC1, c-Myc, and the lncRNA XIST. Furthermore, our circuit perturbation simulations show that five circuits are involved in cell fate determination between senescence and apoptosis. The model thus allows pinpointing the direct cell fate mechanisms of NSCLC. Therefore, our results support that lncRNA XIST is an attractive target of drug development in tumor growth and aggressive proliferation of NSCLC, and promising results can be achieved through tumor suppressor miRNAs.
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Affiliation(s)
- Shantanu Gupta
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil;
- Correspondence: (S.G.); (J.C.M.M.); Tel.: +55-11-30916135 (S.G.); +55-55-32209521 (J.C.M.M.)
| | - Daner A. Silveira
- Departamento de Física, Universidade Federal de Santa Maria, Santa Maria 97105-900, RS, Brazil;
| | - Ronaldo F. Hashimoto
- Departamento de Ciência da Computação, Instituto de Matemática e Estatística, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil;
| | - Jose Carlos M. Mombach
- Departamento de Física, Universidade Federal de Santa Maria, Santa Maria 97105-900, RS, Brazil;
- Correspondence: (S.G.); (J.C.M.M.); Tel.: +55-11-30916135 (S.G.); +55-55-32209521 (J.C.M.M.)
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Asadi-Samani M, Mahmoudian-Sani MR. Association between extract of Euphorbia szovitsii and expression level of microRNAs in MDA-MB-231 cell line. Mol Biol Rep 2022; 49:3531-3537. [PMID: 35132492 DOI: 10.1007/s11033-022-07193-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/25/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND The miRNAs have been shown to be involved in breast cancer. The aim of the present research was to evaluate the impacts of extract from Euphorbia szovitsii Fisch & C.A. Mey on the expression level of microRNAs in triple-negative breast cancer (MDA-MB-231) cell line. METHODS AND RESULT The alterations in the expression level of miRNAs in MDA-MB-231 cell line exposed to the extract of E. szovitsii were determined exploiting qRT-PCR technique. The expression of MDA-MB-231 cell microRNAs including miR-15, miR-16, miR-21, miR-29, miR-34a, miR-146b, miR-151, miR-155, miR-181b, miR-221, miR-222, and Let-7 was evaluated at 24 and 48 h after treatment with the E. szovitsii extract. The treatment of MDA-MB-231 cells with E. szovitsii caused a significant elevation in the expression of miR-155, miR-146b (P < 0.05), miR-16, miR-21, miR-151 (P < 0.01), and miR-34a (P < 0.001) after 24 h, and also miR-155, Let-7 (P < 0.05), miR-15, miR-29, miR-151 (P < 0. 01), miR-146b and miR-34a (P<0.001) after 48 h. CONCLUSIONS The qRT-PCR findings at 24 and 48 h after treatment revealed that the MDA-MB-231 cell line in the presence of E. szovitsii extract showed an alteration in the expression profile of miRNAs implicated in the induction of cell proliferation, apoptosis and migration. These results may be helpful in determining the anticancer activity of E. szovitsii in MDA-MB-231 cell line.
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Affiliation(s)
- Majid Asadi-Samani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Yang L, Yang S, Ren C, Liu S, Zhang X, Sui A. Deciphering the roles of miR-16-5p in Malignant Solid Tumorsmalignant solid tumors. Pharmacotherapy 2022; 148:112703. [PMID: 35149384 DOI: 10.1016/j.biopha.2022.112703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 11/02/2022]
Abstract
MiR-16-5p, a member of the miR-16 family, has been reported to be abnormal expression in tumor tissues and blood of tumor patients, and also downregulated in most cancer cell lines. Aberrant expression of miR-16-5p promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and can also affect the treatment sensitivity, such as radiotherapy and chemotherapy. Generally, miR-16-5p plays an anti-tumor role and these diverse functions of miR-16-5p in tumors collectively indicate that miR-16-5p may become an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. Herein we review the role and utilization of miR-16-5p in malignant tumor in detail.
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Affiliation(s)
- Liuyi Yang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of North China University of Science and Technology, Tangshan, Hebei, China
| | - Sen Yang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of North China University of Science and Technology, Tangshan, Hebei, China
| | - Congcong Ren
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Shihua Liu
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Xiaopei Zhang
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China; Graduate School of Hebei North University, Zhangjiakou, Hebei, China
| | - Aixia Sui
- Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei, China.
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Abstract
MicroRNAs (miRNAs) are small noncoding elements that play essential roles in the posttranscriptional regulation of biochemical processes. miRNAs recognize and target multiple mRNAs; therefore, investigating miRNA dysregulation is an indispensable strategy to understand pathological conditions and to design innovative drugs. Targeting miRNAs in diseases improve outcomes of several therapeutic strategies thus, this present study highlights miRNA targeting methods through experimental assays and bioinformatics tools. The first part of this review focuses on experimental miRNA targeting approaches for elucidating key biochemical pathways. A growing body of evidence about the miRNA world reveals the fact that it is not possible to uncover these molecules' structural and functional characteristics related to the biological processes with a deterministic approach. Instead, a systemic point of view is needed to truly understand the facts behind the natural complexity of interactions and regulations that miRNA regulations present. This task heavily depends both on computational and experimental capabilities. Fortunately, several miRNA bioinformatics tools catering to nonexperts are available as complementary wet-lab approaches. For this purpose, this work provides recent research and information about computational tools for miRNA targeting research.
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Affiliation(s)
- Hossein Ghanbarian
- Biotechnology Department & Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehmet Taha Yıldız
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences-Turkey, Istanbul, Turkey
| | - Yusuf Tutar
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy & Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences-Turkey, Istanbul, Turkey.
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Visser H, Thomas AD. MicroRNAs and the DNA damage response: How is cell fate determined? DNA Repair (Amst) 2021; 108:103245. [PMID: 34773895 DOI: 10.1016/j.dnarep.2021.103245] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022]
Abstract
It is becoming clear that the DNA damage response orchestrates an appropriate response to a given level of DNA damage, whether that is cell cycle arrest and repair, senescence or apoptosis. It is plausible that the alternative regulation of the DNA damage response (DDR) plays a role in deciding cell fate following damage. MicroRNAs (miRNAs) are associated with the transcriptional regulation of many cellular processes. They have diverse functions, affecting, presumably, all aspects of cell biology. Many have been shown to be DNA damage inducible and it is conceivable that miRNA species play a role in deciding cell fate following DNA damage by regulating the expression and activation of key DDR proteins. From a clinical perspective, miRNAs are attractive targets to improve cancer patient outcomes to DNA-damaging chemotherapy. However, cancer tissue is known to be, or to become, well adapted to DNA damage as a means of inducing chemoresistance. This frequently results from an altered DDR, possibly owing to miRNA dysregulation. Though many studies provide an overview of miRNAs that are dysregulated within cancerous tissues, a tangible, functional association is often lacking. While miRNAs are well-documented in 'ectopic biology', the physiological significance of endogenous miRNAs in the context of the DDR requires clarification. This review discusses miRNAs of biological relevance and their role in DNA damage response by potentially 'fine-tuning' the DDR towards a particular cell fate in response to DNA damage. MiRNAs are thus potential therapeutic targets/strategies to limit chemoresistance, or improve chemotherapeutic efficacy.
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Affiliation(s)
- Hartwig Visser
- Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Bristol BS16 1QY, United Kingdom
| | - Adam D Thomas
- Centre for Research in Biosciences, University of the West of England, Frenchay Campus, Bristol BS16 1QY, United Kingdom.
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Microrna analysis of human decidua mesenchymal stromal cells from preeclampsia patients. Placenta 2021; 115:12-19. [PMID: 34534911 DOI: 10.1016/j.placenta.2021.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION In preeclampsia (PE), human decidua mesenchymal stromal cells (hDMSCs) are exposed to abnormally high levels of oxidative stress and inflammatory factors circulating in the maternal blood. MicroRNAs (miRNAs) have been shown to have a significant impact on the differentiation, maturation and function of mesenchymal stromal cells (MSCs). Our aim in the present study is firstly to investigate differentially expressed miRNA levels to be used as a biomarker in the early detection of PE and secondly to investigate whether those differentially expressed miRNAs in hDMSCs have an effect on the pathogenesis of PE. METHODS This study covers miRNA expression analysis of hDMSCs from 7 PE patient and 7 healthy pregnant women and is a preliminary study to investigate putative biomarkers. After cell culture and cell sorting, total RNA including miRNAs were isolated from hDMSCs. Let-7b-3p, let-7f-1-3p, miR-191-3p, miR-550a-5p, miR-33b-3p and miR-425-3p were used for miRNA analysis and U6 snRNA was used for normalization of the samples. MiRNA analysis was performed by droplet digital polymerase chain reaction (ddPCR) method and obtained results were evaluated statistically. RESULTS As a result of the analysis, it was observed that the levels of hsa-miR-33b-3p significantly (AUC: 0.93, p = 0.04, fold change: 4.5) increased in hDMSC of PE patients compared to healthy controls. However, let-7b-3p, let-7f-1-3p, miR-191-3p, miR-550a-5p, and miR-425-3p were not considered as significant because they did not meet the p < 0,05 requirement. DISCUSSION Within the scope of the study, it is predicted that miR-33b-3p (p = 0.004, AUC = 0.93) can be used as a biomarker in detecting PE.
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Cai H, Li D, Wu J, Shi C. miR-519d downregulates LEP expression to inhibit preeclampsia development. Open Med (Wars) 2021; 16:1215-1227. [PMID: 34514168 PMCID: PMC8389502 DOI: 10.1515/med-2021-0244] [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: 10/15/2020] [Revised: 01/21/2021] [Accepted: 01/31/2021] [Indexed: 11/15/2022] Open
Abstract
The purpose of the current study was to characterize role of microRNA (miR)-519d in trophoblast cells and preeclampsia (PE) development and its potential underlying mechanism. Regulation of leptin (LEP) by miR-519d was verified using a dual-luciferase reporter gene assay. Loss- and gain-of-function assays were conducted to detect the roles of miR-519d and LEP in proliferation, migratory ability, and invasive capacity of HTR-8/SVneo cells by means of CCK-8 assay, scratch test, and Transwell invasion assay, respectively. The cell apoptosis rate and cycle distribution were analyzed by flow cytometry. LEP expression was elevated, whereas miR-519d level was suppressed in the PE placenta samples compared with those from normal pregnancy. Depletion of LEP promoted proliferation, migratory ability, and invasive capacity and repressed apoptosis. miR-519d could bind 3' untranslated regions (3'UTRs) of LEP, the extent of which correlated negatively with LEP expression. miR-519d suppressed the expression of LEP in HTR-8/SVneo cells. Moreover, overexpression of miR-519d promoted survival and migratory ability of HTR-8/SVneo cells. Taken together, we find that miR-519d targeted LEP and downregulated its expression, which could likely inhibit the development of PE.
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Affiliation(s)
- Hairui Cai
- Obstetrics and Gynecology Department, Ningbo Women & Children's Hospital, No. 339, Liuting Road, Ningbo 315000, Zhejiang Province, People's Republic of China
| | - Dongmei Li
- Obstetrics and Gynecology Department, Ningbo Women & Children's Hospital, No. 339, Liuting Road, Ningbo 315000, Zhejiang Province, People's Republic of China
| | - Jun Wu
- Obstetrics and Gynecology Department, Ningbo Women & Children's Hospital, No. 339, Liuting Road, Ningbo 315000, Zhejiang Province, People's Republic of China
| | - Chunbo Shi
- Obstetrics and Gynecology Department, Ningbo Women & Children's Hospital, No. 339, Liuting Road, Ningbo 315000, Zhejiang Province, People's Republic of China
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Thu HNN, Vy HTN, Thanh TNN, Giang DTN, Nhan TN, Hoang NP, Hue TN. miRNA-16 as an Internal Control in Breast Cancer Studies: A Systematic Review and Meta-Analysis. Mol Biol 2021. [DOI: 10.1134/s0026893321050137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Learning noncoding RNA biology from viruses. Mamm Genome 2021; 33:412-420. [PMID: 34491378 DOI: 10.1007/s00335-021-09915-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Insights into interactions between viral factors and the cellular machinery usually lead to discoveries concerning host cell biology. Thus, the gene expression field has historically relied on viral model systems to discover mechanisms underlying different cellular processes. In recent years, the functional characterization of the small nuclear noncoding RNAs expressed by the oncogenic Herpesvirus saimiri, called HSURs, resulted in the discovery of two mechanisms for the regulation of gene expression. HSUR1 and HSUR2 associate with host microRNAs, which are small noncoding RNAs that broadly regulate gene expression by binding to messenger RNAs. HSUR1 provided the first example of a process known as target-directed miRNA degradation that operates in cells to regulate miRNA populations. HSUR2 functions as a miRNA adaptor, uncovering an entirely new, indirect mechanism by which miRNAs can inhibit mRNA function. Here, I review the path that led to these discoveries and their implications and postulate new exciting questions about the functions of these fascinating viral noncoding RNAs.
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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Wang P, Zhou Y, Richards AM. Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry. Theranostics 2021; 11:8771-8796. [PMID: 34522211 PMCID: PMC8419061 DOI: 10.7150/thno.62642] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.
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Affiliation(s)
- Peipei Wang
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
| | - Yue Zhou
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
| | - Arthur M. Richards
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
- Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, New Zealand
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Mahmoudian-Sani MR, Asadi-Samani M. Modulation of MicroRNAs by Euphorbia Microsciadia Boiss in MDA-MB-231 Cell Line: New Possibilities in Breast Cancer Therapy. Recent Pat Anticancer Drug Discov 2021; 15:174-184. [PMID: 32603285 DOI: 10.2174/1574892815666200630102944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/16/2020] [Accepted: 06/29/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND A large number of Euphorbia species have been evaluated for anticancer effects; however, their anticancer mechanisms have not been established up to now. OBJECTIVE The present study aimed to evaluate the effects of Euphorbia microsciadia (E. microsciadia) Boiss on the modulation of micro (mi) RNAs in MDA-MB-231 cell line. METHODS As the first step, the inhibitory concentration of hydroalcoholic extract of E. microsciadia on MDA-MB-231 cells was examined using the MTT assay, bypassing 24 and 48h from seeding. The real-time quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was also utilized to determine Let-7, miR-15, miR-16, miR-29, miR-151, miR-155, miR-21, miR-146b, miR-181b, miR-221, miR-222, miR-21, and miR-146b expressions in MDA-MB-231 cells, by passing 24 and 48h from treating with the extract of E. microsciadia. RESULTS The results reveal the cytotoxic effects of E. microsciadia on MDA-MB-231 cell line in a dose-dependent manner. The half maximal Inhibitory Concentrations (IC50) were also equal to 275 and 240μg/ml for E. microsciadia, by passing 24 and 48h from the treatment, respectively. Furthermore, it was confirmed that, E. microsciadia had augmented the expression levels of Let-7, miR-15, miR-16, miR-29, and miR-34a, which lead to an increase in apoptosis. CONCLUSION E. microsciadia could modulate some miRNAs involved in cell cycle arrest and apoptosis in MDA-MB-231 cell line. Accordingly, targeting miRNAs by E. microsciadia can open some newer avenues for breast cancer therapy.
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Affiliation(s)
- Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Asadi-Samani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Sabo AA, Dudau M, Constantin GL, Pop TC, Geilfus CM, Naccarati A, Dragomir MP. Two Worlds Colliding: The Interplay Between Natural Compounds and Non-Coding Transcripts in Cancer Therapy. Front Pharmacol 2021; 12:652074. [PMID: 34295245 PMCID: PMC8290364 DOI: 10.3389/fphar.2021.652074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open
Abstract
Cancer is a devastating disease and has recently become the leading cause of death in western countries, representing an immense public health burden. When it comes to cancer treatment, chemotherapy is one of the main pillars, especially for advanced stage tumors. Over the years, natural compounds have emerged as one of the most valuable resources for new chemotherapies. It is estimated that more than half of the currently used chemotherapeutic agents are derived from natural compounds. Usually, natural compounds are discovered empirically and an important limitation of introducing new anti-cancer natural products is lack of knowledge with regard to their mechanism of action. Recent data has proven that several natural compounds may function via modulating the expression and function of non-coding RNAs (ncRNAs). NcRNAs are a heterogenous class of RNA molecules which are usually not translated into proteins but have an important role in gene expression regulation and are involved in multiple tumorigenic processes, including response/resistance to pharmacotherapy. In this review, we will discuss how natural compounds function via ncRNAs while summarizing the available data regarding their effects on over 15 types of cancer. Moreover, we will critically analyze the current advances and limitations in understanding the way natural compounds exert these health-promoting effects by acting on ncRNAs. Finally, we will propose several hypotheses that may open new avenues and perspectives regarding the interaction between natural compounds and ncRNAs, which could lead to improved natural compound-based therapeutic strategies in cancer.
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Affiliation(s)
- Alexandru A. Sabo
- Pediatrics 2 (General and Special Pediatrics), Klinikum Stuttgart, Olgahospital, Zentrum für Kinder, Jugend- und Frauenmedizin, Stuttgart, Germany
| | - Maria Dudau
- Biochemistry-Proteomics Department, Victor Babes National Institute of Pathology, Bucharest, Romania
- Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - George L. Constantin
- Division of Soil Science and Site Science, Thaer-Institute of Agricultural and Horticultural Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Tudor C. Pop
- Department of Pediatrics, Marie Curie Emergency Clinical Hospital for Children, Bucharest, Romania
| | - Christoph-M. Geilfus
- Division of Controlled Environment Horticulture, Thaer-Institute of Agricultural and Horticultural Sciences, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Alessio Naccarati
- IIGM Italian Institute for Genomic Medicine, Turin, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Mihnea P. Dragomir
- Department of Surgery, Fundeni Clinical Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Anelli L, Zagaria A, Specchia G, Musto P, Albano F. Dysregulation of miRNA in Leukemia: Exploiting miRNA Expression Profiles as Biomarkers. Int J Mol Sci 2021; 22:ijms22137156. [PMID: 34281210 PMCID: PMC8269043 DOI: 10.3390/ijms22137156] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022] Open
Abstract
Micro RNAs (miRNAs) are a class of small non-coding RNAs that have a crucial role in cellular processes such as differentiation, proliferation, migration, and apoptosis. miRNAs may act as oncogenes or tumor suppressors; therefore, they prevent or promote tumorigenesis, and abnormal expression has been reported in many malignancies. The role of miRNA in leukemia pathogenesis is still emerging, but several studies have suggested using miRNA expression profiles as biomarkers for diagnosis, prognosis, and response to therapy in leukemia. In this review, the role of miRNAs most frequently involved in leukemia pathogenesis is discussed, focusing on the class of circulating miRNAs, consisting of cell-free RNA molecules detected in several body fluids. Circulating miRNAs could represent new potential non-invasive diagnostic and prognostic biomarkers of leukemia that are easy to isolate and characterize. The dysregulation of some miRNAs involved in both myeloid and lymphoid leukemia, such as miR-155, miR-29, let-7, and miR-15a/miR-16-1 clusters is discussed, showing their possible employment as therapeutic targets.
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Affiliation(s)
- Luisa Anelli
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Antonella Zagaria
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Giorgina Specchia
- School of Medicine, University of Bari ‘Aldo Moro’, 70100 Bari, Italy;
| | - Pellegrino Musto
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
| | - Francesco Albano
- Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology and Stem Cell Transplantation Unit, University of Bari “Aldo Moro”, 70100 Bari, Italy; (L.A.); (A.Z.); (P.M.)
- Correspondence: ; Tel.: +39(0)-80-547-8031; Fax: +39-(0)80-559-3471
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Fasoulakis Z, Daskalakis G, Diakosavvas M, Papapanagiotou I, Theodora M, Bourazan A, Alatzidou D, Pagkalos A, Kontomanolis EN. MicroRNAs Determining Carcinogenesis by Regulating Oncogenes and Tumor Suppressor Genes During Cell Cycle. Microrna 2021; 9:82-92. [PMID: 31538910 PMCID: PMC7366009 DOI: 10.2174/2211536608666190919161849] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 05/21/2019] [Accepted: 08/03/2019] [Indexed: 02/06/2023]
Abstract
AIM To provide a review considering microRNAs regulating oncogenes and tumor suppressor genes during the different stages of cell cycle, controlling carcinogenesis. METHODS The role of microRNAs involved as oncogenes' and tumor suppressor genes' regulators in cancer was searched in the relevant available literature in MEDLINE, including terms such as "microRNA", "oncogenes", "tumor suppressor genes", "metastasis", "cancer" and others. RESULTS MicroRNAs determine the expression levels of multiple cell cycle regulators, such as cyclins, cyclin dependent kinases and other major cell cycle activators including retinoblastoma 1 (RB- 1) and p53, resulting in alteration and promotion/inhibition of the cell cycle. CONCLUSION MicroRNAs are proven to have a key role in cancer pathophysiology by altering the expression profile of different regulator proteins during cell division cycle and DNA replication. Thus, by acting as oncogenes and tumor suppressor genes, they can either promote or inhibit cancer development and formation, revealing their innovative role as biomarkers and therapeutic tools.
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Affiliation(s)
- Zacharias Fasoulakis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - George Daskalakis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Michail Diakosavvas
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Papapanagiotou
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Marianna Theodora
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Arzou Bourazan
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitra Alatzidou
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Athanasios Pagkalos
- Department of Obstetrics and Gynecology, General Hospital of Xanthi, Thrace, Greece
| | - Emmanuel N Kontomanolis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
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Oleuropein reduces cisplatin resistance in ovarian cancer by targeting apoptotic pathway regulators. Life Sci 2021; 278:119525. [PMID: 33894272 DOI: 10.1016/j.lfs.2021.119525] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 04/05/2021] [Accepted: 04/10/2021] [Indexed: 12/11/2022]
Abstract
AIMS Despite many attempts to treat ovarian cancer, 13,940 individuals perish annually due to this disease worldwide. Chemotherapy is the main approach to ovarian cancer treatment, but the development of drug resistance is a major obstacle to the successful treatment. Oleuropein is a phenolic ingredient with anticancer characteristics. This study was aimed at investigating the effect of oleuropein on cell viability, cisplatin resistance, and apoptosis, as well as the expression levels of miR-34a, miR-125b, miR16, miR-21, and some of their potential target genes in ovarian cancer cells. MAIN METHODS A2780S and A2780/CP cell lines were exposed to different concentrations of oleuropein alone or in combination with cisplatin for 48 h and 72 h. After that, the cell viability and apoptosis were evaluated using MTT assay and flow cytometry, respectively. Bioinformatics analyses were conducted using STRING database and Cytoscape software. The effect of oleuropein and/or cisplatin on the expression of miRNAs and target genes was assessed via Real-time PCR. KEY FINDINGS Upon treatment with oleuropein, the expression of P21, P53, and TNFRSF10B increased while that of Bcl-2 and Mcl1 decreased. Moreover, this is the 1st report of a significant decrease in the expression of miR-21 and increase in the expression of miR-34a, miR-125b, and miR16 by oleuropein and/or cisplatin in ovarian cancer cells. SIGNIFICANCE Altogether, these data revealed that oleuropein regulated the expression of the above-mentioned miRNAs in ovarian cancer cells, which potentially resulted in apoptosis induction, cell proliferation inhibition, and cisplatin resistance decline in ovarian cancer cells. To confirm the results of this study, it is suggested that similar experiments be performed in animal models of ovarian cancer.
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Zhao X, Liu F, Zhang J, Zhang J, Zhang L, Chen L. LINC01128 - miR-16 interaction regulates the migration and invasion of human chorionic trophoblast cells. Hypertens Pregnancy 2021; 40:152-161. [PMID: 33881945 DOI: 10.1080/10641955.2021.1917602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Objective: Pre-eclampsia (PE) is a major complication of pregnancy, but its pathogenesis is unclear. This study explored the role of LINC01128 in the progression of PE, and its interaction with miR-16 on the behaviors of trophoblasts.Methods: The mRNA levels of LINC01128 and miR-16 in placental tissues and HTR-8/SVneo cells were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit (CCK)-8, wound healing assay and transwell assay were used to detect proliferation, migration and invasion. E-Cadherin, Vimentin, Matrix metalloproteinase 2 (MMP2) and MMP9 protein expressions were detected by Western blot. The correlation between LINC01128 and miR-16 was determined and verified by starBase and dual-luciferase assay.Results: The expression of LINC01128 was downregulated in PE. Overexpression of LINC01128 promoted LINC01128 expression, cell proliferation, migration, invasion and the expressions of Vimentin, MMP2 and MMP9, but inhibited the expression of E-Cadherin. SiLINC01128 showed opposite effects. MiR-16 interacted with LINC01128, and miR-16 was high-expressed in PE placentae. MiR-16 inhibitor promoted cell proliferation, migration, invasion and related protein expressions, but inhibited the expression of E-Cadherin. However, siLINC01128 inhibited the regulatory effect of miR-16 inhibitor on HTR-8/Svneo cells.Conclusion: LINC01128/miR-16 is involved in HTR-8/SVneo cells by regulating the migration and invasion of human chorionic trophoblast cells.
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Affiliation(s)
- Xinyuan Zhao
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710038, China
| | - Fei Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, 710038, China
| | - Jin Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710038, China
| | - Jianhua Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710038, China
| | - Ludan Zhang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710038, China
| | - Lin Chen
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Xi'an Medical University, Xi'an, 710038, China
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Xiong Y, Feng Y, Zhao J, Lei J, Qiao T, Zhou Y, Lu Q, Jiang T, Jia L, Han Y. TFAP2A potentiates lung adenocarcinoma metastasis by a novel miR-16 family/TFAP2A/PSG9/TGF-β signaling pathway. Cell Death Dis 2021; 12:352. [PMID: 33824285 PMCID: PMC8024312 DOI: 10.1038/s41419-021-03606-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022]
Abstract
Transcription factor AP-2α (TFAP2A) was previously regarded as a critical regulator during embryonic development, and its mediation in carcinogenesis has received intensive attention recently. However, its role in lung adenocarcinoma (LUAD) has not been fully elucidated. Here, we tried to investigate TFAP2A expression profiling, clinical significance, biological function and molecular underpinnings in LUAD. We proved LUAD possessed universal TFAP2A high expression, indicating a pervasively poorer prognosis in multiple independent datasets. Then we found TFAP2A was not indispensable for LUAD proliferation, and exogenous overexpression even caused repression. However, we found TFAP2A could potently promote LUAD metastasis possibly by triggering epithelial-mesenchymal transition (EMT) in vitro and in vivo. Furthermore, we demonstrated TFAP2A could transactivate Pregnancy-specific glycoprotein 9 (PSG9) to enhance transforming growth factor β (TGF-β)-triggering EMT in LUAD. Meanwhile, we discovered suppressed post-transcriptional silencing of miR-16 family upon TFAP2A partly contributed to TFAP2A upregulation in LUAD. In clinical specimens, we also validated cancer-regulating effect of miR-16 family/TFAP2A/PSG9 axis, especially for lymph node metastasis of LUAD. In conclusion, we demonstrated that TFAP2A could pivotally facilitate LUAD progression, possibly through a novel pro-metastasis signaling pathway (miR-16 family/TFAP2A/PSG9/ TGF-β).
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Affiliation(s)
- Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yangbo Feng
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jie Lei
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Tianyun Qiao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yongsheng Zhou
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Qiang Lu
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
| | - Lintao Jia
- State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
| | - Yong Han
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
- Department of Thoracic Surgery, Air Force Medical Center, PLA, Beijing, China.
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Acetylation of ELF5 suppresses breast cancer progression by promoting its degradation and targeting CCND1. NPJ Precis Oncol 2021; 5:20. [PMID: 33742100 PMCID: PMC7979705 DOI: 10.1038/s41698-021-00158-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 02/04/2021] [Indexed: 02/07/2023] Open
Abstract
E74-like ETS transcription factor 5 (ELF5) is involved in a wide spectrum of biological processes, e.g., mammogenesis and tumor progression. We have identified a list of p300-interacting proteins in human breast cancer cells. Among these, ELF5 was found to interact with p300 via acetylation, and the potential acetylation sites were identified as K130, K134, K143, K197, K228, and K245. Furthermore, an ELF5-specific deacetylase, SIRT6, was also identified. Acetylation of ELF5 promoted its ubiquitination and degradation, but was also essential for its antiproliferative effect against breast cancer, as overexpression of wild-type ELF5 and sustained acetylation-mimicking ELF5 mutant could inhibit the expression of its target gene CCND1. Taken together, the results demonstrated a novel regulation of ELF5 as well as shedding light on its important role in modulation of breast cancer progression.
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50
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Lazarian G, Yin S, Ten Hacken E, Sewastianik T, Uduman M, Font-Tello A, Gohil SH, Li S, Kim E, Joyal H, Billington L, Witten E, Zheng M, Huang T, Severgnini M, Lefebvre V, Rassenti LZ, Gutierrez C, Georgopoulos K, Ott CJ, Wang L, Kipps TJ, Burger JA, Livak KJ, Neuberg DS, Baran-Marszak F, Cymbalista F, Carrasco RD, Wu CJ. A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. Cancer Cell 2021; 39:380-393.e8. [PMID: 33689703 PMCID: PMC8034546 DOI: 10.1016/j.ccell.2021.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 09/25/2020] [Accepted: 02/04/2021] [Indexed: 12/20/2022]
Abstract
Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.
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Affiliation(s)
- Gregory Lazarian
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France
| | - Shanye Yin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Elisa Ten Hacken
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Tomasz Sewastianik
- Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Mohamed Uduman
- Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Alba Font-Tello
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Satyen H Gohil
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Academic Haematology, University College London, London, UK
| | - Shuqiang Li
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ekaterina Kim
- Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heather Joyal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Leah Billington
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Elizabeth Witten
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Mei Zheng
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Teddy Huang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Mariano Severgnini
- Center for Immuno-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Valerie Lefebvre
- Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France
| | | | - Catherine Gutierrez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Katia Georgopoulos
- Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA
| | - Christopher J Ott
- Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Lili Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, CA, USA
| | - Thomas J Kipps
- Division of Hematology-Oncology, Department of Medicine, Moores Cancer Center, University of California, San Diego, USA
| | - Jan A Burger
- Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenneth J Livak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Donna S Neuberg
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Fanny Baran-Marszak
- INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France
| | - Florence Cymbalista
- INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France
| | - Ruben D Carrasco
- Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
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