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1
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He B, Xu HM, Li SW, Zhang YF, Tian JW. Emerging regulatory roles of noncoding RNAs induced by bisphenol a (BPA) and its alternatives in human diseases. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 357:124447. [PMID: 38942269 DOI: 10.1016/j.envpol.2024.124447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/07/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
Bisphenols (BPs), including BPA, BPF, BPS, and BPAF, are synthetic phenolic organic compounds and endocrine-disrupting chemicals. These organics have been broadly utilized to produce epoxy resins, polycarbonate plastics, and other products. Mounting evidence has shown that BPs, especially BPA, may enter into the human body and participate in the development of human diseases mediated by nuclear hormone receptors. Moreover, BPA may negatively affect human health at the epigenetic level through processes such as DNA methylation and histone acetylation. Recent studies have demonstrated that, as part of epigenetics, noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and small nucleolar RNAs (snoRNAs), have vital impacts on BP-related diseases, such as reproductive system diseases, nervous system diseases, digestive system diseases, endocrine system diseases, and other diseases. Moreover, based on the bioinformatic analysis, changes in ncRNAs may be relevant to normal activities and functions and BP-induced diseases. Thus, we conducted a meta-analysis to identify more promising ncRNAs as biomarkers and therapeutic targets for BP exposure and relevant human diseases. In this review, we summarize the regulatory functions of ncRNAs induced by BPs in human diseases and latent molecular mechanisms, as well as identify prospective biomarkers and therapeutic targets for BP exposure and upper diseases.
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Affiliation(s)
- Bo He
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, China; Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Hai-Ming Xu
- Department of Occupational and Environmental Medicine, School of Public Health and Management, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
| | - Shu-Wei Li
- Department of Neurology, Qingdao Huangdao District Central Hospital, Qingdao 266555, China
| | - Yin-Feng Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Deng Zhou Road 38, Qingdao 266021, China.
| | - Jia-Wei Tian
- Department of Emergency Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, Shandong, China.
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2
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Madrid-Elena N, Serrano-Villar S, Gutiérrez C, Sastre B, Morín M, Luna L, Martín L, Santoyo-López J, López-Huertas MR, Moreno E, García-Bermejo ML, Moreno-Pelayo MÁ, Moreno S. Selective miRNA inhibition in CD8 + cytotoxic T lymphocytes enhances HIV-1 specific cytotoxic responses. Front Immunol 2022; 13:998368. [PMID: 36225912 PMCID: PMC9549323 DOI: 10.3389/fimmu.2022.998368] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
miRNAs dictate relevant virus-host interactions, offering new avenues for interventions to achieve an HIV remission. We aimed to enhance HIV-specific cytotoxic responses-a hallmark of natural HIV control- by miRNA modulation in T cells. We recruited 12 participants six elite controllers and six patients with chronic HIV infection on long-term antiretroviral therapy ("progressors"). Elite controllers exhibited stronger HIV-specific cytotoxic responses than the progressors, and their CD8+T cells showed a miRNA (hsa-miR-10a-5p) significantly downregulated. When we transfected ex vivo CD8+ T cells from progressors with a synthetic miR-10a-5p inhibitor, miR-10a-5p levels decreased in 4 out of 6 progressors, correlating with an increase in HIV-specific cytotoxic responses. The effects of miR-10a-5p inhibition on HIV-specific CTL responses were modest, short-lived, and occurred before day seven after modulation. IL-4 and TNF-α levels strongly correlated with HIV-specific cytotoxic capacity. Thus, inhibition of miR-10a-5p enhanced HIV-specific CD8+ T cell capacity in progressors. Our pilot study proves the concept that miRNA modulation is a feasible strategy to combat HIV persistence by enhancing specific cytotoxic immune responses, which will inform new approaches for achieving an antiretroviral therapy-free HIV remission.
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Affiliation(s)
- Nadia Madrid-Elena
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
| | - Sergio Serrano-Villar
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
- Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Carolina Gutiérrez
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
| | - Beatriz Sastre
- Department of Immunology, Instituto de Investigación Sanitaria (IIS)-Fundación Jiménez Díaz, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Matías Morín
- Department of Genetics, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Luna
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
| | - Laura Martín
- Biomarkers and Therapeutic Targets Group and Core Facility, Instituto Ramón y Cajal de Investigación Sanitaria (Instituto de Investigación Sanitaria Ramón y Cajal), Spanish Renal Research Network (REDinREN), Madrid, Spain
| | | | - María Rosa López-Huertas
- Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
| | - Elena Moreno
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, Instituto Ramón y Cajal de Investigación Sanitaria (Instituto de Investigación Sanitaria Ramón y Cajal), Spanish Renal Research Network (REDinREN), Madrid, Spain
| | - Miguel Ángel Moreno-Pelayo
- Department of Genetics, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Santiago Moreno
- Department of Infectious Diseases, Hospital Universitario Ramón y Cajal and Instituto de Investigación Sanitaria Ramón y Cajal (IRYCIS), Madrid, Spain
- Centro de Investigación en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (IRYCIS), Madrid, Spain
- Department of Medicine, Alcalá University, Alcalá de Henares, Spain
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3
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Quillet A, Anouar Y, Lecroq T, Dubessy C. Prediction methods for microRNA targets in bilaterian animals: Toward a better understanding by biologists. Comput Struct Biotechnol J 2021; 19:5811-5825. [PMID: 34765096 PMCID: PMC8567327 DOI: 10.1016/j.csbj.2021.10.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 09/20/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Because of their wide network of interactions, miRNAs have become the focus of many studies over the past decade, particularly in animal species. To streamline the number of potential wet lab experiments, the use of miRNA target prediction tools is currently the first step undertaken. However, the predictions made may vary considerably depending on the tool used, which is mostly due to the complex and still not fully understood mechanism of action of miRNAs. The discrepancies complicate the choice of the tool for miRNA target prediction. To provide a comprehensive view of this issue, we highlight in this review the main characteristics of miRNA-target interactions in bilaterian animals, describe the prediction models currently used, and provide some insights for the evaluation of predictor performance.
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Affiliation(s)
- Aurélien Quillet
- Normandie Université, UNIROUEN, INSERM, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France
| | - Youssef Anouar
- Normandie Université, UNIROUEN, INSERM, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France
| | - Thierry Lecroq
- Normandie Université, UNIROUEN, UNIHAVRE, INSA Rouen, Laboratoire d'Informatique du Traitement de l'Information et des Systèmes, 76000 Rouen, France
| | - Christophe Dubessy
- Normandie Université, UNIROUEN, INSERM, Laboratoire Différenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.,Normandie Université, UNIROUEN, INSERM, PRIMACEN, 76000 Rouen, France
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4
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RNA Structures and Their Role in Selective Genome Packaging. Viruses 2021; 13:v13091788. [PMID: 34578369 PMCID: PMC8472981 DOI: 10.3390/v13091788] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
To generate infectious viral particles, viruses must specifically select their genomic RNA from milieu that contains a complex mixture of cellular or non-genomic viral RNAs. In this review, we focus on the role of viral encoded RNA structures in genome packaging. We first discuss how packaging signals are constructed from local and long-range base pairings within viral genomes, as well as inter-molecular interactions between viral and host RNAs. Then, how genome packaging is regulated by the biophysical properties of RNA. Finally, we examine the impact of RNA packaging signals on viral evolution.
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5
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Hao R, Lu H, Guo Y, Liu Q, Wang L, Wang Y, Huang A, Tu Z. Bioinformatics analysis of constructing a HCV-related hepatocellular carcinoma miRNA-mRNA regulation network. Medicine (Baltimore) 2021; 100:e26964. [PMID: 34414965 PMCID: PMC8376384 DOI: 10.1097/md.0000000000026964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 08/01/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the tumors with a higher mortality rate globally, which significantly threatens people's health. Hepatitis C virus (HCV) infection is a major driving factor of HCC. This study aims to determine the key microRNA (miRNA), hub genes, and related pathways, construct potential miRNA-mRNA regulatory networks, and clarify the new molecular mechanism of HCV-related HCC. In this study, 16 differentially expressed miRNAs (DE miRNAs) were identified. The prediction of potential transcription factors and target genes not only found that SP1 and ERG1 may potentially regulate most of the screened DE miRNAs, but it also obtained 2923 and 1782 predicted target genes for the up-regulation and down-regulation of DE miRNAs, respectively. Subsequently, the introduction of differentially expressed genes dataset GSE62232 for target gene verification yielded 98 and 147 potential up-regulation and down-regulation target genes. The gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway enrichment analysis showed that they were mainly enriched in the cell cycle process, that is, subsequently, 20 hub genes were screened out through the protein-protein interaction network, and related genes were further evaluated using the GEPIA database. Based on the above analysis, the miRNA-hub gene regulatory network was constructed. In short, this research's hub genes and miRNAs closely related to HCV-related HCC were screened and identified through bioinformatics analysis and then built their connection. These results are expected to find potential therapeutic targets for HCV-related HCC.
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Affiliation(s)
- Rui Hao
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - He Lu
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yanan Guo
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Qianqian Liu
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Lu Wang
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Yang Wang
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Ailong Huang
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zeng Tu
- Department of Microbiology, Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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6
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Moradi M, Mozafari F, Hosseini S, Rafiee R, Ghasemi F. A concise review on impacts of microRNAs in biology and medicine of hepatitis C virus. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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7
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Vasadia DJ, Zippay ML, Place SP. Characterization of thermally sensitive miRNAs reveals a central role of the FoxO signaling pathway in regulating the cellular stress response of an extreme stenotherm, Trematomus bernacchii. Mar Genomics 2019; 48:100698. [PMID: 31307923 DOI: 10.1016/j.margen.2019.100698] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/21/2019] [Accepted: 06/25/2019] [Indexed: 01/20/2023]
Abstract
Despite the lack of an inducible heat shock response (HSR), the Antarctic notothenioid fish, Trematomus bernacchii, has retained a level of physiological plasticity that can at least partially compensate for the effects of acute heat stress. Over the last decade, both physiological and transcriptomic studies have signaled these fish can mitigate the effects of acute heat stress by employing other aspects of the cellular stress response (CSR) that help confer thermotolerance as well as drive homeostatic mechanisms during long-term thermal acclimations. However, the regulatory mechanisms that determine temperature-induced changes in gene expression remain largely unexplored in this species. Therefore, this study utilized next generation sequencing coupled with an in silico approach to explore the regulatory role of microRNAs in governing the transcriptomic level response observed in this Antarctic notothenioid with respect to the CSR. Using RNAseq, we characterized the expression of 125 distinct miRNA orthologues in T. bernacchii gill tissue. Additionally, we identified 12 miRNAs that appear to be thermally responsive based on differential expression (DE) analyses performed between fish acclimated to control (-1.5 °C) and an acute heat stress (+4 °C). We further characterized the functional role of these DE miRNAs using bioinformatics pipelines to identify putative gene targets of the DE miRNAs and subsequent gene set enrichment analyses, which together suggest these miRNAs are involved in regulating diverse aspects of the CSR in T. bernacchii.
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Affiliation(s)
- Dipali J Vasadia
- Sonoma State University, Department of Biology, Rohnert Park, CA 94928, United States of America
| | - Mackenzie L Zippay
- Sonoma State University, Department of Biology, Rohnert Park, CA 94928, United States of America
| | - Sean P Place
- Sonoma State University, Department of Biology, Rohnert Park, CA 94928, United States of America.
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8
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Keshavarz M, Mirzaei H, Salemi M, Momeni F, Mousavi MJ, Sadeghalvad M, Arjeini Y, Solaymani-Mohammadi F, Sadri Nahand J, Namdari H, Mokhtari-Azad T, Rezaei F. Influenza vaccine: Where are we and where do we go? Rev Med Virol 2018; 29:e2014. [PMID: 30408280 DOI: 10.1002/rmv.2014] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 09/22/2018] [Accepted: 09/25/2018] [Indexed: 12/11/2022]
Abstract
The alarming rise of morbidity and mortality caused by influenza pandemics and epidemics has drawn attention worldwide since the last few decades. This life-threatening problem necessitates the development of a safe and effective vaccine to protect against incoming pandemics. The currently available flu vaccines rely on inactivated viral particles, M2e-based vaccine, live attenuated influenza vaccine (LAIV) and virus like particle (VLP). While inactivated vaccines can only induce systemic humoral responses, LAIV and VLP vaccines stimulate both humoral and cellular immune responses. Yet, these vaccines have limited protection against newly emerging viral strains. These strains, however, can be targeted by universal vaccines consisting of conserved viral proteins such as M2e and capable of inducing cross-reactive immune response. The lack of viral genome in VLP and M2e-based vaccines addresses safety concern associated with existing attenuated vaccines. With the emergence of new recombinant viral strains each year, additional effort towards developing improved universal vaccine is warranted. Besides various types of vaccines, microRNA and exosome-based vaccines have been emerged as new types of influenza vaccines which are associated with new and effective properties. Hence, development of a new generation of vaccines could contribute to better treatment of influenza.
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Affiliation(s)
- Mohsen Keshavarz
- Department of Medical Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Salemi
- Department of Genomics and Genetic Engineering, Razi Vaccine and Serum Research Institute (RVSRI), Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Fatemeh Momeni
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Javad Mousavi
- Department of Immunology and Allergy, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran.,Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mona Sadeghalvad
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Yaser Arjeini
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Solaymani-Mohammadi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Javid Sadri Nahand
- Department of Medical Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Haideh Namdari
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Talat Mokhtari-Azad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Rezaei
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Schult P, Roth H, Adams RL, Mas C, Imbert L, Orlik C, Ruggieri A, Pyle AM, Lohmann V. microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site. Nat Commun 2018; 9:2613. [PMID: 29973597 PMCID: PMC6031695 DOI: 10.1038/s41467-018-05053-3] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 06/11/2018] [Indexed: 12/24/2022] Open
Abstract
The liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5′ end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential for efficient viral replication. The mechanism relies on a dual function of the 5′ terminal sequence in the complementary positive (translation) and negative strand (replication), requiring different secondary structures. Predictions and experimental evidence argue for several alternative folds involving the miR-binding region (MBR) adjacent to the IRES and interfering with its function. Mutations in the MBR, designed to suppress these dysfunctional structures indeed stimulate translation independently of miR-122. Conversely, MBR mutants favoring alternative folds show impaired IRES activity. Our results therefore suggest that miR-122 binding assists the folding of a functional IRES in an RNA chaperone-like manner by suppressing energetically favorable alternative secondary structures. The liver-specific microRNA-122 is an essential proviral host factor of Hepatitis C virus replication. Here the authors show that microRNA-122 functions as an RNA chaperone that guides the formation of a functional internal ribosome entry site by preventing energetically more favorable secondary structures within the HCV RNA genome.
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Affiliation(s)
- Philipp Schult
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany
| | - Hanna Roth
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany
| | - Rebecca L Adams
- Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect St, New Haven, CT, 06511, USA
| | - Caroline Mas
- University Grenoble Alpes, CNRS, CEA, IBS, 71 Avenue des Martyrs, CS 10090, 38044, Grenoble CEDEX 9, France
| | - Lionel Imbert
- University Grenoble Alpes, CNRS, CEA, IBS, 71 Avenue des Martyrs, CS 10090, 38044, Grenoble CEDEX 9, France
| | - Christian Orlik
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany.,Department of Immunology, Molecular Immunology, University of Heidelberg, 69120, Heidelberg, Germany
| | - Alessia Ruggieri
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany
| | - Anna M Pyle
- Department of Molecular, Cellular and Developmental Biology, Yale University, 219 Prospect St, New Haven, CT, 06511, USA.,Howard Hughes Medical Institute, 219 Prospect St, New Haven, CT, 06511, USA
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany.
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10
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Niepmann M, Shalamova LA, Gerresheim GK, Rossbach O. Signals Involved in Regulation of Hepatitis C Virus RNA Genome Translation and Replication. Front Microbiol 2018; 9:395. [PMID: 29593672 PMCID: PMC5857606 DOI: 10.3389/fmicb.2018.00395] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/21/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) preferentially replicates in the human liver and frequently causes chronic infection, often leading to cirrhosis and liver cancer. HCV is an enveloped virus classified in the genus Hepacivirus in the family Flaviviridae and has a single-stranded RNA genome of positive orientation. The HCV RNA genome is translated and replicated in the cytoplasm. Translation is controlled by the Internal Ribosome Entry Site (IRES) in the 5' untranslated region (5' UTR), while also downstream elements like the cis-replication element (CRE) in the coding region and the 3' UTR are involved in translation regulation. The cis-elements controlling replication of the viral RNA genome are located mainly in the 5'- and 3'-UTRs at the genome ends but also in the protein coding region, and in part these signals overlap with the signals controlling RNA translation. Many long-range RNA-RNA interactions (LRIs) are predicted between different regions of the HCV RNA genome, and several such LRIs are actually involved in HCV translation and replication regulation. A number of RNA cis-elements recruit cellular RNA-binding proteins that are involved in the regulation of HCV translation and replication. In addition, the liver-specific microRNA-122 (miR-122) binds to two target sites at the 5' end of the viral RNA genome as well as to at least three additional target sites in the coding region and the 3' UTR. It is involved in the regulation of HCV RNA stability, translation and replication, thereby largely contributing to the hepatotropism of HCV. However, we are still far from completely understanding all interactions that regulate HCV RNA genome translation, stability, replication and encapsidation. In particular, many conclusions on the function of cis-elements in HCV replication have been obtained using full-length HCV genomes or near-full-length replicon systems. These include both genome ends, making it difficult to decide if a cis-element in question acts on HCV replication when physically present in the plus strand genome or in the minus strand antigenome. Therefore, it may be required to use reduced systems that selectively focus on the analysis of HCV minus strand initiation and/or plus strand initiation.
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Affiliation(s)
- Michael Niepmann
- Medical Faculty, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Lyudmila A Shalamova
- Medical Faculty, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Faculty of Biology and Chemistry, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Gesche K Gerresheim
- Medical Faculty, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany.,Faculty of Biology and Chemistry, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany
| | - Oliver Rossbach
- Faculty of Biology and Chemistry, Institute of Biochemistry, Justus Liebig University Giessen, Giessen, Germany
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11
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Abstract
As masters of genome-wide regulation, miRNAs represent a key component in the complex architecture of cellular processes. Over the last decade, it has become increasingly apparent that miRNAs have many important roles in the development of disease and cancer. Recently, however, their role in viral and bacterial gene regulation as well as host gene regulation during disease progression has become a field of interest. Due to their small size, miRNAs are the ideal mechanism for bacteria and viruses that have limited room in their genomes, as a single miRNA can target up to ~30 genes. Currently, only a limited number of miRNA and miRNA-like RNAs have been found in bacteria and viruses, a number that is sure to increase rapidly in the future. The interactions of these small noncoding RNAs in such primitive species have wide-reaching effects, from increasing viral and bacterial proliferation, better responses to stress, increased virulence, to manipulation of host immune responses to provide a more ideal environment for these pathogens to thrive. Here, we explore those roles to obtain a better grasp of just how complicated disease truly is.
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12
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Zhao B, Lucas KJ, Saha TT, Ha J, Ling L, Kokoza VA, Roy S, Raikhel AS. MicroRNA-275 targets sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA) to control key functions in the mosquito gut. PLoS Genet 2017; 13:e1006943. [PMID: 28787446 PMCID: PMC5560755 DOI: 10.1371/journal.pgen.1006943] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 08/17/2017] [Accepted: 07/26/2017] [Indexed: 12/17/2022] Open
Abstract
The yellow fever mosquito Aedes aegypti is the major vector of arboviruses, causing numerous devastating human diseases, such as dengue and yellow fevers, Chikungunya and Zika. Female mosquitoes need vertebrate blood for egg development, and repeated cycles of blood feeding are tightly linked to pathogen transmission. The mosquito’s posterior midgut (gut) is involved in blood digestion and also serves as an entry point for pathogens. Thus, the mosquito gut is an important tissue to investigate. The miRNA aae-miR-275 (miR-275) has been shown to be required for normal blood digestion in the female mosquito; however, the mechanism of its action has remained unknown. Here, we demonstrate that miR-275 directly targets and positively regulates sarco/endoplasmic reticulum Ca2+adenosine triphosphatase, which is implicated in active transport of Ca2+ from the cytosol to the sarco/endoplasmic reticulum. We utilized a combination of the gut-specific yeast transcription activator protein Gal4/upstream activating sequence (Gal4/UAS) system and miRNA Tough Decoy technology to deplete the endogenous level of miR-275 in guts of transgenic mosquitoes. This gut-specific reduction of miR-275 post blood meal decreased SERCA mRNA and protein levels of the digestive enzyme late trypsin. It also resulted in a significant reduction of gut microbiota. Moreover, the decrease of miR-275 and SERCA correlated with defects in the Notch signaling pathway and assembly of the gut actin cytoskeleton. The adverse phenotypes caused by miR-275 silencing were rescued by injections of miR-275 mimic. Thus, we have discovered that miR-275 directly targets SERCA, and the maintenance of its level is critical for multiple gut functions in mosquitoes. Female mosquitoes transmit numerous devastating human diseases. The mosquito gut, in addition to its primary function as a site of blood digestion, represents the entry point for pathogen colonization in mosquito vectors. The conserved microRNA, miR-275, was shown to be required for blood digestion and egg development. In this study, we investigated the target of miR-275 contributing to the regulation of mosquito gut functions. We achieved spatiotemporal suppression of miR-275 using a transgenic Tough Decoy RNA approach in the A. aegypti female mosquito gut. Furthermore, we have uncovered that miR-275 targets sarco/endoplasmic reticulum Ca2+- adenosine triphosphatase (SERCA), affecting numerous gut functions including blood digestion, production of digestive proteases, and assembly of the gut actin cytoskeleton. SERCA is essential for maintenance of Ca2+ homeostasis, and its disturbance, in humans, leads to cardiac hypertrophy, heart failure and cancers. Therefore, the finding that the miRNA miR-275 targets SERCA not only contributes to the knowledge of mosquito gut regulation but also significantly adds to the general understanding of mechanisms governing this critical molecule.
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Affiliation(s)
- Bo Zhao
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Keira J Lucas
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Tusar T Saha
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Jisu Ha
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
- Graduate Program in Genetics, Genomics and Bioinformatics, University of California Riverside, Riverside, California, United States of America
| | - Lin Ling
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Vladimir A Kokoza
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Sourav Roy
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
| | - Alexander S Raikhel
- Department of Entomology and Institute for Integrative Genome Biology, University of California Riverside, Riverside, California, United States of America
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13
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Tian Y, Jiang Y, Shang Y, Zhang YP, Geng CF, Wang LQ, Chang YQ. Establishment of lysozyme gene RNA interference systemand its involvement in salinity tolerance in sea cucumber (Apostichopus japonicus). FISH & SHELLFISH IMMUNOLOGY 2017; 65:71-79. [PMID: 28359949 DOI: 10.1016/j.fsi.2017.03.046] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 03/22/2017] [Accepted: 03/26/2017] [Indexed: 06/07/2023]
Abstract
The lysozyme gene was silenced using RNA interference (RNAi) to analyze the function of lysozyme in sea cucumber under salt stress. The interfering efficiency of four lysozyme RNAi oligos ranged from 0.55 to 0.70. From the four oligos, p-miR-L245 was used for further interfering experiments because it had the best silencing efficiency. Peristomial film injection of p-miR-L245 (10 μg) was used for further interfering experiments. The lowest gene expression, determined by RT-PCR assay, in muscle, coelomic fluid, and parapodium occurred 48 h after p-miR-L245 injection, while that of body wall and tube foot was 96 h and 24 h, respectively. Lysozyme activity in muscle and body wall was significantly lower than the controls. The lowest lysozyme activity in muscle, body wall and parapodium, was found at 48, 72, and 48 h, respectively, which was consistent with the transcription expression of lysozyme. The lowest point of lysozyme activity was at 96 h in coelomic fluid and tube foot, which was laid behind lysozyme expression in transcription level. The expression profile of the lysozyme transcription level and lysozyme activity in the body wall and tube foot increased at 12 h after p-miR-L245 injection before the interference effect appeared. NKA gene expression was expressed at a high level in the positive control (PC) and negative control (NC) groups at 12, 24, and 48 h, while NKA was expressed at low levels in the lysozyme RNAi injection group at 12 and 24 h. The level of NKA gene expression recovered to the level of the PC and NC group at 48, 72, and 96 h after the lysozyme RNAi injection. NKCC1 gene expression was high in the PC and NC groups at 96 h, while the NKCC1 was expressed at a low level 96 h after lysozyme RNAi injection. The results suggest that lysozyme decay involves NKA and NKCC1 gene expression under salinity 18 psμ. The K+ and Cl- concentration after lysozyme RNAi injection was lower than in the PC and NC group.
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Affiliation(s)
- Yi Tian
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China.
| | - Yanan Jiang
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
| | - Yanpeng Shang
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
| | - Yu-Peng Zhang
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
| | - Chen-Fan Geng
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
| | - Li-Qiang Wang
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
| | - Ya-Qing Chang
- Key Laboratory of Mariculture, Ministry of Agriculture, Dalian Ocean University, 116023, Dalian, China
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14
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Gerresheim GK, Dünnes N, Nieder-Röhrmann A, Shalamova LA, Fricke M, Hofacker I, Höner Zu Siederdissen C, Marz M, Niepmann M. microRNA-122 target sites in the hepatitis C virus RNA NS5B coding region and 3' untranslated region: function in replication and influence of RNA secondary structure. Cell Mol Life Sci 2017; 74:747-760. [PMID: 27677491 PMCID: PMC11107659 DOI: 10.1007/s00018-016-2377-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 08/29/2016] [Accepted: 09/21/2016] [Indexed: 02/08/2023]
Abstract
We have analyzed the binding of the liver-specific microRNA-122 (miR-122) to three conserved target sites of hepatitis C virus (HCV) RNA, two in the non-structural protein 5B (NS5B) coding region and one in the 3' untranslated region (3'UTR). miR-122 binding efficiency strongly depends on target site accessibility under conditions when the range of flanking sequences available for the formation of local RNA secondary structures changes. Our results indicate that the particular sequence feature that contributes most to the correlation between target site accessibility and binding strength varies between different target sites. This suggests that the dynamics of miRNA/Ago2 binding not only depends on the target site itself but also on flanking sequence context to a considerable extent, in particular in a small viral genome in which strong selection constraints act on coding sequence and overlapping cis-signals and model the accessibility of cis-signals. In full-length genomes, single and combination mutations in the miR-122 target sites reveal that site 5B.2 is positively involved in regulating overall genome replication efficiency, whereas mutation of site 5B.3 showed a weaker effect. Mutation of the 3'UTR site and double or triple mutants showed no significant overall effect on genome replication, whereas in a translation reporter RNA, the 3'UTR target site inhibits translation directed by the HCV 5'UTR. Thus, the miR-122 target sites in the 3'-region of the HCV genome are involved in a complex interplay in regulating different steps of the HCV replication cycle.
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Affiliation(s)
- Gesche K Gerresheim
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Nadia Dünnes
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Anika Nieder-Röhrmann
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Lyudmila A Shalamova
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany
| | - Markus Fricke
- Faculty of Mathematics and Computer Science, Friedrich-Schiller-University, 07743, Jena, Germany
| | - Ivo Hofacker
- Institute for Theoretical Chemistry, University of Vienna, 1090, Vienna, Austria
| | - Christian Höner Zu Siederdissen
- Institute for Theoretical Chemistry, University of Vienna, 1090, Vienna, Austria
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, Universität Leipzig, 04107, Leipzig, Germany
| | - Manja Marz
- Faculty of Mathematics and Computer Science, Friedrich-Schiller-University, 07743, Jena, Germany
- FLI Leibniz Institute for Age Research, 07743, Jena, Germany
| | - Michael Niepmann
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany.
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15
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Functional Regulation of an Autographa californica Nucleopolyhedrovirus-Encoded MicroRNA, AcMNPV-miR-1, in Baculovirus Replication. J Virol 2016; 90:6526-6537. [PMID: 27147751 DOI: 10.1128/jvi.00165-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 04/29/2016] [Indexed: 01/01/2023] Open
Abstract
UNLABELLED An Autographa californica nucleopolyhedrovirus-encoded microRNA (miRNA), AcMNPV-miR-1, downregulates the ac94 gene, reducing the production of infectious budded virions and accelerating the formation of occlusion-derived virions. In the current study, four viruses that constitutively overexpress AcMNPV-miR-1 were constructed to further explore the function of the miRNA. In addition to the ac94 gene, two new viral gene targets (ac18 and ac95) of AcMNPV-miR-1 were identified, and the possible interacting proteins were verified and tested. In the context of AcMNPV-miR-1 overexpression, ac18 was slightly upregulated, and ac95 was downregulated. Several interacting proteins were identified, and a functional pathway for AcMNPV-miR-1 was deduced. AcMNPV-miR-1 overexpression decreased budded virus infectivity, reduced viral DNA replication, accelerated polyhedron formation, and promoted viral infection efficiency in Trichoplusia ni larvae, suggesting that AcMNPV-miR-1 restrains virus infection of cells but facilitates virus infection of larvae. IMPORTANCE Recently, microRNAs (miRNAs) have been widely reported as moderators or regulators of mammalian cellular processes, especially disease-related pathways in humans. However, the roles played by miRNAs encoded by baculoviruses, which infect numerous beneficial insects and agricultural pests, have rarely been described. To explore the actions of virus-encoded miRNAs, we investigated an miRNA encoded by Autographa californica nucleopolyhedrovirus (AcMNPV-miR-1). We previously identified this miRNA through the exogenous addition of AcMNPV-miR-1 mimics. In the current study, we constitutively overexpressed AcMNPV-miR-1 and analyzed the resultant effects to more comprehensively assess what is indeed the function of this miRNA during viral infection. In addition, we widely explored the target genes for the miRNA in the viral and host genomes and proposed a possible functional network for AcMNPV-miR-1, which provides a better general understanding of virus-encoded miRNAs. In brief, our study implied that AcMNPV-miR-1 constrains viral replication and cellular infection but enhances larval infection.
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16
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Geisler A, Fechner H. MicroRNA-regulated viral vectors for gene therapy. World J Exp Med 2016; 6:37-54. [PMID: 27226955 PMCID: PMC4873559 DOI: 10.5493/wjem.v6.i2.37] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 03/02/2016] [Accepted: 03/17/2016] [Indexed: 02/06/2023] Open
Abstract
Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene. Besides traditional approaches, such as transcriptional and transductional targeting, microRNA-dependent post-transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. MicroRNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region (UTR) of the mRNA. To control exogenous transgene expression, tandem repeats of artificial microRNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expressing the corresponding microRNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying microRNA-regulation, highlights new developments in this field and gives an overview of applications of microRNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.
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17
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Wu J, Shen L, Chen J, Xu H, Mao L. The role of microRNAs in enteroviral infections. Braz J Infect Dis 2015; 19:510-6. [PMID: 26342975 PMCID: PMC9427576 DOI: 10.1016/j.bjid.2015.06.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/29/2015] [Accepted: 06/04/2015] [Indexed: 01/22/2023] Open
Abstract
The genus Enterovirus, a member of the Picornavirus family, are RNA viruses that can cause poliomyelitis, hand-food-mouth disease, viral meningitis or meningoencephalitis, viral myocarditis and so on. MicroRNAs are a class of highly conserved, small noncoding RNAs recognized as important regulators of gene expression. Recent studies found that MicroRNAs play a significant role in the infection of Enterovirus, such as enterovirus 71, coxsackievirus B3 and other Enterovirus. Enteroviral infection can alter the expression of cellular MicroRNAs, and cellular MicroRNAs can modulate viral pathogenesis and replication by regulating the expression level of viral or host's genes. Herein, this review summarizes the role of MicroRNAs in enteroviral infection.
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Affiliation(s)
- Jing Wu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Li Shen
- Department of Clinical Laboratory, Zhenjiang Center for Disease Control and Prevention, Zhenjiang, Jiangsu Province, China
| | - Jianguo Chen
- Department of Clinical Laboratory, Zhenjiang First People's Hospital, Jiangsu Province, China
| | - Huaxi Xu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China
| | - Lingxiang Mao
- Department of Clinical Laboratory, Zhenjiang Center for Disease Control and Prevention, Zhenjiang, Jiangsu Province, China; School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province, China.
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18
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Lupberger J, Casanova C, Fischer B, Weiss A, Fofana I, Fontaine N, Fujiwara T, Renaud M, Kopp A, Schuster C, Brino L, Baumert TF, Thoma C. PI4K-beta and MKNK1 are regulators of hepatitis C virus IRES-dependent translation. Sci Rep 2015; 5:13344. [PMID: 26323588 PMCID: PMC4555030 DOI: 10.1038/srep13344] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 07/22/2015] [Indexed: 12/12/2022] Open
Abstract
Cellular translation is down-regulated by host antiviral responses. Picornaviridae and Flaviviridae including hepatitis C virus (HCV) evade this process using internal ribosomal entry sequences (IRESs). Although HCV IRES translation is a prerequisite for HCV replication, only few host factors critical for IRES activity are known and the global regulator network remains largely unknown. Since signal transduction is an import regulator of viral infections and the host antiviral response we combined a functional RNAi screen targeting the human signaling network with a HCV IRES-specific reporter mRNA assay. We demonstrate that the HCV host cell cofactors PI4K and MKNK1 are positive regulators of HCV IRES translation representing a novel pathway with a functional relevance for the HCV life cycle and IRES-mediated translation of viral RNA.
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Affiliation(s)
- Joachim Lupberger
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.,Université de Strasbourg, France
| | - Claudia Casanova
- Department of Medicine II, University of Freiburg, Freiburg, Germany
| | - Benoit Fischer
- High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France
| | - Amelie Weiss
- High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France
| | - Isabel Fofana
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.,Université de Strasbourg, France
| | - Nelly Fontaine
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.,Université de Strasbourg, France
| | - Toshinobu Fujiwara
- Laboratory of Hygienic Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Mickael Renaud
- High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France
| | - Arnaud Kopp
- High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France
| | - Catherine Schuster
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.,Université de Strasbourg, France
| | - Laurent Brino
- High Throughput Screening platform, IGBMC, UMR7104 CNRS UdS, Inserm, U964, Illkirch, France
| | - Thomas F Baumert
- Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques Strasbourg, France.,Université de Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Christian Thoma
- Department of Medicine II, University of Freiburg, Freiburg, Germany
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19
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Regulation of Hepatitis C Virus Genome Replication by Xrn1 and MicroRNA-122 Binding to Individual Sites in the 5' Untranslated Region. J Virol 2015; 89:6294-311. [PMID: 25855736 DOI: 10.1128/jvi.03631-14] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 03/27/2015] [Indexed: 02/08/2023] Open
Abstract
UNLABELLED miR-122 is a liver-specific microRNA (miRNA) that binds to two sites (S1 and S2) on the 5' untranslated region (UTR) of the hepatitis C virus (HCV) genome and promotes the viral life cycle. It positively affects viral RNA stability, translation, and replication, but the mechanism is not well understood. To unravel the roles of miR-122 binding at each site alone or in combination, we employed miR-122 binding site mutant viral RNAs, Hep3B cells (which lack detectable miR-122), and complementation with wild-type miR-122, an miR-122 with the matching mutation, or both. We found that miR-122 binding at either site alone increased replication equally, while binding at both sites had a cooperative effect. Xrn1 depletion rescued miR-122-unbound full-length RNA replication to detectable levels but not to miR-122-bound levels, confirming that miR-122 protects HCV RNA from Xrn1, a cytoplasmic 5'-to-3' exoribonuclease, but also has additional functions. In cells depleted of Xrn1, replication levels of S1-bound HCV RNA were slightly higher than S2-bound RNA levels, suggesting that both sites contribute, but their contributions may be unequal when the need for protection from Xrn1 is reduced. miR-122 binding at S1 or S2 also increased translation equally, but the effect was abolished by Xrn1 knockdown, suggesting that the influence of miR-122 on HCV translation reflects protection from Xrn1 degradation. Our results show that occupation of each miR-122 binding site contributes equally and cooperatively to HCV replication but suggest somewhat unequal contributions of each site to Xrn1 protection and additional functions of miR-122. IMPORTANCE The functions of miR-122 in the promotion of the HCV life cycle are not fully understood. Here, we show that binding of miR-122 to each of the two binding sites in the HCV 5' UTR contributes equally to HCV replication and that binding to both sites can function cooperatively. This suggests that active Ago2-miR-122 complexes assemble at each site and can cooperatively promote the association and/or function of adjacent complexes, similar to what has been proposed for translation suppression by adjacent miRNA binding sites. We also confirm a role for miR-122 in protection from Xrn1 and provide evidence that miR-122 has additional functions in the HCV life cycle unrelated to Xrn1. Finally, we show that each binding site may contribute unequally to Xrn1 protection and other miR-122 functions.
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20
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Vernin C, Thenoz M, Pinatel C, Gessain A, Gout O, Delfau-Larue MH, Nazaret N, Legras-Lachuer C, Wattel E, Mortreux F. HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs. Cancer Res 2014; 74:6082-93. [PMID: 25205102 DOI: 10.1158/0008-5472.can-13-3564] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Viruses disrupt the host cell microRNA (miRNA) network to facilitate their replication. Human T-cell leukemia virus type I (HTLV-1) replication relies on the clonal expansion of its host CD4(+) and CD8(+) T cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4(+) phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ-miRNA axis promotes cell proliferation and genetic instability, as indicated by comet assays that showed increased numbers of DNA-strand breaks. Expression profiling of miRNA revealed that infected CD4(+) cells, but not CD8(+) T cells, overexpressed oncogenic miRNAs, including miR17 and miR21. HBZ activated these miRNAs via a posttranscriptional mechanism. These effects were alleviated by knocking down miR21 or miR17 and by ectopic expression of OBFC2A, a DNA-damage factor that is downregulated by miR17 and miR21 in HTLV-1-infected CD4(+) T cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.
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Affiliation(s)
- Céline Vernin
- Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France
| | - Morgan Thenoz
- Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France
| | - Christiane Pinatel
- Centre de Recherche sur le Cancer de Lyon, Centre Léon Bérard, Lyon, France
| | - Antoine Gessain
- Institut Pasteur, Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France
| | - Olivier Gout
- Fondation Rothschild, Service de Neurologie, Paris, France
| | | | - Nicolas Nazaret
- Université Lyon I, Faculté de Médecine et de Pharmacie de Lyon, ISPBL Viroscan3D-Profilexpert, UMR5557, Ecologie Microbienne, Lyon, France
| | - Catherine Legras-Lachuer
- Université Lyon I, Faculté de Médecine et de Pharmacie de Lyon, ISPBL Viroscan3D-Profilexpert, UMR5557, Ecologie Microbienne, Lyon, France
| | - Eric Wattel
- Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France. Université Lyon I, Service d'Hématologie, Pavillon Marcel Bérard, Centre Hospitalier Lyon-Sud, Pierre Bénite, France
| | - Franck Mortreux
- Université de Lyon 1, CNRS UMR5239, Oncovirologie et Biothérapies, Laboratoire de Biologie Moléculaire de la Cellule, Faculté de Médecine Lyon Sud, Pierre Bénite, France.
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21
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Mechanisms of miRNA-Mediated Gene Regulation from Common Downregulation to mRNA-Specific Upregulation. Int J Genomics 2014; 2014:970607. [PMID: 25180174 PMCID: PMC4142390 DOI: 10.1155/2014/970607] [Citation(s) in RCA: 374] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 07/09/2014] [Accepted: 07/17/2014] [Indexed: 12/12/2022] Open
Abstract
Discovered in 1993, micoRNAs (miRNAs) are now recognized as one of the major regulatory gene families in eukaryotes. To date, 24521 microRNAs have been discovered and there are certainly more to come. It was primarily acknowledged that miRNAs result in gene expression repression at both the level of mRNA stability by conducting mRNA degradation and the level of translation (at initiation and after initiation) by inhibiting protein translation or degrading the polypeptides through binding complementarily to 3′UTR of the target mRNAs. Nevertheless, some studies revealed that miRNAs have the capability of activating gene expression directly or indirectly in respond to different cell types and conditions and in the presence of distinct cofactors. This reversibility in their posttranslational gene regulatory natures enables the bearing cells to rapidly response to different cell conditions and consequently block unnecessary energy wastage or maintain the cell state. This paper provides an overview of the current understandings of the miRNA characteristics including their genes and biogenesis, as well as their mediated downregulation. We also review up-to-date knowledge of miRNA-mediated gene upregulation through highlighting some notable examples and discuss the emerging concepts of their associations with other posttranscriptional gene regulation processes.
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22
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Lee CH, Kim JH, Lee SW. The role of microRNAs in hepatitis C virus replication and related liver diseases. J Microbiol 2014; 52:445-51. [PMID: 24871972 DOI: 10.1007/s12275-014-4267-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 05/09/2014] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, only limited therapeutic options and no vaccines are currently available against HCV infection. Recent studies of microRNAs (miRNAs), which are able to regulate HCV replication and its related liver diseases by directly interacting with the HCV genome or indirectly controlling virus-associated host pathways, have broadened our understanding of the HCV life cycle. HCV utilizes host cellular miRNAs and modulates expression of miRNAs in infected hepatocytes for its infection and propagation. Moreover, such miRNAs directly or indirectly alter HCV replication efficiency and induce liver diseases including liver fibrosis, cirrhosis, or HCC. Representatively, miR-122 directly modulates the HCV life cycle by increasing HCV translation and genomic RNA stability. Recently, a phase IIa clinical trial with miravirsen, an LNA form of antimiR-122 oligonucleotides, showed significant reduction in serum HCV levels in patients chronically infected with HCV with no detectible evidence of resistance. In addition to miR-122, other miRNAs involved in the regulation of HCV propagation could be targeted in strategies to modulate HCV replication and pathogenesis. In this review, we summarize the features of miRNAs critical for HCV replication and HCV-mediated liver abnormalities and briefly discuss their potential application as therapeutic reagents for the treatment of HCV infection and its related diseases.
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Affiliation(s)
- Chang Ho Lee
- Department of Molecular Biology, Institute of Nanosensor and Biotechnology, Dankook University, Yongin, 448-701, Republic of Korea,
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Kałużna EM. MicroRNA-155 and microRNA-196b: promising biomarkers in hepatitis C virus infection? Rev Med Virol 2014; 24:169-85. [PMID: 24591085 DOI: 10.1002/rmv.1785] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/16/2014] [Accepted: 01/21/2014] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are a class of small, evolutionarily conserved, noncoding RNA that regulate several important cellular processes. The versatility of these molecules allowed the accurate predictions that they would also affect the replication and life cycle of HCV. In this review, emphasis has been given to two selected miRNAs: miR-155 and miR-196b. Recent data indicate that miR-155 is overexpressed in HCV-infected patients, inducing an inflammatory state, and promoting virus replication and persistence even after the completion of antiviral treatment. It is also associated with the increased proliferation and inhibited apoptosis of hepatocytes, which promotes the growth of liver tumors. In contrast, miR-196b is reported as a factor inhibiting HCV replication with cytoprotective, anti-inflammatory, and antioxidant properties. Growing evidence suggests that these molecules could be used as potential prognostic and predictive factors and their antagonists or mimics as a promising therapeutic approach in HCV-infected patients.
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Conrad KD, Niepmann M. The role of microRNAs in hepatitis C virus RNA replication. Arch Virol 2013; 159:849-62. [PMID: 24158346 DOI: 10.1007/s00705-013-1883-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 09/28/2013] [Indexed: 12/16/2022]
Abstract
Replication of hepatitis C virus (HCV) RNA is influenced by a variety of microRNAs, with the main player being the liver-specific microRNA-122 (miR-122). Binding of miR-122 to two binding sites near the 5' end of the 5' untranslated region (UTR) of the HCV genomic RNA results in at least two different effects. On the one hand, binding of miR-122 and the resulting recruitment of protein complexes containing Argonaute (Ago) proteins appears to mask the viral RNA's 5' end and stabilizes the viral RNA against nucleolytic degradation. On the other hand, this interaction of miR-122 with the 5'-UTR also stimulates HCV RNA translation directed by the internal ribosome entry site (IRES) located downstream of the miR-122 binding sites. However, it is suspected that additional, yet undefined roles of miR-122 in HCV replication may also contribute to HCV propagation. Accordingly, miR-122 is considered to contribute to the liver tropism of the virus. Besides miR-122, let-7b, miR-196, miR-199a* and miR-448 have also been reported to interact directly with the HCV RNA. However, the latter microRNAs inhibit HCV replication, and it has been speculated that miR-199a* contributes indirectly to HCV tissue tropism, since it is mostly expressed in cells other than hepatocytes. Other microRNAs influence HCV replication indirectly. Some of those are advantageous for HCV propagation, while others suppress HCV replication. Consequently, HCV up-regulates or down-regulates, respectively, the expression of most of these miRNAs.
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Affiliation(s)
- K Dominik Conrad
- Institute of Biochemistry, School of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392, Giessen, Germany
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Kinetics of miR-122 expression in the liver during acute HCV infection. PLoS One 2013; 8:e76501. [PMID: 24124569 PMCID: PMC3790687 DOI: 10.1371/journal.pone.0076501] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 08/27/2013] [Indexed: 01/25/2023] Open
Abstract
The relationships among micro RNA-122 (miR-122) expression in the liver, hepatitis C virus (HCV) replication and hepatic damage were analyzed in three chimpanzees observed for 180 days after inoculation with HCV genotype 1a. Levels of miR-122 in the liver and serum were measured by real-time RT PCR in serial liver biopsies and serum samples. Hepatic miR-122 levels were normalized separately for each of three chimpanzees with small RNAs and microRNAs that are endogenous to the liver and are stably expressed. Two- to 4-fold rise in hepatic miR-122 levels was observed at the onset of HCV infection (the first 4 weeks) when HCV titers in the liver and serum increased rapidly in all three chimpanzees in concordance with in vitro data indicating the miR-122 significance for HCV replication. Between 10 to 14 weeks after inoculation, when hepatic and serum HCV RNA titers exceeded 3 logs and alanine aminotransferase (ALT) activity was elevated, hepatic miR-122 levels were in decline. Cumulative data derived from all three chimpanzees from 180 days of observation documented an inverse (negative) correlation between hepatic miR-122 and HCV RNA in the liver and serum and positive correlation between level of serum miR-122 and HCV replication. Subsequent rise of miR-122 level during HCV clearance and ALT normalization suggested a tri-phasic occurrence of the relationship among hepatic miR-122 expression, HCV replication and hepatic destruction, which was the most apparent in one chimpanzee but less evident in two other animals. In vivo kinetics of hepatic and serum miR-122, HCV replication and hepatic destruction reflects complexities of the virus-host interaction during the acute phase of HCV infection.
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Shah N, Nelson JE, Kowdley KV. MicroRNAs in Liver Disease: Bench to Bedside. J Clin Exp Hepatol 2013; 3:231-42. [PMID: 25755505 PMCID: PMC3940370 DOI: 10.1016/j.jceh.2013.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3'UTRs of mRNAs to promote degradation and/or block translation. Aberrant miR expression is associated with development of multiple diseases including hepatic diseases. The role of miRs in the regulation of gene expression and rapid progress in the field of microRNA research are resulting in momentum toward development of diagnostic markers and novel therapeutic strategies for human liver diseases. Recent studies provide clear evidence that miRs are abundant in the liver and modulate a diverse spectrum of biological functions, thereby supporting an association between alterations of miR homeostasis and pathological liver diseases. Here we review the role of miRs in liver as their physiological and pathological importance has been demonstrated in metabolism, immunity, viral hepatitis, oncogenesis, fatty liver diseases (alcoholic and non-alcoholic), drug-induced liver injury, fibrosis as well as acute liver failure.
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Key Words
- ALD, alcoholic liver disease
- ALF, acute liver failure
- DILI, drug-induced liver injury
- HBV, hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HSC, hepatic stellate cell
- IFN, interferon
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PPAR γ, peroxisome proliferator-activated receptor γ
- TGF, transforming growth factor
- TNF, tumor necrosis factor
- UTR, untranslated region
- down-regulation
- liver
- miR-122
- miRs/miRNA, microRNA
- microRNA
- up-regulation
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Affiliation(s)
- Nihar Shah
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - James E. Nelson
- Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States
| | - Kris V. Kowdley
- Liver Center of Excellence, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States,Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, United States,Address for correspondence: Kris V. Kowdley, MD, 1201 9th Ave., Seattle, WA 98101, United States. Tel.: +1 (206) 287 1083; fax: +1 (206) 341 1934.
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Imran M, Manzoor S, Khattak NM, Khalid M, Ahmed QL, Parvaiz F, Tariq M, Ashraf J, Ashraf W, Azam S, Ashraf M. Current and future therapies for hepatitis C virus infection: from viral proteins to host targets. Arch Virol 2013; 159:831-46. [DOI: 10.1007/s00705-013-1803-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2013] [Accepted: 06/19/2013] [Indexed: 12/21/2022]
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Noorbakhsh J, Lang AH, Mehta P. Intrinsic noise of microRNA-regulated genes and the ceRNA hypothesis. PLoS One 2013; 8:e72676. [PMID: 23991139 PMCID: PMC3749174 DOI: 10.1371/journal.pone.0072676] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 07/16/2013] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs are small noncoding RNAs that regulate genes post-transciptionally by binding and degrading target eukaryotic mRNAs. We use a quantitative model to study gene regulation by inhibitory microRNAs and compare it to gene regulation by prokaryotic small non-coding RNAs (sRNAs). Our model uses a combination of analytic techniques as well as computational simulations to calculate the mean-expression and noise profiles of genes regulated by both microRNAs and sRNAs. We find that despite very different molecular machinery and modes of action (catalytic vs stoichiometric), the mean expression levels and noise profiles of microRNA-regulated genes are almost identical to genes regulated by prokaryotic sRNAs. This behavior is extremely robust and persists across a wide range of biologically relevant parameters. We extend our model to study crosstalk between multiple mRNAs that are regulated by a single microRNA and show that noise is a sensitive measure of microRNA-mediated interaction between mRNAs. We conclude by discussing possible experimental strategies for uncovering the microRNA-mRNA interactions and testing the competing endogenous RNA (ceRNA) hypothesis.
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Affiliation(s)
- Javad Noorbakhsh
- Physics Department, Boston University, Boston, Massachusetts, United States of America
| | - Alex H. Lang
- Physics Department, Boston University, Boston, Massachusetts, United States of America
| | - Pankaj Mehta
- Physics Department, Boston University, Boston, Massachusetts, United States of America
- * E-mail:
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29
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MicroRNAs: Critical Regulators of mRNA Traffic and Translational Control with Promising Biotech and Therapeutic Applications. IRANIAN JOURNAL OF BIOTECHNOLOGY 2013. [DOI: 10.5812/ijb.11081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Thibault PA, Wilson JA. Targeting miRNAs to treat Hepatitis C Virus infections and liver pathology: Inhibiting the virus and altering the host. Pharmacol Res 2013; 75:48-59. [PMID: 23541631 DOI: 10.1016/j.phrs.2013.03.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Revised: 03/10/2013] [Accepted: 03/11/2013] [Indexed: 02/06/2023]
Abstract
Hepatitis C Virus (HCV) infection-induced liver disease is a growing problem worldwide, and is the primary cause of liver failure requiring liver transplantation in North America. Improved therapeutic strategies are required to control and possibly eradicate HCV infections, and to modulate HCV-induced liver disease. Cellular microRNAs anneal to and regulate mRNA translation and stability and form a regulatory network that modulates virtually every cellular process. Thus, miRNAs are promising cellular targets for therapeutic intervention for an array of diseases including cancer, metabolic diseases, and virus infections. In this review we outline the features of miRNA regulation and how miRNAs may be targeted in strategies to modulate HCV replication and pathogenesis. In particular, we highlight miR-122, a miRNA that directly modulates the HCV life cycle using an unusual mechanism. This miRNA is very important since miR-122 antagonists dramatically reduced HCV titres in HCV-infected chimpanzees and humans and currently represents the most likely candidate to be the first miRNA-based therapy licensed for use. However, we also discuss other miRNAs that directly or indirectly alter HCV replication efficiency, liver cirrhosis, fibrosis and the development of hepatocellular carcinoma (HCC). We also discuss a few miRNAs that might be targets to treat HCV in cases of HCV/HIV co-infection. Finally, we review methods to deliver miRNA antagonists and mimics to the liver. In the future, it may be possible to design and deliver specific combinations of miRNA antagonists and mimics to cure HCV infection or to limit liver pathogenesis.
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Affiliation(s)
- Patricia A Thibault
- Department of Microbiology and Immunology and Vaccine and Infectious Disease Organization, University of Saskatchewan, Rm 2D01, HSc Bldg, 107 Wiggins Rd, Saskatoon, SK S7N 5E5, Canada
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31
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Calvisi DF, Frau M, Tomasi ML, Feo F, Pascale RM. Deregulation of signalling pathways in prognostic subtypes of hepatocellular carcinoma: novel insights from interspecies comparison. Biochim Biophys Acta Rev Cancer 2013; 1826:215-37. [PMID: 23393659 DOI: 10.1016/j.bbcan.2012.04.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma is a frequent and fatal disease. Recent researches on rodent models and human hepatocarcinogenesis contributed to unravel the molecular mechanisms of hepatocellular carcinoma dedifferentiation and progression, and allowed the discovery of several alterations underlying the deregulation of cell cycle and signalling pathways. This review provides an interpretive analysis of the results of these studies. Mounting evidence emphasises the role of up-regulation of RAS/ERK, P13K/AKT, IKK/NF-kB, WNT, TGF-ß, NOTCH, Hedgehog, and Hippo signalling pathways as well as of aberrant proteasomal activity in hepatocarcinogenesis. Signalling deregulation often occurs in preneoplastic stages of rodent and human hepatocarcinogenesis and progressively increases in carcinomas, being most pronounced in more aggressive tumours. Numerous changes in signalling cascades are involved in the deregulation of carbohydrate, lipid, and methionine metabolism, which play a role in the maintenance of the transformed phenotype. Recent studies on the role of microRNAs in signalling deregulation, and on the interplay between signalling pathways led to crucial achievements in the knowledge of the network of signalling cascades, essential for the development of adjuvant therapies of liver cancer. Furthermore, the analysis of the mechanisms involved in signalling deregulation allowed the identification of numerous putative prognostic markers and novel therapeutic targets of specific hepatocellular carcinoma subtypes associated with different biologic and clinical features. This is of prime importance for the selection of patient subgroups that are most likely to obtain clinical benefit and, hence, for successful development of targeted therapies for liver cancer.
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Affiliation(s)
- Diego F Calvisi
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
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Conrad KD, Giering F, Erfurth C, Neumann A, Fehr C, Meister G, Niepmann M. MicroRNA-122 dependent binding of Ago2 protein to hepatitis C virus RNA is associated with enhanced RNA stability and translation stimulation. PLoS One 2013; 8:e56272. [PMID: 23405269 PMCID: PMC3566042 DOI: 10.1371/journal.pone.0056272] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 01/08/2013] [Indexed: 01/16/2023] Open
Abstract
Translation of Hepatitis C Virus (HCV) RNA is directed by an internal ribosome entry site (IRES) in the 5′-untranslated region (5′-UTR). HCV translation is stimulated by the liver-specific microRNA-122 (miR-122) that binds to two binding sites between the stem-loops I and II near the 5′-end of the 5′-UTR. Here, we show that Argonaute (Ago) 2 protein binds to the HCV 5′-UTR in a miR-122-dependent manner, whereas the HCV 3′-UTR does not bind Ago2. miR-122 also recruits Ago1 to the HCV 5’-UTR. Only miRNA duplex precursors of the correct length stimulate HCV translation, indicating that the duplex miR-122 precursors are unwound by a complex that measures their length. Insertions in the 5′-UTR between the miR-122 binding sites and the IRES only slightly decrease translation stimulation by miR-122. In contrast, partially masking the miR-122 binding sites in a stem-loop structure impairs Ago2 binding and translation stimulation by miR-122. In an RNA decay assay, also miR-122-mediated RNA stability contributes to HCV translation stimulation. These results suggest that Ago2 protein is directly involved in loading miR-122 to the HCV RNA and mediating RNA stability and translation stimulation.
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Affiliation(s)
- K. Dominik Conrad
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
| | - Florian Giering
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
| | - Corinna Erfurth
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
| | - Angelina Neumann
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
| | - Carmen Fehr
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
| | - Gunter Meister
- Institute of Biochemistry, Faculty of Biology and Preclinical Medicine, University of Regensburg, Regensburg, Germany
| | - Michael Niepmann
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
- * E-mail:
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33
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Wang JW, Li K, Hellermann G, Lockey RF, Mohapatra S, Mohapatra S. Regulating the Regulators: microRNA and Asthma. World Allergy Organ J 2013; 4:94-103. [PMID: 23282474 PMCID: PMC3651079 DOI: 10.1186/1939-4551-4-6-94] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
One obstacle to developing an effective therapeutic strategy to treat or prevent asthma is that the fundamental causes of asthma are not totally understood. Asthma is thought to be a chronic TH2 immune-mediated inflammatory disease. Epigenetic changes are recognized to play a role in the initiation and maintenance of a TH2 response. MicroRNAs (miRNAs) are key epigenetic regulators of gene expression, and their expression is highly regulated, therefore, deregulation of miRNAs may play an important role in the pathogenesis of asthma. Profiling circulating miRNA might provide the highest specificity and sensitivity to diagnose asthma; similarly, correcting potential defects in the miRNA regulation network may lead to new therapeutic modalities to treat this disease.
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Affiliation(s)
- Jia-Wang Wang
- Department of Internal Medicine Division of Translational Medicine and Nanomedicine Research Center1, and Division of Allergy and Immunology2, Department of Molecular Medicine3, University of South Florida College of Medicine, and James A. Haley VA Hospital and Medical Research Center4, Tampa, FL 33612
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34
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35
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Lee S, Vasudevan S. Post-transcriptional stimulation of gene expression by microRNAs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 768:97-126. [PMID: 23224967 DOI: 10.1007/978-1-4614-5107-5_7] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
MicroRNAs are small noncoding RNA regulatory molecules that control gene expression by guiding associated effector complexes to other RNAs via sequence-specific recognition of target sites. Misregulation of microRNAs leads to a wide range of diseases including cancers, inflammatory and developmental disorders. MicroRNAs were found to mediate deadenylation-dependent decay and translational repression of messages through partially complementary microRNA target sites in the 3'-UTR (untranslated region). A growing series of studies has demonstrated that microRNAs and their associated complexes (microRNPs) elicit alternate functions that enable stimulation of gene expression in addition to their assigned repressive roles. These reports, discussed in this chapter, indicate that microRNA-mediated effects via natural 3' and 5'-UTRs can be selective and controlled, dictated by the RNA sequence context, associated complex, and cellular conditions. Similar to the effects of repression, upregulated gene expression by microRNAs varies from small refinements to significant amplifications in expression. An emerging theme from this literature is that microRNAs have a versatile range of abilities to manipulate post-transcriptional control mechanisms leading to controlled gene expression. These studies reveal new potentials for microRNPs in gene expression control that develop as responses to specific cellular conditions.
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36
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The role and clinical implications of microRNAs in hepatocellular carcinoma. SCIENCE CHINA-LIFE SCIENCES 2012; 55:906-19. [PMID: 23108868 DOI: 10.1007/s11427-012-4384-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis.
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38
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Vasudevan S. Functional validation of microRNA-target RNA interactions. Methods 2012; 58:126-34. [PMID: 22910526 DOI: 10.1016/j.ymeth.2012.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Revised: 08/05/2012] [Accepted: 08/06/2012] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs are small, non-coding RNA regulators of gene expression with important outcomes in cell state, proliferation, metabolism, immunity and development; their deregulation leads to significant clinical consequences. MicroRNAs and their associated target RNAs can be identified by genetic, bioinformatic and biochemical methods. MicroRNAs can recognize target mRNAs via direct base-pairing and recruit effector complexes to modulate their gene expression in a sequence-specific manner. MicroRNA interactions with target RNAs produce their roles in gene expression. The following are some of the validation methods employed to confirm functionally relevant microRNA interactions with their target mRNAs. Each method involves interference with the microRNA or the target mRNA to disable their interaction, which should lead to loss of microRNA-mediated gene expression if the interaction is functionally consequential. Subsequent alleviation of the interference and restoration of productive base-pairing interactions between the microRNA and target should rescue microRNA-mediated gene expression and confirm the functional requirement for direct microRNA-target mRNA interaction. Characterization of functional microRNA interactions with their target mRNAs will provide significant insights into their gene expression regulatory mechanism and lead to the development of potential therapeutic approaches to manipulate these interactions and their consequent gene expression outcomes.
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Affiliation(s)
- S Vasudevan
- Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States.
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39
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Goergen D, Niepmann M. Stimulation of Hepatitis C Virus RNA translation by microRNA-122 occurs under different conditions in vivo and in vitro. Virus Res 2012; 167:343-52. [PMID: 22677772 DOI: 10.1016/j.virusres.2012.05.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2012] [Revised: 05/18/2012] [Accepted: 05/21/2012] [Indexed: 02/07/2023]
Abstract
Translation of the Hepatitis C Virus (HCV) positive strand RNA genome is directed by an internal ribosome entry site (IRES) in the viral RNA's 5'-untranslated region (5'-UTR). HCV propagates preferentially in the liver, and HCV translation is stimulated by the liver-specific microRNA-122 (miR-122) acting on two target sites in the 5'-UTR. This stimulation is effective in living cells containing miR-122 and also in the rabbit reticulocyte lysate in vitro-translation system after addition of miR-122. Another RNA sequence located in the Core protein coding sequence can base-pair in a long-range RNA-RNA interaction to the HCV 5'-UTR, overlapping with the miR-122 target sites and the short spacer between them, and thereby inhibits HCV translation. Here we show genetic evidence that in reticulocyte lysate single-stranded miR-122 interferes with this inhibitory long-range RNA-RNA interaction and thereby contributes to enhanced HCV translation, involving not only the 5'-seed sequence of miR-122 but also sequences at its 3'-end. Also RNA oligonucleotides shorter than a typical microRNA stimulate HCV translation, confirming that in the reticulocyte lysate the stimulation of HCV translation functions by displacement of the inhibitory long-range interaction by miR-122. In contrast, in transfected HuH-7 hepatoma cells and in HeLa cells this interference of miR-122 with the inhibitory long-range RNA-RNA interaction plays not a major role, but only duplex miR-122 RNAs of the correct length stimulate HCV translation. These results suggest that: (1) the processing of the microRNA precursors and (2) the events occurring at the HCV RNA differ between cells and reticulocyte lysate.
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Affiliation(s)
- Dagmar Goergen
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany
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40
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Ren M, Qin D, Li K, Qu J, Wang L, Wang Z, Huang A, Tang H. Correlation between hepatitis B virus protein and microRNA processor Drosha in cells expressing HBV. Antiviral Res 2012; 94:225-31. [PMID: 22554933 DOI: 10.1016/j.antiviral.2012.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 04/11/2012] [Accepted: 04/11/2012] [Indexed: 12/17/2022]
Abstract
Drosha regulates the biogenesis of microRNAs (miRNAs) and plays an essential role in the regulation of gene expression. Infection with hepatitis B virus (HBV) causes chronic hepatitis and liver cirrhosis. It is also a major risk factor for hepatocellular carcinoma. Emerging evidence suggests that HBV alters miRNA expression profiles, but the mechanisms underlying this process have not yet been fully elucidated. We therefore examined how HBV affected the production of miRNAs. We found that Drosha mRNA and protein expression were downregulated in cells expressing the HBV genome. This was associated with a reduction in the activity of the Drosha gene promoter. Gene silencing of HBx by RNA interference significantly restored the expression of Drosha. In conclusion, our data show that HBV could downregulate Drosha expression by inhibiting promoter activity, and the transcription factors SP1 and AP-2α may be involved in this process. This provides a new understanding of the mechanism of HBV-induced miRNAs dysregulation.
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Affiliation(s)
- Min Ren
- Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
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Fehr C, Conrad KD, Niepmann M. Differential stimulation of hepatitis C virus RNA translation by microRNA-122 in different cell cycle phases. Cell Cycle 2012; 11:277-85. [PMID: 22189820 DOI: 10.4161/cc.11.2.18699] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Hepatitis C virus (HCV) replicates preferentially in the liver, and in most cases the HCV infection becomes chronic and often results in hepatocellular carcinoma. When the HCV plus-strand RNA genome has been delivered to the cytosol of the infected cell, its translation is directed by the Internal Ribosome Entry Site (IRES) in the 5'-untranslated region (5'-UTR) of the viral RNA. Thereby, IRES activity is modulated by several host factors. In particular, the liver-specific microRNA-122 (miR-122) interacts with two target sites in the HCV 5'-UTR and stimulates HCV translation, thereby most likely contributing to HCV liver tropism. Here we show that HCV IRES-dependent translation efficiency in the hepatoma cell line Huh7 is highest during the G₀ and G₁ phases of the cell cycle but significantly drops during the S phase and even more in the G₂/M phase. The superimposed stimulation of HCV translation by ectopic miR-122 works best during the G₀, G₁ and G₂/M phases but is lower during the S phase. However, the levels of Ago2 protein do not substantially change during cell cycle phases, indicating that other cellular factors involved in HCV translation stimulation by miR-122 may be differentially expressed in different cell cycle phases. Moreover, the levels of endogenously expressed miR-122 in Huh7 cells are lowest in the S phase, indicating that the predominant G₀/G₁ state of non-dividing hepatocytes in the liver facilitates high expression of the HCV genome and stimulation by miR-122, with yet unknown factors involved in the differential extent of stimulation by miR-122.
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Affiliation(s)
- Carmen Fehr
- Institute of Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany
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Adeli K. Translational control mechanisms in metabolic regulation: critical role of RNA binding proteins, microRNAs, and cytoplasmic RNA granules. Am J Physiol Endocrinol Metab 2011; 301:E1051-64. [PMID: 21971522 DOI: 10.1152/ajpendo.00399.2011] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Regulated cell metabolism involves acute and chronic regulation of gene expression by various nutritional and endocrine stimuli. To respond effectively to endogenous and exogenous signals, cells require rapid response mechanisms to modulate transcript expression and protein synthesis and cannot, in most cases, rely on control of transcriptional initiation that requires hours to take effect. Thus, co- and posttranslational mechanisms have been increasingly recognized as key modulators of metabolic function. This review highlights the critical role of mRNA translational control in modulation of global protein synthesis as well as specific protein factors that regulate metabolic function. First, the complex lifecycle of eukaryotic mRNAs will be reviewed, including our current understanding of translational control mechanisms, regulation by RNA binding proteins and microRNAs, and the role of RNA granules, including processing bodies and stress granules. Second, the current evidence linking regulation of mRNA translation with normal physiological and metabolic pathways and the associated disease states are reviewed. A growing body of evidence supports a key role of translational control in metabolic regulation and implicates translational mechanisms in the pathogenesis of metabolic disorders such as type 2 diabetes. The review also highlights translational control of apolipoprotein B (apoB) mRNA by insulin as a clear example of endocrine modulation of mRNA translation to bring about changes in specific metabolic pathways. Recent findings made on the role of 5'-untranslated regions (5'-UTR), 3'-UTR, RNA binding proteins, and RNA granules in mediating insulin regulation of apoB mRNA translation, apoB protein synthesis, and hepatic lipoprotein production are discussed.
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Affiliation(s)
- Khosrow Adeli
- Program in Molecular Structure & Function, Research Institute, The Hospital for Sick Children, Atrium 3653, 555 University Ave., Toronto, ON, M5G 1X8 Canada.
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Vasudevan S. Posttranscriptional upregulation by microRNAs. WILEY INTERDISCIPLINARY REVIEWS-RNA 2011; 3:311-30. [PMID: 22072587 DOI: 10.1002/wrna.121] [Citation(s) in RCA: 345] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
MicroRNAs are small non-coding RNA guide molecules that regulate gene expression via association with effector complexes and sequence-specific recognition of target sites on other RNAs; misregulated microRNA expression and functions are linked to a variety of tumors, developmental disorders, and immune disease. MicroRNAs have primarily been demonstrated to mediate posttranscriptional downregulation of expression; translational repression, and deadenylation-dependent decay of messages through partially complementary microRNA target sites in mRNA untranslated regions (UTRs). However, an emerging assortment of studies, discussed in this review, reveal that microRNAs and their associated protein complexes (microribonucleoproteins or microRNPs) can additionally function to posttranscriptionally stimulate gene expression by direct and indirect mechanisms. These reports indicate that microRNA-mediated effects can be selective, regulated by the RNA sequence context, and associated with RNP factors and cellular conditions. Like repression, translation upregulation by microRNAs has been observed to range from fine-tuning effects to significant alterations in expression. These studies uncover remarkable, new abilities of microRNAs and associated microRNPs in gene expression control and underscore the importance of regulation, in cis and trans, in directing appropriate microRNP responses.
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Targeting microRNAs in neurons: tools and perspectives. Exp Neurol 2011; 235:419-26. [PMID: 22085592 DOI: 10.1016/j.expneurol.2011.10.031] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 10/25/2011] [Accepted: 10/30/2011] [Indexed: 12/21/2022]
Abstract
In the past few years, the understanding of microRNA (miRNA) biogenesis, the molecular mechanisms by which miRNAs regulate gene expression, and the functional roles of miRNAs has been expanded. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system, suggesting that their post-transcriptional regulation may be particularly relevant in neural development and function. miRNA studies in neurobiology have shown their involvement in synaptic plasticity and brain diseases. Approaches for manipulating miRNA levels in neuronal cells in vitro and in vivo are described here. Recent applications of miRNA antisense oligonucleotides, miRNA gene knockout and miRNA sponges in neuronal cells are reviewed. Finally, miRNA-based therapies for neurological pathologies related to alterations in miRNA functions are discussed.
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Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, Mijatovic S, Maksimovic-Ivanic D, Stivala F, Mazzarino MC, Donia M, Fagone P, Malaponte G, Nicoletti F, Libra M, Milella M, Tafuri A, Bonati A, Bäsecke J, Cocco L, Evangelisti C, Martelli AM, Montalto G, Cervello M, McCubrey JA. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY) 2011; 3:192-222. [PMID: 21422497 PMCID: PMC3091517 DOI: 10.18632/aging.100296] [Citation(s) in RCA: 481] [Impact Index Per Article: 34.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health.
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Affiliation(s)
- Linda S Steelman
- Department of Microbiology and Immunology, East Carolina University, Greenville, NC 27858, USA
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Abstract
INTRODUCTION Gastric cancer remains a major cancer burden in the world, with a poor 5-year survival rate. It is necessary to develop new effective therapeutic strategies to improve the long-term clinical outcome. MicroRNA (miRNA), a class of small non-coding RNA, has been identified as a key regulator of gene expression, and is implicated in the pathogenesis of gastric cancer. AREAS COVERED This review summarizes the role of miRNAs in gastric carcinogenesis, with an emphasis on the expression and function of miR-375 in gastric cancer and beyond. It also discusses the opportunities and challenges of miR-375 as a potential therapeutic target for gastric cancer. The genes targeted by miR-375, including JAK2 and 3'-phosphoinositide dependent protein kinase-1 (PDK1), are also candidates for gastric cancer therapy. EXPERT OPINION Although radical surgery and rational chemotherapy are still the main treatment for gastric cancer, targeting miRNAs, in combination with other conventional therapies, may serve as a promising therapy strategy to improve the clinical outcome.
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Affiliation(s)
- Yanjun Xu
- Zhejiang University School of Medicine, Department of Cell Biology, Program in Molecular Cell Biology, Hangzhou, China
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Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutat Res 2011; 717:85-90. [PMID: 21402084 DOI: 10.1016/j.mrfmmm.2011.03.004] [Citation(s) in RCA: 470] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 03/03/2011] [Accepted: 03/07/2011] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) are a recently discovered class of small, non-coding RNAs that regulate protein levels post-transcriptionally. miRNAs play important regulatory roles in many cellular processes, including differentiation, neoplastic transformation, and cell replication and regeneration. Because of these regulatory roles, it is not surprising that aberrant miRNA expression has been implicated in several diseases. Recent studies have reported significant levels of miRNAs in serum and other body fluids, raising the possibility that circulating miRNAs could serve as useful clinical biomarkers. Here, we provide a brief overview of miRNA biogenesis and function, the identification and potential roles of circulating extracellular miRNAs, and the prospective uses of miRNAs as clinical biomarkers. Finally, we address several issues associated with the accurate measurement of miRNAs from biological samples.
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Law PTY, Wong N. Emerging roles of microRNA in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol 2011; 26:437-49. [PMID: 21332540 DOI: 10.1111/j.1440-1746.2010.06512.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs of 19-23 nucleotides that negatively regulate gene expression through binding to the 3'-untranslated regions of target messenger RNAs (mRNAs). Although the miRNA family constitutes only a minor fraction of the human genome, they hold fundamental importance in diverse physiological and developmental processes due to their pleiotropic effects on the post-transcriptional regulation of many vital genes. This class of regulatory RNAs has also emerged as important players in carcinogenesis; most, if not all, cancer types have abnormal miRNA expression patterns. In hepatocellular carcinoma (HCC), miRNA dysregulation plays a key role in mediating the pathogenicity of several etiologic risk factors and, more importantly, they promote a number of cancer-inducing signaling pathways. Recent studies have also demonstrated their potential values in the clinical management of HCC patients as some miRNAs may be used as prognostic or diagnostic markers. The significance of miRNAs in liver carcinogenesis emphasizes their values as therapeutic targets, while technological advances in the delivery of miRNA has shed new possibilities for their use as novel therapeutic agents against HCC.
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Affiliation(s)
- Priscilla T-Y Law
- Department of Anatomical and Cellular Pathology at the Li Ka-Shing Institute of Health Sciences, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong
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Gelman MA, Glenn JS. Mixing the right hepatitis C inhibitor cocktail. Trends Mol Med 2011; 17:34-46. [PMID: 21106440 PMCID: PMC3085044 DOI: 10.1016/j.molmed.2010.10.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 09/23/2010] [Accepted: 10/11/2010] [Indexed: 01/06/2023]
Abstract
Therapy for hepatitis C virus (HCV) infection is on the cusp of a new era. Until now, standard-of-care therapy has involved interferon (IFN) and ribavirin. With the first successful Phase III trials of specific targeted antiviral therapy for HCV (STAT-C) compounds, as well as three trials in progress giving the first glimpse of IFN-free combinations of STAT-C agents, this review looks ahead to the new classes of anti-HCV agents currently in clinical development. Successful pharmacologic control of HIV and TB frames the discussion, as well as consideration of the mutation frequency of HCV replication. Maximizing synergy between agents and minimizing cumulative toxicity will be critical to the design of future IFN-free STAT-C regimens.
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Affiliation(s)
- Michael A. Gelman
- Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Jeffrey S. Glenn
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
- Veterans Administration Medical Center, Palo Alto, California
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Bao CY, Li JF, Zhou YS. Advances in understanding the roles of microRNA in hepatitis virus infection. Shijie Huaren Xiaohua Zazhi 2010; 18:3756-3760. [DOI: 10.11569/wcjd.v18.i35.3756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause viral hepatitis. HBV or HCV infection is the major risk factor for cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) can regulate post-transcriptional gene expression and participate in the control of diverse biological processes. Recent studies have identified the important roles of miRNAs in multiple aspects of hepatitis viruses, including replication, gene expression and pathogensis. MiRNA-based drugs may shed light on the treatment of hepatitis virus infection. In this review, we discuss the latest advances in the research of miRNAs involved in hepatitis virus infection.
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