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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Kimura M, Kothari S, Gohir W, Camargo JF, Husain S. MicroRNAs in infectious diseases: potential diagnostic biomarkers and therapeutic targets. Clin Microbiol Rev 2023; 36:e0001523. [PMID: 37909789 PMCID: PMC10732047 DOI: 10.1128/cmr.00015-23] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023] Open
Abstract
MicroRNAs (miRNAs) are conserved, short, non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They have been implicated in the pathogenesis of cancer and neurological, cardiovascular, and autoimmune diseases. Several recent studies have suggested that miRNAs are key players in regulating the differentiation, maturation, and activation of immune cells, thereby influencing the host immune response to infection. The resultant upregulation or downregulation of miRNAs from infection influences the protein expression of genes responsible for the immune response and can determine the risk of disease progression. Recently, miRNAs have been explored as diagnostic biomarkers and therapeutic targets in various infectious diseases. This review summarizes our current understanding of the role of miRNAs during viral, fungal, bacterial, and parasitic infections from a clinical perspective, including critical functional mechanisms and implications for their potential use as biomarkers and therapeutic targets.
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Affiliation(s)
- Muneyoshi Kimura
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sagar Kothari
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Wajiha Gohir
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Jose F. Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shahid Husain
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
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3
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Roles of microRNAs in Hepatitis C Virus Replication and Pathogenesis. Viruses 2022; 14:v14081776. [PMID: 36016398 PMCID: PMC9413378 DOI: 10.3390/v14081776] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/11/2022] [Accepted: 08/13/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is associated with the development of chronic liver diseases, e.g., fibrosis, cirrhosis, even hepatocellular carcinoma, and/or extra-hepatic diseases such as diabetes. As an obligatory intracellular pathogen, HCV absolutely relies on host cells to propagate and is able to modulate host cellular factors in favor of its replication. Indeed, lots of cellular factors, including microRNAs (miRNAs), have been identified to be dysregulated during HCV infection. MiRNAs are small noncoding RNAs that regulate protein synthesis of their targeting mRNAs at the post-transcriptional level, usually by suppressing their target gene expression. The miRNAs dysregulated during HCV infection could directly or indirectly modulate HCV replication and/or induce liver diseases. Regulatory mechanisms of various miRNAs in HCV replication and pathogenesis have been characterized. Some dysregulated miRNAs have been considered as the biomarkers for the detection of HCV infection and/or HCV-related diseases. In this review, we intend to briefly summarize the identified miRNAs functioning at HCV replication and pathogenesis, focusing on the recent developments.
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Joshi N, Chandane Tak M, Mukherjee A. The involvement of microRNAs in HCV and HIV infection. Ther Adv Vaccines Immunother 2022; 10:25151355221106104. [PMID: 35832725 PMCID: PMC9272158 DOI: 10.1177/25151355221106104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Approximately 2.3 million people are suffering from human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infection worldwide. Faster disease progression and increased mortality rates during the HIV/HCV co-infection have become global health concerns. Effective therapeutics against co-infection and complete infection eradication has become a mandatory requirement. The study of small non-coding RNAs in cellular processes and viral infection has so far been beneficial in various terms. Currently, microRNAs are an influential candidate for disease diagnosis and treatment. Dysregulation in miRNA expression can lead to unfavorable outcomes; hence, this exact inevitable nature has made various studies a focal point. A considerable improvement in comprehending HIV and HCV mono-infection pathogenesis is seen using miRNAs. The prominent reason behind HIV/HCV co-infection is seen to be their standard route of transmission, while some pieces of evidence also suspect viral interplay between having a role in increased viral infection. This review highlights the involvement of microRNAs in HIV/HCV co-infection, along with their contribution in HIV mono- and HCV mono-infection. We also discuss miRNAs that carry the potentiality of becoming a biomarker for viral infection and early disease progression.
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Affiliation(s)
- Nicky Joshi
- Division of Virology, ICMR-National AIDS Research Institute, Pune, India
| | | | - Anupam Mukherjee
- Scientist D & RAMANUJAN Fellow, Division of Virology, ICMR-National AIDS Research Institute, Plot No. 73, 'G' Block, MIDC, Bhosari, Pune 411026, Maharashtra, India
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5
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Duecker RP, Adam EH, Wirtz S, Gronau L, Khodamoradi Y, Eberhardt FJ, Donath H, Gutmann D, Vehreschild MJGT, Zacharowski K, Kreyenberg H, Chiocchetti AG, Zielen S, Schubert R. The MiR-320 Family Is Strongly Downregulated in Patients with COVID-19 Induced Severe Respiratory Failure. Int J Mol Sci 2021; 22:ijms221910351. [PMID: 34638691 PMCID: PMC8508658 DOI: 10.3390/ijms221910351] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/17/2021] [Accepted: 09/23/2021] [Indexed: 01/08/2023] Open
Abstract
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0-3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
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Affiliation(s)
- Ruth P. Duecker
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
- Correspondence:
| | - Elisabeth H. Adam
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy 2, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (E.H.A.); (K.Z.)
| | - Sarah Wirtz
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
| | - Lucia Gronau
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
- Department of Food Technology, University of Applied Sciences Fulda, 36037 Fulda, Germany
| | - Yascha Khodamoradi
- Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (Y.K.); (F.J.E.); (M.J.G.T.V.)
| | - Fabian J. Eberhardt
- Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (Y.K.); (F.J.E.); (M.J.G.T.V.)
| | - Helena Donath
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
| | - Desiree Gutmann
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
| | - Maria J. G. T. Vehreschild
- Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (Y.K.); (F.J.E.); (M.J.G.T.V.)
| | - Kai Zacharowski
- Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy 2, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (E.H.A.); (K.Z.)
| | - Hermann Kreyenberg
- Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany;
| | - Andreas G. Chiocchetti
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany;
| | - Stefan Zielen
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
| | - Ralf Schubert
- Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, University Hospital Frankfurt, Goethe-University, 60590 Frankfurt am Main, Germany; (S.W.); (L.G.); (H.D.); (D.G.); (S.Z.); (R.S.)
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Huang W, Song L, Zhang J, Yan X, Yan H. Effects of miR-185-5p on replication of hepatitis C virus. Open Life Sci 2021; 16:752-757. [PMID: 34395911 PMCID: PMC8330614 DOI: 10.1515/biol-2021-0067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/02/2021] [Accepted: 04/23/2021] [Indexed: 12/13/2022] Open
Abstract
This article was designed to explore the effects and mechanisms of miR-185-5p on the replication of hepatitis C virus (HCV). Quantitative reverse transcription PCR (qRT-PCR) was performed for detecting the abundance of miR-185-5p and HCV RNA in HCV-infected primary hepatocytes and Huh7.5 cells. Dual-luciferase reporter gene assay was used for exploring the interaction between miR-185-5p and GALNT8. Western blot analyzed protein expression of GALNT8, NS3, and NS5A. miR-185-5p was remarkably downregulated in HCV-infected primary hepatocytes and Huh7.5 cells. miR-185-5p upregulation inhibited HCV RNA expression, while its inhibition promoted HCV replication. miR-185-5p induced accumulation of NS3 and NS5A in the cells. Dual-luciferase reporter gene assay verified the targeted relationship between miR-185-5p and GALNT8. In addition, the effects of overexpressing or knocking down miR-185-5p on HCV replication could be correspondingly eliminated by the overexpression or knockdown of GALNT8. miR-185-5p may target GALNT8 in JFH1-infected Huh7.5 cells and then inhibit HCV replication. miR-185-5p may be a potential target for treating HCV.
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Affiliation(s)
- Wei Huang
- Department of Laboratory Medicine, Heping Hospital Affiliated to Changzhi Medical College, No. 110 Yan’an Nan Road, Changzhi 046000, China
| | - Lingyan Song
- Department of Laboratory Medicine, Heping Hospital Affiliated to Changzhi Medical College, No. 110 Yan’an Nan Road, Changzhi 046000, China
| | - Jingyan Zhang
- Department of Laboratory Medicine, Heping Hospital Affiliated to Changzhi Medical College, No. 110 Yan’an Nan Road, Changzhi 046000, China
| | - Xueqiang Yan
- Department of Laboratory Medicine, Heping Hospital Affiliated to Changzhi Medical College, No. 110 Yan’an Nan Road, Changzhi 046000, China
| | - Hui Yan
- Department of Laboratory Medicine, Heping Hospital Affiliated to Changzhi Medical College, No. 110 Yan’an Nan Road, Changzhi 046000, China
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Lenart M, Działo E, Kluczewska A, Węglarczyk K, Szaflarska A, Rutkowska-Zapała M, Surmiak M, Sanak M, Pituch-Noworolska A, Siedlar M. miRNA Regulation of NK Cells Antiviral Response in Children With Severe and/or Recurrent Herpes Simplex Virus Infections. Front Immunol 2021; 11:589866. [PMID: 33679688 PMCID: PMC7931645 DOI: 10.3389/fimmu.2020.589866] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 12/07/2020] [Indexed: 12/21/2022] Open
Abstract
Severe and/or recurrent infection with Herpes simplex virus (HSV) is observed in a large group of patients treated in clinical immunology facilities. Atypical and prolonged HSV infection is the most common clinical manifestation of disturbed NK cell development and functions, yet the molecular basis of these disorders is still largely unknown. Since recent findings indicated the importance of miRNA in regulating NK cell development, maturation and functions, the aim of our study was to investigate miRNA expression pattern in NK cells in patients with severe and/or recurrent infections with HSV and analyze the role of these miRNAs in NK cell antiviral response. As a result, miRNA expression pattern analysis of human best known 754 miRNAs revealed that patients with severe and/or recurrent HSV infection had substantially upregulated expression of four miRNAs: miR-27b, miR-199b, miR-369-3p and miR-491-3p, when compared to healthy controls. Selective inhibition of miR-27b, miR-199b, miR-369-3p and miR-491-3p expression in NK-92 cells resulted in profound upregulation of 4 genes (APOBEC3G, MAP2K3, MAVS and TLR7) and downregulation of 36 genes taking part in antiviral response or associated with signaling pathways of Toll-like receptors (TLR), NOD-like receptors, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and type I IFN-related response. Additionally, flow cytometry analysis revealed that miR-369-3p and miR-491-3p inhibitors downregulated NK cell intracellular perforin expression, while the expression of granzyme B and IFNγ remained unchanged. Taken together, our study suggests a novel mechanism which may promote recurrence and severity of HSV infection, based on miRNAs-dependent posttranscriptional regulation of genes taking part in antiviral response of human NK cells.
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Affiliation(s)
- Marzena Lenart
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Edyta Działo
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Kluczewska
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Kazimierz Węglarczyk
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Szaflarska
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Magdalena Rutkowska-Zapała
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Marcin Surmiak
- II Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Marek Sanak
- II Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Anna Pituch-Noworolska
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
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Cabral B, Hoffmann L, Bottaro T, Costa P, Ramos A, Coelho H, Villela-Nogueira C, Ürményi T, Faffe D, Silva R. Circulating microRNAs associated with liver fibrosis in chronic hepatitis C patients. Biochem Biophys Rep 2020; 24:100814. [PMID: 33015376 PMCID: PMC7520427 DOI: 10.1016/j.bbrep.2020.100814] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Revised: 09/06/2020] [Accepted: 09/14/2020] [Indexed: 12/21/2022] Open
Abstract
A major challenge in hepatitis C research is the detection of early potential for progressive liver disease. MicroRNAs (miRNAs) are small RNAs that regulate gene expression and can be biomarkers of pathological processes. In this study, we compared circulating miRNAs identified in hepatitis C virus (HCV)-infected patients presenting two extremes of liver disease: mild/moderate fibrosis and cirrhosis. The patients in the cirrhosis group subsequently developed hepatocellular carcinoma (HCC). We identified 163 mature miRNAs in the mild/moderate fibrosis group and 171 in the cirrhosis group, with 144 in common to both groups. Differential expression analysis revealed 5 upregulated miRNAs and 2 downregulated miRNAs in the cirrhosis group relative to the mild/moderate fibrosis group. Functional analyses of regulatory networks (target gene and miRNA) identified gene categories involved in cell cycle biological processes and metabolic pathways related to cell cycle, cancer, and apoptosis. These results suggest that the differentially expressed circulating miRNAs observed in this work (miR-215-5p, miR-483-5p, miR-193b-3p, miR-34a-5p, miR-885-5p, miR-26b-5p and miR -197-3p) may be candidates for biomarkers in the prognosis of liver disease.
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Affiliation(s)
- B.C.A. Cabral
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - L. Hoffmann
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Departamento de Biotecnologia, Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro, Brazil
| | - T. Bottaro
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - P.F. Costa
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - A.L.A. Ramos
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - H.S.M. Coelho
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - C.A. Villela-Nogueira
- Departamento de Clínica Médica, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - T.P. Ürményi
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - D.S. Faffe
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - R. Silva
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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10
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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis. Viruses 2020; 12:v12121364. [PMID: 33260407 PMCID: PMC7761224 DOI: 10.3390/v12121364] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/18/2020] [Accepted: 11/27/2020] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin's lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.
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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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12
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Xu T, Luo Y, Wang J, Zhang N, Gu C, Li L, Qian D, Cai W, Fan J, Yin G. Exosomal miRNA-128-3p from mesenchymal stem cells of aged rats regulates osteogenesis and bone fracture healing by targeting Smad5. J Nanobiotechnology 2020; 18:47. [PMID: 32178675 PMCID: PMC7077029 DOI: 10.1186/s12951-020-00601-w] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 03/05/2020] [Indexed: 02/08/2023] Open
Abstract
Transplantation of mesenchymal stem cells (MSCs) has been considered an effective therapeutic treatment for a variety of diseases including bone fracture. However, there are associated complications along with MSCs transplantation. There is evidence to show that exosomes (Exos) derived from MSCs exert a similar paracrine function. In addition, repair capabilities of MSCs decline with age. Hence, this study aims to confirm whether the Exos protective function on osteogenic differentiation and fracture healing from aged MSCs was attenuated. This information was used in order to investigate the underlying mechanism. MSCs were successfully isolated and identified from young and aged rats, and Exos were then obtained. Aged-Exos exhibited significantly attenuated effects on MSCs osteogenic differentiation in vitro and facture healing in vivo. Using miRNA array analysis, it was shown that miR-128-3p was markedly upregulated in Aged-Exos. In vitro experiments confirmed that Smad5 is a direct downstream target of miR-128-3p, and was inhibited by overexpressed miR-128-3p. A series gain- and loss- function experiment indicated that miR-128-3P serves a suppressor role in the process of fracture healing. Furthermore, effects caused by miR-128-3P mimic/inhibitor were reversed by the application of Smad5/siSmad5. Taken together, these results suggest that the therapeutic effects of MSCs-derived Exos may vary according to differential expression of miRNAs. Exosomal miR-128-3P antagomir may act as a promising therapeutic strategy for bone fracture healing, especially for the elderly.
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Affiliation(s)
- Tao Xu
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Yongjun Luo
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Jiaxing Wang
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Ning Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Changjiang Gu
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Linwei Li
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Dingfei Qian
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China
| | - Weihua Cai
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Jin Fan
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
| | - Guoyong Yin
- Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
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13
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Biological Differentiation of Dampness-Heat Syndromes in Chronic Hepatitis B: From Comparative MicroRNA Microarray Profiling to Biomarker Identification. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:7234893. [PMID: 32051688 PMCID: PMC6995329 DOI: 10.1155/2020/7234893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/11/2019] [Accepted: 12/18/2019] [Indexed: 11/26/2022]
Abstract
Increasing interest is aroused by traditional Chinese medicine (TCM) treatment of chronic hepatitis B (CHB) based on specific TCM syndrome. As the most common CHB syndromes, spleen-stomach dampness-heat (SSDH) syndrome and liver-gallbladder dampness-heat (LGDH) syndrome are still apt to be confused in TCM diagnosis, greatly hindering the stable exertion of TCM effectiveness. It is urgently needed to provide objective and biological evidences for differentiation and identification of the two significant syndromes. In this study, microRNA (miRNA) microarray analyses coupled with bioinformatics were employed for comparative miRNA profiling of SSDH and LGDH patients. It was found that the two syndromes had both the same and different significantly differentially expressed miRNAs (SDE-miRNAs). Commonness and specificity were also both found between their SDE-miRNA-based bioinformatics analyses, including Hierarchical Clustering, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and miRNA-GO/pathway networks. Furthermore, syndrome-specific SDE-miRNAs were identified as the potential biomarkers, including hsa-miR-1273g-3p and hsa-miR-4419b for SSDH as well as hsa-miR-129-1-3p and hsa-miR-129-2-3p for LGDH. All these laid biological and clinical bases for classification and diagnosis of the two significant CHB dampness-heat syndromes including SSDH and LGDH, providing more opportunities for better application of TCM efficacy and superiority in CHB treatment.
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Vychytilova-Faltejskova P, Slaby O. MicroRNA-215: From biology to theranostic applications. Mol Aspects Med 2019; 70:72-89. [PMID: 30904345 DOI: 10.1016/j.mam.2019.03.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/10/2019] [Accepted: 03/17/2019] [Indexed: 02/07/2023]
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15
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Su J, Wu F, Xia H, Wu Y, Liu S. Accurate cancer cell identification and microRNA silencing induced therapy using tailored DNA tetrahedron nanostructures. Chem Sci 2019; 11:80-86. [PMID: 32110359 PMCID: PMC7012044 DOI: 10.1039/c9sc04823e] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 10/30/2019] [Indexed: 12/16/2022] Open
Abstract
Accurate cancer cell identification and efficient therapy are extremely desirable and challenging in clinics. Here, we reported the first example of DNA tetrahedron nanostructures (DTNSs) to real-time monitor and image three intracellular miRNAs based on the fluorescence "OFF" to "ON" mode, as well as to realize cancer therapy induced by miRNA silencing. DTNSs were self-assembled by seven customized single-stranded nucleic acid chains containing three recognition sequences for target miRNAs. In the three vertexes of DTNSs, fluorophores and quenchers were brought into close proximity, inducing fluorescence quenching. In the presence of target miRNAs, fluorophores and quenchers would be separated, resulting in fluorescence recovery. Owing to the unique tetrahedron-like spatial structure, DTNSs displayed improved resistance to enzymatic digestion and high cellular uptake efficiency, and exhibited the ability to simultaneously monitor three intracellular miRNAs. DTNSs not only effectively distinguished tumor cells from normal cells, but also identified cancer cell subtypes, which avoided false-positive signals and significantly improved the accuracy of cancer diagnosis. Moreover, the DTNSs could also act as an anti-cancer drug; antagomir-21 (one recognition sequence) was detached from DTNSs to silence endogenous miRNA-21 inside cells, which would suppress cancer cell migration and invasion, and finally induce cancer cell apoptosis; the result was demonstrated by experiments in vitro and in vivo. It is anticipated that the development of smart nanoplatforms will open a door for cancer diagnosis and treatment in clinical systems.
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Affiliation(s)
- Juan Su
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
| | - Fubing Wu
- Department of Pathology , School of Basic Medical Sciences , Department of Oncology , The Affiliated Sir Run Run Hospital , State Key Laboratory of Reproductive Medicine , Key Laboratory of Antibody Technique of National Health Commission , Nanjing Medical University , Nanjing 211166 , China
| | - Hongping Xia
- Department of Pathology , School of Basic Medical Sciences , Department of Oncology , The Affiliated Sir Run Run Hospital , State Key Laboratory of Reproductive Medicine , Key Laboratory of Antibody Technique of National Health Commission , Nanjing Medical University , Nanjing 211166 , China
| | - Yafeng Wu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
| | - Songqin Liu
- Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device , School of Chemistry and Chemical Engineering , Southeast University , Nanjing 211189 , China
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16
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Birkett N, Al-Zoughool M, Bird M, Baan RA, Zielinski J, Krewski D. Overview of biological mechanisms of human carcinogens. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2019; 22:288-359. [PMID: 31631808 DOI: 10.1080/10937404.2019.1643539] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This review summarizes the carcinogenic mechanisms for 109 Group 1 human carcinogens identified as causes of human cancer through Volume 106 of the IARC Monographs. The International Agency for Research on Cancer (IARC) evaluates human, experimental and mechanistic evidence on agents suspected of inducing cancer in humans, using a well-established weight of evidence approach. The monographs provide detailed mechanistic information about all carcinogens. Carcinogens with closely similar mechanisms of action (e.g. agents emitting alpha particles) were combined into groups for the review. A narrative synopsis of the mechanistic profiles for the 86 carcinogens or carcinogen groups is presented, based primarily on information in the IARC monographs, supplemented with a non-systematic review. Most carcinogens included a genotoxic mechanism.
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Affiliation(s)
- Nicholas Birkett
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Mustafa Al-Zoughool
- Department of Community and Environmental Health, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Michael Bird
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Robert A Baan
- International Agency for Research on Cancer, Lyon, France
| | - Jan Zielinski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Daniel Krewski
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
- McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Risk Sciences International, Ottawa, Canada
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Long H, Zhu Y, Lin Z, Wan J, Cheng L, Zeng M, Tang Y, Zhao R. miR-381 modulates human bone mesenchymal stromal cells (BMSCs) osteogenesis via suppressing Wnt signaling pathway during atrophic nonunion development. Cell Death Dis 2019; 10:470. [PMID: 31209205 PMCID: PMC6572824 DOI: 10.1038/s41419-019-1693-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 05/19/2019] [Accepted: 05/23/2019] [Indexed: 12/19/2022]
Abstract
The osteogenic differentiation of human bone mesenchymal stromal cells (BMSCs) has been considered as a central issue in fracture healing. Wnt signaling could promote BMSC osteogenic differentiation through inhibiting PPARγ. During atrophic nonunion, Wnt signaling-related factors, WNT5A and FZD3 proteins, were significantly reduced, along with downregulation of Runx2, ALP, and Collagen I and upregulation of PPARγ. Here, we performed a microarray analysis to identify differentially expressed miRNAs in atrophic nonunion tissues that were associated with Wnt signaling through targeting related factors. Of upregulated miRNAs, miR-381 overexpression could significantly inhibit the osteogenic differentiation in primary human BMSCs while increase in PPARγ protein level. Through binding to the 3'UTR of WNT5A and FZD3, miR-381 modulated the osteogenic differentiation via regulating β-catenin nucleus translocation. Moreover, PPARγ, an essential transcription factor inhibiting osteogenic differentiation, could bind to the promoter region of miR-381 to activate its expression. Taken together, PPARγ-induced miR-381 upregulation inhibits the osteogenic differentiation in human BMSCs through miR-381 downstream targets, WNT5A and FZD3, and β-catenin nucleus translocation in Wnt signaling. The in vivo study also proved that inhibition of miR-381 promoted the fracture healing. Our finding may provide a novel direction for atrophic nonunion treatment.
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Affiliation(s)
- Haitao Long
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Zhu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhangyuan Lin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jun Wan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Liang Cheng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Min Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yifu Tang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ruibo Zhao
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
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18
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Tian H, He Z. miR-215 Enhances HCV Replication by Targeting TRIM22 and Inactivating NF-κB Signaling. Yonsei Med J 2018; 59:511-518. [PMID: 29749134 PMCID: PMC5949293 DOI: 10.3349/ymj.2018.59.4.511] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 03/26/2018] [Accepted: 03/28/2018] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Hepatitis C virus (HCV) infection is a major cause of liver disease. Several miRNAs have been found to be associated with HCV infection. This study aimed to investigate the functional roles and possible molecular mechanisms of miR-215 in HCV replication. MATERIALS AND METHODS The expression levels of miR-215 and TRIM22 were detected by quantitative real-time PCR (qRT-PCR) and western blot analysis in Con1b subgenomic genotype 1b HCV replicon cells (Con1b cells) and JFH1 full genome infecting Huh7.5.1 cells (Huh7.5.1 cells). HCV RNA levels were measured by qRT-PCR. The protein levels of NS3, NS5A, p65 subunit of NF-κB (p65), and phosphorylated p65 (p-p65) were determined by western blot analysis. The relationship between miR-215 and TRIM22 were explored by target prediction and luciferase reporter analysis. RESULTS miR-215 overexpression enhanced HCV replication in Con1b cells, while miR-215 knockdown suppressed HCV replication in Huh7.5.1 cells. TRIM22 was confirmed to be a direct target of miR-215. TRIM22 upregulation resulted in a decline in HCV replication, while TRIM22 inhibition led to enhancement of HCV replication. Additionally, exogenous expression of TRIM22 reversed the facilitating effect of miR-215 on HCV replication, while TRIM22 downregulation counteracted the inhibitory effect of miR-215 knockdown on HCV replication. Furthermore, miR-215 targeted TRIM22 to block the NF-κB pathway, and exerted a positively regulatory role on HCV replication. CONCLUSION miR-215 facilitated HCV replication via inactivation of the NF-κB pathway by inhibiting TRIM22, providing a novel potential target for HCV infection.
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Affiliation(s)
- Hui Tian
- Department of Infectious Disease, Huaihe Hospital of Henan University, Kaifeng, China
| | - Zhenkun He
- Department of Infectious Disease, Huaihe Hospital of Henan University, Kaifeng, China.
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19
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miRNAs regulate immune response and signaling during hepatitis C virus infection. Eur J Med Res 2018; 23:19. [PMID: 29669594 PMCID: PMC5907448 DOI: 10.1186/s40001-018-0317-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 04/09/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C is one of the most common types of viral hepatitis that impair human health. At present, there is still no effective specific therapy for hepatitis C virus infection. As host immunity is an important mechanism to defend against or clear infections, the interactions between the virus and the host immune response are crucial to the progress of the disease. Of note, hepatitis C virus infection has been reported to regulate cellular miRNAs, which play significant roles in many processes, including infection and immunity. In this review, we describe how miRNAs regulate the host immune response to hepatitis C virus via complex signaling pathways.
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20
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The Role of miRNAs in Virus-Mediated Oncogenesis. Int J Mol Sci 2018; 19:ijms19041217. [PMID: 29673190 PMCID: PMC5979478 DOI: 10.3390/ijms19041217] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/12/2018] [Accepted: 04/13/2018] [Indexed: 12/16/2022] Open
Abstract
To date, viruses are reported to be responsible for more than 15% of all tumors worldwide. The oncogenesis could be influenced directly by the activity of viral oncoproteins or by the chronic infection or inflammation. The group of human oncoviruses includes Epstein–Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human herpesvirus 8 (HHV-8) or polyomaviruses, and transregulating retroviruses such as HIV or HTLV-1. Most of these viruses express short noncoding RNAs called miRNAs to regulate their own gene expression or to influence host gene expression and thus contribute to the carcinogenic processes. In this review, we will focus on oncogenic viruses and summarize the role of both types of miRNAs, viral as well as host’s, in the oncogenesis.
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21
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Zekri ARN, El-Sisi ER, Youssef ASED, Kamel MM, Nassar A, Ahmed OS, El Kassas M, Barakat AB, Abd El-Motaleb AI, Bahnassy AA. MicroRNA Signatures for circulating CD133-positive cells in hepatocellular carcinoma with HCV infection. PLoS One 2018; 13:e0193709. [PMID: 29534065 PMCID: PMC5849309 DOI: 10.1371/journal.pone.0193709] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
AIM Molecular characterization of the CD133+ stem cells associated with hepatocarinogensis through identifying the expression patterns of specific microRNAs (miRNAs). METHODS We investigated the expression pattern of 13 miRNAs in purified CD133+ cells separated from the peripheral blood of healthy volunteers, chronic hepatitis C (CHC), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) patients a long with bone marrow samples from the healthy volunteers and the LC patients using custom miScript miRNA PCR array. RESULTS The differential expression of the 13 studied miRNAs in CD133+ cells separated from the HCC patients' peripheral blood compared to the controls revealed that miR-602, miR-181b, miR-101, miR-122, miR-192, miR-125a-5p, and miR-221 were significantly up regulated (fold change = 1.8, 1.7, 2, 5.4, 1.6, 2.9 & 1.5 P value = 0.039, 0.0019, 0.0013, 0.0370, 00024, 0.000044 &0.000007 respectively). As for the HCC group compared to the CHC group; miR-602, miR-122, miR-181b, miR-125a-5p, and miR-192 were significantly up regulated (fold change = 13, 3.1, 2.8, 1.6 & 1.56, P value = 0.01, 0.001, 0.000004, 0.002 & 0.007 respectively). Upon comparing the HCC group to the LC group; miR-199a-3p, miR-192, miR-122, miR-181b, miR-224, miR-125a-5p, and miR-885-5p were significantly up regulated (fold change = 5, 6.7, 2.3, 3, 2.5, 4.2 & 39.5 P value = 0.001025, 0.000024, 0.000472, 0.000278, 0.000004, 0.000075 & 0.0000001 respectively) whereas miR-22 was significantly down regulated (fold change = 0.57 P value = 0.00002). Only, miR-192, miR-122, miR-181b and miR-125a-5p were significant common miRNAs in CD133+ cells of the HCC group compared to the other non-malignant groups. CONCLUSION We identified a miRNA panel comprised of four miRNAs (miR-192, miR-122, miR-181b and miR-125a-5p) that may serve as a molecular tool for characterization of the CD133+ cells associated with different stages of hepatocarinogensis. This panel may aid in developing a new target therapy specific for those CD133+ cells.
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Affiliation(s)
- Abdel-Rahman N. Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Enas Reda El-Sisi
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Amira Salah El-Din Youssef
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mahmoud M. Kamel
- Clinical Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Auhood Nassar
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
| | - Ola Sayed Ahmed
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Photobiology and Molecular Biology Department, Laser Institute for Research and Applications (LIRA), Beni-Suef University, Beni Suef, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Helwan, Egypt
| | | | | | - Abeer A. Bahnassy
- Tissue Culture and Cytogenetics Unit, Pathology Department, National Cancer Institute, Cairo University, Cairo, Egypt
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22
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Schwartz N, Pellach M, Glick Y, Gil R, Levy G, Avrahami D, Barbiro-Michaely E, Nahmias Y, Gerber D. Neuregulin 1 discovered as a cleavage target for the HCV NS3/4A protease by a microfluidic membrane protein array. N Biotechnol 2018; 45:113-122. [PMID: 29438748 DOI: 10.1016/j.nbt.2018.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/22/2018] [Accepted: 02/07/2018] [Indexed: 12/26/2022]
Abstract
The hepatitis C virus (HCV) non-structural protein 3 (NS3) is essential for HCV maturation. The NS3/4A protease is a target for several HCV treatments and is a well-known target for HCV drug discovery. The protein is membrane associated and thus probably interacts with other membrane proteins. However, the vast majority of known NS3 host partners are soluble proteins rather than membrane proteins, most likely due to lack of appropriate platforms for their discovery. Utilization of an integrated microfluidics platform enables analysis of membrane proteins in their native form. We screened over 2800 membrane proteins for interaction with NS3 and 90 previously unknown interactions were identified. Of these, several proteins were selected for validation by co-immunoprecipitation and for NS3 proteolytic activity. Bearing in mind the considerable number of interactions formed, together with the popularity of NS3/4A protease as a drug target, it was striking to note its lack of proteolytic activity. Only a single protein, Neuregulin1, was observed to be cleaved, adding to the 3 known NS3/4A cleavage targets. Neuregulin1 participates in neural proliferation. Recent studies have shown its involvement in HCV infection and hepatocellular carcinoma. We showed that NS3/4A triggers an increase in neuregulin1 mRNA levels in HCV infected cells. Despite this increase, its protein concentration is decreased due to proteolytic cleavage. Additionally, its EGF-like domain levels were increased, possibly explaining the ErbB2 and EGFR upregulation in HCV infected cells. The newly discovered protein interactions may provide insights into HCV infection mechanisms and potentially provide new therapeutic targets against HCV.
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Affiliation(s)
- Nika Schwartz
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Michal Pellach
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Yair Glick
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Reuven Gil
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Gahl Levy
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel; Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Dorit Avrahami
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Efrat Barbiro-Michaely
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel
| | - Yaakov Nahmias
- Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel; Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Doron Gerber
- Mina and Everard Goodman Faculty of Life Sciences and Bar Ilan Institute for Nanotechnology and Advanced Materials, Anna Web Nanotechnology bld. (206), Bar Ilan University, Ramat Gan, 5290002, Israel.
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Singhal A, Agrawal A, Ling J. Regulation of insulin resistance and type II diabetes by hepatitis C virus infection: A driver function of circulating miRNAs. J Cell Mol Med 2018; 22:2071-2085. [PMID: 29411512 PMCID: PMC5867149 DOI: 10.1111/jcmm.13553] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a serious worldwide healthcare issue. Its association with various liver diseases including hepatocellular carcinoma (HCC) is well studied. However, the study on the relationship between HCV infection and the development of insulin resistance and diabetes is very limited. Current research has already elucidated some underlying mechanisms, especially on the regulation of metabolism and insulin signalling by viral proteins. More studies have emerged recently on the correlation between HCV infection‐derived miRNAs and diabetes and insulin resistance. However, no studies have been carried out to directly address if these miRNAs, especially circulating miRNAs, have causal effects on the development of insulin resistance and diabetes. Here, we proposed a new perspective that circulating miRNAs can perform regulatory functions to modulate gene expression in peripheral tissues leading to insulin resistance and diabetes, rather than just a passive factor associated with these pathological processes. The detailed rationales were elaborated through comprehensive literature review and bioinformatic analyses. miR‐122 was identified to be one of the most potential circulating miRNAs to cause insulin resistance. This result along with the idea about the driver function of circulating miRNAs will promote further investigations that eventually lead to the development of novel strategies to treat HCV infection‐associated extrahepatic comorbidities.
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Affiliation(s)
- Adit Singhal
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
| | | | - Jun Ling
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
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24
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Xie Z, Xiao Z, Wang F. Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway. Mol Cells 2017; 40:202-210. [PMID: 28343379 PMCID: PMC5386958 DOI: 10.14348/molcells.2017.2299] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/21/2017] [Accepted: 02/22/2017] [Indexed: 02/08/2023] Open
Abstract
The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus (HCV) RNA genome is a multifunctional phosphoprotein. To analyse the influence of NS5A on apoptosis, we established an Hep-NS5A cell line (HepG2 cells that stably express NS5A) and induced apoptosis using tumour necrosis factor (TNF)-α. We utilised the MTT assay to detect cell viability, real-time quantitative polymerase chain reaction and Western blot to analyse gene and protein expression, and a luciferase reporter gene experiment to investigate the targeted regulatory relationship. Chromatin immunoprecipitation was used to identify the combination of NF-κB and miR-503. We found that overexpression of NS5A inhibited TNF-αinduced hepatocellular apoptosis via regulating miR-503 expression. The cell viability of the TNF-α induced Hep-mock cells was significantly less than the viability of the TNF-α induced Hep-NS5A cells, which demonstrates that NS5A inhibited TNF-α-induced HepG2 cell apoptosis. Under TNF-α treatment, miR-503 expression was decreased and cell viability and B-cell lymphoma 2 (bcl-2) expression were increased in the Hep-NS5A cells. Moreover, the luciferase reporter gene experiment verified that bcl-2 was a direct target of miR-503, NS5A inhibited TNF-α-induced NF-κB activation and NF-κB regulated miR-503 transcription by combining with the miR-503 promoter. After the Hep-NS5A cells were transfected with miR-503 mimics, the data indicated that the mimics could reverse TNF-α-induced cell apoptosis and blc-2 expression. Collectively, our findings suggest a possible molecular mechanism that may contribute to HCV treatment in which NS5A inhibits NF-κB activation to decrease miR-503 expression and increase bcl-2 expression, which leads to a decrease in hepatocellular apoptosis.
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Affiliation(s)
- Zhengyuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital, Nanchang University, Nanchang 330006,
China
| | - Zhihua Xiao
- Department of Gastroenterology, The Second Affiliated Hospital, Nanchang University, Nanchang 330006,
China
| | - Fenfen Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Nanchang University, Nanchang 330006,
China
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Hanisch C, Sharbati J, Kutz-Lohroff B, Huber O, Einspanier R, Sharbati S. TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS. Cell Death Discov 2017; 3:16106. [PMID: 28149533 PMCID: PMC5279457 DOI: 10.1038/cddiscovery.2016.106] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 12/17/2016] [Indexed: 12/21/2022] Open
Abstract
Tumour necrosis factor-α (TNF-α) is a double-edged cytokine associated with pathogenesis of inflammatory-related cancers being also able to induce cancer cell death. In the process of tumour development or metastasis, cancer cells can become resistant to TNF-α. In trefoil factor 3 (TFF3) overexpressing colorectal adenocarcinoma cells (HT-29/B6), we observed enhanced resistance against TNF-α/interferon gamma-induced apoptosis. TFF3 is a secreted small peptide that supports intestinal tissue repair but is also involved in intestinal tumour progression and scattering. We hypothesised that TFF3 rescues intestinal epithelial cancer cells from TNF-α-induced apoptosis by involving regulatory RNA networks. In silico-based expression analysis revealed TFF3-mediated regulation of selected microRNAs as well as long non-coding RNAs (lncRNAs), whereas miR-491-5p was identified to target the lncRNA ‘psoriasis susceptibility-related RNA gene induced by stress’ (PRINS). RNA interference-based gain- and loss-of-function experiments examined miR-491-PRINS axis to exert the TFF3-mediated phenotype. Chemical inhibition of selected pathways showed that phosphatidylinositol 3-kinase/AKT accounts for TFF3-mediated downregulation of miR-491-5p and accumulation of PRINS. Moreover, we showed that PRINS colocalises with PMAIP1 (NOXA) in nuclei of HT-29/B6 possessing inhibitory effects. Immunoprecipitation experiments proved molecular interaction of PMAIP1 with PRINS. Our study provides an insight into RNA regulatory networks that determine resistance of colorectal cancer cells to apoptosis.
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Affiliation(s)
- Carlos Hanisch
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Jutta Sharbati
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin, Berlin, Germany; Lise Meitner School of Science, Berlin, Germany
| | - Barbara Kutz-Lohroff
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Otmar Huber
- Institute of Biochemistry II, Jena University Hospital , Jena, Germany
| | - Ralf Einspanier
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
| | - Soroush Sharbati
- Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany
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26
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Chen W, Qiu Y. Ginsenoside Rh2 Targets EGFR by Up-Regulation of miR-491 to Enhance Anti-tumor Activity in Hepatitis B Virus-Related Hepatocellular Carcinoma. Cell Biochem Biophys 2017; 72:325-31. [PMID: 25561284 DOI: 10.1007/s12013-014-0456-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive tumors in humans. The typical therapeutic strategies include a combination of chemotherapy, radiotherapy, and surgery, whereas the survival rate of patients is very poor. Ginsenoside Rh2 has been reported to have therapeutic effects on some tumors, but its effect on HCC has not been extensively evaluated. Here, we show that ginsenoside Rh2 can effectively inhibit the proliferation and cell survival of HCC cells in vitro and in a mouse model. Moreover, the inhibition of the tumor growth appears to result from combined effects on decreased tumor cell proliferation and cell viability. Further analyses suggest that ginsenoside Rh2 may have its anti-tumor effect through inhibition of epidermal growth factor receptor (EGFR) signaling pathway. Recombinant EGFR was given together with ginsenoside Rh2 to the tumor cells, which completely blocked the anti-tumor effect of ginsenoside Rh2. Our data also show that miR-491 is up-regulated in SMMC-7721 cells after Rh2 treatment. There is a negative correlation between EGFR and miR-491 levels in SMMC-7721 cells and miR-491 directly targeted EGFR at translational level. Our data not only reveal an anti-tumor effect of ginsenoside Rh2 but also demonstrate that this effect may function via activation and inhibition of EGFR signaling in HCC cells. The results suggest miR-491 can be a promising regulatory factor in EGFR signal transduction.
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Affiliation(s)
- Weiwen Chen
- Medical Laboratories, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yurong Qiu
- Medical Laboratories, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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27
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Ohde D, Brenmoehl J, Walz C, Tuchscherer A, Wirthgen E, Hoeflich A. Comparative analysis of hepatic miRNA levels in male marathon mice reveals a link between obesity and endurance exercise capacities. J Comp Physiol B 2016; 186:1067-1078. [PMID: 27278158 DOI: 10.1007/s00360-016-1006-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 05/24/2016] [Accepted: 06/01/2016] [Indexed: 12/23/2022]
Abstract
Dummerstorf marathon mice (DUhTP) are characterized by increased accretion of peripheral body fat with fast mobilization in response to mild physical activity if running wheels were included in their home cages. The obese phenotype coincides with elevated hepatic lipogenesis if compared to unselected controls. We now asked, if microRNA (miRNA) species present in the liver may contribute to the obese phenotype of DUhTP mice and if miRNAs respond to mild physical activity in our mouse model. Total RNA was extracted from livers of sedentary or physically active marathon mice and controls and analyzed by array hybridization or real-time PCR using locked nucleic acid probes. Pathway analysis of altered miRNA concentrations identified fatty acid biosynthesis as the most important target for the effects of miRNAs in the liver. A miRNA signature consisting of miR-21, 27, 33, 122, and 143 was present at higher abundance (p < 0.01) in the liver of sedentary or active DUhTP mice indicating involvement of miRNAs with hepatic lipogenesis. Furthermore, in protein lysates from the liver of DUhTP mice, significantly reduced concentrations of total and phosphorylated AKT and lower levels of phosphorylated AMPK were found (p < 0.05). Our results indicate active involvement of miRNAs in the control of hepatic energy metabolism and discuss effects on signal transduction as a potentially direct effect of miR-143 in the liver of DUhTP mice.
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Affiliation(s)
- Daniela Ohde
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Julia Brenmoehl
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Christina Walz
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Armin Tuchscherer
- Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Elisa Wirthgen
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany
| | - Andreas Hoeflich
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196, Dummerstorf, Germany.
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28
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Du L, Tang H. miRNA antagonism and direct-acting antivirals: could this be a novel combination treatment against HCV? Future Virol 2016. [DOI: 10.2217/fvl-2016-0109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
- Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, & Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
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29
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Yu J, Wang L, Yang H, Ding D, Zhang L, Wang J, Chen Q, Zou Q, Jin Y, Liu X. Rab14 Suppression Mediated by MiR-320a Inhibits Cell Proliferation, Migration and Invasion in Breast Cancer. J Cancer 2016; 7:2317-2326. [PMID: 27994670 PMCID: PMC5166543 DOI: 10.7150/jca.15737] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 09/17/2016] [Indexed: 12/11/2022] Open
Abstract
We found that microRNA-320a (miR-320a) was an attractive prognostic biomarker in breast cancer (BC) previously, whereas its regulatory mechanism in BC was not well understood. Our aim was to identify miR-320a target gene, examine the clinical relationship between miR-320a and its target, and further explore the functions of its target in BC. In this study, miR-320a downstream target gene was determined in HEK-293T cells by dual luciferase reporter assay. Then western blotting and immunohistochemistry were used to assess miR-320a target gene expression in fresh frozen (n=19, breast cancer and matched non-malignant adjacent tissue samples) and formalin-fixed paraffin-embedded (FFPE) (n=130, invasive BC tissues, the same panel detected for miR-320a expression previously) breast tissues, respectively. The results suggested that miR-320a could significantly suppressed Rab14 3'-untranslated region luciferase-reporter activity, and thus Rab14 was first identified as miR-320a target in BC. In 19 matched breast tissues, 12 (63%) breast cancer tissues showed high expression of Rab14 compared with the corresponding normal tissues. Rab14 immunoreactivity was mainly detected in the cytoplasm, 77/130 (59.2%) showed high expression. Furthermore, Rab14 expression was found to be inversely correlated with miR-320a expression in fresh-frozen breast tissues as well as in FFPE invasive breast cancer samples. In addition, Rab14 expression levels were positively related to tumor size (P = 0.034), lymph node metastasis (P < 0.001), distant metastasis (P = 0.001), histological grade (P = 0.035) and clinical tumor lymph-node metastasis stage (P = 0.001). Patients with higher Rab14 expression showed shorter overall survival time. Moreover, silencing of Rab14 could suppress proliferation, migration and invasion in breast cancer cell lines. Collectively, our results indicate that miR-320a could target Rab14 and that they could interact biologically in BC.
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Affiliation(s)
- Juan Yu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Lei Wang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Haiping Yang
- Department of Pathology, People's Hospital, Linzi District, Zibo City, Shandong 255400, China
| | - Di Ding
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jigang Wang
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Qi Chen
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Qiang Zou
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yiting Jin
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiuping Liu
- Department of Pathology, the Fifth People's Hospital, Fudan University, Shanghai 200240, China
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30
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Hepatitis C virus infection stimulates transforming growth factor-β1 expression through up-regulating miR-192. J Microbiol 2016; 54:520-6. [PMID: 27350618 DOI: 10.1007/s12275-016-6240-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 06/07/2016] [Accepted: 06/07/2016] [Indexed: 12/22/2022]
Abstract
The objective of this study was to determine the molecular mechanisms underlying chronic liver injury and fibrosis caused by hepatitis C virus (HCV). This study revealed that miR-192 expreßsion was induced by HCV infection without affecting viral replication. However, viral-induced miR-192 up-regulated transforming growth factor-ß1 (TGF-ß1) expreßsion in liver cells at transcriptional level. TGF-ß1 stimulation by HCV-induced miR-192 was caused through ZEB1 down-regulation and TGF-ß1 increased miR-192 level via positive feedback pathway. Increase in miR-192 expreßsion by HCV infection was due to HCV core protein released and/or expressed by viral infection. TGF-ß1 promoter activity was also increased by HCV core protein in liver cells. Taken together, HCV infection resulted in increased TGF-ß1 transcription in hepatocytes through ZEB1 down-regulation by HCV core-mediated miR-192 stimulation. Importantly, miR-192 inhibition with anti-miR-192 rescued ZEB1 expression down-regulated by HCV infection, thus reducing the level of TGF-ß1 expression increased by HCV infection in hepatocytes. These results suggest a novel mechanism of HCV-mediated liver fibrogenesis with miR-192 being a potential molecular target to ameliorate viral pathogenesis.
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31
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Piedade D, Azevedo-Pereira JM. MicroRNAs, HIV and HCV: a complex relation towards pathology. Rev Med Virol 2016; 26:197-215. [PMID: 27059433 DOI: 10.1002/rmv.1881] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 03/11/2016] [Accepted: 03/15/2016] [Indexed: 12/13/2022]
Abstract
MicroRNAs are small non-coding RNAs that modulate protein production by post-transcriptional gene regulation. They impose gene expression control by interfering with mRNA translation and stability in cell cytoplasm through a mechanism involving specific binding to mRNA based on base pair complementarity. Because of their intracellular replication cycle it is no surprise that viruses evolved in a way that allows them to use microRNAs to infect, replicate and persist in host cells. Several ways of interference between virus and host-cell microRNA machinery have been described. Most of the time, viruses drastically alter host-cell microRNA expression or synthesize their own microRNA to facilitate infection and pathogenesis. HIV and HCV are two prominent examples of this complex interplay revealing how fine-tuning of microRNA expression is crucial for controlling key host pathways that allow viral infection and replication, immune escape and persistence. In this review we delve into the mechanisms underlying cellular and viral-encoded microRNA functions in the context of HIV and HCV infections. We focus on which microRNAs are differently expressed and deregulated upon viral infection and how these alterations dictate the fate of virus and cell. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Diogo Piedade
- Host-Pathogen Interaction Unit, iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Portugal
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32
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MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:280. [PMID: 26927063 PMCID: PMC4813144 DOI: 10.3390/ijms17030280] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 01/19/2016] [Accepted: 02/19/2016] [Indexed: 02/07/2023] Open
Abstract
Serum levels of liver enzymes, such as alanine transaminase, aspartate transaminase, and α-fetoprotein, provide insight into liver function and are used during treatment of liver disease, but such information is limited. In the case of hepatocellular carcinoma (HCC), which is often not detected until an advanced stage, more sensitive biomarkers may help to achieve earlier detection. Serum also contains microRNAs, a class of small non-coding RNAs that play an important role in regulating gene expression. miR-122 is specific to the liver and correlates strongly with liver enzyme levels and necroinflammatory activity, and other microRNAs are correlated with the degree of fibrosis. miR-122 has also been found to be required for hepatitis C virus (HCV) infection, whereas other microRNAs have been shown to play antiviral roles. miR-125a-5p and miR-1231 have been shown to directly target hepatitis B virus (HBV) transcripts, and others are up- or down-regulated in infected individuals. MicroRNA profiles also differ in the case of HBV and HCV infection as well as between HBeAg-positive and negative patients, and in patients with occult versus active HBV infection. In such patients, monitoring of changes in microRNA profiles might provide earlier warning of neoplastic changes preceding HCC.
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33
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Li H, Jiang JD, Peng ZG. MicroRNA-mediated interactions between host and hepatitis C virus. World J Gastroenterol 2016; 22:1487-1496. [PMID: 26819516 PMCID: PMC4721982 DOI: 10.3748/wjg.v22.i4.1487] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/25/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs. More than 2500 mature miRNAs are detected in plants, animals and several types of viruses. Hepatitis C virus (HCV), which is a positive-sense, single-stranded RNA virus, does not encode viral miRNA. However, HCV infection alters the expression of host miRNAs, either in cell culture or in patients with liver disease progression, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. In turn, host miRNAs regulate HCV life cycle through directly binding to HCV RNAs or indirectly targeting cellular mRNAs. Increasing evidence demonstrates that miRNAs are one of the centered factors in the interaction network between virus and host. The competitive viral and host RNA hypothesis proposes a latent cross-regulation pattern between host mRNAs and HCV RNAs. High loads of HCV RNA sequester and de-repress host miRNAs from their normal host targets and thus disturb host gene expression, indicating a means of adaptation for HCV to establish a persistent infection. Some special miRNAs are closely correlated with liver-specific disease progression and the changed levels of miRNAs are even higher sensitivity and specificity than those of traditional proteins. Therefore, some of them can serve as novel diagnostic/prognostic biomarkers in HCV-infected patients with liver diseases. They are also attractive therapeutic targets for development of new anti-HCV agents.
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34
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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35
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van der Ree MH, van der Meer AJ, van Nuenen AC, de Bruijne J, Ottosen S, Janssen HL, Kootstra NA, Reesink HW. Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma. Aliment Pharmacol Ther 2016; 43:102-13. [PMID: 26503793 DOI: 10.1111/apt.13432] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 08/29/2015] [Accepted: 09/25/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients. AIM To assess the plasma level of various miRNAs in patients dosed with miravirsen. METHODS We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) miravirsen or placebo (n = 4) over a 4-week period in a double-blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with miravirsen or placebo. RESULTS Median plasma miR-122 level at baseline in patients receiving miravirsen was 3.9 × 10(3) compared to 1.3 × 10(4) copies/4 μL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR-210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period. CONCLUSIONS We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122.
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Affiliation(s)
- M H van der Ree
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
| | - A J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - A C van Nuenen
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
| | - J de Bruijne
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - S Ottosen
- Santaris Pharma A/S, Hørsholm, Denmark
| | - H L Janssen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.,Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada
| | - N A Kootstra
- Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
| | - H W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.,Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
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36
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El Sobky SA, El-Ekiaby NM, Mekky RY, Elemam NM, Mohey Eldin MA, El-Sayed M, Esmat G, Abdelaziz AI. Contradicting roles of miR-182 in both NK cells and their host target hepatocytes in HCV. Immunol Lett 2016; 169:52-60. [PMID: 26518141 DOI: 10.1016/j.imlet.2015.10.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 10/16/2015] [Accepted: 10/21/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Natural killer cells are part of the innate immunity involved in viral eradication and were shown to be greatly affected by HCV infection. Epigenetic regulation of NK cell function by microRNAs was not efficiently studied before and was never studied in HCV infection; therefore the aim of this study was to assess for the first time the role of microRNAs in regulating the function of NK cells of HCV-infected patients and hence viral replication in the target HCV-infected Huh7 cells. METHODOLOGY NK cells were isolated from PBMCs of HCV-infected patients as well as controls, and HCV-infected liver biopsies as well as Huh7 cells infected with the virus were used. For the infection of Huh7 cells, first viral vector was in-vitro transcribed into viral RNA that was then used to infect naїve Huh7 cells. Supernatant from the infected cells was then collected and used for further infection. For manipulation of NK cells or Huh7 cells, miR-182 mimics and inhibitors were transfected via lipofection method. RNA was extracted from each cell population, reverse transcribed. Gene expression as well as viral load was quantified using qPCR. RESULTS Screening of NKG2A and NKG2D between patients and controls showed no difference in expression of NKG2A, while NKG2D was found to be downregulated. In view of that, bioinformatics analysis was performed and showed that miR-182 has potential binding sites on both the inhibitory receptor NKG2A and the activating receptor NKG2D, and on its ligand ULBP2, as well as on the viral genome itself. In NK cells of HCV-infected patients, miR-182 was found to be over-expressed compared to controls; its ectopic expression was found to decrease NKG2D mRNA level, while miR-182 inhibitors were able to decrease NKG2A mRNA compared to untransfected cells. In addition, co-culturing genotype 4 or 2 HCV-infected Huh7 cells with miR-182 mimicked NK cells of HCV-infected patients showed decreased viral replication, suggesting an enhanced NK cell function. On the other hand, miR-182 and ULBP2 were both found to be downregulated in HCV liver tissues and HCV-infected Huh7 cells compared to their controls. miR-182 mimics were found to decrease ULBP2 mRNA and increase viral replication in genotypes 4 and 2 HCV-infected target (Huh7) cells compared to controls, while miR-182 inhibitor decreased viral replication in the cell models. CONCLUSION miR-182 was never investigated before, neither in HCV infection nor in NK cells, and we found it to have dysregulated expression in both liver tissues and NK cells of HCV-infected patients compared to control. In addition to that, miR-182 was found to have a contradicting effect in both effector cell and its HCV-infected target cell regarding HCV replication.
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Affiliation(s)
- Shereen A El Sobky
- Department of Pharmaceutical Biology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Nada M El-Ekiaby
- Department of Pharmacology & Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Radwa Y Mekky
- Department of Pharmacology & Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Noha M Elemam
- Department of Pharmacology & Toxicology, German University in Cairo, New Cairo City, Main Entrance Al Tagamoa Al Khames, 11835 Cairo, Egypt
| | - Mohammad A Mohey Eldin
- Department of Tropical Medicine and Hepatology, Cairo University Kasr El-Aini St, Cairo, Egypt
| | - Mohammed El-Sayed
- Department of Tropical Medicine and Hepatology, Cairo University Kasr El-Aini St, Cairo, Egypt
| | - Gamal Esmat
- Department of Tropical Medicine and Hepatology, Cairo University Kasr El-Aini St, Cairo, Egypt
| | - Ahmed I Abdelaziz
- Department of Biology, American University in Cairo New Cairo, Egypt.
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Gragnani L, Piluso A, Fognani E, Zignego AL. MicroRNA expression in hepatitis C virus-related malignancies: A brief review. World J Gastroenterol 2015; 21:8562-8568. [PMID: 26229398 PMCID: PMC4515837 DOI: 10.3748/wjg.v21.i28.8562] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Not only is chronic hepatitis C virus (HCV) infection a major public health problem, but also it can cause hepatocellular carcinoma and, more rarely, non-Hodgkin’s lymphoma. These characteristics mean that HCV is the only virus infecting humans that is able to cause two different cancers. The fine pathogenetic and molecular mechanisms by which HCV induces these two malignancies are not completely clear. In the last decade, it has been shown that microRNAs (miRNAs), a class of 21-23-nucleotide molecules modulating post-transcriptional gene expression, make an important contribution to the pathogenesis of several cancers and are also considered highly promising biomarkers. Here, we briefly describe the current knowledge about microRNAs’ involvement in HCV-related molecular oncogenesis. We decided to focus our attention on studies fully conducted on ex vivo samples with this specific etiology, and on cultured cell lines partially or completely expressing the HCV genome. Some of the results reported in this review are controversial, possibly because of methodological issues, differences in sampling size and features, and ethnicity of patients. What is certain is that miRNAs play a remarkable role in regulating gene expression during oncogenetic processes and in viral infection. A clear understanding of their effects is fundamental to elucidating the mechanisms underlying virus-induced malignancies.
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Schwerk J, Jarret AP, Joslyn RC, Savan R. Landscape of post-transcriptional gene regulation during hepatitis C virus infection. Curr Opin Virol 2015; 12:75-84. [PMID: 25890065 DOI: 10.1016/j.coviro.2015.02.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 02/11/2015] [Indexed: 12/11/2022]
Abstract
Post-transcriptional regulation of gene expression plays a pivotal role in various gene regulatory networks including, but not limited to metabolism, embryogenesis and immune responses. Different mechanisms of post-transcriptional regulation, which can act individually, synergistically, or even in an antagonistic manner have been described. Hepatitis C virus (HCV) is notorious for subverting host immune responses and indeed exploits several components of the host's post-transcriptional regulatory machinery for its own benefit. At the same time, HCV replication is post-transcriptionally targeted by host cell components to blunt viral propagation. This review discusses the interplay of post-transcriptional mechanisms that affect host immune responses in the setting of HCV infection and highlights the sophisticated mechanisms both host and virus have evolved in the race for superiority.
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Affiliation(s)
- Johannes Schwerk
- Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Abigail P Jarret
- Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Rochelle C Joslyn
- Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Ram Savan
- Department of Immunology, University of Washington, Seattle, WA 98109, USA.
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Difference in microRNA expression and editing profile of lung tissues from different pig breeds related to immune responses to HP-PRRSV. Sci Rep 2015; 5:9549. [PMID: 25856272 PMCID: PMC5381705 DOI: 10.1038/srep09549] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 01/26/2015] [Indexed: 12/21/2022] Open
Abstract
Porcine reproductive and respiratory syndrome (PRRS) is one of the most devastating diseases for the pig industry. Our goal was to identify microRNAs involved in the host immune response to PRRS. We generated microRNA expression profiles of lung tissues from Tongcheng or Landrace pigs infected with a highly pathogenic PRRS virus (PRRSV) at 3, 5, 7 dpi (day post infection) and control individuals from these two breeds. Our data showed that 278 known and 294 novel microRNAs were expressed in these combined microRNA transcriptomes. Compared with control individuals, almost half of the known microRNAs (116 in Tongcheng and 153 in Landrace) showed significantly differential expression (DEmiRNAs) at least once. The numbers of down-regulated DEmiRNAs were larger than the corresponding number of up-regulated DEmiRNAs in both breeds. Interestingly, miR-2320-5p, which was predicted to bind to conserved sequences of the PRRSV genome, was down-regulated significantly at 3 dpi after PRRSV infection in both breeds. In addition, PRRSV infection induced a significant increase of microRNA editing level in both breeds. Our results provide novel insight into the role of microRNA in response to PRRSV infection in vivo, which will aid the research for developing novel therapies against PRRSV.
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Serum interferon-related microRNAs as biomarkers to predict the response to interferon therapy in chronic hepatitis C genotype 4. PLoS One 2015; 10:e0121524. [PMID: 25811198 PMCID: PMC4374907 DOI: 10.1371/journal.pone.0121524] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 02/03/2015] [Indexed: 12/31/2022] Open
Abstract
Background Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response. Methods RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR). Results The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5. Conclusion and Significance miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments.
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Serum interferon-related microRNAs as biomarkers to predict the response to interferon therapy in chronic hepatitis C genotype 4. PLoS One 2015; 10:e0120794. [PMID: 25790297 PMCID: PMC4366211 DOI: 10.1371/journal.pone.0120794] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 01/26/2015] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs are messengers during interferon-virus interplay and are involved in antiviral immunity, however, little is known about interferon-related microRNAs regarding their detection in serum and their potential use as non-invasive diagnostic and prognostic biomarkers in chronic hepatitis C (CHC). To elucidate some of the molecular aspects underlying failure of pegylated interferon-α/ribavirin therapy, we investigated pretreatment expression profiles of seven selected interferon-related microRNAs (miR-146a, miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296) by quantitative RT-PCR custom array technology in serum of Egyptian CHC genotype 4 patients and whether their pretreatment levels would predict patient response to the combination therapy. One hundred and six CHC patients and forty matched healthy controls were included. Patients were divided into sustained virological response (SVR) and non-responder (NR) groups. Serum miR-34a, miR-130a, miR-19a, miR-192, miR-195, and miR-296 were upregulated, whereas serum miR-146a was downregulated in CHC compared to controls. Significant correlations were found between expression levels of studied microRNAs and also with clinical data. Pretreatment levels of miR-34a, miR-130a, and miR-195 were significantly higher, whereas miR-192 and miR-296 levels were significantly lower in SVR than NR patients. miR-19a and miR-146a levels were not significantly different between the two groups. miR-34a was superior to differentiate CHC from controls, whereas miR-296 was superior to discriminate SVR from NR patients by receiver operating characteristic analysis. Multivariate logistic analysis revealed miR-34a and miR-195 as independent predictors for SVR and miR-192 as an independent variable for non-response. In conclusion, pretreatment expression profiles of five interferon-related microRNAs are associated with treatment outcome in CHC. Of these, miR-34a, miR-195, and miR-192 could predict treatment response. The profiling results could be used as novel non-invasive diagnostic and prognostic pharmacogenetic biomarkers for treatment personalization in CHC and could help to identify new microRNA-based antivirals.
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Abstract
Hepatitis C virus (HCV) is a global health burden with an estimated 170-200 million peoples chronically infected worldwide. HCV infection remains as an independent risk factor for chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and a major reason for liver transplantation. Discovery of direct acting antiviral (DAA) drugs have shown promising results with more than 90% success rate in clearing the HCV RNA in patients, although long-term consequences remain to be evaluated. microRNAs (miRNAs) are important players in establishment of HCV infection and target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Altered expression of miRNAs is involved in the pathogenesis associated with HCV infection by controlling signaling pathways such as immune response, proliferation and apoptosis. miRNA is emerging as a means of communication between various cell types inside the liver. There is likely possibility of developing circulating miRNAs as biomarkers of disease progression and can also serve as diagnostic tool with potential of early therapeutic intervention in HCV associated end stage liver disease. This review focuses on recent studies highlighting the contribution of miRNAs in HCV life cycle and their coordinated regulation in HCV mediated liver disease progression.
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Affiliation(s)
| | - Robert Steele
- Departments of Pathology, Saint Louis University, St. Louis, Missouri, USA
| | - Ranjit Ray
- Departments of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
| | - Ratna B Ray
- Departments of Pathology, Saint Louis University, St. Louis, Missouri, USA
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Liu B, Xiang Y, Zhang HS. Circulating microRNA-196a as a candidate diagnostic biomarker for chronic hepatitis C. Mol Med Rep 2015; 12:105-10. [PMID: 25738504 PMCID: PMC4438874 DOI: 10.3892/mmr.2015.3386] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 01/22/2015] [Indexed: 02/07/2023] Open
Abstract
Previous studies have demonstrated the inhibitory effect of microRNA (miR)-196a on hepatitis C virus (HCV) expression in human hepatocytes. However, the clinical implications of aberrant miR-196a expression and the application of circulating miR-196a in the diagnosis and management of chronic hepatitis C (CHC) require further investigation. The present study aimed to examine the possibility of using serum miR-196a as a biomarker for CHC. The Affymetrix miRNA array platform was used for miRNA expression profiling in adenovirus (Ad)-HCV core-infected (HepG2-HCV) and Ad-enhanced green fluorescence protein (EGFP)-infected HepG2 cells (HepG2-control). miR-196a downregulation and levels were analyzed using stem-loop reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis of the sera of 43 patients with CHC and 22 healthy controls. A total of six miRNAs were identified as significantly different (≥1.5 fold; P≤0.05) between the two groups. Of note, significant miR-196a downregulation was observed in HepG2-HCV as compared with HepG2-EGFP. Furthermore, as compared with that of the healthy control group, serum miR-196a was demonstrated to be significantly lower in patients with CHC. In addition, analysis of the receiver operating characteristic (ROC) curve for serum miR-196a revealed an area under the ROC curve of 0.849 (95% confidence interval, 0.756–0.941; P<0.001) with 81.8% sensitivity and 76.7% specificity in discriminating chronic HCV infection from healthy controls at a cut-off value of 6.115×10‒5, demonstrating significant diagnostic value for CHC. However, no correlation was identified between serum miR-196a and alanine aminotransferase, aspartate aminotransferase or HCV-RNA. In conclusion, the present study identified circulating miR-196a as a specific and noninvasive candidate biomarker for the diagnosis of CHC.
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Affiliation(s)
- Bo Liu
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ying Xiang
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Heng-Shu Zhang
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122--a key factor and therapeutic target in liver disease. J Hepatol 2015; 62:448-57. [PMID: 25308172 DOI: 10.1016/j.jhep.2014.10.004] [Citation(s) in RCA: 480] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/26/2014] [Accepted: 10/02/2014] [Indexed: 02/06/2023]
Abstract
Being the largest internal organ of the human body with the unique ability of self-regeneration, the liver is involved in a wide variety of vital functions that require highly orchestrated and controlled biochemical processes. Increasing evidence suggests that microRNAs (miRNAs) are essential for the regulation of liver development, regeneration and metabolic functions. Hence, alterations in intrahepatic miRNA networks have been associated with liver disease including hepatitis, steatosis, cirrhosis and hepatocellular carcinoma (HCC). miR-122 is the most frequent miRNA in the adult liver, and a central player in liver biology and disease. Furthermore, miR-122 has been shown to be an essential host factor for hepatitis C virus (HCV) infection and an antiviral target, complementary to the standard of care using direct-acting antivirals or interferon-based treatment. This review summarizes our current understanding of the key role of miR-122 in liver physiology and disease, highlighting its role in HCC and viral hepatitis. We also discuss the perspectives of miRNA-based therapeutic approaches for viral hepatitis and liver disease.
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Affiliation(s)
- Simonetta Bandiera
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - Sébastien Pfeffer
- Université de Strasbourg, Strasbourg, France; Architecture et Réactivité de l'ARN - UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
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microRNAs: novel players in hepatitis C virus infection. Clin Res Hepatol Gastroenterol 2014; 38:664-75. [PMID: 24875730 DOI: 10.1016/j.clinre.2014.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 03/23/2014] [Accepted: 04/15/2014] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus. About 70% of patients exposed to HCV develop a chronic infection, which can lead to scarring of the liver and ultimately to cirrhosis, liver failure, and hepatocellular carcinoma. For the past decade, the standard therapy for HCV infection has been a combination of interferon-α and ribavirin. In recent years, direct-acting antiviral agents, boceprevir and telaprevir, have been added to the therapeutic regimen and considerably improve the cure rates for HCV infection. However, the treatment continues to cause substantial side effects and is associated with drug resistance due to frequent mutations in the HCV RNA genome resulting from the low fidelity of its RNA polymerase. MicroRNAs (miRNAs) are a class of small, non-coding RNAs approximately 22 nucleotides in length. They are derived from cellular or viral transcripts and bind to their target mRNAs in a sequence-specific manner, resulting in either mRNA cleavage or translational repression and subsequent modulation of the expression of the majority of the protein-coding genes. miRNAs have been implicated in regulating multiple aspects of HCV life cycles and certain miRNAs serve as essential mediators for the interferon-based antiviral therapy. Furthermore, recent studies have documented the potential values of miRNAs as novel therapeutic targets against hepatitis C infectivity.
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46
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MicroRNAs in virus-induced tumorigenesis and IFN system. Cytokine Growth Factor Rev 2014; 26:183-94. [PMID: 25466647 DOI: 10.1016/j.cytogfr.2014.11.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 11/05/2014] [Indexed: 12/13/2022]
Abstract
Numerous microRNAs (miRNAs), small non-coding RNAs encoded in the human genome, have been shown to be involved in cancer pathogenesis and progression. There is evidence that some of these miRNAs possess proapoptotic or proliferation promoting roles in the cell by negatively regulating target mRNAs. Oncogenic viruses are able to produce persistent infection, favoring tumor development by deregulating cell proliferation and inhibiting apoptosis. It has been recently suggested that cellular miRNAs may participate in host-virus interactions, influencing viral replication. Many mammalian viruses counteract this cellular antiviral defense by using viral proteins but also by encoding viral miRNAs involved in virus-induced tumorigenesis. Interferons (IFNs) modulate a number of non-coding RNA genes, especially miRNAs, that may be used by mammalian organisms as a mechanism of IFN system to combat viral infection and related diseases. In particular, IFNs might induce specific cellular miRNAs that target viral transcripts thereby using this strategy as part of their effectiveness against invading viruses. Therefore IFNs, interferon stimulated genes and miRNAs could act synergistically as innate response to virus infection to induce a potent non-permissive cellular environment for virus replication and virus-induced cancer. The relevance of this reviewed research topic is clearly related to the observation that although virus infections are responsible of specific tumors, other unidentified genetic alterations are likely involved in the induction of malignant transformation. The identification of such genetic alterations, i.e. miRNA expression in transformed cells, would be of considerable importance for the analysis of the pathogenesis and for the treatment of cancer induced by specific viruses as well as for the advancement of the current knowledge on the molecular mechanisms underlying virus-host interaction. In this respect, we will review also the important, still little explored, roles of miRNAs acting both as IFN-stimulated anti-viral molecules and as critical regulators of IFNs and IFN-stimulated genes.
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Oksuz Z, Serin MS, Kaplan E, Dogen A, Tezcan S, Aslan G, Emekdas G, Sezgin O, Altintas E, Tiftik EN. Serum microRNAs; miR-30c-5p, miR-223-3p, miR-302c-3p and miR-17-5p could be used as novel non-invasive biomarkers for HCV-positive cirrhosis and hepatocellular carcinoma. Mol Biol Rep 2014; 42:713-20. [PMID: 25391771 DOI: 10.1007/s11033-014-3819-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Accepted: 11/08/2014] [Indexed: 02/06/2023]
Abstract
Recently, serum miRNAs have been evolved as possible biomarkers for different diseases including hepatocellular carcinoma and other types of cancers. Investigating certain serum miRNAs as novel non-invasive markers for early detection of HCV-positive cirrhosis and hepatocellular carcinoma (HCC). The expression profiles of 58 miRNA were analyzed in patient's plasma of chronic hepatitis C (CHC), HCV-positive cirrhosis and HCV-positive HCC and compared with control group samples. Totally 94 plasma samples; 64 patient plasma (26 CHC, 30 HCV-positive cirrhosis, 8 HCV-positive HCC) and 28 control group plasma, were included. The expression profiles of 58 miRNAs were detected for all patient and control group plasma samples by qRT-PCR using BioMarkTM 96.96 Dynamic Array (Fluidigm Corporation) system. In CHC group, expression profiles of miR-30a-5p, miR-30c-5p, miR-206 and miR-302c-3p were found significantly deregulated (p < 0.05) when compared versus control group. In HCV-positive cirrhosis group, expression profiles of miR-30c-5p, miR-223-3p, miR-302c-3p, miR-17-5p, miR-130a-3p, miR-93-5p, miR-302c-5p and miR-223-3p were found significantly deregulated (p < 0.05). In HCV-positive HCC group, expression profiles of miR-17-5p, miR-223-3p and miR-24-3p were found significant (p < 0.05). When all groups were compared versus control, miR-30c-5p, miR-223-3p, miR-302c-3p and miR-17-5p were found significantly deregulated for cirrhosis and HCC. These results imply that miR-30c-5p, miR-223-3p, miR-302c-3p and miR-17-5p could be used as novel non-invasive biomarkers of HCV-positive HCC in very early, even at cirrhosis stage of liver disease.
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Affiliation(s)
- Zehra Oksuz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Yenisehir, Mersin, 33169, Turkey
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Song Q, Zhao C, Ou S, Meng Z, Kang P, Fan L, Qi F, Ma Y. Co-expression analysis of differentially expressed genes in hepatitis C virus-induced hepatocellular carcinoma. Mol Med Rep 2014; 11:21-8. [PMID: 25339452 PMCID: PMC4237098 DOI: 10.3892/mmr.2014.2695] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 03/21/2014] [Indexed: 12/11/2022] Open
Abstract
The aim of the current study was to investigate the molecular mechanisms underlying hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) using the expression profiles of HCV-infected Huh7 cells at different time points. The differentially expressed genes (DEGs) were identified with the Samr package in R software once the data were normalized. Functional and pathway enrichment analysis of the identified DEGs was also performed. Subsequently, MCODE in Cytoscape software was applied to conduct module analysis of the constructed co-expression networks. A total of 1,100 DEGs were identified between the HCV-infected and control samples at 12, 18, 24 and 48 h post-infection. DEGs at 24 and 48 h were involved in the same signaling pathways and biological processes, including sterol biosynthetic processes and tRNA amino-acylation. There were 22 time series genes which were clustered into 3 expression patterns, and the demarcation point of the 2 expression patterns that 401 overlapping DEGs at 24 and 48 h clustered into was 24 h post-infection. tRNA synthesis-related biological processes emerged at 24 and 48 h. Replication and assembly of HCV in HCV-infected Huh7 cells occurred mainly at 24 h post-infection. In view of this, the screened time series genes have the potential to become candidate target molecules for monitoring, diagnosing and treating HCV-induced HCC.
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Affiliation(s)
- Qingfeng Song
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Chang Zhao
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Shengqiu Ou
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhibin Meng
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Ping Kang
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Liwei Fan
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Feng Qi
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yilong Ma
- Department of Interventional Radiology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Fan HX, Tang H. Complex interactions between microRNAs and hepatitis B/C viruses. World J Gastroenterol 2014; 20:13477-13492. [PMID: 25309078 PMCID: PMC4188899 DOI: 10.3748/wjg.v20.i37.13477] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 03/28/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
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Xu G, Yang F, Ding CL, Wang J, Zhao P, Wang W, Ren H. MiR-221 accentuates IFN׳s anti-HCV effect by downregulating SOCS1 and SOCS3. Virology 2014; 462-463:343-50. [PMID: 25019494 DOI: 10.1016/j.virol.2014.06.024] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 06/11/2014] [Accepted: 06/17/2014] [Indexed: 12/30/2022]
Abstract
MiR-221 was reported to be upregulated and play roles in tumorigenesis of hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC). However, the role of miR-221 in HCV infection remains unknown. In this study, it was found that miR-221 was upregulated in serum of HCV chronic hepatitis patients and Huh7.5.1 cells infected with HCVcc. Further studies indicated that miR-221 mimic could accentuate anti-HCV effect of IFN-α in HCVcc model, miR-221 mimic could further repressed 10% HCV RNA expression and 35-42% HCV core or NS5A protein expression in HCVcc infected Huh7.5.1 cells treated with 100IU/mL IFN-α, and miR-221 inhibitor resulted in the reverse effects. Furthermore, two members of suppressor of cytokine signaling (SOCS) family, SOCS1 and SOCS3, which are well established inhibitory factors on IFN/JAK/STAT pathway, were identified as the targets of miR-221 and were involved in the effect of miR-221. In conclusion, miR-221 could accentuate IFN׳s anti-HCV effect by targeting SOCS1 and SOCS3.
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Affiliation(s)
- Gang Xu
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China
| | - Fang Yang
- Department of Hepatobiliary Surgery, Fuzhou General Hospital of Nanjing Military Area Command, Fuzhou 350025, China
| | - Cui-Ling Ding
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China
| | - Jing Wang
- Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Ping Zhao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China
| | - Wen Wang
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai 200433, China.
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