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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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Fu MX, Simmonds P, Andersson M, Harvala H. Biomarkers of transfusion transmitted occult hepatitis B virus infection: Where are we and what next? Rev Med Virol 2024; 34:e2525. [PMID: 38375981 DOI: 10.1002/rmv.2525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 02/10/2024] [Accepted: 02/13/2024] [Indexed: 02/21/2024]
Abstract
Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a complex entity to detect using surrogate blood biomarkers for intrahepatic viral transcriptional activity, requiring a continually refined battery of tests utilised for screening. This review aims to critically evaluate the latest advances in the current blood biomarkers to guide the identification of OBI donors and discuss novel HBV markers that could be introduced in future diagnostic practice. Challenges in detecting low HBV surface antigen levels, mutants, and complexes necessitate ultrasensitive multivalent dissociation assays, whilst HBV DNA testing requires improved sensitivity but worsens inaccessibility. Anti-core antibody assays defer almost all potentially infectious donations but have low specificity, and titres of anti-surface antibodies that prevent infectivity are poorly defined with suboptimal sensitivity. The challenges associated with these traditional blood HBV markers create an urgent need for alternative biomarkers that would help us better understand the OBI. Emerging viral biomarkers, such as pre-genomic RNA and HBV core-related antigen, immunological HBV biomarkers of T-cell reactivity and cytokine levels, and host biomarkers of microRNA and human leucocyte antigen molecules, present potential advances to gauge intrahepatic activity more accurately. Further studies on these markers may uncover an optimal diagnostic algorithm for OBI using quantification of various novel and traditional blood HBV markers. Addressing critical knowledge gaps identified in this review would decrease the residual risk of transfusion-transmitted HBV infection without compromising the sustainability of blood supplies.
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Affiliation(s)
- Michael X Fu
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Monique Andersson
- Department of Infection, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Heli Harvala
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Microbiology Services, NHS Blood and Transplant, Colindale, UK
- Infection and Immunity, University College London, London, UK
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Rezaeepoor M, Keramat F, Jourghasemi S, Rahmanpour M, Lipsa A, Hajilooi M, Solgi G. MicroRNA -21 expression as an auxiliary diagnostic biomarker of acute brucellosis. Mol Biol Rep 2024; 51:264. [PMID: 38302783 DOI: 10.1007/s11033-023-09193-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 12/21/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND This study aimed to measure the expression levels of peripheral blood miRNAs in brucellosis and their involvement in the different phases of the brucellosis. METHODS The expression levels of miRNAs including miR-210, miR-155, miR-150, miR-146a, miR-139-3p, miR-125a-5p, miR-29 and miR-21 were quantified in 57 brucellosis patients subgrouped into acute, under treatment & relapse phase and 30 healthy controls (HCs) using real-time polymerase chain reaction (RT-PCR). The receiver operating characteristic (ROC) analysis curve analysis was performed to find a biomarker for discrimination of different phases of brucellosis. RESULTS The expression of miR-155, miR-146a, miR-125a-5p, miR-29, and miR-21 was found to be elevated in the acute brucellosis patients compared to HCs. miR-29 changed in under-treatment patients, while miR-139-3p and miR-125a-5p showed alterations in relapse cases. The ROC curve analysis depicted the potential involvement of miR-21 in the pathogenesis of acute brucellosis. CONCLUSION The expression level of miR-21 is significantly augmented in acute brucellosis and has the potential to be a contributing diagnostic factor for acute infection.
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Affiliation(s)
- Mahsa Rezaeepoor
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Fariba Keramat
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
- Department of Infectious Diseases, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sanaz Jourghasemi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Mina Rahmanpour
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran
| | - Anuja Lipsa
- Cancer Genetic Laboratory, Advanced Centre for Treatment Research and Education in Cancer-Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, 410210, India
| | - Mehrdad Hajilooi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran.
| | - Ghasem Solgi
- Department of Immunology, Faculty of Medicine, Hamadan University of Medical Sciences, Shariati Ave, Opposite to Lona Park, P.O. Box: 6517838736, Hamadan, Iran.
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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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Naeli P, Zhang X, Snell PH, Chatterjee S, Kamran M, Ladak RJ, Orr N, Duchaine T, Sonenberg N, Jafarnejad SM. The SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression. J Cell Sci 2023; 136:jcs261286. [PMID: 37732428 PMCID: PMC10617620 DOI: 10.1242/jcs.261286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023] Open
Abstract
Viruses use microRNAs (miRNAs) to impair the host antiviral response and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. miRNAs inhibit translation initiation of their target mRNAs by recruiting the GIGYF2-4EHP (or EIF4E2) translation repressor complex to the mRNA 5'-cap structure. We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-encoded non-structural protein 2 (NSP2) interacts with GIGYF2. This interaction is critical for blocking translation of the Ifnb1 mRNA that encodes the cytokine interferon β, and thereby impairs the host antiviral response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with argonaute 2 (AGO2), the core component of the miRNA-induced silencing complex (miRISC), via GIGYF2 and enhances the translational repression mediated by natural miRNA-binding sites in the 3' untranslated region of cellular mRNAs. Our data reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program by co-opting the host miRNA-mediated silencing machinery.
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Affiliation(s)
- Parisa Naeli
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Xu Zhang
- Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, H3A 1A3, Canada
| | - Patric Harris Snell
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Susanta Chatterjee
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Muhammad Kamran
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Reese Jalal Ladak
- Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, H3A 1A3, Canada
| | - Nick Orr
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
| | - Thomas Duchaine
- Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, H3A 1A3, Canada
| | - Nahum Sonenberg
- Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, H3A 1A3, Canada
| | - Seyed Mehdi Jafarnejad
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, BT9 7AE, UK
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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Megahed F, Tabll A, Atta S, Ragheb A, Smolic R, Petrovic A, Smolic M. MicroRNAs: Small Molecules with Significant Functions, Particularly in the Context of Viral Hepatitis B and C Infection. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:173. [PMID: 36676797 PMCID: PMC9862007 DOI: 10.3390/medicina59010173] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023]
Abstract
A MicroRNA (miRNA) is defined as a small molecule of non-coding RNA (ncRNA). Its molecular size is about 20 nucleotides (nt), and it acts on gene expression's regulation at the post-transcription level through binding to the 3'untranslated regions (UTR), coding sequences, or 5'UTR of the target messenger RNAs (mRNAs), which leads to the suppression or degradation of the mRNA. In recent years, a huge evolution has identified the origin and function of miRNAs, focusing on their important effects in research and clinical applications. For example, microRNAs are key players in HCV infection and have important host cellular factors required for HCV replication and cell growth. Altered expression of miRNAs affects the pathogenicity associated with HCV infection through regulating different signaling pathways that control HCV/immunity interactions, proliferation, and cell death. On the other hand, circulating miRNAs can be used as novel biomarkers and diagnostic tools for HCV pathogenesis and early therapeutic response. Moreover, microRNAs (miRNA) have been involved in hepatitis B virus (HBV) gene expression and advanced antiviral discovery. They regulate HBV/HCV replication and pathogenesis with different pathways involving facilitation, inhibition, activation of the immune system (innate and adaptive), and epigenetic modifications. In this short review, we will discuss how microRNAs can be used as prognostic, diagnostic, and therapeutic tools, especially for chronic hepatitis viruses (HBV and HCV), as well as how they could be used as new biomarkers during infection and advanced treatment.
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Affiliation(s)
- Fayed Megahed
- Nucleic Acid Research Department, Genetic Engineering and Biotechnological Research Institute (GEBRI), City for Scientific Researches and Technological Applications (SRTA-City), Alexandria 21934, Egypt
| | - Ashraf Tabll
- Microbial Biotechnology Department, National Research Centre, Giza 12622, Egypt
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Shimaa Atta
- Department of Immunology, Theodor Bilharz Research Institute, Cairo 12411, Egypt
| | - Ameera Ragheb
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Robert Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ana Petrovic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Martina Smolic
- Faculty of Dental Medicine and Health Osijek, University of Osijek, Crkvena 21, 31000 Osijek, Croatia
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8
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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Das D, Podder S. Deregulation of ceRNA Networks in Frontal Cortex and Choroid Plexus of Brain during SARS-CoV-2 Infection Aggravates Neurological Manifestations: An Insight from Bulk and Single-Cell Transcriptomic Analyses. Adv Biol (Weinh) 2022; 6:e2101310. [PMID: 35661455 PMCID: PMC9348399 DOI: 10.1002/adbi.202101310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/20/2022] [Indexed: 01/28/2023]
Abstract
Although transcriptomic studies of SARS-CoV-2-infected brains have depicted variability in gene expression, the landscape of deregulated cell-specific regulatory circuits has not been elucidated yet. Hence, bulk and single-cell RNA-seq data are analyzed to gain detailed insights. Initially, two ceRNA networks with 19 and 3 differentially expressed (DE) hub lncRNAs are reconstructed in SARS-CoV-2 infected Frontal Cortex (FC) and Choroid Plexus (CP), respectively. Functional and pathway enrichment analyses of downstream mRNAs of deregulated ceRNA axes demonstrate impairment of neurological processes. Mapping of hub lncRNA-mRNA pairs from bulk RNA-seq with snRNA-seq data has indicated that NORAD, NEAT1, and STXBP5-AS1 are downregulated across 4, 4, and 2 FC cell types, respectively. At the same time, MIRLET7BHG and MALAT1 are upregulated in excitatory neurons of FC and neurons of CP, respectively. Here, it is hypothesized that downregulation of NORAD, NEAT1, and STXBP5-AS1, and upregulation of MIRLET7BHG and MALAT1 might deregulate respectively 51, 6, and 37, and 31 and 19 mRNAs in cell types of FC and CP. Afterward, 13 therapeutic miRNAs are traced that might safeguard against deregulated lncRNA-mRNA pairs of NORAD, NEAT1, and MIRLET7BHG in FC. This study helps to explain the plausible mechanism of post-COVID neurological manifestation and also to devise therapeutics against it.
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Affiliation(s)
- Deepyaman Das
- Department of MicrobiologyRaiganj UniversityRaiganjUttar DinajpurWest Bengal733134India
| | - Soumita Podder
- Department of MicrobiologyRaiganj UniversityRaiganjUttar DinajpurWest Bengal733134India
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10
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Gherlan GS. Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus. World J Clin Cases 2022; 10:5518-5530. [PMID: 35979101 PMCID: PMC9258381 DOI: 10.12998/wjcc.v10.i17.5518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.
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Affiliation(s)
- George Sebastian Gherlan
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy, Bucharest 030303, Romania
- Department of Infectious Diseases, “Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Bucharest 030303, Romania
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11
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Abbasi-Kolli M, Sadri Nahand J, Kiani SJ, Khanaliha K, Khatami A, Taghizadieh M, Torkamani AR, Babakhaniyan K, Bokharaei-Salim F. The expression patterns of MALAT-1, NEAT-1, THRIL, and miR-155-5p in the acute to the post-acute phase of COVID-19 disease. Braz J Infect Dis 2022; 26:102354. [PMID: 35500644 PMCID: PMC9035361 DOI: 10.1016/j.bjid.2022.102354] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Introduction One of the hallmarks of COVID-19 is overwhelming inflammation, which plays a very important role in the pathogenesis of COVID-19. Thus, identification of inflammatory factors that interact with the SARS-CoV-2 can be very important to control and diagnose the severity of COVID-19. The aim of this study was to investigate the expression patterns of inflammation-related non-coding RNAs (ncRNAs) including MALAT-1, NEAT-1, THRIL, and miR-155-5p from the acute phase to the recovery phase of COVID-19. Methods Total RNA was extracted from Peripheral Blood Mononuclear Cell (PBMC) samples of 20 patients with acute COVID-19 infection and 20 healthy individuals and the expression levels of MALAT-1, NEAT-1, THRIL, and miR-155-5p were evaluated by real-time PCR assay. Besides, in order to monitor the expression pattern of selected ncRNAs from the acute phase to the recovery phase of COVID-19 disease, the levels of ncRNAs were re-measured 6‒7 weeks after the acute phase. Result The mean expression levels of MALAT-1, THRIL, and miR-155-5p were significantly increased in the acute phase of COVID-19 compared with a healthy control group. In addition, the expression levels of MALAT-1 and THRIL in the post-acute phase of COVID-19 were significantly lower than in the acute phase of COVID-19. According to the ROC curve analysis, these ncRNAs could be considered useful biomarkers for COVID-19 diagnosis and for discriminating between acute and post-acute phase of COVID-19. Discussion Inflammation-related ncRNAs (MALAT-1, THRIL, and miR-150-5p) can act as hopeful biomarkers for the monitoring and diagnosis of COVID-19 disease.
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Affiliation(s)
| | - Javid Sadri Nahand
- Tabriz University of Medical Sciences, Infectious and Tropical Diseases Research Center, Tabriz, Iran
| | - Seyed Jalal Kiani
- Iran University of Medical Sciences, School of Medicine, Department of Virology, Tehran, Iran
| | - Khadijeh Khanaliha
- University of Medical Sciences, Institute of Immunology and Infectious Diseases, Research Center of Pediatric Infectious Diseases, Tehran, Iran
| | - AliReza Khatami
- Iran University of Medical Sciences, School of Medicine, Department of Virology, Tehran, Iran
| | - Mohammad Taghizadieh
- Tabriz University of Medical Sciences, Center for Women's Health Research Zahra, School of Medicine, Department of Pathology, Tabriz, Iran
| | - Ali Rajabi Torkamani
- Tehran University of Medical Sciences, School of Medicine, Department of Clinical Biochemistry, Tehran, Iran
| | - Kimiya Babakhaniyan
- Iran University of Medical Sciences, School of Nursing and Midwifery, Department of Medical Surgical Nursing, Tehran, Iran
| | - Farah Bokharaei-Salim
- Iran University of Medical Sciences, School of Medicine, Department of Virology, Tehran, Iran.
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12
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Research Progress on the Mechanism of Persistent Low-Level HBsAg Expression in the Serum of Patients with Chronic HBV Infection. J Immunol Res 2022; 2022:1372705. [PMID: 35465353 PMCID: PMC9020929 DOI: 10.1155/2022/1372705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 03/28/2022] [Indexed: 12/17/2022] Open
Abstract
Among HBV-infected persons, there is a group of people with hepatitis B surface antigen (HBsAg) showing persistently low levels of expression. The production of low-level HBsAg does not mean a good outcome of chronic HBV infection. Patients still have virus replication and sustained liver damage, and they have the potential to transmit the infection. This risk poses a challenge to clinical diagnosis and blood transfusion safety and is a major concern of experts. However, the mechanism behind persistent low-level HBsAg expression in serum is not completely clear, and complete virus clearance by the host is vital. In this review, we summarize the research progress on the mechanism behind low-level expression of HBsAg in patients with chronic HBV infection in recent years.
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13
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Xiong W, Yao W, Gao Z, Liu K. Rs12976445 polymorphism is associated with the risk of post-SAH re-bleeding by modulating the expression of microRNA-125 and ET-1. Sci Rep 2022; 12:2062. [PMID: 35136075 PMCID: PMC8825803 DOI: 10.1038/s41598-021-04330-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 08/24/2021] [Indexed: 11/28/2022] Open
Abstract
This study aimed to study the association between rs12976445 polymorphism and the incidence of IA re-bleeding. Genotype and allele frequency analysis was performed to study the association between rs12976445 polymorphism and the risk of IA re-bleeding. Western blot, ELISA and real-time RT-PCR were conducted to measure the relative expression of miR-125a, ET1 mRNA and ET1 protein. Computational analysis and luciferase assays were utilized to investigate the association between the expression of miR-125a and ET1 mRNA. No significant differences were observed between IA patients with or without symptoms of re-bleeding. Subsequent analyses indicated that the T allele was significantly associated with the reduced risk of IA re-bleeding. In patients carrying the CC genotype, miR-125a level was up-regulated while ET1 mRNA/protein levels were reduced compared with those in patients carrying the CT or TT genotype. And ET1 mRNA was identified as a virtual target gene of miR-125a with a potential miR-125a binding site located on its 3’UTR. Accordingly, the ET mRNA/protein levels could be suppressed by the transfection of miR-125a precursors, but the transfection of ET1 siRNA exhibited no effect on the expression of miR-125a. Therefore, an increased level of miR-125a can lead to the increased risk of IA re-bleeding. Since miR-125a level is higher in CC-genotyped patients, it can be concluded that the presence of T allele in the rs12976445 polymorphism is associated with a lower risk of IA re-bleeding, and miR-125a may be used as a novel diagnostic and therapeutic target for IA rupture.
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Affiliation(s)
- Wenping Xiong
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, China
| | - Weiqi Yao
- Department of Hematology, Union Hospital, Huazhong University of Science and Technology, Hubei Engineering Research Center for Human Stem Cell Preparation and Application and Resource Conservation, Wuhan, 430022, China
| | - Zeyuan Gao
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, China
| | - Kui Liu
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, China.
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14
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Zhou J, Wang L, Cui Y, Tang L. miR-125a-5p-targeted regulation of TRA2β expression inhibits proliferation and metastasis of hepatocellular carcinoma cells. Am J Transl Res 2021; 13:14074-14080. [PMID: 35035750 PMCID: PMC8748114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 08/03/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To explore the regulation of miR-125a-5p in hepatocellular carcinoma (HCC) and its mechanisms. METHODS By transfecting a miR-125a-5p sequence and an interfering sequence of miR-125a-5p-s into human HCC cell lines HCC-LM3 and HepG2, miR-125a-5p-related levels were assesed by Western blot. The abilities of cell proliferation and migration were assessed by cell culture and Transwell assay, respectively. RESULTS HepG2 cells showed increased miR-125a-5p levels compared with HCC-LM3 cells (P < 0.01). However, compared with QZG cells, the level of miR-125a-5p in HepG2 and HCC-LM3 cells was down-regulated. Compared with miR-125a-5p groups, miR-125a-5p-s groups showed increased colony formation rate and mobility (P < 0.01). After being transfected with miR-125a-5p, the transformation factor 2β (TRA2β) and mRNA levels were decreased, whereas 5p-s expression was increased (P < 0.01). Inhibition of TRA2β by small interfering RNA (siRNA) diminished the ability of cells. CONCLUSION miR-125a-5p inhibits the invasive capacity of HCC cells through targeting the TRA2β pathway.
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Affiliation(s)
- Junde Zhou
- Ward 3 of General Surgery, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, Heilongjiang, China
| | - Linna Wang
- The Sixth Department of Oncology, General Hospital of Heilongjiang General Bureau of Land ReclamationHarbin 150088, Heilongjiang, China
| | - Yunfu Cui
- Ward 1 of General Surgery, The Second Affiliated Hospital of Harbin Medical UniversityHarbin 150086, Heilongjiang, China
| | - Lanhua Tang
- Department of Oncology, Xiangya Hospital, Central South UniversityChangsha 410008, Hunan, China
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15
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Wang C, Xue M, Wu P, Wang H, Liu Z, Wu G, Liu P, Wang K, Xu W, Feng L. Coronavirus transmissible gastroenteritis virus antagonizes the antiviral effect of the microRNA miR-27b via the IRE1 pathway. SCIENCE CHINA. LIFE SCIENCES 2021; 65:1413-1429. [PMID: 34826094 PMCID: PMC8617553 DOI: 10.1007/s11427-021-1967-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/18/2021] [Indexed: 12/16/2022]
Abstract
Although the functional parameters of microRNAs (miRNAs) have been explored to some extent, the roles of these molecules in coronavirus infection and the regulatory mechanism of miRNAs in virus infection are still unclear. Transmissible gastroenteritis virus (TGEV) is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets. Here, we demonstrated that microRNA-27b-3p (miR-27b-3p) suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6 (SOCS6), while TGEV infection downregulated miR-27b-3p expression in swine testicular (ST) cells and in piglets. Mechanistically, the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositol-requiring enzyme 1 (IRE1) pathway of the endoplasmic reticulum (ER) stress. Further studies showed that when ER stress was induced by TGEV, IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced mRNA encoding a potent transcription factor, X-box-binding protein 1 (Xbp1s). Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p. Therefore, our findings indicate that TGEV inhibits the expression of an anti-coronavirus microRNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection.
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Affiliation(s)
- Changlin Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Mei Xue
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Peng Wu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Honglei Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Zhongqing Liu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Guangzheng Wu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China
| | - Pinghuang Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China
| | - Keliang Wang
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. .,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
| | - Wanhai Xu
- Department of Urology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. .,NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, Harbin, 150001, China.
| | - Li Feng
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, 150069, China.
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16
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Milenkovic D, Ruskovska T, Rodriguez-Mateos A, Heiss C. Polyphenols Could Prevent SARS-CoV-2 Infection by Modulating the Expression of miRNAs in the Host Cells. Aging Dis 2021; 12:1169-1182. [PMID: 34341700 PMCID: PMC8279534 DOI: 10.14336/ad.2021.0223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/23/2021] [Indexed: 12/19/2022] Open
Abstract
Coronaviruses (CoVs) are single-stranded RNA viruses which following virus attachment and entry into the host cell, particularly type 2 pneumocytes but also endothelial cells, release RNA into cytosol where it serves as a matrix for the host translation machinery to produce viral proteins. The viral RNA in cytoplasm can interact with host cell microRNAs which can degrade viral RNA and/or prevent viral replication. As such host cellular miRNAs represent key cellular mediators of antiviral defense. Polyphenols, plant food bioactives, exert antiviral properties, which is partially due to their capacity to modulate the expression of miRNAs. The objective of this work was to assess if polyphenols can play a role in prevention of SARS-CoV-2 associated complications by modulating the expression of host miRNAs. To test this hypothesis, we performed literature search to identify miRNAs that could bind SARS-CoV-2 RNA as well as miRNAs which expression can be modulated by polyphenols in lung, type 2 pneumocytes or endothelial cells. We identified over 600 miRNAs that have capacity to bind viral RNA and 125 miRNAs which expression can be modulated by polyphenols in the cells of interest. We identified that there are 17 miRNAs with both the capacity to bind viral RNA and which expression can be modulated by polyphenols. Some of these miRNAs have been identified as having antiviral properties or can target genes involved in regulation of processes of viral replication, apoptosis or viral infection. Taken together this analysis suggests that polyphenols could modulate expression of miRNAs in alveolar and endothelial cells and exert antiviral capacity.
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Affiliation(s)
- Dragan Milenkovic
- Université Clermont Auvergne, INRAE, UNH, F-63000 Clermont-Ferrand, France.
- Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA.
| | - Tatjana Ruskovska
- Faculty of Medical Sciences, Goce Delcev University, Stip, North Macedonia.
| | | | - Christian Heiss
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Science and Medicine, King's College London, London, UK.
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17
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Siniscalchi C, Di Palo A, Russo A, Potenza N. Human MicroRNAs Interacting With SARS-CoV-2 RNA Sequences: Computational Analysis and Experimental Target Validation. Front Genet 2021; 12:678994. [PMID: 34163530 PMCID: PMC8215607 DOI: 10.3389/fgene.2021.678994] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/19/2021] [Indexed: 12/17/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA virus affecting humans, causing a form of acute pulmonary respiratory disorder named COVID-19, declared a pandemic by the World Health Organization. MicroRNAs (miRNA) play an emerging and important role in the interplay between viruses and host cells. Although the impact of host miRNAs on SARS-CoV-2 infection has been predicted, experimental data are still missing. This study started by a bioinformatics prediction of cellular miRNAs potentially targeting viral RNAs; then, a number of criteria also based on experimental evidence and virus biology were applied, giving rise to eight promising binding miRNAs. Their interaction with viral sequences was experimentally validated by transfecting luciferase-based reporter plasmids carrying viral target sequences or their inverted sequences into the lung A549 cell line. Transfection of the reporter plasmids resulted in a reduction of luciferase activity for five out of the eight potential binding sites, suggesting responsiveness to endogenously expressed miRNAs. Co-transfection of the reporter plasmids along with miRNA mimics led to a further and strong reduction of luciferase activity, validating the interaction between miR-219a-2-3p, miR-30c-5p, miR-378d, miR-29a-3p, miR-15b-5p, and viral sequences. miR-15b was also able to repress plasmid-driven Spike expression. Intriguingly, the viral target sequences are fully conserved in more recent variants such as United Kingdom variant B.1.1.7 and South Africa 501Y.V2. Overall, this study provides a first experimental evidence of the interaction between specific cellular miRNAs and SARS-CoV-2 sequences, thus contributing to understanding the molecular mechanisms underlying virus infection and pathogenesis to envisage innovative therapeutic interventions and diagnostic tools.
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Affiliation(s)
- Chiara Siniscalchi
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Armando Di Palo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
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18
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Tan B, Liu M, Wang L, Wang J, Xiong F, Bao X, Gao Y, Yu L, Lu J. Serum microRNAs predict response of patients with chronic hepatitis B to antiviral therapy. Int J Infect Dis 2021; 108:37-44. [PMID: 33992764 DOI: 10.1016/j.ijid.2021.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/01/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To investigate the feasibility of using serum microRNAs to predict the response of chronic hepatitis B (CHB) patients to antiviral therapy over 48 weeks. METHODS Sixty-five CHB patients were divided into responder and non-responder groups according to whether hepatitis B e antigen seroconversion occurred at week 48. Serum microRNAs were dynamically detected. RESULTS At baseline, the responder group had lower miR-122-5p (P = 0.006) and higher miR-1307-3p (P = 0.018) than the non-responder group. After therapy, miR-320a-3p and miR-320c were higher in the responder group than the non-responder group (P = 0.043 and 0.031, respectively). In the responder group, 9 microRNAs-let-7d-5p, let-7f-5p, let-7i-5p, miR-126-3p, miR-1307-3p, miR-181a-5p, miR-21-5p, miR-425-5p and miR-652-3p-were significantly lower at week 48 than at baseline (P < 0.05); however, miR-320a-3p was significantly elevated after therapy (P < 0.001). In the non-responder group, miR-122-5p significantly decreased after therapy compared with baseline (P = 0.005). Finally, miR-122-5p was positively correlated with titer of hepatitis B virus DNA (r = 0.438, P = 0.008) and hepatitis B e antigen (r = 0.610, P < 0.001), and miR-320a-3p was negatively correlated with hepatitis B virus DNA titer (r = -0.366, P = 0.028) at baseline. CONCLUSIONS The dynamic fluctuations of serum microRNAs might predict the efficacy of antiviral therapy for CHB.
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Affiliation(s)
- Bingqin Tan
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China; Department of Infectious Diseases, Weifang People's Hospital, Weifang, Shandong 261000, PR China
| | - Mei Liu
- Laboratory of Cell and Molecular Biology and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China
| | - Jinhuan Wang
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Fang Xiong
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Xuli Bao
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Yao Gao
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Lele Yu
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China
| | - Jun Lu
- Hepatology and Cancer Biotherapy Ward/Department of Medical Oncology, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, PR China.
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19
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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20
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Zhao W, Yu J, Jiang F, Wang W, Kang L, Cui F. Coordination between terminal variation of the viral genome and insect microRNAs regulates rice stripe virus replication in insect vectors. PLoS Pathog 2021; 17:e1009424. [PMID: 33690727 PMCID: PMC7984632 DOI: 10.1371/journal.ppat.1009424] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 03/22/2021] [Accepted: 02/25/2021] [Indexed: 12/31/2022] Open
Abstract
Maintenance of a balance between the levels of viral replication and selective pressure from the immune systems of insect vectors is one of the prerequisites for efficient transmission of insect-borne propagative phytoviruses. The mechanism regulating the adaptation of RNA viruses to insect vectors by genomic variation remains unknown. Our previous study demonstrated an extension of the 3’-untranslated terminal region (UTR) of two genomic segments of rice stripe virus (RSV). In the present study, a reverse genetic system for RSV in human cells and an insect vector, the small brown planthopper Laodelphax striatellus, was used to demonstrate that the 3’-terminal extensions suppressed viral replication in vector insects by inhibiting promoter activity due to structural interference with the panhandle structure formed by viral 3’- and 5’-UTRs. The extension sequence in the viral RNA1 segment was targeted by an endogenous insect microRNA, miR-263a, which decreased the inhibitory effect of the extension sequence on viral promoter activity. Surprisingly, the expression of miR-263a was negatively regulated by RSV infection. This elaborate coordination between terminal variation of the viral genome and endogenous insect microRNAs controls RSV replication in planthopper, thus reflecting a distinct strategy of adaptation of phytoviruses to insect vectors. Mutations frequently happen when insect-transmitted RNA viruses circulate between insect vectors and plant or mammalian hosts. However, the significance of these mutations for viral fitness in the two distinct organisms is poorly understood. We discovered that a high proportion of rice stripe virus (RSV) had terminally extended genomes when the virus infected insect vectors. In the present study, we found that the extension sequence suppressed viral replication in insect vectors by impairing a special structure formed by the two ends of the viral genomes. An endogenous insect small RNA was able to bind the extension sequence to relieve the inhibitory effect. However, the expression of this small RNA was reduced in the presence of RSV to ultimately maintain the inhibitory effect of the extension sequence. This elaborate coordination between virus and vector enables a limited level of RSV replication that does not produce serious damage to vectors, thus reflecting a distinct strategy of adaptation of insect-transmitted plant viruses.
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Affiliation(s)
- Wan Zhao
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
| | - Jinting Yu
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
| | - Feng Jiang
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - Wei Wang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Le Kang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China
| | - Feng Cui
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing, China
- * E-mail:
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21
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Huang JH, Han TT, Li LX, Qu T, Zhang XY, Liao X, Zhong Y. Host microRNAs regulate expression of hepatitis B virus genes during transmission from patients' sperm to embryo. Reprod Toxicol 2021; 100:1-6. [PMID: 33338580 DOI: 10.1016/j.reprotox.2020.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 09/21/2020] [Accepted: 11/06/2020] [Indexed: 02/05/2023]
Abstract
Human sperm nucleus contains diverse RNA populations. This study aimed to screen and identify host microRNAs (miRs) that regulate gene expression of hepatitis B virus (HBV) during transmission from patients' sperm to sperm-derived embryos. Using microarrays, 336 miRs were found to be differentially expressed. After validation using real-time quantitative RT-PCR (RT-qPCR), four miRs were selected as targets. Using RT-qPCR and enzyme-linked immunosorbent assays, when patients' sperm were treated with mimics (or inhibitors) specific for hsa-miR-19a-3p and hsa-miR-29c-3p, the S gene transcription in sperm and translation in sperm-derived embryos was downregulated (or upregulated). There were significant differences in transcriptional and translational levels of the S gene between the test and control groups. These findings suggest that hsa-miR-19a-3p and hsa-miR-29c-3p significantly suppressed expression of the S gene, offering potential therapeutic targets for treating patients with HBV infection, and further reducing the negative impact of HBV infection on sperm fertilizing capacity.
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Affiliation(s)
- Ji-Hua Huang
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ting-Ting Han
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China; Research Center for Reproductive Medicine, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, China.
| | - Ling-Xiao Li
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ting Qu
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Xin-Yue Zhang
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Xue Liao
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
| | - Ying Zhong
- Chengdu Jinxin Research Institute for Reproductive Medicine and Genetics, 66 Bisheng Road, Chengdu, China.
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22
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Sardar R, Satish D, Gupta D. Identification of Novel SARS-CoV-2 Drug Targets by Host MicroRNAs and Transcription Factors Co-regulatory Interaction Network Analysis. Front Genet 2020; 11:571274. [PMID: 33173539 PMCID: PMC7591747 DOI: 10.3389/fgene.2020.571274] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/25/2020] [Indexed: 01/19/2023] Open
Abstract
Understanding the host regulatory mechanisms opposing virus infection and virulence can provide actionable insights to identify novel therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used a network biology approach to elucidate the crucial factors involved in host responses involving host-microRNA (miRNA) interactions with host and virus genes using recently published experimentally verified protein-protein interaction data. We were able to identify 311 host genes to be potentially targetable by 2,197 human miRNAs. These miRNAs are known to be involved in various biological processes, such as T-cell differentiation and activation, virus replication, and immune system. Among these, the anti-viral activity of 38 miRNAs to target 148 host genes is experimentally validated. Six anti-viral miRNAs, namely, hsa-miR-1-3p, hsa-miR-17-5p, hsa-miR-199a-3p, hsa-miR-429, hsa-miR-15a-5p, and hsa-miR-20a-5p, are previously reported to be anti-viral in respiratory diseases and were found to be downregulated. The interaction network of the 2,197 human miRNAs and interacting transcription factors (TFs) enabled the identification of 51 miRNAs to interact with 77 TFs inducing activation or repression and affecting gene expression of linked genes. Further, from the gene regulatory network analysis, the top five hub genes HMOX1, DNMT1, PLAT, GDF1, and ITGB1 are found to be involved in interferon (IFN)-α2b induction, epigenetic modification, and modulation of anti-viral activity. The comparative miRNAs target identification analysis in other respiratory viruses revealed the presence of 98 unique host miRNAs targeting SARS-CoV-2 genome. Our findings identify prioritized key regulatory interactions that include miRNAs and TFs that provide opportunities for the identification of novel drug targets and development of anti-viral drugs.
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Affiliation(s)
- Rahila Sardar
- Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
- Department of Biochemistry, Jamia Hamdard, New Delhi, India
| | - Deepshikha Satish
- Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Dinesh Gupta
- Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
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23
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Zhang BY, Chai DP, Wu YH, Qiu LP, Zhang YY, Ye ZH, Yu XP. Potential Drug Targets Against Hepatitis B Virus Based on Both Virus and Host Factors. Curr Drug Targets 2020; 20:1636-1651. [PMID: 31362671 DOI: 10.2174/1389450120666190729115646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Hepatitis B is a very harmful and epidemic disease caused by hepatitis B virus (HBV). Although an effective anti-HBV vaccine is available, chronic infection poses still a huge health burden in the whole world. The present anti-HBV drugs including nucleoside analogues and interferonalpha have their limitations without exception. There is no effective drug and therapeutic method that can really and truly cure hepatitis B so far. The variability of HBV genome results in that a significant number of patients develop drug resistance during the long-term use of anti-HBV drugs. Hence, it is urgently needed to discover novel targets and develop new drugs against hepatitis B. OBJECTIVE The review aims to provide the theory support for designing of the anti-HBV innovative drugs by offering a summary of the current situation of antiviral potential targets. RESULTS AND CONCLUSION Since HBV is obligate intracellular parasite, and as such it depends on host cellular components and functions to replicate itself. The targeting both virus and host might be a novel therapeutic option for hepatitis B. Accordingly, we analyse the advances in the study of the potential drug targets for anti-HBV infection, focusing on targeting virus genome, on targeting host cellular functions and on targeting virus-host proteins interactions, respectively. Meanwhile, the immune targets against chronic hepatitis B are also emphasized. In short, the review provides a summary of antiviral therapeutic strategies to target virus factors, host factors and immune factors for future designing of the innovative drug against HBV infection.
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Affiliation(s)
- Bing-Yi Zhang
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Dan-Ping Chai
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Yi-Hang Wu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Li-Peng Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Yong-Yong Zhang
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Zi-Hong Ye
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
| | - Xiao-Ping Yu
- Department of Pharmacy, Zhejiang Provincial Key Laboratory of Biometrology and Inspection & Quarantine, College of Life Sciences, China Jiliang University, Hangzhou 310018, China
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24
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Ochi M, Otsuka M, Maruyama R, Koike K. HBx increases EGFR expression by inhibiting miR129-5p function. Biochem Biophys Res Commun 2020; 529:198-203. [PMID: 32703411 DOI: 10.1016/j.bbrc.2020.06.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/04/2020] [Indexed: 12/29/2022]
Abstract
Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy.
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Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Reo Maruyama
- Project for Cancer Epigenomics, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
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25
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Xia Y, Guo H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Res 2020; 180:104824. [PMID: 32450266 PMCID: PMC7387223 DOI: 10.1016/j.antiviral.2020.104824] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/03/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide with about 257 million individuals chronically infected. Current therapies can effectively control HBV replication and slow down disease progress, but cannot cure HBV infection. Upon infection, HBV establishes a pool of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The cccDNA exists as a minichromosome and resists to antivirals, thus a therapeutic eradication of cccDNA from the infected cells remains unattainable. In this review, we summarize the state of knowledge on the mechanisms underlying cccDNA formation and regulation, and discuss the possible strategies that may contribute to the eradication of HBV through targeting cccDNA.
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Affiliation(s)
- Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
| | - Haitao Guo
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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26
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Xu J, An P, Winkler CA, Yu Y. Dysregulated microRNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Potential as Biomarkers and Therapeutic Targets. Front Oncol 2020; 10:1271. [PMID: 32850386 PMCID: PMC7399632 DOI: 10.3389/fonc.2020.01271] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 06/19/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding small RNAs that can function as gene regulators and are involved in tumorigenesis. We review the commonly dysregulated miRNAs in liver tumor tissues and plasma/serum of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The frequently reported up-regulated miRNAs in liver tumor tissues include miR-18a, miR-21, miR-221, miR-222, and miR-224, whereas down-regulated miRNAs include miR-26a, miR-101, miR-122, miR-125b, miR-145, miR-199a, miR-199b, miR-200a, and miR-223. For a subset of these miRNAs (up-regulated miR-222 and miR-224, down-regulated miR-26a and miR-125b), the pattern of dysregulated circulating miRNAs in plasma/serum is mirrored in tumor tissue based on multiple independent studies. Dysregulated miRNAs target oncogenes or tumor suppressor genes involved in hepatocarcinogenesis. Normalization of dysregulated miRNAs by up- or down-regulation has been shown to inhibit HCC cell proliferation or sensitize liver cancer cells to chemotherapeutic treatment. miRNAs hold as yet unrealized potential as biomarkers for early detection of HCC and as precision therapeutic targets, but further studies in diverse populations and across all stages of HCC are needed.
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Affiliation(s)
- Jinghang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Ping An
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Cheryl A. Winkler
- Basic Research Laboratory, Molecular Genetic Epidemiology Section, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Yanyan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Peking University, Beijing, China
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27
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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28
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Liu F, Seto WK, Wong DKH, Huang FY, Cheung KS, Mak LY, Sharma R, Zhang S, Fung J, Lai CL, Yuen MF. Plasma Fibronectin Levels Identified via Quantitative Proteomics Profiling Predicts Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B. J Infect Dis 2020; 220:940-950. [PMID: 31056649 DOI: 10.1093/infdis/jiz223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Accepted: 05/01/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Seroclearance of hepatitis B surface antigen (HBsAg) is a potentially achievable target of chronic hepatitis B (CHB). Plasma proteins relevant to HBsAg seroclearance remain undetermined. METHODS We prospectively recruited treatment-naive CHB patients with spontaneous HBsAg seroclearance and matched HBsAg-positive controls. Plasma protein profiling was performed using isobaric tags for relative and absolute quantitation-based proteomics, with the expression of candidate proteins validated in a separate cohort. The predictive value of fibronectin was assessed at 3 years, 1 year (Year -1) before, and at the time (Year 0) of HBsAg seroclearance. RESULTS Four hundred eighty-seven plasma proteins were identified via proteomics, with 97 proteins showing altered expression. In the verification cohort (n = 90), median plasma fibronectin levels in patients with HBsAg seroclearance was higher than in controls (P = .009). In the longitudinal cohort (n = 164), patients with HBsAg seroclearance, compared with controls, had a higher median fibronectin levels at Year -1 (413.26 vs 227.95 µg/mL) and Year 0 (349.45 vs 208.72 µg/mL) (both P < .001). In patients with an annual HBsAg log reduction >0.5, Year -1 fibronectin level achieved an area under the receiving operator characteristic of 0.884 in predicting HBsAg seroclearance. CONCLUSIONS Using proteomics-based technology, plasma fibronectin may be associated with HBsAg seroclearance and a potential predictor of "functional cure".
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Affiliation(s)
- Fen Liu
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, China
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Ka-Shing Cheung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - Rakesh Sharma
- Proteomics and Metabolomics Core Facility, Li Ka Shing Faculty of Medicine, The University of Hong Kong
| | - Saisai Zhang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, China.,State Key Laboratory for Liver Research, The University of Hong Kong, China
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29
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Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
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Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
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30
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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31
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Rana MA, Ijaz B, Daud M, Tariq S, Nadeem T, Husnain T. Interplay of Wnt β-catenin pathway and miRNAs in HBV pathogenesis leading to HCC. Clin Res Hepatol Gastroenterol 2019; 43:373-386. [PMID: 30377095 DOI: 10.1016/j.clinre.2018.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 09/05/2018] [Accepted: 09/24/2018] [Indexed: 02/04/2023]
Abstract
The prevalence of Hepatocellular carcinoma (HCC) has been identified world-wide. Plethora of factors including chronic infection of HBV/HCV has been characterized for the development of HCC. Although the onset and progression of HCC has been linked with awry of various signaling pathways but precise mechanism, still lies under the multitude layers of curiosity. HBV is spreading with insane speed throughout the world and has been found a main culprit in HCC development after regulating the several cellular pathways including Wnt/β-catenin, Raf/MAPK, Akt and affecting cell multiplication to genomic instability. The role of Wnt/FZD/β-catenin signaling pathway is centralized in liver functions and its anomalous activation leads to HCC development. β-catenin mainly plays a pivotal role in canonical pathway of the system. Altered mainly overexpression of β-catenin along its nuclear localization tunes the aberrations in liver functions and set disease progression. In the development of HCC, modulation of Wnt/FZD/β-catenin signaling pathway by HBV has been established. As HBV infects the cell it affects the miRNAs, the master regulators of cell. Previous studies showed the connection between HBV and cellular miRNAs. In the present review, we unveiled how HBV is deciphering the cellular miRNAs like miR-26a, miR-15a, miR-16-1, miR-148a, miR-132, miR-122, miR-34a, miR-21, miR-29a, miR-222 and miR-199a/b-3p to modulate the Wnt/FZD/β-catenin signaling pathway and develop HCC. These HBV mediated miRNAs may prove future therapeutic options to treat HBV-Wnt/FZD/β-catenin associated HCC.
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Affiliation(s)
- Muhammad Adeel Rana
- Department of microbiology, Quaid-i-Azam University, Islamabad, Pakistan; Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
| | - Bushra Ijaz
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan.
| | - Muhammad Daud
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
| | - Sommyya Tariq
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
| | - Tariq Nadeem
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
| | - Tayyab Husnain
- Centre of Excellence in Molecular Biology, University of the Punjab, Lahore Pakistan
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Oura K, Fujita K, Morishita A, Iwama H, Nakahara M, Tadokoro T, Sakamoto T, Nomura T, Yoneyama H, Mimura S, Tani J, Kobara H, Okano K, Suzuki Y, Masaki T. Serum microRNA-125a-5p as a potential biomarker of HCV-associated hepatocellular carcinoma. Oncol Lett 2019; 18:882-890. [PMID: 31289566 DOI: 10.3892/ol.2019.10385] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 02/27/2019] [Indexed: 02/06/2023] Open
Abstract
During diagnosis of early stage hepatocellular carcinoma (HCC), single or small lesions are difficult to identify using screening ultrasonography, and conventional tumor markers are frequently negative. MicroRNAs (miRNAs) are small non-coding RNAs that suppress the translation of target mRNAs and exert significance as biomarkers. The aim of the present study was to use samples of patients with HCC and those with other liver diseases caused by hepatitis C virus (HCV) infection to investigate the expression profile of serum miRNAs, and identify a miRNA that can serve as a HCC biomarker. Initially, changes in 2,555 miRNAs between pre- and post-curative treatment serum from 12 patients with early stage HCC were examined using microarray analysis. The serum levels of miR-125a-5p in 40 individuals with HCV-associated chronic hepatitis (CH), liver cirrhosis (LC) or HCC were measured using reverse transcription-quantitative polymerase chain reaction, and 5 miRNAs, including miR-125a-5p, miR-423-5p, miR-1247, miR-1304 and miR-3648, were identified to be downregulated following curative treatment in patients with HCC. Among these, miR-125a-5p was identified to be similarly decreased following treatment in all patients. Additionally, the expression levels of miR-125a-5p were significantly upregulated in patients with HCC in the early and advanced stages of disease, compared with patients with CH or LC (P<0.05). Serum miR-125a-5p fluctuates depending on the presence of HCC, and may serve as a noninvasive biomarker to aid in diagnosing early carcinogenesis in HCV-associated chronic liver diseases.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Miki 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University, Miki 761-0793, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University, Miki 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Miki 761-0793, Japan
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Tian JH, Liu WD, Zhang ZY, Tang LH, Li D, Tian ZJ, Lin SW, Li YJ. Influence of miR-520e-mediated MAPK signalling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2. J Viral Hepat 2019; 26:496-505. [PMID: 30521133 DOI: 10.1111/jvh.13048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/09/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
We determined the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EPH receptor A2 (EphA2) in HBV-positive HCC tissues and cells were detected, and we studied the impact of miR-520e and the EphA2 receptor in cellular and murine HBV replication models. We find that MiR-520e was upregulated and EphA2 was downregulated in HBV-positive HCC tissues and cells. MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but was dose-dependently elevated after interfering with HBx. Additionally, miR-520e mimic and si-EphA2 groups were reduced in association with increases in HBV DNA content, HBsAg and HBeAg levels, cell proliferation and were enhanced in the expressions of EphA2, p-p38MAPK/p38MAPK, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2)/ERK1/2 and cell apoptosis. Furthermore, si-EphA2 reversed the promotion effect of miR-520e inhibitor on HBV replication and tumour cell growth. Upregulating miR-520e in rAAV8-1.3HBV-infected mouse resulted in reduced EphA2 in liver tissues and HBV DNA content in serum. We find that MiR-520e was decreased in HBV-positive HCC, while overexpression of miR-520e blocked p38MAPK and ERK1/2 signalling pathways by an inhibitory effect on EphA2 and ultimately reduced HBV replication and inhibited tumour cell growth. These data indicate a role for miR-520e in the regulation of HBV replication.
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Affiliation(s)
- Jing-Hui Tian
- Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, China.,School of Public Health, Taishan Medical University, Taian, China
| | - Wen-Dong Liu
- Department of Blood Transfusion, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zhi-Yong Zhang
- Clinical Laboratory, Dezhou People's Hospital, Dezhou, China
| | - Li-Hua Tang
- Department of Blood Transfusion, Tai'an City Central Hospital, Tai'an, China
| | - Dong Li
- School of Public Health, Taishan Medical University, Taian, China
| | - Zhao-Ju Tian
- School of Public Health, Taishan Medical University, Taian, China
| | - Shao-Wei Lin
- School of Public Health, Taishan Medical University, Taian, China
| | - Ying-Jie Li
- Department of Health Examination, Qilu Hospital, Shandong University, Jinan, China
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Wu Y, Gao C, Cai S, Xia M, Liao G, Zhang X, Peng J. Circulating miR-122 Is a Predictor for Virological Response in CHB Patients With High Viral Load Treated With Nucleos(t)ide Analogs. Front Genet 2019; 10:243. [PMID: 30967899 PMCID: PMC6440383 DOI: 10.3389/fgene.2019.00243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 03/04/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B (CHB) infection remains worldwide health problem. Antiviral treatment options for CHB patients include nucleos(t)ide analogs (NAs) and interferon. Most of the current biomarkers for predicting treatment response are virus-dependent. MicroRNA-122 is the most abundant liver-specific miRNA and has been identified involved in multiple liver physiology and pathology including hepatotropic virus infection. To identify the role of miR-122 in NA therapy, 80 CHB patients with high viral load (HVL) were enrolled and serum miR-122 levels at baseline, week 12 and week 24 were measured. Serum miR-122 levels were significantly lower in patients who developed virological response (VR), compared with non-VR group. Levels of miR-122 at week 12 and week 24 were determined to be independent prognostic indicators for a VR with satisfactory AUROC values at 0.812 and 0.800, respectively. During NA therapy, serum miR-122 level deceased steadily and an earlier reduction was observed in VR group, indicating early reduction of miR-122 level might increase the possibility of developing virological response. In conclusion, we identified the dynamic change of serum miR-122 level and miR-122 levels at week 12 and week 24 as independent predictors for VR in CHB patients with HVL treated with NAs.
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Affiliation(s)
- Yin Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chang Gao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shaohang Cai
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Muye Xia
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guichan Liao
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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Russo A, Potenza N. Antiproliferative Activity of microRNA-125a and its Molecular Targets. Microrna 2018; 8:173-179. [PMID: 30394225 DOI: 10.2174/2211536608666181105114739] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/18/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND MicroRNA-125a is present in all animals with bilateral symmetry and displays a conserved nucleotide sequence with a section of 11 bases including the seed region that is identical in all considered species. It primarily downregulates the expression of LIN28, thereby promoting cell differentiation and larval phase transitions in nematodes, mammals and insects. OBJECTIVE In this review, we focus on the cellular control of miR-125a expression and its antiproliferative activity. RESULTS In mammalians, microRNA-125a is present in most adult organs and tissues in which it targets proteins involved in the mitogenic response, such as membrane receptors, intracellular signal transducers, or transcription factors, with the overall effect of inhibiting cell proliferation. Tissue levels of miR-125a generally raise during differentiation but it is often downregulated in cancers, e.g. colon, cervical, gastric, ovarian, lung, and breast cancers, osteosarcoma, neuroblastoma, glioblastoma, medulloblastoma, retinoblastoma and hepatocellular carcinoma. CONCLUSION The antiproliferative activity of miR-125a, demonstrated in many cell types, together with the notion that this miRNA is downregulated in several kinds of cancers, give a substantial support to the concept that miR-125a plays an oncosuppressive role.
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Affiliation(s)
- Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy
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Huang X, Zhang T, Li G, Guo X, Liu X. Regulation of miR‐125a expression by rs12976445 single‐nucleotide polymorphism is associated with radiotherapy‐induced pneumonitis in lung carcinoma patients. J Cell Biochem 2018; 120:4485-4493. [PMID: 30302847 DOI: 10.1002/jcb.27736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 08/30/2018] [Indexed: 11/09/2022]
Affiliation(s)
- Xuan Huang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University Harbin China
| | - Tianze Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University Harbin China
| | - Guanghua Li
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University Harbin China
| | - Xiaona Guo
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University Harbin China
| | - Xuesong Liu
- Nursing Department, The Second Affiliated Hospital of Harbin Medical University Harbin China
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Mitra B, Thapa RJ, Guo H, Block TM. Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B. Antiviral Res 2018; 158:185-198. [PMID: 30145242 PMCID: PMC6193490 DOI: 10.1016/j.antiviral.2018.08.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/21/2018] [Accepted: 08/22/2018] [Indexed: 02/06/2023]
Abstract
Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus' life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions.
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Affiliation(s)
- Bidisha Mitra
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
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Sagnelli E, Potenza N, Onorato L, Sagnelli C, Coppola N, Russo A. Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. World J Hepatol 2018; 10:558-570. [PMID: 30310534 PMCID: PMC6177563 DOI: 10.4254/wjh.v10.i9.558] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 04/24/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy.
| | - Nicoletta Potenza
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Aniello Russo
- DISTABIF, University of Campania "Luigi Vanvitelli", Naples 80100, Italy
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Chen L, Zhou Y, Li H. LncRNA, miRNA and lncRNA-miRNA interaction in viral infection. Virus Res 2018; 257:25-32. [PMID: 30165080 DOI: 10.1016/j.virusres.2018.08.018] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/25/2018] [Accepted: 08/26/2018] [Indexed: 12/27/2022]
Abstract
Noncoding RNAs (ncRNAs) are key components of the transcriptome and play an important role in both normal biological activity and pathological processes such as viral infection and tumorigenesis. LncRNAs and miRNAs are the most important elements of ncRNAs and function as vital regulatory elements. Their complex regulatory relationship has therefore attracted a lot of attention. In this review, we address the generation, classification, and regulatory mechanisms of lncRNAs and miRNAs in the interaction between virus and host, focusing on their mutual regulation in viral replication and pathogenesis. In-depth analysis of the underlying mechanisms will provide new information for the prevention of viral infections and development of antiviral drugs.
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Affiliation(s)
- Linlin Chen
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, 935 Jiaoling Road, Kunming 650118, China.
| | - Yan Zhou
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, 935 Jiaoling Road, Kunming 650118, China.
| | - Hongjun Li
- Department of Molecular Biology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, 935 Jiaoling Road, Kunming 650118, China.
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Coppola N, Onorato L, Panella M, de Stefano G, Mosca N, Minichini C, Messina V, Potenza N, Starace M, Alessio L, Farella N, Sagnelli E, Russo A. Correlation Between the Hepatic Expression of Human MicroRNA hsa-miR-125a-5p and the Progression of Fibrosis in Patients With Overt and Occult HBV Infection. Front Immunol 2018; 9:1334. [PMID: 29951066 PMCID: PMC6008383 DOI: 10.3389/fimmu.2018.01334] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 05/29/2018] [Indexed: 12/16/2022] Open
Abstract
AIMS To evaluate the correlation between the hepatic expression pattern of hsa-miR-125a-5p and HBV-DNA and the progression of fibrosis in patients with overt or occult HBV infection. METHODS We enrolled all the HBsAg-positive treatment naive patients (overt HBV group) and all the HBsAg-negative patients with hepatocellular carcinoma and with a positive HBV-DNA in their hepatic tissue (occult HBV group), who underwent a diagnostic liver biopsy between April 2007 and April 2015. Tissue concentrations of HBV-DNA and hsa-miR-125a-5p were then analyzed by real-time quantitative PCR. Necroinflammatory activity and fibrosis were evaluated according to the Ishak score. RESULTS During the study period, we enrolled 64 patients with overt and 10 patients with occult HBV infection. In the overt HBV group, 35 of 64 (54.7%) showed a mild fibrosis (staging 0-2), 17 (26.6%) a moderate fibrosis (staging 3-4), while the remaining 12 (18.7%) had a cirrhosis. All patients in the occult HBV group were cirrhotic. Patients with more advanced fibrosis stage showed a higher mean age when compared with those with mild (p < 0.00001) or moderate fibrosis (p < 0.00001) and were more frequently male than patients with staging 0-2 (p = 0.04). Similarly, patients with occult B infection were older than HBsAg-positive patients. Liver concentrations of miR-125a-5p were significantly higher in patients with cirrhosis (9.75 ± 4.42 AU) when compared with patients with mild (1.39 ± 0.94, p = 0.0002) or moderate fibrosis (2.43 ± 2.18, p = 0.0006) and were moderately higher in occult than in overt HBV infection (p = 0.09). Moreover, we found an inverse correlation, although not statistically significant, between the tissue HBV-DNA levels and the staging of fibrosis. CONCLUSION This study suggests a correlation between the tissue expression of hsa-miR-125a-5p and the progression of liver damage in a group of patients with occult or overt HBV infection. If confirmed, these data suggest the hsa-miR-125a-5p may be a novel biomarker of hepatic damage.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Giorgio de Stefano
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Vincenzo Messina
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Loredana Alessio
- Infectious Diseases Unit, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | - Nunzia Farella
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, Luigi Vanvitelli, Caserta, Italy
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Coppola N, de Stefano G, Panella M, Onorato L, Iodice V, Minichini C, Mosca N, Desiato L, Farella N, Starace M, Liorre G, Potenza N, Sagnelli E, Russo A. Lowered expression of microRNA-125a-5p in human hepatocellular carcinoma and up-regulation of its oncogenic targets sirtuin-7, matrix metalloproteinase-11, and c-Raf. Oncotarget 2018; 8:25289-25299. [PMID: 28445974 PMCID: PMC5421930 DOI: 10.18632/oncotarget.15809] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/07/2017] [Indexed: 12/12/2022] Open
Abstract
Human microRNA-125a-5p (miR-125a) is expressed in most tissues where it downregulates the expression of membrane receptors or intracellular transductors of mitogenic signals, thus limiting cell proliferation. Expression of this miRNA generally increases with cell differentiation whereas it is downregulated in several types of tumors, such as breast, lung, ovarian, gastric, colon, and cervical cancers, neuroblastoma, medulloblastoma, glioblastoma, and retinoblastoma. In this study, we focused on hepatocellular carcinoma and used real-time quantitative PCR to measure miR-125a expression in 55 tumor biopsies and in matched adjacent non-tumor liver tissues. This analysis showed a downregulation of miR-125a in 80 % of patients, with a mean decrease of 4.7-fold. Comparison of miRNA downregulation with clinicopathological parameters of patients didn't yield significant correlations except for serum bilirubin. We then evaluated the expression of known targets of miR-125a and found that sirtuin-7, matrix metalloproteinase-11, and c-Raf were up-regulated in tumor tissue by 2.2-, 3-, and 1.7-fold, respectively. Overall, these data support a tumor suppressor role for miR-125a and encourage further studies aimed at the comprehension of the molecular mechanisms governing its expression, eventually leading to treatments to restore its expression in tumor cells.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Giorgio de Stefano
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Valentina Iodice
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Carmine Minichini
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Luisa Desiato
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Nunzia Farella
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Mario Starace
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Giulia Liorre
- IX Interventional Ultrasound Unit for Infectious Diseases, AORN dei Colli, P.O. Cotugno, Naples, Italy
| | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy
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Qiu GH, Yang X, Zheng X, Huang C. The eukaryotic genome is structurally and functionally more like a social insect colony than a book. Epigenomics 2017; 9:1469-1483. [PMID: 28972397 DOI: 10.2217/epi-2017-0059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Traditionally, the genome has been described as the 'book of life'. However, the metaphor of a book may not reflect the dynamic nature of the structure and function of the genome. In the eukaryotic genome, the number of centrally located protein-coding sequences is relatively constant across species, but the amount of noncoding DNA increases considerably with the increase of organismal evolutional complexity. Therefore, it has been hypothesized that the abundant peripheral noncoding DNA protects the genome and the central protein-coding sequences in the eukaryotic genome. Upon comparison with the habitation, sociality and defense mechanisms of a social insect colony, it is found that the genome is similar to a social insect colony in various aspects. A social insect colony may thus be a better metaphor than a book to describe the spatial organization and physical functions of the genome. The potential implications of the metaphor are also discussed.
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Affiliation(s)
- Guo-Hua Qiu
- Fujian Provincial Key Laboratory for the Prevention & Control of Animal Infectious Diseases & Biotechnology, College of Life Sciences, Longyan University, Longyan 364012, Fujian, PR China
| | - Xiaoyan Yang
- Fujian Provincial Key Laboratory for the Prevention & Control of Animal Infectious Diseases & Biotechnology, College of Life Sciences, Longyan University, Longyan 364012, Fujian, PR China
| | - Xintian Zheng
- Fujian Provincial Key Laboratory for the Prevention & Control of Animal Infectious Diseases & Biotechnology, College of Life Sciences, Longyan University, Longyan 364012, Fujian, PR China
| | - Cuiqin Huang
- Fujian Provincial Key Laboratory for the Prevention & Control of Animal Infectious Diseases & Biotechnology, College of Life Sciences, Longyan University, Longyan 364012, Fujian, PR China
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Lu G, Ma Y, Jia C, Yang H, Xie R, Luo P, Chai L, Cai H, Cai M, Lv Z, Cong X, Fu D. Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer. Oncol Lett 2017; 14:5952-5958. [PMID: 29113231 PMCID: PMC5661598 DOI: 10.3892/ol.2017.6902] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/15/2017] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) serve an important role in tumorigenesis and development. Although a low expression of miR-125a in hepatocellular carcinoma (HCC) has been reported, the clinical significance remains unknown. In the current study, the data of Gene Expression Omnibus datasets was analyzed and significantly low expression of miR-125a in HCC was verified. Furthermore, the expression and clinical significance of miR-125a was investigated in 27 normal liver and 98 HCC tissue samples using reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that the level of miR-125a expression was lower in HCC biopsies compared with that in normal liver tissues. Survival analysis established that miR-125a expression was negatively associated with the prognosis of HCC. Multivariate survival analysis demonstrated that patients with HCC with lowmiR-125a and Ki67-positive expression have shorter overall, and disease-free survival times. Altogether, the results of the current study provide the first evidence that reducedmiR-125a expression is associated with HCC progression and poor prognosis in patients, suggesting that miR-125a may have potential prognostic value as a tumor biomarker for patients with HCC.
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Affiliation(s)
- Gaixia Lu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yushui Ma
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chengyou Jia
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Huiqiong Yang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ruting Xie
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Pei Luo
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Li Chai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Haidong Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Mingxiang Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xianling Cong
- Tissue Bank, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Da Fu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.,Research Center of Clinical Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Potenza N, Panella M, Castiello F, Mosca N, Amendola E, Russo A. Molecular mechanisms governing microRNA-125a expression in human hepatocellular carcinoma cells. Sci Rep 2017; 7:10712. [PMID: 28878257 PMCID: PMC5587745 DOI: 10.1038/s41598-017-11418-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 08/24/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNA-125a-5p (miR-125a) is a vertebrate homolog of lin-4, the first discovered microRNA, and plays a fundamental role in embryo development by downregulating Lin-28 protein. MiR-125a is also expressed in differentiated cells where it generally acts as an antiproliferative factor by targeting membrane receptors or intracellular transductors of mitogenic signals. MiR-125a expression is downregulated in several tumors, including hepatocellular carcinoma (HCC) where it targets sirtuin-7, matrix metalloproteinase-11, VEGF-A, Zbtb7a, and c-Raf. In this study, we have isolated the transcription promoter of human miR-125a and characterized its activity in HCC cells. It is a TATA-less Pol II promoter provided with an initiator element and a downstream promoter element, located 3939 bp upstream the genomic sequence of the miRNA. The activity of the promoter is increased by the transcription factor NF-kB, a master regulator of inflammatory response, and miR-125a itself was found to strengthen this activation through inhibition of TNFAIP3, a negative regulator of NF-kB. This finding contributes to explain the increased levels of miR-125a observed in the liver of patients with chronic hepatitis B.
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Affiliation(s)
- Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Filomena Castiello
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy
| | - Elena Amendola
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131, Napoli, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100, Caserta, Italy.
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Jo A, Im J, Lee HE, Jang D, Nam GH, Mishra A, Kim WJ, Kim W, Cha HJ, Kim HS. Evolutionary conservation and expression of miR-10a-3p in olive flounder and rock bream. Gene 2017; 628:16-23. [PMID: 28698161 DOI: 10.1016/j.gene.2017.07.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 07/01/2017] [Accepted: 07/07/2017] [Indexed: 12/19/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that mainly bind to the seed sequences located within the 3' untranslated region (3' UTR) of target genes. They perform an important biological function as regulators of gene expression. Different genes can be regulated by the same miRNA, whilst different miRNAs can be regulated by the same genes. Here, the evolutionary conservation and expression pattern of miR-10a-3p in olive flounder and rock bream was examined. Binding sites (AAAUUC) to seed region of the 3' UTR of target genes were highly conserved in various species. The expression pattern of miR-10a-3p was ubiquitous in the examined tissues, whilst its expression level was decreased in gill tissues infected by viral hemorrhagic septicemia virus (VHSV) compared to the normal control. In the case of rock bream, the spleen, kidney, and liver tissues showed dominant expression levels of miR-10a-3p. Only the liver tissues in the rock bream samples infected by the iridovirus indicated a dominant miR-10a-3p expression. The gene ontology (GO) analysis of predicted target genes for miR-10a-3p revealed that multiple genes are related to binding activity, catalytic activity, cell components as well as cellular and metabolic process. Overall the results imply that the miR-10a-3p could be used as a biomarker to detect VHSV infection in olive flounder and iridovirus infection in rock bream. In addition, the data provides fundamental information for further study of the complex interaction between miR-10a-3p and gene expression.
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Affiliation(s)
- Ara Jo
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Genetic Engineering Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Jennifer Im
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Hee-Eun Lee
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Genetic Engineering Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Dongmin Jang
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea
| | - Gyu-Hwi Nam
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Genetic Engineering Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Anshuman Mishra
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Genetic Engineering Institute, Pusan National University, Busan 46241, Republic of Korea
| | - Woo-Jin Kim
- Genetics and Breeding Research Center, National Institute of Fisheries Science, Geoje 53334, Republic of Korea
| | - Won Kim
- School of Biological Sciences, Seoul National University, Seoul 08824, Republic of Korea
| | - Hee-Jae Cha
- Departments of Parasitology and Genetics, College of Medicine, Kosin University, Busan 49267, Republic of Korea
| | - Heui-Soo Kim
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea; Genetic Engineering Institute, Pusan National University, Busan 46241, Republic of Korea.
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Wu HJ, Zhuo Y, Zhou YC, Wang XW, Wang YP, Si CY, Wang XH. miR-29a promotes hepatitis B virus replication and expression by targeting SMARCE1 in hepatoma carcinoma. World J Gastroenterol 2017; 23:4569-4578. [PMID: 28740345 PMCID: PMC5504372 DOI: 10.3748/wjg.v23.i25.4569] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/27/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the functional role and underlying molecular mechanism of miR-29a in hepatitis B virus (HBV) expression and replication.
METHODS The levels of miR-29a and SMARCE1 in HBV-infected HepG2.2.15 cells were measured by quantitative real-time PCR and western blot analysis. HBV DNA replication was measured by quantitative PCR and Southern blot analysis. The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 (CCK-8) was used to detect the viability of HepG2.2.15 cells. The relationship between miR-29a and SMARCE1 were identified by target prediction and luciferase reporter analysis.
RESULTS miR-29a promoted HBV replication and expression, while SMARCE1 repressed HBV replication and expression. Cell viability detection indicated that miR-29a transfection had no adverse effect on the host cells. Moreover, SMARCE1 was identified and validated to be a functional target of miR-29a. Furthermore, restored expression of SMARCE1 could relieve the increased HBV replication and expression caused by miR-29a overexpression.
CONCLUSION miR-29a promotes HBV replication and expression through regulating SMARCE1. As a potential regulator of HBV replication and expression, miR-29a could be a promising therapeutic target for patients with HBV infection.
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Deng W, Zhang X, Ma Z, Lin Y, Lu M. MicroRNA-125b-5p mediates post-transcriptional regulation of hepatitis B virus replication via the LIN28B/let-7 axis. RNA Biol 2017; 14:1389-1398. [PMID: 28267418 DOI: 10.1080/15476286.2017.1293770] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
MicroRNAs (miRNAs) are able to modulate hepatitis B virus (HBV) replication and play an important role in the pathogenesis of HBV infection. Recently, we have identified that serum miR-125b-5p levels correlated with HBV DNA levels and liver necroinflammation. In the present study, we addressed how miR-125b-5p regulated HBV replication at the different steps, inclduing viral transcription, assembly, and virion production and investigated the underlying mechanisms. We found that miR-125b-5p overexpression increased HBV replication without altering HBV transcription. This is the first demonstration of post-transcriptional miRNA regulation of HBV replication. In contrast, transfection of miR-125b-5p inhibitor resulted in downregulation of HBV replication in hepatoma cells. Further, miR-125b-5p inhibited the phosphorylation of retinoblastoma protein and blocked cell cycle progression at the G1/S phase in hepatoma cell lines. Our results indicate that certain miRNAs are able to arrest the cell cycle at G1 phase and may increase HBV replication. RNA sequencing revealed several liver-specific metabolic pathways regulated by miR-125b-5p, which was also found to suppress LIN28B and induce let-7 family members. Additional data demonstrated that miR-125b-5p targeted the LIN28B/let-7 axis to stimulate HBV replication at a post-transcriptional step.
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Affiliation(s)
- Wanyu Deng
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany.,b College of Life Science, Shangrao Normal University , Shangrao , China
| | - Xiaoyong Zhang
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Zhiyong Ma
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Yong Lin
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Mengji Lu
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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50
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Potenza N, Mosca N, Zappavigna S, Castiello F, Panella M, Ferri C, Vanacore D, Giordano A, Stiuso P, Caraglia M, Russo A. MicroRNA-125a-5p Is a Downstream Effector of Sorafenib in Its Antiproliferative Activity Toward Human Hepatocellular Carcinoma Cells. J Cell Physiol 2017; 232:1907-1913. [PMID: 27982429 DOI: 10.1002/jcp.25744] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 12/15/2016] [Indexed: 12/11/2022]
Abstract
Sorafenib is an antitumor drug for treatment of advanced hepatocellular carcinoma (HCC). It acts as a multikinase inhibitor suppressing cell proliferation and angiogenesis. Human microRNA-125a-5p (miR-125a) is endowed with similar activities and is frequently downregulated in HCC. Looking for a potential microRNA-based mechanism of action of the drug, we found that sorafenib increases cellular expression of miR-125a in cultured HuH-7 and HepG2 HCC cells. Upregulation of the microRNA inhibited cell proliferation by suppression of sirtuin-7, a NAD(+)-dependent deacetylase, and p21/p27-dependent cell cycle arrest in G1. Later, recruitment of miR-125a in the antiproliferative activity of sorafenib was inquired by modulating its expression in combination with the drug treatment. This analysis showed that intracellular delivery of miR-125a had no additive effect on the antiproliferative activity of sorafenib, whereas a miR-125a inhibitor could counteract it. Finally, evaluation of other oncogenic targets of miR-125a revealed its ability to interfere with the expression of matrix metalloproteinase-11, Zbtb7a proto-oncogene, and c-Raf, possibly contributing to the antiproliferative activity of the drug. J. Cell. Physiol. 232: 1907-1913, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Nicola Mosca
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Silvia Zappavigna
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Filomena Castiello
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Marta Panella
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
| | - Carmela Ferri
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Daniela Vanacore
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine & Center for Biotechnology, Temple University, Philadelphia, Pennsylvania
| | - Paola Stiuso
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy
| | - Aniello Russo
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy
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