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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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2
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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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3
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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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4
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The Role of miRNAs in Virus-Mediated Oncogenesis. Int J Mol Sci 2018; 19:ijms19041217. [PMID: 29673190 PMCID: PMC5979478 DOI: 10.3390/ijms19041217] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/12/2018] [Accepted: 04/13/2018] [Indexed: 12/16/2022] Open
Abstract
To date, viruses are reported to be responsible for more than 15% of all tumors worldwide. The oncogenesis could be influenced directly by the activity of viral oncoproteins or by the chronic infection or inflammation. The group of human oncoviruses includes Epstein–Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human herpesvirus 8 (HHV-8) or polyomaviruses, and transregulating retroviruses such as HIV or HTLV-1. Most of these viruses express short noncoding RNAs called miRNAs to regulate their own gene expression or to influence host gene expression and thus contribute to the carcinogenic processes. In this review, we will focus on oncogenic viruses and summarize the role of both types of miRNAs, viral as well as host’s, in the oncogenesis.
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5
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Ge J, Huang Z, Liu H, Chen J, Xie Z, Chen Z, Peng J, Sun J, Hou J, Zhang X. Lower Expression of MicroRNA-155 Contributes to Dysfunction of Natural Killer Cells in Patients with Chronic Hepatitis B. Front Immunol 2017; 8:1173. [PMID: 29018442 PMCID: PMC5614978 DOI: 10.3389/fimmu.2017.01173] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 09/05/2017] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs have been reported to be regulated in different ways in a variety of liver diseases. As a key modulator of cellular function in both innate and adaptive immunity, the role of miR-155 in chronic hepatitis B virus infection remains largely unknown. Here, we investigated the expression and function of miR-155 in chronic hepatitis B (CHB) patients. It was found that miR-155 expression in peripheral blood mononuclear cells (PBMCs) was lower in CHB patients than healthy controls (HC). Among CHB infection, immune-active (IA) patients with abnormal alanine aminotransferase (ALT) levels had relatively higher miR-155 expression in PBMCs and serum than immune-tolerant carriers, but were comparable to inactive carriers. Moreover, there was a positive correlation between miR-155 expression and ALT levels in CHB patients. Particularly, miR-155 expression in natural killer (NK) cells was significantly downregulated in IA patients compared with HC. Inversely, suppressor of cytokine signaling 1 (SOCS1), a target of miR-155, was upregulated in NK cells of IA patients. Overexpression of miR-155 in NK cells from IA patients led to a decrease in SOCS1 expression and an increase of IFN-γ production. Finally, accompanied by the normalization of ALT, miR-155 expression in PBMCs gradually decreased during telbivudine or peg-IFN-α-2a therapy. Interestingly, higher miR-155 expression at baseline was associated with better response to telbivudine therapy, but not peg-IFN-α-2a. In conclusion, our data suggested that miR-155 downregulation in NK cells of IA patients impaired IFN-γ production by targeting SOCS1, which may contribute to immune dysfunction during CHB infection. Additionally, baseline miR-155 expression could predict the treatment response to telbivudine therapy.
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Affiliation(s)
- Jun Ge
- 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
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Haptobiliary Hospital of Fujian Medical University, Fuzhou, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, China
| | - Hongyan Liu
- 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
| | - Jiehua Chen
- 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
| | - Zhanglian Xie
- 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
| | - Zide Chen
- 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
| | - Jian Sun
- 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
| | - Jinlin Hou
- 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
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Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication. J Virol 2017; 91:JVI.01919-16. [PMID: 28148795 DOI: 10.1128/jvi.01919-16] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV+ hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection.IMPORTANCE Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.
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7
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Abstract
Virology is probably the most rapidly developing field within clinical laboratory medicine. Adequate diagnostic methods exist for the diagnostics of most acute viral infections. However, emergence of pathogenic viruses or virus strains and new disease associations of known viruses require the establishment of new diagnostic methods, sometimes very rapidly. In the field of chronic or persistent viral diseases, particularly those involving potential of malignant or fatal development, there is a constant need for improved differential diagnostics, monitoring, prognosis and risk assessment. Increasing understanding of disease pathogenesis also enables better patient management and personalized medicine, where companion diagnostics can offer precise and specific tools for individual care. Very often the new tools are offered by molecular diagnostic techniques, and this includes the detection of microRNAs (miRNAs). miRNAs are small regulatory RNA molecules, which regulate the expression of their target genes. They are encoded both by viruses and their host, and both can target either viral or cellular gene expression. In this review the diagnostic possibilities offered by miRNA will be discussed. The focus will be on selected viral and human miRNAs in viral diseases, and examples of miRNAs of putative diagnostic potential will be presented.
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Affiliation(s)
- Eeva Auvinen
- Department of Virology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, POB 21, 00014, Helsinki, Finland.
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8
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MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:280. [PMID: 26927063 PMCID: PMC4813144 DOI: 10.3390/ijms17030280] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 01/19/2016] [Accepted: 02/19/2016] [Indexed: 02/07/2023] Open
Abstract
Serum levels of liver enzymes, such as alanine transaminase, aspartate transaminase, and α-fetoprotein, provide insight into liver function and are used during treatment of liver disease, but such information is limited. In the case of hepatocellular carcinoma (HCC), which is often not detected until an advanced stage, more sensitive biomarkers may help to achieve earlier detection. Serum also contains microRNAs, a class of small non-coding RNAs that play an important role in regulating gene expression. miR-122 is specific to the liver and correlates strongly with liver enzyme levels and necroinflammatory activity, and other microRNAs are correlated with the degree of fibrosis. miR-122 has also been found to be required for hepatitis C virus (HCV) infection, whereas other microRNAs have been shown to play antiviral roles. miR-125a-5p and miR-1231 have been shown to directly target hepatitis B virus (HBV) transcripts, and others are up- or down-regulated in infected individuals. MicroRNA profiles also differ in the case of HBV and HCV infection as well as between HBeAg-positive and negative patients, and in patients with occult versus active HBV infection. In such patients, monitoring of changes in microRNA profiles might provide earlier warning of neoplastic changes preceding HCC.
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9
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Louten J, Beach M, Palermino K, Weeks M, Holenstein G. MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations. Biomark Insights 2016; 10:25-52. [PMID: 26819546 PMCID: PMC4718089 DOI: 10.4137/bmi.s29512] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Revised: 10/22/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus.
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Affiliation(s)
- Jennifer Louten
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Michael Beach
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Kristina Palermino
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Maria Weeks
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
| | - Gabrielle Holenstein
- Department of Molecular and Cellular Biology, Kennesaw State University, Kennesaw, GA, USA
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10
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Wu SY, Lan SH, Liu HS. Autophagy and microRNA in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 2016; 22:176-187. [PMID: 26755869 PMCID: PMC4698484 DOI: 10.3748/wjg.v22.i1.176] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/15/2015] [Accepted: 10/26/2015] [Indexed: 02/06/2023] Open
Abstract
Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis.
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11
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Wang L, Li G, Yao ZQ, Moorman JP, Ning S. MicroRNA regulation of viral immunity, latency, and carcinogenesis of selected tumor viruses and HIV. Rev Med Virol 2015; 25:320-41. [PMID: 26258805 DOI: 10.1002/rmv.1850] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Revised: 06/09/2015] [Accepted: 06/28/2015] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) function as key regulators in immune responses and cancer development. In the contexts of infection with oncogenic viruses, miRNAs are engaged in viral persistence, latency establishment and maintenance, and oncogenesis. In this review, we summarize the potential roles and mechanisms of viral and cellular miRNAs in the host-pathogen interactions during infection with selected tumor viruses and HIV, which include (i) repressing viral replication and facilitating latency establishment by targeting viral transcripts, (ii) evading innate and adaptive immune responses via toll-like receptors, RIG-I-like receptors, T-cell receptor, and B-cell receptor pathways by targeting signaling molecules such as TRAF6, IRAK1, IKKε, and MyD88, as well as downstream targets including regulatory cytokines such as tumor necrosis factor α, interferon γ, interleukin 10, and transforming growth factor β, (iii) antagonizing intrinsic and extrinsic apoptosis pathways by targeting pro-apoptotic or anti-apoptotic gene transcripts such as the Bcl-2 family and caspase-3, (iv) modulating cell proliferation and survival through regulation of the Wnt, PI3K/Akt, Erk/MAPK, and Jak/STAT signaling pathways, as well as the signaling pathways triggered by viral oncoproteins such as Epstein-Barr Virus LMP1, by targeting Wnt-inhibiting factor 1, SHIP, pTEN, and SOCSs, and (v) regulating cell cycle progression by targeting cell cycle inhibitors such as p21/WAF1 and p27/KIP1. Further elucidation of the interaction between miRNAs and these key biological events will facilitate our understanding of the pathogenesis of viral latency and oncogenesis and may lead to the identification of miRNAs as novel targets for developing new therapeutic or preventive interventions.
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Affiliation(s)
- Ling Wang
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Guangyu Li
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Zhi Q Yao
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City, TN, USA
| | - Jonathan P Moorman
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Hepatitis (HCV/HIV) Program, James H Quillen VA Medical Center, Johnson City, TN, USA
| | - Shunbin Ning
- Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.,Division of Infectious Diseases, Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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12
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Sarkar N, Chakravarty R. Hepatitis B Virus Infection, MicroRNAs and Liver Disease. Int J Mol Sci 2015; 16:17746-62. [PMID: 26247932 PMCID: PMC4581219 DOI: 10.3390/ijms160817746] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 07/21/2015] [Accepted: 07/22/2015] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus (HBV) attacks the liver and can cause both acute as well as chronic liver diseases which might lead to liver cirrhosis and hepatocellular carcinoma. Regardless of the availability of a vaccine and numerous treatment options, HBV is a major cause of morbidity and mortality across the world. Recently, microRNAs (miRNAs) have emerged as important modulators of gene function. Studies on the role of miRNA in the regulation of hepatitis B virus gene expression have been the focus of modern antiviral research. miRNAs can regulate viral replication and pathogenesis in a number of different ways, which includefacilitation, direct or indirect inhibition, activation of immune response, epigenetic modulation, etc. Nevertheless, these mechanisms can appropriately be used with a diagnosticand/or therapeutic approach. The present review is an attempt to classify specific miRNAs that are reported to be associated with various aspects of hepatitis B biology, in order to precisely present the participation of individual miRNAs in multiple aspects relating to HBV.
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Affiliation(s)
- Neelakshi Sarkar
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata-700010, India.
| | - Runu Chakravarty
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata-700010, India.
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13
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Kitab B, Alj HS, Ezzikouri S, Benjelloun S. MicroRNAs as Important Players in Host-hepatitis B Virus Interactions. J Clin Transl Hepatol 2015; 3:149-61. [PMID: 26357642 PMCID: PMC4548348 DOI: 10.14218/jcth.2015.00002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 03/09/2015] [Accepted: 03/09/2015] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) infection, a major public health problem, causes acute and chronic hepatitis that is often complicated by liver cirrhosis and hepatocellular carcinoma. The pathogenic mechanisms of HBV-related liver disease are not well understood, and the current licensed therapies are not effective in permanently clearing virus from the circulation. In recent years, the role of micro-ribonucleic acids (miRNAs) in HBV infection has attracted great interest. Cellular miRNAs can influence HBV replication directly by binding to HBV transcripts and indirectly by targeting cellular factors relevant to the HBV life cycle. They are also involved in the regulation of cellular genes and signaling pathways that have critical roles in HBV pathogenesis. HBV infection, in turn, can trigger changes in cellular miRNA expression that are associated with distinctive miRNA expression profiles depending on the phase of liver disease. These alterations in miRNA expression have been linked to disease progression and hepatocarcinogenesis. We provide here an up to date review regarding the field of miRNAs and HBV interplay and highlight the potential utility of miRNAs as diagnostic biomarkers and therapeutic targets for the management of HBV-related liver disease.
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Affiliation(s)
- Bouchra Kitab
- Viral Hepatitis Laboratory, Virology Unit, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Hanane Salih Alj
- Laboratory of Biology and Health, URAC34, Faculty of Sciences Ben M’sik, University Hassan II Casablanca, Morocco
| | - Sayeh Ezzikouri
- Viral Hepatitis Laboratory, Virology Unit, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Viral Hepatitis Laboratory, Virology Unit, Institut Pasteur du Maroc, Casablanca, Morocco
- Correspondence to: Soumaya Benjelloun, Virology Unit, Institut Pasteur du Maroc, 1 Place Louis Pasteur, Casablanca 20360, Morocco. Tel: +212‐527‐016‐076; +212‐522‐434‐450, Fax: +212‐522‐260‐957, E‐mail:
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14
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Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122--a key factor and therapeutic target in liver disease. J Hepatol 2015; 62:448-57. [PMID: 25308172 DOI: 10.1016/j.jhep.2014.10.004] [Citation(s) in RCA: 482] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/26/2014] [Accepted: 10/02/2014] [Indexed: 02/06/2023]
Abstract
Being the largest internal organ of the human body with the unique ability of self-regeneration, the liver is involved in a wide variety of vital functions that require highly orchestrated and controlled biochemical processes. Increasing evidence suggests that microRNAs (miRNAs) are essential for the regulation of liver development, regeneration and metabolic functions. Hence, alterations in intrahepatic miRNA networks have been associated with liver disease including hepatitis, steatosis, cirrhosis and hepatocellular carcinoma (HCC). miR-122 is the most frequent miRNA in the adult liver, and a central player in liver biology and disease. Furthermore, miR-122 has been shown to be an essential host factor for hepatitis C virus (HCV) infection and an antiviral target, complementary to the standard of care using direct-acting antivirals or interferon-based treatment. This review summarizes our current understanding of the key role of miR-122 in liver physiology and disease, highlighting its role in HCC and viral hepatitis. We also discuss the perspectives of miRNA-based therapeutic approaches for viral hepatitis and liver disease.
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Affiliation(s)
- Simonetta Bandiera
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - Sébastien Pfeffer
- Université de Strasbourg, Strasbourg, France; Architecture et Réactivité de l'ARN - UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
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15
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Abstract
The hepatitis B virus (HBV) infection is the leading cause of persistent liver diseases, cirrhosis, and hepatocellular carcinoma (HCC). However, the precise mechanism underlying the development of HBV-related diseases is not fully understood. In addition, the therapeutic strategies for the diseases are less than optimum. microRNAs (miRNAs) are small noncoding RNAs that have been described as a "fine-tuner" in various cellular events. The dysregulation of miRNAs play a role in the development of the cancer as well as viral interference. Recent articles have demonstrated that several miRNAs are deregulated by HBV infection and contribute to viral replication and pathogenesis. Thus, it suggests that the precise mechanism between miRNA and HBV biology will be leading to the development of the novel diagnosis and therapy. This chapter aims to provide the basic principals of miRNAs in development of the HBV-related diseases. We also discuss about the possibility of miRNAs on the clinical application for diagnosis and therapy of HBV-related diseases.
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16
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Fiorino S, Bacchi-Reggiani L, Sabbatani S, Grizzi F, di Tommaso L, Masetti M, Fornelli A, Bondi A, de Biase D, Visani M, Cuppini A, Jovine E, Pession A. Possible role of tocopherols in the modulation of host microRNA with potential antiviral activity in patients with hepatitis B virus-related persistent infection: a systematic review. Br J Nutr 2014; 112:1751-1768. [PMID: 25325563 DOI: 10.1017/s0007114514002839] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatitis B virus (HBV) infection represents a serious global health problem and persistent HBV infection is associated with an increased risk of cirrhosis, hepatocellular carcinoma and liver failure. Recently, the study of the role of microRNA (miRNA) in the pathogenesis of HBV has gained considerable interest as well as new treatments against this pathogen have been approved. A few studies have investigated the antiviral activity of vitamin E (VE) in chronic HBV carriers. Herein, we review the possible role of tocopherols in the modulation of host miRNA with potential anti-HBV activity. A systematic research of the scientific literature was performed by searching the MEDLINE, Cochrane Library and EMBASE databases. The keywords used were 'HBV therapy', 'HBV treatment', 'VE antiviral effects', 'tocopherol antiviral activity', 'miRNA antiviral activity' and 'VE microRNA'. Reports describing the role of miRNA in the regulation of HBV life cycle, in vitro and in vivo available studies reporting the effects of VE on miRNA expression profiles and epigenetic networks, and clinical trials reporting the use of VE in patients with HBV-related chronic hepatitis were identified and examined. Based on the clinical results obtained in VE-treated chronic HBV carriers, we provide a reliable hypothesis for the possible role of this vitamin in the modulation of host miRNA profiles perturbed by this viral pathogen and in the regulation of some cellular miRNA with a suggested potential anti-HBV activity. This approach may contribute to the improvement of our understanding of pathogenetic mechanisms involved in HBV infection and increase the possibility of its management and treatment.
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Affiliation(s)
- S Fiorino
- Unità Operativa di Medicina Interna, Ospedale di Budrio,Via Benni 44,40065Budrio, Bologna,Italy
| | - L Bacchi-Reggiani
- Istituto di Cardiologia, Policlinico S. Orsola-Malpighi, Università degli Studi di Bologna,Bologna,Italy
| | - S Sabbatani
- Istituto di Malattie Infettive, Policlinico S. Orsola-Malpighi, Università degli Studi di Bologna,Bologna,Italy
| | - F Grizzi
- Humanitas Clinical and Research Center,Rozzano, Milano,Italy
| | - L di Tommaso
- Humanitas Clinical and Research Center,Rozzano, Milano,Italy
| | - M Masetti
- Unità Operativa di Chirurgia A, Ospedale Maggiore Bologna,Bologna,Italy
| | - A Fornelli
- Servizio di Anatomia Patologica, Ospedale Maggiore,Bologna,Italy
| | - A Bondi
- Servizio di Anatomia Patologica, Ospedale Maggiore,Bologna,Italy
| | - D de Biase
- Dipartimento di Medicina Sperimentale,Università di Bologna, Ospedale Bellaria,Bologna,Italy
| | - M Visani
- Dipartimento di Farmacia e Biotecnologie,Università di Bologna,Bologna,Italy
| | - A Cuppini
- Unità Operativa di Medicina Interna, Ospedale di Budrio,Via Benni 44,40065Budrio, Bologna,Italy
| | - E Jovine
- Unità Operativa di Chirurgia A, Ospedale Maggiore Bologna,Bologna,Italy
| | - A Pession
- Dipartimento di Farmacia e Biotecnologie,Università di Bologna,Bologna,Italy
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17
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Fan HX, Tang H. Complex interactions between microRNAs and hepatitis B/C viruses. World J Gastroenterol 2014; 20:13477-13492. [PMID: 25309078 PMCID: PMC4188899 DOI: 10.3748/wjg.v20.i37.13477] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 03/28/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma (HCC) initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or as tools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.
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18
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Xu X, Ye Q. Regulation of viral oncogenesis by microRNAs. Mol Cell Oncol 2014; 1:e29910. [PMID: 27308317 PMCID: PMC4905170 DOI: 10.4161/mco.29910] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Revised: 06/26/2014] [Accepted: 06/30/2014] [Indexed: 02/07/2023]
Abstract
Viral infection may play a causative role in human cancers, for example hepatitis B virus (HBV) or hepatitis C virus (HCV) in liver cancer, human papilloma virus (HPV) in cervical cancer, and Epstein-Barr virus (EBV) in nasopharyngeal carcinoma. Virally infected cells express viral-encoded genes that are critical for oncogenesis. Some viruses also encode microRNA (miRNA) species. miRNAs are small noncoding RNA molecules that play an important role in cancer development and progression. Recent studies indicate an important interplay among viral oncoproteins, virus-encoded miRNAs, cellular miRNAs, and cellular genes. This review focuses on modulation of HBV-, HCV-, HPV-, and EBV-associated cancers by cellular and/or viral miRNA. An understanding of the mechanisms underlying the regulation of viral carcinogenesis by miRNAs may provide new targets for the development of specific viral therapies.
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Affiliation(s)
- Xiaojie Xu
- Department of Medical Molecular Biology; Beijing Institute of Biotechnology; Beijing, PR China
| | - Qinong Ye
- Department of Medical Molecular Biology; Beijing Institute of Biotechnology; Beijing, PR China
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19
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Tan YLJ, Chen WN. MicroRNAs as therapeutic strategy for hepatitis B virus-associated hepatocellular carcinoma: Current status and future prospects. World J Gastroenterol 2014; 20:5973-5986. [PMID: 24876720 PMCID: PMC4033437 DOI: 10.3748/wjg.v20.i20.5973] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/13/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains to be one of the top causing cancer-related deaths today. The majority of HCC cases are reported to be the result of chronic hepatitis B virus (HBV) infection. Current treatments for HBV-related HCC revolve around the use of drugs to inhibit viral replication, as a high level of viral load and antigen in circulation often presents a poor patient prognosis. However, existing therapies are inefficient in the complete eradication of HBV, often resulting in tumour recurrence. The involvement of microRNAs (miRNAs) in important processes in HBV-related HCC makes it an important player in the progression of HCC in chronic hepatitis B infected patients. In this review, we discuss the key aspects of HBV infection and the important viral products that may regulate cancer-related processes via their interaction with miRNAs or their closely related protein machinery. Conversely, we also look at how miRNAs may go about regulating the virus, especially in vital processes like viral replication. Apart from miRNAs acting as either oncogenes or tumour-suppressors, we also look at how miRNAs may function as biomarkers that may possibly serve as better candidates than those currently employed in the diagnosis of HBV infection or HBV-related HCC. A summary of the roles of miRNAs in HBV-related HCC will hopefully lead to a gain in understanding of the pathogenesis process and pave the way for new insights in medical therapy.
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20
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Roles of microRNAs in the hepatitis B virus infection and related diseases. Viruses 2013; 5:2690-703. [PMID: 24212236 PMCID: PMC3856410 DOI: 10.3390/v5112690] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 10/28/2013] [Accepted: 10/29/2013] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B virus (HBV) is a small enveloped DNA virus that belongs to the Hepadnaviridae family. HBV can cause acute and persistent infection which can lead to hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play a crucial role in the main cellular events. The dysregulation of their expression has been linked to the development of the cancer as well as to viral interference. This chapter will describe the involvement of miRNAs in the case of HBV infection and their implication in the development of the HBV-related diseases.
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21
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Wei YF, Cui GY, Ye P, Chen JN, Diao HY. MicroRNAs may solve the mystery of chronic hepatitis B virus infection. World J Gastroenterol 2013; 19:4867-4876. [PMID: 23946591 PMCID: PMC3740416 DOI: 10.3748/wjg.v19.i30.4867] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Revised: 06/04/2013] [Accepted: 07/05/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem that causes persistent liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. A large amount of people die annually from HBV infection. However, the pathogenesises of the HBV-related diseases are ill defined and the therapeutic strategies for the diseases are less than optimum. The recently discovered microRNAs (miRNAs) are tiny noncoding RNAs that regulate gene expression primarily at the post-transcriptional level by binding to mRNAs. miRNAs contribute to a variety of physiological and pathological processes. A number of miRNAs have been found to play a pivotal role in the host-virus interaction including host-HBV interaction. Numerous studies have indicated that HBV infection could change the cellular miRNA expression patterns and different stages of HBV associated disease have displayed distinctive miRNA profiles. Furthermore, the differential expressed miRNAs have been found involved in the progression of HBV-related diseases, for instance some miRNAs are involved in liver tumorigenesis and tumor metastasis. Studies have also shown that the circulating miRNA in serum or plasma might be a very useful biomarker for the diagnosis and prognosis of HBV-related diseases. In addition, miRNA-based therapy strategies have attracted increasing attention, indicating a promising future in the treatment of HBV-related diseases.
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22
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Datta S, Chatterjee S, Policegoudra RS, Gogoi HK, Singh L. Hepatitis viruses and non-Hodgkin’s lymphoma: A review. World J Virol 2012; 1:162-73. [PMID: 24175222 PMCID: PMC3782277 DOI: 10.5501/wjv.v1.i6.162] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 06/06/2012] [Accepted: 11/07/2012] [Indexed: 02/05/2023] Open
Abstract
Non-Hodgkin’s lymphoma (NHL) is among the haematological malignancies with high prevalence worldwide, causing estimated 355 900 new cases and 191 400 deaths in 2008. High prevalence of NHL is documented in economically more developed areas while low prevalence is observed in less developed areas of the globe. A wide array of environmental factors have been reported to be either directly involved or in modifying the risk of NHL development. In addition to these factors, a number of infectious agents, chiefly viruses have also been implicated in the development of NHL. This article reviews the available literature to discuss the role of hepatitis viruses in NHL development, possible mechanisms of lymphomagenesis and also identify the areas in which further research is required to better understand this disease. A brief discussion on the clinical aspects such as classification, staging, treatment approaches have also been included in this article.
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Affiliation(s)
- Sibnarayan Datta
- Sibnarayan Datta, Soumya Chatterjee, Rudragoud S Policegoudra, Hemant K Gogoi, Lokendra Singh, Biotechnology Division, Defence Research Laboratory, Tezpur, Assam, PIN-784001, India
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23
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The role and clinical implications of microRNAs in hepatocellular carcinoma. SCIENCE CHINA-LIFE SCIENCES 2012; 55:906-19. [PMID: 23108868 DOI: 10.1007/s11427-012-4384-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis.
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24
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Zhang Q, Pu R, Du Y, Han Y, Su T, Wang H, Cao G. Non-coding RNAs in hepatitis B or C-associated hepatocellular carcinoma: potential diagnostic and prognostic markers and therapeutic targets. Cancer Lett 2012; 321:1-12. [PMID: 22425745 DOI: 10.1016/j.canlet.2012.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Revised: 03/07/2012] [Accepted: 03/08/2012] [Indexed: 02/06/2023]
Abstract
Non-coding RNA (ncRNA), a class of RNAs that do not code protein but have regulatory functions, can regulate gene expression and replication of hepatitis B virus or hepatitis C virus and play an important role in the virus-host interaction and the development of hepatocellular carcinoma (HCC). Deregulated ncRNAs in surgically removed hepatic tissues and circulation can be prognostic and diagnostic markers, respectively. ncRNAs functioning as either tumor suppressors or oncogenes can be therapeutic options. Here, we summarize the deregulated ncRNAs associated with the infections and HCC and focus on their roles on early diagnosis, prognosis prediction and therapeutic option of HCC.
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Affiliation(s)
- Qi Zhang
- Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China
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25
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Ha TY. MicroRNAs in Human Diseases: From Lung, Liver and Kidney Diseases to Infectious Disease, Sickle Cell Disease and Endometrium Disease. Immune Netw 2011; 11:309-23. [PMID: 22346770 PMCID: PMC3275699 DOI: 10.4110/in.2011.11.6.309] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 10/07/2011] [Accepted: 10/15/2011] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of naturally occurring small non-coding RNAs of about 22 nucleotides that have recently emerged as important regulators of gene expression at the posttranscriptional level. Recent studies provided clear evidence that microRNAs are abundant in the lung, liver and kidney and modulate a diverse spectrum of their functions. Moreover, a large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as infectious diseases, sickle cell disease and endometrium diseases as well as lung, liver and kidney diseases. As a consequence of extensive participation of miRNAs in normal functions, alteration and/or abnormalities in miRNAs should have importance in human diseases. Beside their important roles in patterning and development, miRNAs also orchestrated responses to pathogen infections. Particularly, emerging evidence indicates that viruses use their own miRNAs to manipulate both cellular and viral gene expression. Furthermore, viral infection can exert a profound impact on the host cellular miRNA expression profile, and several RNA viruses have been reported to interact directly with cellular miRNAs and/or to use these miRNAs to augment their replication potential. Here I briefly summarize the newly discovered roles of miRNAs in various human diseases including infectious diseases, sickle cell disease and enodmetrium diseases as well as lung, liver and kidney diseases.
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Affiliation(s)
- Tai-You Ha
- Department of Immunology, Chonbuk National University Medical School, Jeonju 561-180, Korea
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26
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Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver of global importance. Recent studies of the expression and role of microRNA (miRNA) in HCC are providing new insights into disease pathogenesis. In addition, therapeutic efforts targeting specific miRNAs are being evaluated in animal models of HCC. The potential of miRNAs as biomarkers of disease or prognostic markers is being explored. Herein, we review studies of miRNA expression in human HCC, and discuss recent advances in knowledge about the involvement and role of selected miRNAs in disease pathogenesis, as biomarkers, or as therapeutic targets for HCC.
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27
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28
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Sun G, Rossi JJ. MicroRNAs and their potential involvement in HIV infection. Trends Pharmacol Sci 2011; 32:675-81. [PMID: 21862142 DOI: 10.1016/j.tips.2011.07.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 07/15/2011] [Accepted: 07/21/2011] [Indexed: 12/12/2022]
Abstract
Treatment and cure of HIV-1 infection remain one of the greatest therapeutic challenges owing to its persistent infection, which often leads to AIDS. Although it has been 28 years since the discovery of the virus, the development of an effective vaccine is still years away. Relatively newly discovered miRNAs are a family of small noncoding RNAs that can regulate gene expression primarily by binding to the 3' untranslated region of targeted transcripts. An understanding of how HIV-1 infection affects the host miRNA pathway could generate new insights into the basic mechanisms underlying HIV-1-mediated pathologies and T-lymphocyte depletion. Here, we review literature on the biogenesis of HIV-1-encoded miRNAs, cellular miRNAs that can directly target HIV-1 or essential cellular factors required for HIV-1 replication. We also discuss the feasibility of using miRNAs for HIV-1 therapy.
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Affiliation(s)
- Guihua Sun
- Irell & Manella Graduate School of Biological Science, Beckman Research Institute of the City of Hope, 1500 E. Duarte Road, Duarte, CA 91010-3000, USA
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29
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McDermott AM, Heneghan HM, Miller N, Kerin MJ. The therapeutic potential of microRNAs: disease modulators and drug targets. Pharm Res 2011; 28:3016-29. [PMID: 21818713 DOI: 10.1007/s11095-011-0550-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 07/26/2011] [Indexed: 12/19/2022]
Abstract
MiRNAs are a class of small, naturally occurring RNA molecules that play critical roles in modulating numerous biological pathways by regulating gene expression. The knowledge that miRNA expression is dysregulated in many pathological disease processes, including cancer, has led to a rapidly expanding body of literature as we try to unveil their mechanism of action. Their putative role as oncogenes or tumour suppressor genes presents a wonderful opportunity to provide targeted cancer treatment strategies. Additionally, their documented function in a host of benign diseases broadens the potential market for miRNA-based therapeutics. The present review outlines the underlying rationales for considering mi(cro)RNAs as therapeutic agents or targets. We highlight the potential of manipulating miRNAs for the treatment of many common diseases, particularly cancers. Finally, we summarize the challenges that need to be overcome to fully harness the potential of miRNA-based therapies so they become the next generation of pharmaceutical products.
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Affiliation(s)
- Ailbhe M McDermott
- Surgery, School of Medicine, National University of Ireland, Galway, Ireland.
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30
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Zhang ZZ, Liu X, Wang DQ, Teng MK, Niu LW, Huang AL, Liang Z. Hepatitis B virus and hepatocellular carcinoma at the miRNA level. World J Gastroenterol 2011; 17:3353-8. [PMID: 21876625 PMCID: PMC3160541 DOI: 10.3748/wjg.v17.i28.3353] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 09/09/2010] [Accepted: 09/16/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.
METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection; HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model; and HepG2.2.15 cell line, which is derived from HepG2 and stably transfected with a complete HBV genome, as a chronic infection model. The miRNA levels were examined using microarray technology. To explore the relationship between HBV infection and HCC genesis at the miRNA level, we downloaded from national center for biotechnology information Gene Expression Omnibus an miRNA expression dataset derived from HCC patients, most of whom are HBV carriers. We compared the miRNA expression alterations during HBV infection with those in HCC patients, by analyzing miRNA expression change profiles statistically.
RESULTS: Seventy-seven and 48 miRNAs were differentially expressed during acute and chronic HBV infection, respectively. Among these miRNAs, 25 were in common, the intersection of which was significant under the hypergeometric test (P = 1.3 × 10-11). Fourteen miRNAs were observed to change coherently in the acute and chronic infections, with one upregulated and 13 downregulated. Eleven showed inverse changes during the two phases of infection; downregulated in the acute infection and upregulated in the chronic infection. The results imply that common and specific mechanisms exist at the miRNA level during acute and chronic HBV infection. Besides, comparative analysis of the miRNA expression changes during HBV infection with those in HCC indicates that, although miRNA expression changes during HBV infection are distinct from those in HCC patients (P < 2.2 × 10-16), they exhibited significant correlations (P = 0.0229 for acute infection; P = 0.0084 for chronic infection). Perturbation of miRNA expression during chronic HBV infection was closer to that in HCC patients than that during acute HBV infection. This observation implies the contribution of miRNAs to HCC genesis from HBV infection. According to their patterns of differential expression in acute and chronic HBV infection, as well as in HCC, miRNAs of potential research interest could be identified, such as miR-18a/miR-18b, miR-106a, miR-221 and miR-101. For instance, the gradient expression alteration of miR-221 in the above three phases, which is downregulated in acute HBV infection, normally expressed in chronic HBV infection, and upregulated in HCC, indicates that it may be a key effector for progression of the disease.
CONCLUSION: Our analysis provides insights into HBV infection and related HCC in relation to miRNAs, and reveals some candidate miRNAs for future studies.
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31
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Su C, Hou Z, Zhang C, Tian Z, Zhang J. Ectopic expression of microRNA-155 enhances innate antiviral immunity against HBV infection in human hepatoma cells. Virol J 2011; 8:354. [PMID: 21762537 PMCID: PMC3169510 DOI: 10.1186/1743-422x-8-354] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Accepted: 07/18/2011] [Indexed: 02/06/2023] Open
Abstract
Background Host innate antiviral immunity is the first line of defense against viral infection, and is precisely regulated by thousands of genes at various stages, including microRNAs. MicroRNA-155 (miR-155) was found to be up-regualted during viral infection, and influence the host immune response. Besides, the expression of miR-155, or its functional orthologs, may also contribute to viral oncogenesis. HBV is known to cause hepatocellular carcinoma, and there is evidence that attenuated intracellular immune response is the main reason for HBV latency. Thus, we assume miR-155 may affect the immune response during HBV infection in human hepatoma cells. Results We found that ectopic expression of miR-155 upregulated the expression of several IFN-inducible antiviral genes in human hepatoma cells. And over-expression of miR-155 suppressed suppressor of cytokine signaling 1 (SOCS1) expression and subsequently enhanced signal transducers and activators of transcription1 (STAT1) and signal transducers and activators of transcription3 (STAT3) phosphorylation. We further demonstrate that ectopic expression of miR-155 inhibits HBV X gene expression to some extent in vitro. Conclusion MiR-155 enhances innate antiviral immunity through promoting JAK/STAT signaling pathway by targeting SOCS1, and mildly inhibits HBV infection in human hepatoma cells.
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Affiliation(s)
- Chenhe Su
- School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
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32
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Drakaki A, Iliopoulos D. MicroRNA Gene Networks in Oncogenesis. Curr Genomics 2011; 10:35-41. [PMID: 19721809 PMCID: PMC2699834 DOI: 10.2174/138920209787581299] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Revised: 12/05/2008] [Accepted: 12/14/2008] [Indexed: 12/27/2022] Open
Abstract
MicroRNAs are small non-coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. They are involved in cellular development, differentiation, proliferation and apoptosis and play a significant role in cancer. Examination of tumor-specific microRNA expression profiles has revealed widespread deregulation of these molecules in diverse cancers. Several studies have shown that microRNAs function either as tumor suppressor genes or oncogenes, whose loss or overexpression respectively has diagnostic and prognostic significance. It seems that microRNAs act as major regulators of gene expression. In this review, we discuss microRNAs’ role in cancer and how microRNAs exert their functions through regulation of their gene targets. Bioinformatic analysis of putative miRNA binding sites has indicated several novel potential gene targets involved in apoptosis, angiogenesis and metastatic mechanisms. Matching computational prediction analysis together with microarray data seems the best method for microRNA gene target identification. MicroRNAs together with transcription factors generate a complex combinatorial code regulating gene expression. Thus, manipulation of microRNA-transcription factor gene networks may be provides a novel approach for developing cancer therapies.
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Affiliation(s)
- Alexandra Drakaki
- Caritas St Elizabeth Medical Center, Tufts University, Boston, MA, USA
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33
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Zhang G, Wang Q, Xu R. Therapeutics Based on microRNA: A New Approach for Liver Cancer. Curr Genomics 2011; 11:311-25. [PMID: 21286309 PMCID: PMC2944997 DOI: 10.2174/138920210791616671] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Revised: 04/11/2010] [Accepted: 04/16/2010] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious public health hazard. Polygenes involvement, accumulation of genetic and epigenetic changes and immune response of viral vector during gene therapy have resulted in the high mortality rate without marked change. To provide a safeguard for gene therapy and the feasibility for a clinical application, efforts have been focused predominantly upon constructing liver-targeted vector recently. MicroRNAs (miRNAs), a class of short endogenous RNAs, regulate the gene expression at the post-transcriptional level through imperfect base pairing with the 3′-untranslated region of target mRNAs. miRNAs, especially the liver-specific miRNA: miR-122, have multiple functions in liver development and abnormal expression of miRNAs could lead to liver diseases. Altered miRNA expressions have been observed in HCCs, viral hepatitis and hepatic fibrosis. The different expression profiles of miRNAs in HCC suggest that miRNAs may serve as either novel potential targets acting directly as oncogenes or therapeutic molecules working as tumor suppressor genes. Moreover, the abundance in general and liver specificity in particular, all together make them attractive to be considered as elements for hepatic specific targeting viral vector. This review describes recent progress in miRNA investigation on liver associated for better understanding the relationship between miRNA and liver cancer in order to raise prospects for therapy.
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Affiliation(s)
- G Zhang
- Institute of Molecular Medicine, Huaqiao University & Engineering Research Center of Molecular Medicine, Ministry of Education, Quanzhou, Fujian, 362021, China
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34
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Huang Y, Shen XJ, Zou Q, Zhao QL. Biological functions of microRNAs. RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY 2011; 36:747-52. [PMID: 21317939 DOI: 10.1134/s1068162010060026] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The small regulatory non-coding RNA molecules, known as microRNAs (miRNAs), have been recognized as potential regulator of gene expression and modulate the gene function at the post-transcriptional level. It is now clear that miRNA biogenesis and function are related to the molecular mechanisms of various clinical diseases, which can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, apoptotic cell death viral infection and tumorgenesis. Here, we review recent work and provide insight into the diverse roles of miRNAs.
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Affiliation(s)
- Yong Huang
- Jiang Su University of Science and Technology, Zhenjiang City, 212018, Jiangsu Province, PR China
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35
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Hemida MG, Ye X, Thair S, Yang D. Exploiting the therapeutic potential of microRNAs in viral diseases: expectations and limitations. Mol Diagn Ther 2011; 14:271-82. [PMID: 21053993 PMCID: PMC7099301 DOI: 10.1007/bf03256383] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
New therapeutic approaches are urgently needed for serious diseases, including cancer, cardiovascular diseases, viral infections, and others. A recent direction in drug development is the utilization of nucleic acidbased therapeutic molecules, such as antisense oligonucleotides, ribozymes, short interfering RNA (siRNA), and microRNA (miRNA). miRNAs are endogenous, short, non-coding RNA molecules. Some viruses encode their own miRNAs, which play pivotal roles in viral replication and immune evasion strategies. Conversely, viruses that do not encode miRNAs may manipulate host cell miRNAs for the benefits of their replication. miRNAs have therefore become attractive tools for the study of viral pathogenesis. Lately, novel therapeutic strategies based on miRNA technology for the treatment of viral diseases have been progressing rapidly. Although this new generation of molecular therapy is promising, there are still several challenges to face, such as targeting delivery to specific tissues, avoiding off-target effects of miRNAs, reducing the toxicity of the drugs, and overcoming mutations and drug resistance. In this article, we review the current knowledge of the role and therapeutic potential of miRNAs in viral diseases, and discuss the limitations of these therapies, as well as strategies to overcome them to provide safe and effective clinical applications of these new therapeutics.
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Affiliation(s)
- Maged Gomaa Hemida
- Department of Pathology and Laboratory Medicine, University of British Columbia, Heart and Lung Institute, St Paul's Hospital, Vancouver, British Columbia, Canada
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36
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Bao CY, Li JF, Zhou YS. Advances in understanding the roles of microRNA in hepatitis virus infection. Shijie Huaren Xiaohua Zazhi 2010; 18:3756-3760. [DOI: 10.11569/wcjd.v18.i35.3756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) can cause viral hepatitis. HBV or HCV infection is the major risk factor for cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) can regulate post-transcriptional gene expression and participate in the control of diverse biological processes. Recent studies have identified the important roles of miRNAs in multiple aspects of hepatitis viruses, including replication, gene expression and pathogensis. MiRNA-based drugs may shed light on the treatment of hepatitis virus infection. In this review, we discuss the latest advances in the research of miRNAs involved in hepatitis virus infection.
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37
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Targets for human encoded microRNAs in HBV genes. Virus Genes 2010; 42:157-61. [PMID: 21113793 DOI: 10.1007/s11262-010-0555-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2010] [Accepted: 11/13/2010] [Indexed: 12/17/2022]
Abstract
MicroRNAs (miRNAs) are increasingly being shown to play vital roles in development, apoptosis, and oncogenesis by interfering with gene expression at the post-transcriptional level. miRNAs, in principle, can contribute to the repertoire of host-pathogen interactions during infection by the Hepatitis B virus (HBV). Using a consensus-scoring approach, high-scoring miRNA-target pairs were selected, which were identified by four well-established target-prediction softwares. The miRNAs miR-7, miR196b, miR433, and miR511 target the polymerase or S gene of HBV, miR205 targets the X gene, and miR345 targets the preC gene. The minimum free-energy values for the bound complexes were the lowest, and the rules so far observed for miRNA-target pairing, namely, (1) pairing at a continuous stretch of 6-7 bases toward the 5'-end of the miRNA and (2) incomplete complementarity with the target sequence, were found to be valid. The target regions were highly conserved across the various clades of HBV. miRNA expression profiles from previously reported Solexa-sequencing based experiments showed that the four human miRNAs are expressed in the liver. This is the first report of human miRNAs that can target crucial HBV genes.
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38
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Suppression of hepatitis B virus replication by microRNA-199a-3p and microRNA-210. Antiviral Res 2010; 88:169-75. [PMID: 20728471 DOI: 10.1016/j.antiviral.2010.08.008] [Citation(s) in RCA: 182] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Revised: 07/31/2010] [Accepted: 08/13/2010] [Indexed: 12/12/2022]
Abstract
Accumulating evidence suggests that microRNAs (miRNAs) control the replication of both RNA and DNA viruses. In order to determine whether host-encoded miRNAs affect hepatitis B virus (HBV) replication, antisense oligonucleotides (ASOs) of 328 identified human miRNAs were transfected into HepG2 2.2.15 cells, respectively. ELISA and MTS assay were used to measure the expression level of HBV S protein (HBsAg), HBV e antigen (HBeAg) and cell proliferation. Compared to experimental controls, miR-199a-3p and miR-210 efficiently reduced HBsAg expression without affecting HepG2 2.2.15 cell proliferation. Quantification of HBV DNA by real-time PCR showed that both miRNAs suppressed viral replication. Bioinformatics analysis indicated a putative binding site for miR-199a-3p in the HBsAg coding region and a putative binding site for miR-210 in the HBV pre-S1 region. The direct effect of miRNAs on the target region in HBV transcripts was validated by a fluorescent reporter assay, and the suppression of HBs gene expression by both miRNAs was measured by real-time PCR and Western blot. These results suggest that up-regulation of miR-199a-3p and miR-210 in HepG2 2.2.15 cells compared to HepG2 cells may play a role in regulating HBV replication and maintenance of a suitable level of virion production in persistent infection by targeting crucial HBV genes.
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39
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Li M, Li J, Ding X, He M, Cheng SY. microRNA and cancer. AAPS JOURNAL 2010; 12:309-17. [PMID: 20422339 DOI: 10.1208/s12248-010-9194-0] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 11/20/2009] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs), a class of small, regulatory, non-coding RNA molecules, display aberrant expression patterns and functional abnormalities in human diseases including cancers. This review summarizes the abnormally expressed miRNAs in various types of human cancers, possible mechanisms underlying such abnormalities, and miRNA-modulated molecular pathways critical for cancer development. Practical implications of miRNAs as biomarkers, novel drug targets and therapeutic tools for diagnosis, prognosis, and treatments of human cancers are also discussed.
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Affiliation(s)
- Mengfeng Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, 74 Zhongshan Road II, Guangzhou 510080, China.
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40
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Abstract
Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.
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Affiliation(s)
- A F Fernandez
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08907 Barcelona, Catalonia, Spain
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41
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Sotiropoulou G, Pampalakis G, Lianidou E, Mourelatos Z. Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell. RNA (NEW YORK, N.Y.) 2009; 15:1443-1461. [PMID: 19561119 PMCID: PMC2714746 DOI: 10.1261/rna.1534709] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Transformation of normal cells into malignant tumors requires the acquisition of six hallmark traits, e.g., self-sufficiency in growth signals, insensitivity to antigrowth signals and self-renewal, evasion of apoptosis, limitless replication potential, angiogenesis, invasion, and metastasis, which are common to all cancers (Hanahan and Weinberg 2000). These new cellular traits evolve from defects in major regulatory microcircuits that are fundamental for normal homeostasis. The discovery of microRNAs (miRNAs) as a new class of small non-protein-coding RNAs that control gene expression post-transcriptionally by binding to various mRNA targets suggests that these tiny RNA molecules likely act as molecular switches in the extensive regulatory web that involves thousands of transcripts. Most importantly, accumulating evidence suggests that numerous microRNAs are aberrantly expressed in human cancers. In this review, we discuss the emergent roles of microRNAs as switches that function to turn on/off known cellular microcircuits. We outline recent compelling evidence that deregulated microRNA-mediated control of cellular microcircuits cooperates with other well-established regulatory mechanisms to confer the hallmark traits of the cancer cell. Furthermore, these exciting insights into aberrant microRNA control in cancer-associated circuits may be exploited for cancer therapies that will target deregulated miRNA switches.
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Affiliation(s)
- Georgia Sotiropoulou
- Department of Pharmacy, School of Health Sciences, University of Patras, Rion-Patras 26500, Greece.
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42
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43
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Silencing viral microRNA as a novel antiviral therapy? J Biomed Biotechnol 2009; 2009:419539. [PMID: 19704916 PMCID: PMC2688686 DOI: 10.1155/2009/419539] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2008] [Accepted: 03/20/2009] [Indexed: 12/16/2022] Open
Abstract
Viruses are intracellular parasites that ensure their existence by converting host cells into viral particle producing entities or into hiding places rendering the virus invisible to the host immune system. Some viruses may also survive by transforming the infected cell into an immortal tumour cell. MicroRNAs are small non-coding transcripts that function as posttranscriptional regulators of gene expression. Viruses encode miRNAs that regulate expression of both cellular and viral genes, and contribute to the pathogenic properties of viruses. Hence, neutralizing the action of viral miRNAs expression by complementary single-stranded oligonucleotides or so-called anti-miRNAs may represent a strategy to combat viral infections and viral-induced pathogenesis. This review describes the miRNAs encoded by human viruses, and discusses the possible therapeutic applications of anti-miRNAs against viral diseases.
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Abstract
MicroRNAs (miRNAs) are an emerging class of highly conserved non-coding small RNAs that regulate gene expression at the post-transcriptional level. It is now clear that miRNAs can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, apoptotic cell death, viral infection and tumorigenesis. Recent studies provide clear evidence that miRNAs are abundant in the liver and modulate a diverse spectrum of liver functions. Deregulation of miRNA expression may be a key pathogenetic factor in many liver diseases including viral hepatitis, hepatocellular cancer and polycystic liver diseases. A clearer understanding of the mechanisms involved in miRNA deregulation will offer new diagnostic and therapeutic strategies to treat liver diseases. Moreover, better understanding of miRNA regulation and identification of tissue-specific miRNA targets employing transgenic/knockout models and/or modulating oligonucleotides will improve our knowledge of liver physiology and diseases.
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45
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Chen XM. MicroRNA signatures in liver diseases. World J Gastroenterol 2009; 15:1665-72. [PMID: 19360909 PMCID: PMC2668771 DOI: 10.3748/wjg.15.1665] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 03/03/2009] [Accepted: 03/10/2009] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are an emerging class of highly conserved non-coding small RNAs that regulate gene expression at the post-transcriptional level. It is now clear that miRNAs can potentially regulate every aspect of cellular activity, including differentiation and development, metabolism, proliferation, apoptotic cell death, viral infection and tumorigenesis. Recent studies provide clear evidence that miRNAs are abundant in the liver and modulate a diverse spectrum of liver functions. Deregulation of miRNA expression may be a key pathogenetic factor in many liver diseases including viral hepatitis, hepatocellular cancer and polycystic liver diseases. A clearer understanding of the mechanisms involved in miRNA deregulation will offer new diagnostic and therapeutic strategies to treat liver diseases. Moreover, better understanding of miRNA regulation and identification of tissue-specific miRNA targets employing transgenic/knockout models and/or modulating oligonucleotides will improve our knowledge of liver physiology and diseases.
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Abstract
MicroRNAs (miRNAs) are endogenous small RNAs that can regulate target mRNAs by binding to their 3'-UTRs. A single miRNA can regulate many mRNA targets, and several miRNAs can regulate a single mRNA. These have been reported to be involved in a variety of functions, including developmental transitions, neuronal patterning, apoptosis, adipogenesis metabolism and hematopoiesis in different organisms. Many oncogenes and tumor suppressor genes are regulated by miRNAs. Studies conducted in the past few years have demonstrated the possible association between miRNAs and several human malignancies and infectious diseases. In this article, we have focused on the mechanism of miRNA biogenesis and the role of miRNAs in human health and disease.
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Affiliation(s)
- Sunit K Singh
- Section of Infectious Diseases and Immunobiology, Centre for Cellular and Molecular Biology, Hyderabad, India.
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Girard M, Jacquemin E, Munnich A, Lyonnet S, Henrion-Caude A. miR-122, a paradigm for the role of microRNAs in the liver. J Hepatol 2008; 48:648-56. [PMID: 18291553 DOI: 10.1016/j.jhep.2008.01.019] [Citation(s) in RCA: 292] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent studies have uncovered profound and unexpected roles for a family of tiny regulatory RNAs, known as microRNAs (miRNAs), in the control of diverse aspects of hepatic function and dysfunction, including hepatocyte growth, stress response, metabolism, viral infection and proliferation, gene expression, and maintenance of hepatic phenotype. In liver cancer, misexpression of specific miRNAs suggests diagnostic and prognostic significance. Here, we review the biology of the most abundant miRNA in human liver, miR-122, and consider the diversity of its roles in the liver. We provide a compilation of all miRNAs expressed in the liver, and consider some possible therapeutic opportunities for exploiting miRNAs in the different settings of liver diseases.
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Abstract
MicroRNA is a kind of endogenous non-coding small RNA, is universally present in animals, plants and viruses and plays an important role in the development, proliferation, differentiation and apoptosis of organisms through complementary pairing with target mRNA, which can regulate its expression or translation. Recent studies indicate that miRNA is closely associated with tumors. Study on tumor-associated miRNA using techniques of experimental biology and bioinformatics is currently a hot subject of research. Recent studies on hepatocellular carcinoma(HCC) have shown that HCC is correlated with abnormal expression of several miRNAs, such as miRNA-122, -21, -195, -18, -199a. However, few studies on miRNA expression in HBV-infected diseases are available. This paper reviews researches on the association of microRNA with the development of liver cancer.
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Yamamoto K, Takenaka K, Matsumata T, Shimada M, Itasaka H, Shirabe K, Sugimachi K. Right hepatic lobectomy in elderly patients with hepatocellular carcinoma. ACTA ACUST UNITED AC 1997. [PMID: 9164528 DOI: 10.4236/ojim.2012.23024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND/AIMS The outcome of hepatectomy in elderly patients with hepatocellular carcinoma have been reported, however neither the morphological nor functional hepatic regeneration in elderly patients have been fully investigated. MATERIALS AND METHODS Fifty-six patients with hepatocellular carcinoma, who underwent a right hepatic lobectomy over an 8-year period, were classified into three groups according to their age; group 1 (n = 7), more than 70 years of age; group 2 (n = 40), patients from 50 to 69 years of age and group 3 (n = 9), under 50 years of age. There were no significant differences regarding backgrounds or intra-operative parameters among the three groups. The perioperative hepatic function, postoperative complications and the regeneration rate of the remnant left lobe at 1 month after operation were compared. RESULTS No differences were found in the regeneration rate, however, the levels of the hepaplastin test and lecithin:cholesterol acyltransferase at 7 days after hepatectomy in group 1 (31.3%, 8.8 U) were significantly lower than those in groups 2 and 3 (37.4%, 18.4 U; 47.9%, 29.4 U, respectively). The incidence of hospital death due to hepatic failure in group 1 (42.9%) was also significantly higher than that of group 2 (5.0%) or group 3 (0%). CONCLUSION The decline of postoperative protein synthesis regardless of the voluminal regeneration is a characteristic of the elderly. This phenomenon might thus be an important promoter of postoperative hepatic failure which remains unpredictable using any type of examination. Therefore, at this time, a major hepatectomy is not recommended as a viable treatment alternative in the elderly.
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Affiliation(s)
- K Yamamoto
- Department of Surgery II, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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