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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Xu ZY, Gao JS, He Y, Xiao XQ, Gong GZ, Zhang M. Hepatitis B virus confers innate immunity evasion through hepatitis B virus-miR-3 down-regulation of cGAS-Sting-IFN signaling. World J Hepatol 2025; 17:99292. [PMID: 40027574 PMCID: PMC11866139 DOI: 10.4254/wjh.v17.i2.99292] [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] [Received: 07/19/2024] [Revised: 12/05/2024] [Accepted: 01/18/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) evades the innate immunity and leads to persistent chronic infection, but the molecular mechanism is still not well known. AIM To investigate whether HBV-miR-3 is involved in HBV immune evasion. METHODS HBV-miR-3 agomir and antagomir were employed to verify the effectiveness of HBV-miR-3 on cGAS-Sting-IFN pathway through the experiments on relative luciferase activity, cGAS protein expression, Sting phosphorylation and interferon (IFN) production. RESULTS HBV-miR-3 down-regulates cGAS protein expression post-transcriptionally by inhibition of cGAS 3'-untranslated region (3'-UTR) activity, which results in lower Sting phosphorylation and IFN production. HBV-miR-3 antagomir rescued cGAS protein expression, Sting phosphorylation and IFN-β production. CONCLUSION HBV-miR-3 plays an important role in HBV immunity evasion by targeting cGAS 3'-UTR and interfering with cGAS-Sting-IFN pathway.
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Affiliation(s)
- Zhen-Yu Xu
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Jia-Shi Gao
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Ying He
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Xin-Qiang Xiao
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Guo-Zhong Gong
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.
| | - Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
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Tavakolian S, Eshkiki ZS, Akbari A, Faghihloo E, Tabaeian SP. PTEN regulation in virus-associated cancers. Pathol Res Pract 2025; 266:155749. [PMID: 39642806 DOI: 10.1016/j.prp.2024.155749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 11/10/2024] [Accepted: 11/29/2024] [Indexed: 12/09/2024]
Abstract
Despite advancements in science, researchers still face challenges in curing patients with malignancies. This health issue is linked to various risk factors, including alcohol consumption, age, sex, and infectious diseases. Among these, viral agents play a significant role in cancer-related health problems and are currently a subject of ongoing research. In this review, we summarize how several viruses-such as herpesviruses, human papillomavirus, hepatitis B virus, hepatitis C virus, and adenovirus-impact cancer signaling pathways through their effects on the tumor suppressor PTEN.
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Affiliation(s)
- Shaian Tavakolian
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Zahra Shokati Eshkiki
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Abolfazl Akbari
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Faghihloo
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Seidamir Pasha Tabaeian
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Ma Q, Li W, Wu W, Sun M. Exploring the active ingredients and mechanisms of Liujunzi decoction in treating hepatitis B: a study based on network pharmacology, molecular docking, and molecular dynamics simulations. Comput Methods Biomech Biomed Engin 2024:1-25. [PMID: 39534925 DOI: 10.1080/10255842.2024.2427117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/24/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Liujunzi decoction (LJZD) is commonly used to treat hepatitis B virus (HBV), though its active ingredients and mechanisms are not fully known. This study identified core targets and active components of LJZD for treating hepatitis B (HB) through network pharmacology, molecular docking, and molecular dynamics simulation. Screening from databases yielded 533 active components, 2619 targets for LJZD, and 2910 for HB, with 891 intersecting targets. STRING and CytoHubba analyses identified AR and VDR as core targets, with key pathways including PI3K-Akt and MAPK. The findings clarify LJZD's multicomponent, multitarget mechanisms, supporting its clinical application for HB treatment.
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Affiliation(s)
- Qing Ma
- Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenying Wu
- Department of Pharmacy, The Ninth People's Hospital of Chongqing, Chongqing, China
| | - Mei Sun
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Wang X, Zhao W. Research progress on miRNAs function in the interaction between human infectious viruses and hosts: A review. BIOMOLECULES & BIOMEDICINE 2024; 24:1452-1462. [PMID: 39101759 PMCID: PMC11496870 DOI: 10.17305/bb.2024.10821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/01/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024]
Abstract
MicroRNAs (miRNAs) represent a class of non-coding small RNAs that are prevalent in eukaryotes, typically comprising approximately 22 nucleotides, and have the ability to post-transcriptionally regulate gene expression. miRNAs exhibit diverse types and functions, with mechanisms of action that include cell differentiation, proliferation, apoptosis, and regulation of signaling pathways. Both viruses and their hosts can encode miRNAs, which serve as crucial effector molecules in the complex interaction between viruses and host cells. Host miRNAs can either directly interact with the virus genome to inhibit virus replication or facilitate virus replication by providing necessary substances. Viral miRNAs can directly bind to host mRNAs, thereby influencing translation efficiency, suppressing the immune response, and ultimately enhancing virus replication. This article comprehensively reviews the roles of miRNAs in virus-host interactions, aiming to provide valuable insights into viral pathogenic mechanisms and potential therapeutic approaches.
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Affiliation(s)
- Xiaotong Wang
- Heilongjiang University of Traditional Chinese Medicine, Heilongjiang, China
| | - Wenchang Zhao
- School of Pharmacy, Guangdong Medical University, Dongguan, China
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Xu Z, Xu Y, Wu Z, Wang S, Zhang M, Jiang Y, Gong G. HBV-miR-3 is closely related to HBV replication and strongly predictive of HBeAg seroconversion in PegIFN-α treated patients. Sci Rep 2024; 14:1502. [PMID: 38233602 PMCID: PMC10794194 DOI: 10.1038/s41598-024-52060-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/12/2024] [Indexed: 01/19/2024] Open
Abstract
HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 < 3log at week 12 achieved HBeAg seroconversion, otherwise, with HBV-miR-3 > 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.
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Affiliation(s)
- Zhenyu Xu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Yun Xu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhenyu Wu
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Sujuan Wang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Min Zhang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
- FuRong Laboratory, Changsha, Hunan, China.
- Clinical Medical Research Center for Viral Hepatitis in Hunan Province, Hunan, China.
| | - Guozhong Gong
- Department of Infectious Diseases, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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Chen H, Cao D, Han N, Zhang M, Jiang W, Wang X, Zeng Q, Tang H. Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Inhibits FIH-1 Expression to Promote Tumor Angiogenesis in HBV-Related Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:2337-2353. [PMID: 38163053 PMCID: PMC10757782 DOI: 10.2147/jhc.s436926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/08/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1). Results By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3'-UTR of FIH-1 mRNA by luciferase activity assay. Conclusion HBV-miR-3 was related to HCC patients' overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC.
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Affiliation(s)
- Han Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Dan Cao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Mingming Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Xin Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Qinmin Zeng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
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8
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Zulian V, Fiscon G, Paci P, Garbuglia AR. Hepatitis B Virus and microRNAs: A Bioinformatics Approach. Int J Mol Sci 2023; 24:17224. [PMID: 38139051 PMCID: PMC10743825 DOI: 10.3390/ijms242417224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/20/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
In recent decades, microRNAs (miRNAs) have emerged as key regulators of gene expression, and the identification of viral miRNAs (v-miRNAs) within some viruses, including hepatitis B virus (HBV), has attracted significant attention. HBV infections often progress to chronic states (CHB) and may induce fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The presence of HBV can dysregulate host miRNA expression, influencing several biological pathways, such as apoptosis, innate and immune response, viral replication, and pathogenesis. Consequently, miRNAs are considered a promising biomarker for diagnostic, prognostic, and treatment response. The dynamics of miRNAs during HBV infection are multifaceted, influenced by host variability and miRNA interactions. Given the ability of miRNAs to target multiple messenger RNA (mRNA), understanding the viral-host (human) interplay is complex but essential to develop novel clinical applications. Therefore, bioinformatics can help to analyze, identify, and interpret a vast amount of miRNA data. This review explores the bioinformatics tools available for viral and host miRNA research. Moreover, we introduce a brief overview focusing on the role of miRNAs during HBV infection. In this way, this review aims to help the selection of the most appropriate bioinformatics tools based on requirements and research goals.
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Affiliation(s)
- Verdiana Zulian
- Virology Laboratory, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy;
| | - Giulia Fiscon
- Department of Computer, Control and Management Engineering, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (P.P.)
- Institute for Systems Analysis and Computer Science “Antonio Ruberti”, National Research Council, 00185 Rome, Italy
| | - Paola Paci
- Department of Computer, Control and Management Engineering, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (P.P.)
- Institute for Systems Analysis and Computer Science “Antonio Ruberti”, National Research Council, 00185 Rome, Italy
| | - Anna Rosa Garbuglia
- Virology Laboratory, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, 00149 Rome, Italy;
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Kozlov D, Rodimova S, Kuznetsova D. The Role of MicroRNAs in Liver Functioning: from Biogenesis to Therapeutic Approaches (Review). Sovrem Tekhnologii Med 2023; 15:54-79. [PMID: 39967915 PMCID: PMC11832066 DOI: 10.17691/stm2023.15.5.06] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Indexed: 01/03/2025] Open
Abstract
Molecular diagnostics based on small non-coding RNA molecules (in particular microRNA) is a new direction in modern biomedicine and is considered a promising method for identification of a wide range of pathologies at an early stage, clinical phenotype assessment, as well as monitoring the course of the disease, evaluation of therapy efficacy and the risk of the disease recurrence. Currently, the role of microRNAs as the most important epigenetic regulator in cancer development has been proven within the studies of normal and pathogenic processes. However, currently, there are insignificant studies devoted to studying the role of microRNAs in functioning of other organs and tissues, as well as to development of possible therapeutic approaches based on microRNAs. A huge number of metabolic processes in the liver are controlled by microRNAs, which creates enormous potential for the use of microRNAs as a diagnostic marker and makes it a target for therapeutic intervention in metabolic, oncological, and even viral diseases of this organ. This review examines various aspects of biological functions of microRNAs in different types of liver cells. Both canonical and non-canonical pathways of biogenesis, epigenetic regulation mediated by microRNAs, as well as the microRNAs role in intercellular communication and the course of viral diseases are shown. The potential of microRNAs as a diagnostic marker for various liver pathologies is described, as well as therapeutic approaches and medicines based on microRNAs, which are approved for clinical use and currently being developed.
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Affiliation(s)
- D.S. Kozlov
- Laboratory Assistant, Scientific Laboratory of Molecular Biotechnologies, I Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Student, Institute of Biology and Biomedicine; National Research Lobachevsky State University of Nizhny Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603022, Russia
| | - S.A. Rodimova
- Junior Researcher, Laboratory of Regenerative Medicine; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Junior Researcher, Scientific Laboratory of Molecular Biotechnologies, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - D.S. Kuznetsova
- PhD, Head of the Scientific Laboratory of Molecular Biotechnologies, Research Institute of Experimental Oncology and Biomedical Technologies; Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia; Head of the Research Laboratory for Molecular Genetic Researches, Institute of Clinical Medicine; National Research Lobachevsky State University of Nizhny Novgorod, 23 Prospekt Gagarina, Nizhny Novgorod, 603022, Russia
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10
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Shoraka S, Hosseinian SM, Hasibi A, Ghaemi A, Mohebbi SR. The role of hepatitis B virus genome variations in HBV-related HCC: effects on host signaling pathways. Front Microbiol 2023; 14:1213145. [PMID: 37588887 PMCID: PMC10426804 DOI: 10.3389/fmicb.2023.1213145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/12/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, with a high prevalence in many regions. There are variations in the etiology of HCC in different regions, but most cases are due to long-term infection with viral hepatitis. Hepatitis B virus (HBV) is responsible for more than 50% of virus-related HCC, which highlights the importance of HBV in pathogenesis of the disease. The development and progression of HBV-related HCC is a complex multistep process that can involve host, viral, and environmental factors. Several studies have suggested that some HBV genome mutations as well as HBV proteins can dysregulate cell signaling pathways involved in the development of HCC. Furthermore, it seems that the pathogenicity, progression of liver diseases, response to treatment and also viral replication are different among HBV mutants. Understanding the relationship between HBV genome variations and host signaling pathway alteration will improve our understanding of the molecular pathogenesis of HBV-related HCC. Furthermore, investigating commonly dysregulated pathways in HBV-related HCC is necessary to discover more specific therapeutic targets and develop more effective strategies for HCC treatment. The objective of this review is to address the role of HBV in the HCC progression and primarily focus on the impacts of HBV genome variations on HCC-related signaling pathways.
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Affiliation(s)
- Shahrzad Shoraka
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Seyed Mahdi Hosseinian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ayda Hasibi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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11
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Zhang C, Dai D, Zhang W, Yang W, Guo Y, Wei Q. Role of m6A RNA methylation in the development of hepatitis B virus-associated hepatocellular carcinoma. J Gastroenterol Hepatol 2022; 37:2039-2050. [PMID: 36066844 DOI: 10.1111/jgh.15999] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/10/2022] [Accepted: 09/03/2022] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy that can be developed from hepatitis B and cirrhosis. Many pathophysiological alterations, including hepatitis B virus (HBV) DNA integration, oxidative stress, cytokine release, telomerase homeostasis, mitochondrial damage, epigenetic modification, and tumor microenvironment, are involved in the biological process from hepatitis B to cirrhosis and HCC. N6-methyladenosine (m6A), as an epitranscriptomic modification of RNAs, can regulate the stability, splicing, degradation, transcription, and translation of downstream target RNAs in HBV and liver cancer cells. m6A regulators (writers, erasers, and readers) play an important role in the pathogenesis of HBV-associated HCC by regulating cell proliferation, apoptosis, migration, autophagy, differentiation, inflammation, angiogenesis, and tumor microenvironment. This review summarizes the current progress of m6A methylation in the molecular mechanisms, biological functions, and potential clinical implications of HBV-associated HCC.
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Affiliation(s)
- Cheng Zhang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.,Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dongjun Dai
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wangjian Zhang
- School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yinglu Guo
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qichun Wei
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Effects of Exosomal Viral Components on the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14143552. [PMID: 35884611 PMCID: PMC9317196 DOI: 10.3390/cancers14143552] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/13/2022] [Accepted: 07/19/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Oncogenic viral infection may lead to cancers, such as nasopharyngeal carcinoma, hepatocellular carcinoma, and cervical cancer. In addition to the tumor cells themselves, the tumor microenvironment also plays a decisive role in tumor evolution. Oncogenic viruses can affect the tumor microenvironment via exosomes influencing the occurrence and development of tumors by encapsulating and transporting viral components. This review focuses on the effects of virus-infected cancer exosomes on tumor microenvironment and tumor progression. Abstract Exosomes are extracellular membrane vesicles with a diameter of 30–100 nm, produced by different eukaryotic cells that contain multitudinous lipids, nucleic acids, and proteins. They transfer membrane components and nucleic acids between cells, thereby performing an information exchange between cells. Many studies have shown that a variety of tumor-associated viruses can exert their biological functions through exosomes. The tumor microenvironment (TME) is very important in the occurrence, development, and chemoresistance of tumors. It is composed of tumor cells, fibroblasts, endothelial cells, immune cells, stromal cells, and acellular components, such as exosomes and cytokines. This review focuses on the effects of virus-related components secreted by tumor cells over the TME in several virus-associated cancers.
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Viral Encoded miRNAs in Tumorigenesis: Theranostic Opportunities in Precision Oncology. Microorganisms 2022; 10:microorganisms10071448. [PMID: 35889167 PMCID: PMC9321719 DOI: 10.3390/microorganisms10071448] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.
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Kitsou K, Iliopoulou M, Spoulou V, Lagiou P, Magiorkinis G. Viral Causality of Human Cancer and Potential Roles of Human Endogenous Retroviruses in the Multi-Omics Era: An Evolutionary Epidemiology Review. Front Oncol 2021; 11:687631. [PMID: 34778024 PMCID: PMC8586426 DOI: 10.3389/fonc.2021.687631] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022] Open
Abstract
Being responsible for almost 12% of cancers worldwide, viruses are among the oldest known and most prevalent oncogenic agents. The quality of the evidence for the in vivo tumorigenic potential of microorganisms varies, thus accordingly, viruses were classified in 4 evidence-based categories by the International Agency for Research on Cancer in 2009. Since then, our understanding of the role of viruses in cancer has significantly improved, firstly due to the emergence of high throughput sequencing technologies that allowed the “brute-force” recovery of unknown viral genomes. At the same time, multi-omics approaches unravelled novel virus-host interactions in stem-cell biology. We now know that viral elements, either exogenous or endogenous, have multiple sometimes conflicting roles in human pathophysiology and the development of cancer. Here we integrate emerging evidence on viral causality in human cancer from basic mechanisms to clinical studies. We analyze viral tumorigenesis under the scope of deep-in-time human-virus evolutionary relationships and critically comment on the evidence through the eyes of clinical epidemiology, firstly by reviewing recognized oncoviruses and their mechanisms of inducing tumorigenesis, and then by examining the potential role of integrated viruses in our genome in the process of carcinogenesis.
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Affiliation(s)
- Konstantina Kitsou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Immunobiology and Vaccinology Research Laboratory, First Department of Peadiatrics, "Aghia Sophia" Children's Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Iliopoulou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Vana Spoulou
- Immunobiology and Vaccinology Research Laboratory, First Department of Peadiatrics, "Aghia Sophia" Children's Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Gkikas Magiorkinis
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Pietropaolo V, Prezioso C, Moens U. Role of Virus-Induced Host Cell Epigenetic Changes in Cancer. Int J Mol Sci 2021; 22:ijms22158346. [PMID: 34361112 PMCID: PMC8346956 DOI: 10.3390/ijms22158346] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor viruses human T-lymphotropic virus 1 (HTLV-1), hepatitis C virus (HCV), Merkel cell polyomavirus (MCPyV), high-risk human papillomaviruses (HR-HPVs), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpes virus (KSHV) and hepatitis B virus (HBV) account for approximately 15% of all human cancers. Although the oncoproteins of these tumor viruses display no sequence similarity to one another, they use the same mechanisms to convey cancer hallmarks on the infected cell. Perturbed gene expression is one of the underlying mechanisms to induce cancer hallmarks. Epigenetic processes, including DNA methylation, histone modification and chromatin remodeling, microRNA, long noncoding RNA, and circular RNA affect gene expression without introducing changes in the DNA sequence. Increasing evidence demonstrates that oncoviruses cause epigenetic modifications, which play a pivotal role in carcinogenesis. In this review, recent advances in the role of host cell epigenetic changes in virus-induced cancers are summarized.
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Affiliation(s)
- Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- Correspondence: (V.P.); (U.M.)
| | - Carla Prezioso
- Department of Public Health and Infectious Diseases, “Sapienza” University, 00185 Rome, Italy;
- IRCSS San Raffaele Roma, Microbiology of Chronic Neuro-Degenerative Pathologies, 00161 Rome, Italy
| | - Ugo Moens
- Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø—The Arctic University of Norway, 9037 Tromsø, Norway
- Correspondence: (V.P.); (U.M.)
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Loureiro D, Tout I, Narguet S, Benazzouz SM, Mansouri A, Asselah T. miRNAs as Potential Biomarkers for Viral Hepatitis B and C. Viruses 2020; 12:E1440. [PMID: 33327640 PMCID: PMC7765125 DOI: 10.3390/v12121440] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.
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Affiliation(s)
| | | | | | | | | | - Tarik Asselah
- Department of Hepatology, Université de Paris, CRI, INSERM UMR 1149, AP-HP Hôpital Beaujon, 92110 Clichy, France; (D.L.); (I.T.); (S.N.); (S.M.B.); (A.M.)
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