|
1
|
Deng Y, Zheng J, Li F, Zou H, Tian S, Zhao Z, Zeng H, Zhai Y, Deng W, Zhang J, Lu M, Jia B, Lin Y. Hepatocyte-Enriched miRNA-193b-3p Promotes Hepatitis B Virus Replication by Dual Activation of Viral Core Promoter Activity and Autophagy Induction by Targeting IGF-1R. J Med Virol 2025; 97:e70330. [PMID: 40195593 DOI: 10.1002/jmv.70330] [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: 12/24/2024] [Revised: 03/14/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025]
Abstract
Hepatitis B virus (HBV) infection is a principal cause of severe liver disease in humans and is associated with increased levels of specific serum or intracellular microRNAs (miRNAs). Among these, miR-193b-3p is a liver-enriched miRNA; however, its role in HBV replication remains unknown. This study aimed to investigate the influence of chronic HBV infection on miR-193b-3p levels in the peripheral blood and liver tissues of patients with chronic hepatitis B (CHB), evaluate the effect of miR-193b-3p on HBV replication both in vitro and in vivo, and elucidate the potential underlying mechanisms. We showed that hepatic miR-193b-3p levels in patients with CHB were significantly elevated compared with those in healthy controls. Ectopic expression of miR-193b-3p significantly enhanced HBV replication and transcription in different hepatoma cell lines. Furthermore, we identified IGF-1R as a direct target through which miR-193b-3p regulates HBV replication. Mechanistically, miR-193b-3p increased HBV core promoter activity via the IGF-1R/FXRα axis, thereby enhancing HBV transcription. Additionally, miR-193b-3p increased IGF-1R/Akt/MDM2/p53 signaling-mediated autophagy induction, which in turn facilitated increased HBV post-transcriptional activity. Collectively, hepatocyte-enriched miR-193b-3p exerts a proviral effect on HBV replication through dual synergistic mechanisms, offering novel insights into its role in HBV replication and potential therapeutic implications in CHB infection.
Collapse
Affiliation(s)
- Yingying Deng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
| | - Jiaxin Zheng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
- Center for Laboratory Medicine, Sichuan Tianfu New Area People's Hospital, No. 33, Section 3, Fumin Road, Huayang Street, Chengdu, China
| | - Fahong Li
- Department of Infectious Diseases, Huashan hospital, Fudan University, No. 12, Middle Wulumuqi Road, Shanghai, China
| | - Hecun Zou
- College of Pharmacy, Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
| | - Shijun Tian
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, China
| | - Zhenyu Zhao
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
| | - Huaqing Zeng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
| | - Yongzhen Zhai
- Department of Infectious Disease, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Shenyang, China
| | - Wanyu Deng
- College of Life Science, Shangrao Normal University, No. 401, Zhimin Avenue, Shangrao, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan hospital, Fudan University, No. 12, Middle Wulumuqi Road, Shanghai, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, Essen, Germany
| | - Bei Jia
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Chongqing, China
| | - Yong Lin
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, No. 1, Yixueyuan Road, Chongqing, China
| |
Collapse
|
|
2
|
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.
Collapse
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
| | | | | | | |
Collapse
|
|
3
|
Sartorius K, Wang Y, Sartorius B, Antwi SO, Li X, Chuturgoon A, Yu C, Lu Y, Wang Y. The interactive role of microRNA and other non-coding RNA in hepatitis B (HBV) associated fibrogenesis. Funct Integr Genomics 2025; 25:24. [PMID: 39847120 DOI: 10.1007/s10142-024-01519-4] [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: 09/30/2024] [Revised: 11/27/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025]
Abstract
One of the outstanding features of chronic hepatitis B infection (CHB) is its strong association with liver fibrosis. CHB induced inflammation and injury trigger multiple biochemical and physical changes that include the promotion of a wide range of cytokines, chemokines and growth factors that activate hepatic stellate cells (HSCs) CHB induced activation of hepatic stellate cells (HSCs) is regarded as a central event in fibrogenesis to directly promote the synthesis of myofibroblasts and the expression of a range of materials to repair injured liver tissue. Fibrogenesis is modulated by the mainstream epigenetic machinery, as well as by non-coding RNA (ncRNA) that are often referred to as an ancillary epigenetic response to fine tune gene expression. Although extensive research has explained the regulatory role of ncRNA in liver fibrogenesis, most of this research relates to non-CHB etiologies. This review paper outlines the complex interactive regulatory role of microRNA (miRNA) and their interaction with long non-coding RNA (lncRNA), circular RNA (circRNA) and the mainstream epigenetic machinery in CHB induced liver fibrosis. The paper also illustrates some of the difficulties involved in translating candidate ncRNA into approved drugs or diagnostic tools. In conclusion, the important regulatory role of ncRNA in CHB induced liver fibrosis warrants further investigation to exploit their undoubted potential as diagnostic and therapeutic agents.
Collapse
MESH Headings
- Humans
- Liver Cirrhosis/genetics
- Liver Cirrhosis/pathology
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/virology
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Epigenesis, Genetic
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/pathology
- Hepatitis B virus/genetics
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- Animals
- Hepatic Stellate Cells/metabolism
- Hepatic Stellate Cells/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
Collapse
Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa.
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
| | - Yanglong Wang
- Department of General Surgery, Xinyi People's Hospital, Xinyi, Jiangsu, China
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, Australia
| | - Samuel O Antwi
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
- Division of Epidemiology Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, AL, USA
| | - Xiaodong Li
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, UKZN, Durban, South Africa
| | - Chongyuan Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunjie Lu
- Africa Hepatobiliarypancreato Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, AL, USA.
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Yu Wang
- Department of Hepatobiliary Surgery, Jintan Affiliated Hospital of Jiangsu University, 213200, Changzhou, Jiangsu, China.
| |
Collapse
|
|
4
|
Zhang Y, Cao W, Wang S, Zhang L, Li X, Zhang Z, Xie Y, Li M. Epigenetic modification of hepatitis B virus infection and related hepatocellular carcinoma. Virulence 2024; 15:2421231. [PMID: 39460469 PMCID: PMC11583590 DOI: 10.1080/21505594.2024.2421231] [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: 06/10/2024] [Revised: 09/18/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection poses a challenge to global public health. Persistent liver infection with HBV is associated with an increased risk of developing severe liver disease. The complex interaction between the virus and the host is the reason for the persistent presence of HBV and the risk of tumor development. Chronic liver inflammation, integration of viral genome with host genome, expression of HBx protein, and viral genotype are all key participants in the pathogenesis of hepatocellular carcinoma (HCC). Epigenetic regulation in HBV-associated HCC involves complex interactions of molecular mechanisms that control gene expression and function without altering the underlying DNA sequence. These epigenetic modifications can significantly affect the onset and progression of HCC. This review summarizes recent research on the epigenetic regulation of HBV persistent infection and HBV-HCC development, including DNA methylation, histone modification, RNA modification, non-coding RNA, etc. Enhanced knowledge of these mechanisms will offer fresh perspectives and potential targets for intervention tactics in HBV-HCC.
Collapse
Affiliation(s)
- Yaqin Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xinxin Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ziyu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| |
Collapse
|
|
5
|
Zhang Z, Liu J, Yu L, Zeng R, Pan W. The hijacking of HBV by small extracellular vesicles inhibits M1 macrophages to facilitate immune evasion. Sci Rep 2024; 14:19917. [PMID: 39198597 PMCID: PMC11358331 DOI: 10.1038/s41598-024-70924-3] [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: 06/04/2024] [Accepted: 08/21/2024] [Indexed: 09/01/2024] Open
Abstract
Small extracellular vesicles (sEVs) have the ability to transfer genetic material between cells, but their role in mediating HBV infection and regulating M1 macrophages to promote immune evasion remains unclear. In this study, we utilized PMA + LPS + IFN-γ to induce THP-1 into M1 macrophages. We then extracted sEVs from HepG2.2.15 cell and treated the M1 macrophages with these sEVs. QPCR detection revealed the presence of HBV-DNA in the M1 macrophages. Additionally, RT-qPCR and WB analysis demonstrated a significantly decreased in the expression of TLR4, NLRP3, pro-caspase-1, caspase-1p20, IL-1β and IL-18 in the M1 macrophages (P < 0.05). Furthermore, RT-qPCR results displayed high expression levels of that miR-146a and FEN-1 in the sEVs derived from HepG2.2.15 cells (P < 0.01). RT -qPCR and WB analysis showed that these sEVs enhanced the expression of FEN-1 or miR-146a in the M1 macrophages through miR-146a or FEN-1 (P < 0.05), while simultaneously reducing the expression of TLR4, NLRP3, caspase-1p20, IL-1β and IL-18 in the M1 macrophages (P < 0.05). In summary, our findings indicate that sEVs loaded with HBV inhibit the inflammatory function of M1 macrophages and promote immune escape. Additionally, miR-146a and FEN-1 present in the sEVs play a crucial role in this process.
Collapse
Affiliation(s)
- Zili Zhang
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China
- Xichong County People's Hospital, Nanchong, 637200, Sichuan, China
| | - Jiamin Liu
- The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, 621000, China
| | - Ling Yu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Rong Zeng
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China
| | - Wanlong Pan
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, 637000, China.
| |
Collapse
|
|
6
|
Dutta S, Ganguly A, Ghosh Roy S. An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 386:81-131. [PMID: 38782502 DOI: 10.1016/bs.ircmb.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Autophagy and Unfolded Protein Response (UPR) can be regarded as the safe keepers of cells exposed to intense stress. Autophagy maintains cellular homeostasis, ensuring the removal of foreign particles and misfolded macromolecules from the cytoplasm and facilitating the return of the building blocks into the system. On the other hand, UPR serves as a shock response to prolonged stress, especially Endoplasmic Reticulum Stress (ERS), which also includes the accumulation of misfolded proteins in the ER. Since one of the many effects of viral infection on the host cell machinery is the hijacking of the host translational system, which leaves in its wake a plethora of misfolded proteins in the ER, it is perhaps not surprising that UPR and autophagy are common occurrences in infected cells, tissues, and patient samples. In this book chapter, we try to emphasize how UPR, and autophagy are significant in infections caused by six major oncolytic viruses-Epstein-Barr (EBV), Human Papilloma Virus (HPV), Human Immunodeficiency Virus (HIV), Human Herpesvirus-8 (HHV-8), Human T-cell Lymphotropic Virus (HTLV-1), and Hepatitis B Virus (HBV). Here, we document how whole-virus infection or overexpression of individual viral proteins in vitro and in vivo models can regulate the different branches of UPR and the various stages of macro autophagy. As is true with other viral infections, the relationship is complicated because the same virus (or the viral protein) exerts different effects on UPR and Autophagy. The nature of this response is determined by the cell types, or in some cases, the presence of diverse extracellular stimuli. The vice versa is equally valid, i.e., UPR and autophagy exhibit both anti-tumor and pro-tumor properties based on the cell type and other factors like concentrations of different metabolites. Thus, we have tried to coherently summarize the existing knowledge, the crux of which can hopefully be harnessed to design vaccines and therapies targeted at viral carcinogenesis.
Collapse
Affiliation(s)
- Shovan Dutta
- Center for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Anirban Ganguly
- Department of Biochemistry, All India Institute of Medical Sciences, Deoghar, Jharkhand, India
| | - Sounak Ghosh Roy
- Henry M Jackson for the Advancement of Military Medicine, Naval Medical Research Command, Silver Spring, MD, United States.
| |
Collapse
|
|
7
|
Li J, Lin Y, Wang X, Lu M. Interconnection of cellular autophagy and endosomal vesicle trafficking and its role in hepatitis B virus replication and release. Virol Sin 2024; 39:24-30. [PMID: 38211880 PMCID: PMC10877419 DOI: 10.1016/j.virs.2024.01.001] [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: 09/07/2023] [Accepted: 01/06/2024] [Indexed: 01/13/2024] Open
Abstract
Hepatitis B virus (HBV) produces and releases various particle types, including complete virions, subviral particles with envelope proteins, and naked capsids. Recent studies demonstrate that HBV exploits distinct intracellular membrane trafficking pathways, including the endosomal vesicle trafficking and autophagy pathway, to assemble and release viral and subviral particles. Herein, we summarize the findings about the distinct roles of autophagy and endosomal membrane trafficking and the interaction of both pathways in HBV replication, assembly, and release.
Collapse
Affiliation(s)
- Jia Li
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, 45122, Germany
| | - Yong Lin
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Xueyu Wang
- The Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310000, China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, 45122, Germany.
| |
Collapse
|
|
8
|
Kimura M, Kothari S, Gohir W, Camargo JF, Husain S. MicroRNAs in infectious diseases: potential diagnostic biomarkers and therapeutic targets. Clin Microbiol Rev 2023; 36:e0001523. [PMID: 37909789 PMCID: PMC10732047 DOI: 10.1128/cmr.00015-23] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023] Open
Abstract
MicroRNAs (miRNAs) are conserved, short, non-coding RNAs that play a crucial role in the post-transcriptional regulation of gene expression. They have been implicated in the pathogenesis of cancer and neurological, cardiovascular, and autoimmune diseases. Several recent studies have suggested that miRNAs are key players in regulating the differentiation, maturation, and activation of immune cells, thereby influencing the host immune response to infection. The resultant upregulation or downregulation of miRNAs from infection influences the protein expression of genes responsible for the immune response and can determine the risk of disease progression. Recently, miRNAs have been explored as diagnostic biomarkers and therapeutic targets in various infectious diseases. This review summarizes our current understanding of the role of miRNAs during viral, fungal, bacterial, and parasitic infections from a clinical perspective, including critical functional mechanisms and implications for their potential use as biomarkers and therapeutic targets.
Collapse
Affiliation(s)
- Muneyoshi Kimura
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sagar Kothari
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Wajiha Gohir
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Jose F. Camargo
- Department of Medicine, Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shahid Husain
- Transplant Infectious Diseases, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
|
9
|
Yao Y, Li S, Zhu Y, Xu Y, Hao S, Guo S, Feng WH. miR-204 suppresses porcine reproductive and respiratory syndrome virus (PRRSV) replication via inhibiting LC3B-mediated autophagy. Virol Sin 2023; 38:690-698. [PMID: 37454810 PMCID: PMC10590697 DOI: 10.1016/j.virs.2023.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 07/07/2023] [Indexed: 07/18/2023] Open
Abstract
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) has been regarded as a persistent challenge for the swine farms worldwide. microRNAs (miRNAs) play key roles in regulating almost every important biological process, including virus-host interaction. In this study, we found that miR-204 was highly expressed in cells that were not permissive to PRRSV infection compared with cells susceptible to PRRSV infection. Subsequently, we demonstrated that overexpression of miR-204 significantly inhibited PRRSV replication in porcine alveolar macrophages (PAMs). Through bioinformatic analysis, we found that there existed a potential binding site of miR-204 on the 3'UTR of microtubule associated protein 1 light chain 3B (MAP1LC3B, LC3B), a hallmark of autophagy. Applying experiments including luciferase reporter assay and UV cross-linking and immunoprecipitation (CLIP) assay, we demonstrated that miR-204 directly targeted LC3B, thereby downregulating autophagy. Meanwhile, we investigated the interplay between autophagy and PRRSV replication in PAMs, confirming that PRRSV infection induces autophagy, which in turn facilitates viral replication. Overall, we verify that miR-204 suppresses PRRSV replication via inhibiting LC3B-mediated autophagy in PAMs. These findings will provide a novel potential approach for us to develop antiviral therapeutic agents and controlling measures for future PRRSV outbreaks.
Collapse
Affiliation(s)
- Yao Yao
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Sihan Li
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yingqi Zhu
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Yangyang Xu
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Siyuan Hao
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Shuyuan Guo
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China
| | - Wen-Hai Feng
- State Key Laboratory of Animal Biotech Breeding, Frontiers Science Center for Molecular Design Breeding, Ministry of Agriculture Key Laboratory of Soil Microbiology, and Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.
| |
Collapse
|
|
10
|
Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
Collapse
Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
| |
Collapse
|
|
11
|
Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
Collapse
|
|
12
|
Chen L, Zhu L, Lu X, Ming X, Yang B. TRPM2 regulates autophagy to participate in hepatitis B virus replication. J Viral Hepat 2022; 29:627-636. [PMID: 35633088 DOI: 10.1111/jvh.13710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/13/2022] [Accepted: 04/30/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis B virus (HBV) affects over 300 million people across the world and is further associated with the self-digesting process of autophagy. Accordingly, the current study set out to explore the role of transient receptor potential cation channel subfamily M member 2 (TRPM2) in HBV replication. Firstly, Huh-7 cells were transfected with the pHBV1.3 plasmid to detect the expression patterns of TRPM2 and neutrophil cytosolic factor 1 (p47 phox), followed by evaluating the role of TRPM2 in autophagy and HBV replication and exploring the interaction between TRPM2 and p47 phox. Collaborative experiments were further designed to explore the role of p47 phox and autophagy in TRPM2 regulation of HBV replication, in addition to animal experimentation to validate the role of TRPM2/p47 phox axis in vivo. It was found that TRPM2 up-regulation was associated with HBV replication. On the other hand, silencing of TRPM2 inhibited HBV replication and autophagy in vitro and in vivo, as evidenced by reduced HBV DNA load, HBV mRNA, HBeAg and HBsAg, and diminished autophagic spot number, LC3 II/I ratio, Beclin-1 expressions and increased p62 expressions. Mechanistic experimentation illustrated that TRPM2 interacted with p47 phox and positively regulated p47 phox, such that p47 phox up-regulation or use of Rapamycin (autophagy activator) weakened the inhibitory role of silencing TRPM2. Collectively, our findings indicated that HBV infection promotes TRPM2 expression, and TRPM2 interacts with p47 phox to induce autophagy and facilitate HVB replication.
Collapse
Affiliation(s)
- Liyan Chen
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Harbin City, China
| | - Liying Zhu
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Harbin City, China
| | - Xingyu Lu
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Harbin City, China
| | - Xiaoyu Ming
- Department of Orthopedics, The First affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin City, China
| | - Baoshan Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Harbin Medical University, Harbin City, China
| |
Collapse
|
|
13
|
Li S, Gao L, Zhang W, Yu Y, Zheng J, Liang X, Xin S, Ren W, Zhi K. MiR-152-5p suppresses osteogenic differentiation of mandible mesenchymal stem cells by regulating ATG14-mediated autophagy. Stem Cell Res Ther 2022; 13:359. [PMID: 35883156 PMCID: PMC9327198 DOI: 10.1186/s13287-022-03018-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Osteoporosis affects the mandible resulting in bone loss. Though impairments are not life threatening, they affect a person's quality-of-life particularly vulnerable elderly. MicroRNAs (miRNAs) are novel regulatory factors that play an important role in regulating bone metabolism. Autophagy is evolutionarily conserved intracellular self-degradation process and is vital in the maintenance of both miRNA and bone homeostasis. However, the role of autophagy in the pathogenesis of miRNA regulating osteoporosis remains unclear. METHODS In the study, we established a rat osteoporosis model induced by ovariectomy (OVX) and isolated mesenchymal stem cells from mandible (MMSCs-M). Several miRNAs were identified to regulate osteoporosis in some studies. qRT-PCR was applied to examine the expression of miRNA, autophagy and osteogenic differentiation-related genes. Western blotting assays were performed to detect the expression of autophagy and osteogenic differentiation proteins. Immunofluorescence and transmission electron microscope were used to verify the autophagy activity. Transfecting technology was used to enhance or suppress the expression of miR-152-5p which enable us to observe the relationship between miR-152-5p, autophagy and osteogenic differentiation. Additionally, the measurement of reactive oxygen species was used to investigate the mechanism of autophagy affecting osteogenic differentiation. RESULTS We found an upregulated expression of miR-152-5p in MMSCs-M in OVX group. Downregulated autophagy-related gene, proteins and autophagosome were detected in vitro of OVX group compared with sham group. Moreover, downregulation of miR-152-5p promoted osteogenic differentiation of MMSCs-M as well as enhanced autophagy-related proteins in OVX group. Conversely, overexpression of miR-152-5p showed opposite effect in sham group. Meanwhile, we found Atg14 (autophagy-related protein homolog 14) was identified to be a direct target of miR-152-5p theoretically and functionally. In other words, we confirmed inhibition of miR-152-5p promoted the osteogenic differentiation via promoting ATG14-mediated autophagy. Furthermore, miR-152-5p/ATG14-mediated autophagy regulated osteogenic differentiation by reducing the endogenous ROS accumulation and maintaining cellular redox homeostasis. CONCLUSION Our data suggest that miR-152-5p is the first identified to regulate osteogenic differentiation by directly targeting autophagy-related protein ATG14 and regulating oxidative stress and therapeutic inhibition of miR-152-5p may be an efficient anabolic strategy for osteoporosis.
Collapse
Affiliation(s)
- Shaoming Li
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Ling Gao
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.412521.10000 0004 1769 1119Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266555 China
| | - Weidong Zhang
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Yanbin Yu
- grid.412508.a0000 0004 1799 3811College of Safety and Environmental Engineering, Shandong University of Science and Technology, Qingdao, 266590 China
| | - Jingjing Zheng
- grid.412521.10000 0004 1769 1119Department of Endodontics, The Affiliated Hospital of Qingdao University, Qingdao, 266003 China
| | - Xiao Liang
- grid.412008.f0000 0000 9753 1393Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway
| | - Shanshan Xin
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.410645.20000 0001 0455 0905School of Stomatology, Qingdao University, Qingdao, 266003 China
| | - Wenhao Ren
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China
| | - Keqian Zhi
- grid.412521.10000 0004 1769 1119Department of Oral and Maxillofacial Surgery, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Huangdao district, Qingdao, 266555 Shandong China ,grid.412521.10000 0004 1769 1119Key Lab of Oral Clinical Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266555 China
| |
Collapse
|
|
14
|
Li Y, Li R, Cheng D, Fu X, Fu L, Peng S. The potential of CircRNA1002 as a biomarker in hepatitis B virus-related hepatocellular carcinoma. PeerJ 2022; 10:e13640. [PMID: 35782101 PMCID: PMC9248787 DOI: 10.7717/peerj.13640] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 06/06/2022] [Indexed: 01/17/2023] Open
Abstract
Background Although hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, there is a lack of effective diagnostic measures. Circular RNAs (circRNAs) can be used as biomarkers for monitoring the occurrence and development of HCC. However, a convenient and reliable serum circRNA biomarker is not currently available. Materials & Methods CircRNA expression profiles were explored using high-throughput sequencing technology, and targeted circRNAs and mRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). The biological functions of circRNAs were investigated using Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Downstream miRNAs and mRNAs of dysregulated circRNAs were predicted using TargetScan, miRanda, and miRDB; then circRNA-miRNA-mRNA interaction networks were constructed based on sequencing data and the Cancer Genome Atlas (TCGA). Results A total of 50,327 circRNAs were identified, with 1,187 circRNAs significantly differentially expressed between hepatitis B virus (HBV)-related HCC and HBV asymptomatic carriers. Among these circRNAs, four (circRNA1002, circRNA7941, circRNA 39338, and circRNA44142) were validated by RT-qPCR as being statistically different either in HCC tissue or serum samples. circRNA1002 was significantly down-regulated in both HCC serum and tissue, indicating its reliability. Bioinformatics analysis showed that circRNA1002-associated genes were enriched in GO terms relating to hormone pathway and cell-cell interaction processes, which are involved in the progression of HCC. Conclusion Our circRNA analysis of HCC patients and HBV asymptomatic carriers showed that circRNA1002 may be a reliable serum biomarker for HCC. These results could provide an improved assay for the early detection of HCC.
Collapse
Affiliation(s)
- Ying Li
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Ronghua Li
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Da Cheng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Xiaoyu Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha Hunan, China
| |
Collapse
|
|
15
|
Cheng D, Wu C, Li Y, Liu Y, Mo J, Fu L, Peng S. METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194782. [PMID: 34968770 DOI: 10.1016/j.bbagrm.2021.194782] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/01/2021] [Accepted: 12/13/2021] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m6A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m6A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m6A modification were measured by MTT assay, flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m6A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m6A inhibitor). METTL3 overexpression enhanced m6A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo. HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF.
Collapse
Affiliation(s)
- Da Cheng
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Cichun Wu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Ying Li
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Yao Liu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Juan Mo
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Lei Fu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China..
| | - Shifang Peng
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China..
| |
Collapse
|
|
16
|
You H, Qin S, Zhang F, Hu W, Li X, Liu D, Kong F, Pan X, Zheng K, Tang R. Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection. Front Immunol 2022; 13:829923. [PMID: 35251017 PMCID: PMC8891514 DOI: 10.3389/fimmu.2022.829923] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open
Abstract
As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.
Collapse
Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Suping Qin
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Wei Hu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Dongsheng Liu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
17
|
Aslani M, Mortazavi-Jahromi SS, Mirshafiey A. Cytokine storm in the pathophysiology of COVID-19: Possible functional disturbances of miRNAs. Int Immunopharmacol 2021; 101:108172. [PMID: 34601331 PMCID: PMC8452524 DOI: 10.1016/j.intimp.2021.108172] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.
Collapse
Affiliation(s)
- Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
18
|
Wang S, Sun Y, Wang Y, Wang A, Kou B, Che Y, Chen D, Zhang Y, Shi Y. ASPP2 inhibits hepatitis B virus replication by preventing nucleus translocation of HSF1 and attenuating the transactivation of ATG7. J Cell Mol Med 2021; 25:6899-6908. [PMID: 34085409 PMCID: PMC8278078 DOI: 10.1111/jcmm.16699] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/22/2021] [Accepted: 05/12/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) is a kind of virus with the capability to induce autophagy, thereby facilitating its replication. Reducing hepatocyte autophagy is proved to be a useful way to inhibit HBV replication. Herein, we reported that p53-binding protein 2 (apoptosis-stimulating protein of p53-2, ASPP2) could attenuate HBV-induced hepatocyte autophagy in a p53-independent manner. Mechanistically, overexpressed ASPP2 binds to HSF1 in cytoplasm of HBV-infected cells, which prevents the translocation of HSF1 to nuclei, thereby inhibiting the transactivation of Atg7. By regulating the transcription of Atg7, ASPP2 reduces hepatocyte autophagy, thereby inhibiting HBV replication. Therefore, ASPP2 is a key regulator of cell autophagy, and overexpression of ASPP2 could be a novel method to inhibit HBV replication in hepatocytes.
Collapse
Affiliation(s)
- Shanshan Wang
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Yu Sun
- Minimally Invasive Interventional Centre of OncologyBeijing You’an HospitalCapital Medical UniversityBeijingChina
| | - Yang Wang
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Anna Wang
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
| | - Buxin Kou
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Yang Che
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Dexi Chen
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| | - Yulin Zhang
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
| | - Ying Shi
- Capital Medical University Affiliated Beijing You’an HospitalBeijingChina
- Beijing Institute of HepatologyBeijingChina
| |
Collapse
|
|
19
|
Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol 2021; 27:3182-3207. [PMID: 34163105 PMCID: PMC8218364 DOI: 10.3748/wjg.v27.i23.3182] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/23/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.
Collapse
Affiliation(s)
- Prashika Singh
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Dylan Kairuz
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| | - Kristie Bloom
- Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
| |
Collapse
|
|
20
|
Lei Y, Xu X, Liu H, Chen L, Zhou H, Jiang J, Yang Y, Wu B. HBx induces hepatocellular carcinogenesis through ARRB1-mediated autophagy to drive the G 1/S cycle. Autophagy 2021; 17:4423-4441. [PMID: 33866937 DOI: 10.1080/15548627.2021.1917948] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The hepatitis B virus X protein (HBx) is involved in the process of hepatocellular carcinoma via the activation of various oncogenes. Our previous study indicated that ARBB1 (arrestin beta 1) promotes hepatocellular carcinogenesis (HCC). However, the role of ARRB1 in HBx-related HCC remains unclear. Herein, we identified that ARRB1 was upregulated by HBx in vivo and in vitro. Arrb1 deficiency suppressed HBx-induced hepatocellular carcinogenesis in several mouse models. Furthermore, knockdown of ARRB1 blocked HBx-induced macroautophagic/autophagic flux and disrupted the formation of autophagosomes. ARRB1 interacted with HBx, and the autophagic core protein MAP1LC3/LC3, a scaffolding protein, was essential for complete autophagy. Inhibition of autophagy by 3-methyladenine or interference of ATG5 or ATG7 attenuated HBx-induced cell cycle acceleration and the subsequent proliferative response via the induction of G1/S arrest. The absence of autophagy abolished the phosphorylation of CDK2 and the activity of the CDK2-CCNE1 complex. Our results demonstrate that ARRB1 plays a critical role in HBV-related HCC via modulating autophagy and the CDKN1B-CDK2-CCNE1-E2F1 axis and indicate that ARRB1 may be a potential therapeutic target for HCC.
Collapse
Affiliation(s)
- Yiming Lei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Xuan Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Lingjun Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Haoxiong Zhou
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Jie Jiang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Yidong Yang
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.,Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| |
Collapse
|
|
21
|
Abstract
Viral infections lead to the death of more than a million people each year around the world, both directly and indirectly. Viruses interfere with many cell functions, particularly critical pathways for cell death, by affecting various intracellular mediators. MicroRNAs (miRNAs) are a major example of these mediators because they are involved in many (if not most) cellular mechanisms. Virus-regulated miRNAs have been implicated in three cell death pathways, namely, apoptosis, autophagy, and anoikis. Several molecules (e.g., BECN1 and B cell lymphoma 2 [BCL2] family members) are involved in both apoptosis and autophagy, while activation of anoikis leads to cell death similar to apoptosis. These mechanistic similarities suggest that common regulators, including some miRNAs (e.g., miR-21 and miR-192), are involved in different cell death pathways. Because the balance between cell proliferation and cell death is pivotal to the homeostasis of the human body, miRNAs that regulate cell death pathways have drawn much attention from researchers. miR-21 is regulated by several viruses and can affect both apoptosis and anoikis via modulating various targets, such as PDCD4, PTEN, interleukin (IL)-12, Maspin, and Fas-L. miR-34 can be downregulated by viral infection and has different effects on apoptosis, depending on the type of virus and/or host cell. The present review summarizes the existing knowledge on virus-regulated miRNAs involved in the modulation of cell death pathways. Understanding the mechanisms for virus-mediated regulation of cell death pathways could provide valuable information to improve the diagnosis and treatment of many viral diseases.
Collapse
|
|
22
|
Fu S, Liu J, Xu J, Zuo S, Zhang Y, Guo L, Qiu Y, Ye C, Liu Y, Wu Z, Hou Y, Hu CAA. The effect of baicalin on microRNA expression profiles in porcine aortic vascular endothelial cells infected by Haemophilus parasuis. Mol Cell Biochem 2020; 472:45-56. [PMID: 32519231 DOI: 10.1007/s11010-020-03782-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 06/04/2020] [Indexed: 01/10/2023]
Abstract
Glässer's disease, caused by Haemophilus parasuis (H. parasuis), is associated with vascular damage and vascular inflammation in pigs. Therefore, early assessment and treatment are essential to control the inflammatory disorder. MicroRNAs have been shown to be involved in the vascular pathology. Baicalin has important pharmacological functions, including anti-inflammatory, antimicrobial and antioxidant effects. In this study, we investigated the changes of microRNAs in porcine aortic vascular endothelial cells (PAVECs) induced by H. parasuis and the effect of baicalin in this model by utilizing high-throughput sequencing. The results showed that 155 novel microRNAs and 76 differentially expressed microRNAs were identified in all samples. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the target genes of the differentially expressed microRNAs demonstrated that regulation of actin cytoskeleton, focal adhesion, ECM-receptor interaction, bacterial invasion of epithelial cells, and adherens junction were the most interesting pathways after PAVECs were infected with H. parasuis. In addition, when the PAVECs were pretreated with baicalin, mismatch repair, peroxisome, oxidative phosphorylation, DNA replication, and ABC transporters were the most predominant signaling pathways. STRING analysis showed that most of the target genes of the differentially expressed microRNAs were associated with each other. The expression levels of the differentially expressed microRNAs were negatively co-regulated with their target genes' mRNA following pretreatment with baicalin in the H. parasuis-induced PAVECs using co-expression networks analysis. This is the first report that microRNAs might have key roles in inflammatory damage of vascular tissue during H. parasuis infection. Baicalin regulated the microRNAs changes in the PAVECs following H. parasuis infection, which may represent useful novel targets to prevent or treat H. parasuis infection.
Collapse
Affiliation(s)
- Shulin Fu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Jun Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Jianfeng Xu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Sanling Zuo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Yunfei Zhang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Ling Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Yinsheng Qiu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China.
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China.
| | - Chun Ye
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Yu Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Zhongyuan Wu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Yongqing Hou
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, 430023, People's Republic of China
| | - Chien-An Andy Hu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, 430023, People's Republic of China
- Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA
| |
Collapse
|
|
23
|
Mortazavi-Jahromi SS, Aslani M, Mirshafiey A. A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases. Immunol Lett 2020; 227:8-27. [PMID: 32810557 DOI: 10.1016/j.imlet.2020.07.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/10/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases. Its deregulated expression pattern and inefficient function have been reported in a wide spectrum of these illnesses. Based on the existing evidence, this miRNA qualifies as an ideal biomarker for diagnosis, prognosis, and activity evaluation of immune and non-immune inflammatory disorders. Moreover, much attention has recently been paid to therapeutic potential of miR-146a and several researchers have assessed the effects of different drugs on expression and function of this miRNA at diverse experimental, animal, besides human levels, reporting motivating results in the treatment of the diseases. Here, in this comprehensive review, we provide an overview of miR-146a role in the pathogenesis and progression of several immune and non-immune inflammatory diseases such as Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Multiple sclerosis, Psoriasis, Graves' disease, Atherosclerosis, Hepatitis, Chronic obstructive pulmonary disease, etc., discuss about its eligibility for being a desirable biomarker for these disorders, and also highlight its therapeutic potential. Understanding these mechanisms underlies the selecting and designing the proper therapeutic targets and medications, which eventually facilitate the treatment process.
Collapse
Affiliation(s)
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
24
|
Yang J, Guo R, Yan D, Lu H, Zhang H, Ye P, Jin L, Diao H, Li L. Plasma Level of ADAMTS13 or IL-12 as an Indicator of HBeAg Seroconversion in Chronic Hepatitis B Patients Undergoing m-ETV Treatment. Front Cell Infect Microbiol 2020; 10:335. [PMID: 32793509 PMCID: PMC7393286 DOI: 10.3389/fcimb.2020.00335] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 06/03/2020] [Indexed: 02/05/2023] Open
Abstract
The ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin motif repeats 13) is a key factor involved in coagulation process and plays a vital role in the progression and prognosis of chronic hepatitis B (CHB) patients with antiviral treatment. However, there are few reports about the profile of plasma ADAMTS13 in CHB patients during entecavir maleate (m-ETV) treatment. One hundred two HBV e antigen (HBeAg)-positive CHB patients on continuous m-ETV naive for at least 96 weeks were recruited. Patients with liver cirrhosis were excluded using liver biopsies and real-time elastography. Plasma ADAMTS13 and interleukin 12 (IL-12) levels were evaluated at baseline and12, 24, 48, 72, and 96 weeks, respectively. The change of ADAMTS13 (ΔADAMTS13) and IL-12 (ΔIL-12) possesses a significant relationship in CHB patients with HBeAg seroconversion (SC) at 48-week m-ETV treatment (p < 0.001), but no significance in patients without SC. Furthermore, Cox multivariate analysis demonstrated that the change of ADAMTS13 (IL-12) is an independent predictor for HBeAg SC at week 96, and the area under the receiver operating characteristic curve for the ΔADAMTS13 (ΔIL-12) in CHB patients with 48-week m- ETV treatment is 0.8204 (0.8354) (p < 0.001, both) to predict HBeAg SC at week 96. The results suggested that higher increased ADAMTS13 and IL-12 after 48-week m-ETV treatment contributed to an enhanced probability of HBeAg SC, although the mechanism is undetermined. Quantification of ADAMTS13 (IL-12) during m-ETV treatment may help to predict long-term HBeAg SC in CHB patients.
Collapse
Affiliation(s)
- Jiezuan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Renyong Guo
- Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province, Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Haifeng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hua Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ping Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Linfeng Jin
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
25
|
Liu Y, Wang M, Cheng A, Yang Q, Wu Y, Jia R, Liu M, Zhu D, Chen S, Zhang S, Zhao XX, Huang J, Mao S, Ou X, Gao Q, Wang Y, Xu Z, Chen Z, Zhu L, Luo Q, Liu Y, Yu Y, Zhang L, Tian B, Pan L, Rehman MU, Chen X. The role of host eIF2α in viral infection. Virol J 2020; 17:112. [PMID: 32703221 PMCID: PMC7376328 DOI: 10.1186/s12985-020-01362-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/23/2020] [Indexed: 12/24/2022] Open
Abstract
Background eIF2α is a regulatory node that controls protein synthesis initiation by its phosphorylation or dephosphorylation. General control nonderepressible-2 (GCN2), protein kinase R-like endoplasmic reticulum kinase (PERK), double-stranded RNA (dsRNA)-dependent protein kinase (PKR) and heme-regulated inhibitor (HRI) are four kinases that regulate eIF2α phosphorylation. Main body In the viral infection process, dsRNA or viral proteins produced by viral proliferation activate different eIF2α kinases, resulting in eIF2α phosphorylation, which hinders ternary tRNAMet-GTP-eIF2 complex formation and inhibits host or viral protein synthesis. The stalled messenger ribonucleoprotein (mRNP) complex aggregates under viral infection stress to form stress granules (SGs), which encapsulate viral RNA and transcription- and translation-related proteins, thereby limiting virus proliferation. However, many viruses have evolved a corresponding escape mechanism to synthesize their own proteins in the event of host protein synthesis shutdown and SG formation caused by eIF2α phosphorylation, and viruses can block the cell replication cycle through the PERK-eIF2α pathway, providing a favorable environment for their own replication. Subsequently, viruses can induce host cell autophagy or apoptosis through the eIF2α-ATF4-CHOP pathway. Conclusions This review summarizes the role of eIF2α in viral infection to provide a reference for studying the interactions between viruses and hosts.
Collapse
Affiliation(s)
- Yuanzhi Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China. .,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China. .,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Xin-Xin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Juan Huang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Sai Mao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Xumin Ou
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Qun Gao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Bin Tian
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Leichang Pan
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Mujeeb Ur Rehman
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China.,Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, Sichuan, 611130, P.R. China
| |
Collapse
|
|
26
|
Cao H, Chen X, Wang Z, Wang L, Xia Q, Zhang W. The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation. Cell Death Discov 2020; 6:53. [PMID: 32595984 PMCID: PMC7305227 DOI: 10.1038/s41420-020-0287-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4+T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.
Collapse
Affiliation(s)
- Hui Cao
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Xiaosong Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Zhijun Wang
- Department of Traditional Chinese Medicine, Putuo People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Lei Wang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Wei Zhang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| |
Collapse
|
|
27
|
Fu X, Ouyang Y, Mo J, Li R, Fu L, Peng S. Upregulation of microRNA-328-3p by hepatitis B virus contributes to THLE-2 cell injury by downregulating FOXO4. J Transl Med 2020; 18:143. [PMID: 32228643 PMCID: PMC7106851 DOI: 10.1186/s12967-020-02299-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis B virus (HBV) remains a major cause of chronic hepatitis and hepatocellular carcinoma, and miRNAs play important roles in HBV pathogenesis. Our previous study has shown that miR-328-3p is upregulated in HBV-infected patients and serves as a potent predictor for the prognosis of HBV-related liver failure. Methods Here, the role of miR-328-3p in modulating cell injury in HBV-infected liver cells THLE-2 was investigated in detail. MiR-328-3p expression was examined using qRT-PCR. The levels of pro-inflammatory cytokines were measured using ELISA. HBV RNA and HBV DNA levels were quantified. The interactions between STAT3 and miR-328-3p promoter as well as miR-328-3p and FOXO4 were analyzed using chromatin immunoprecipitation (CHIP) assay and luciferase reporter assay, respectively. THLE-2 cell injury was evaluated by examining cell viability and apoptosis. Results HBV promoted expression of miR-328-3p through the STAT3 signal pathway and that increasingly expressed miR-328-3p downregulated its target FOXO4, leading to the promotion of cell injury in HBV-infected liver cells THLE-2. Conclusion These data demonstrate that HBV-STAT3-miR-328-3p-FOXO4 regulation pathway may play an important role in the pathogenesis of HBV infection.
Collapse
Affiliation(s)
- Xiaoyu Fu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Yi Ouyang
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Juan Mo
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Ronghua Li
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lei Fu
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
| | - Shifang Peng
- Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
| |
Collapse
|
|
28
|
Chen L, Ming X, Li W, Bi M, Yan B, Wang X, Yang P, Yang B. The microRNA-155 mediates hepatitis B virus replication by reinforcing SOCS1 signalling-induced autophagy. Cell Biochem Funct 2020; 38:436-442. [PMID: 31930529 DOI: 10.1002/cbf.3488] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 12/05/2019] [Accepted: 12/17/2019] [Indexed: 12/19/2022]
Abstract
As small conserved RNAs without a coding function, microRNAs are expressed in multicellular organisms and contribute to the modulation of multiple cellular reactions, such as viral replication, as well as autophagy. microRNAs can regulate host gene expression and inhibit or reinforce hepatitis B virus (HBV) replication. Hepatic cells express miR-155 noticeably. Consequently, our study explored miR-155 modulation of HBV replication and investigated the potential mechanism involved. miR-155 was inhibited on HBV infection. miR-155 transfection remarkably reinforced HBV replication, antigen expression, and progeny secretion in HepG2215 cells. Moreover, miR-155 impaired the inhibition of the cytokine signalling 1 (SOCS1)/Akt/mTOR axis and reinforced HepG2215 autophagy. Additionally, the autophagy inhibitor (3-MA) eliminated HBsAg secretion triggered by miR-155. Taken together, miR-155 reinforced HBV replication by reinforcing SOCS1-triggered autophagy. SIGNIFICANCE OF THE STUDY: The research studied the potential mechanism involved in HBV replication and miR-155 that miR-155 reinforces HBV replication by reinforcing the SOCS1/Akt/mTOR axis-stimulated autophagy, and therefore, it can provide medical practitioners with the inspiration that chronic HBV might be cured or improved by regulating the activation of miR-155 in cells. In the study, the experiments show that autophagy inhibitors (3-MA) counteracted miR-155 contribution to HBV replication, and it might be a practicable way to improve HBV through some therapies that can repress the autophagy in related cells.
Collapse
Affiliation(s)
- Liyan Chen
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Xiaoyu Ming
- Department of Orthopedics, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Haerbin, China
| | - Wensong Li
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Manru Bi
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Bingzhu Yan
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Xiaoren Wang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Pengfei Yang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| | - Baoshan Yang
- Department of Infection, The Second Affiliated Hospital of Harbin Medical University, Haerbin, China
| |
Collapse
|
|
29
|
Zhao Y, Wang Z, Zhang W, Zhang L. MicroRNAs play an essential role in autophagy regulation in various disease phenotypes. Biofactors 2019; 45:844-856. [PMID: 31418958 PMCID: PMC6916288 DOI: 10.1002/biof.1555] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 07/31/2019] [Indexed: 12/16/2022]
Abstract
Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.
Collapse
Affiliation(s)
- Yunyi Zhao
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
| | - Ze Wang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
| | - Wenhui Zhang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
- Ministry of Education, Engineering Research Center for Bioreactor and Pharmaceutical DevelopmentJilin Agricultural UniversityChangchunChina
| | - Linbo Zhang
- Laboratory of Pathogenic Microbiology and ImmunologyCollege of Life Science, Jilin Agricultural UniversityChangchunChina
- Ministry of Education, Engineering Research Center for Bioreactor and Pharmaceutical DevelopmentJilin Agricultural UniversityChangchunChina
| |
Collapse
|
|
30
|
Abstract
The aim of this study was to investigate the alterations of urinary microRNA (miRNA) expression and explore its clinical significance in patients with chronic hepatitis B (CHB).The expression levels of urinary miRNA were detected by miRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 106 CHB and 40 healthy controls (Ctrl) subjects. The correlation between the levels of miRNA expression and clinical characteristics were analyzed. Receiver-operator characteristic (ROC) curves were generated to determine the specificity and sensitivity of each individual miRNA. MiRNAs expression were further measured by PCR from exosomes, which were isolated from urine samples. LX2 cells were transfected with miRNA inhibitor and accumulation of cytoplasmic lipid droplets was analyzed by Oil Red O staining.miRNA expression profile analysis showed that 22 miRNAs were upregulated and 55 miRNAs were downregulated in CHB patients compared with Ctrl subjects (fold-change>1.5 and P < .05). miR-92b-3p, miR-770-5p, miR-5196-5p, and miR-7855-5p were significantly higher (P < .0001) in CHB subjects than in Ctrl subjects. ROC curve analysis showed that these four miRNAs were sensitive and specific enough to distinguish CHB and Ctrl subjects. The levels of miR-92b-3p expression were negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and APOA-1. Moreover, in vitro experiments indicated that inhibition of miR-92b-3p increased lipid droplet formation in LX2 cells.Aberrant expression of miRNAs has been observed in urine of CHB patients. Our findings may provide novel insights into the pathogenesis of CHB and may assist in the diagnosis of patients with CHB.
Collapse
Affiliation(s)
- Jia-Wei Shang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Xiu-Li Yan
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China
| | - Hui Zhang
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| | - Shi-Bing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research
| |
Collapse
|