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Li J, Kemper T, Broering R, Lin Y, Wang X, Lu M. Amphisome plays a role in HBV production and release through the endosomal and autophagic pathways. Hepatol Commun 2025; 9:e0654. [PMID: 40079732 PMCID: PMC11908759 DOI: 10.1097/hc9.0000000000000654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 01/08/2025] [Indexed: 03/15/2025] Open
Abstract
BACKGROUND Autophagic and endosomal pathways coordinately contribute to HBV virions and subviral particles (SVPs) production. To date, limited evidence supports that HBV and exosomes have a common pathway for their biogenesis and secretion. The final steps of HBV production and release have not yet been well studied. METHODS We examined the production and release of HBV virions and SVPs by using GW4869 (N,N'-Bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-3,3'-pht hal amide dihydrochloride), a small molecule inhibiting ceramide-mediated inward membrane budding. Neutral sphingomyelinase, the target of GW4869, and RAB27A and -B, 2 small GTPases involved in exosome release control, were silenced using gene silencing to confirm the results obtained. Western blot, immunofluorescence staining, and confocal microscopy were applied. RESULTS GW4869 inhibited HBV virion release, causing their accumulation along with SVPs in hepatocytes. This triggered cellular endoplasmic reticulum stress, leading to protein kinase B-mechanistic target of rapamycin kinase signaling pathway inactivation. GW4869 treatment increased autophagosome formation and impaired autophagic degradation by blocking autophagosome-lysosome fusion. Consequently, HBsAg is increasingly localized to autophagosomes and late endosomes/multivesicular bodies. Silencing neutral sphingomyelinase yielded consistent results. Similarly, RAB27A silencing inhibited HBV virion and SVP secretion, causing their accumulation within hepatoma cells. Notably, GW4869 treatment, as well as RAB27A and -B silencing, increased the presence of LC3+CD63+HBsAg+ complexes. CONCLUSIONS Our results demonstrate the involvement of the autophagosome-late endosome/multivesicular bodies-exosome axis in regulating HBV production and release, highlighting amphisomes as a potential platform for HBV release.
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Affiliation(s)
- Jia Li
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Thekla Kemper
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yong Lin
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xueyu Wang
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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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.
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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
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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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Chuang YC, Ou JHJ. Hepatitis B virus entry, assembly, and egress. Microbiol Mol Biol Rev 2024; 88:e0001424. [PMID: 39440957 DOI: 10.1128/mmbr.00014-24] [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] [Indexed: 10/25/2024] Open
Abstract
SUMMARYHepatitis B virus (HBV) is an important human pathogen that chronically infects approximately 250 million people in the world, resulting in ~1 million deaths annually. This virus is a hepatotropic virus and can cause severe liver diseases including cirrhosis and hepatocellular carcinoma. The entry of HBV into hepatocytes is initiated by the interaction of its envelope proteins with its receptors. This is followed by the delivery of the viral nucleocapsid to the nucleus for the release of its genomic DNA and the transcription of viral RNAs. The assembly of the viral capsid particles may then take place in the nucleus or the cytoplasm and may involve cellular membranes. This is followed by the egress of the virus from infected cells. In recent years, significant research progresses had been made toward understanding the entry, the assembly, and the egress of HBV particles. In this review, we discuss the molecular pathways of these processes and compare them with those used by hepatitis delta virus and hepatitis C virus , two other hepatotropic viruses that are also enveloped. The understanding of these processes will help us to understand how HBV replicates and causes diseases, which will help to improve the treatments for HBV patients.
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Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - J-H James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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Zhao Y, Zhou L, Zheng H, Gao L, Cao H, Li X, Zheng SJ, Wang Y. Gga-miR-200a-3p suppresses avian reovirus-induced apoptosis and viral replication via targeting GRB2. Vet Microbiol 2024; 295:110149. [PMID: 38909417 DOI: 10.1016/j.vetmic.2024.110149] [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: 03/21/2024] [Revised: 06/03/2024] [Accepted: 06/05/2024] [Indexed: 06/25/2024]
Abstract
Avian reovirus (ARV) is a significant pathogen that causes various clinical diseases in chickens, including viral arthritis, chronic respiratory diseases, retarded growth, and malabsorption syndrome. These conditions result in substantial economic losses for the global poultry industry. MicroRNAs (miRNAs), a type of small noncoding RNAs that regulate gene expression post transcriptionally by silencing or degrading their RNA targets, play crucial roles in response to pathogenic infections. In this study, transfection of DF-1 cells with gga-miR-200a-3p, an upregulated miRNA observed in ARV-infected cells, significantly suppressed ARV-induced apoptosis by directly targeting GRB2 and impeded ARV replication. Conversely, knockdown of endogenous gga-miR-200a-3p in DF-1 cells using a specific miRNA inhibitor enhanced ARV-induced apoptosis and promoted GRB2 expression, thereby facilitating viral growth within cells. Consistently, inhibition of GRB2 activity through siRNA-mediated knockdown reduced viral titers. Therefore, gga-miR-200a-3p plays a vital antiviral role in the host response to ARV infection by suppressing apoptosis via direct targeting of GRB2 protein. This information enhances our understanding of the mechanisms by which host cells combat against ARV infection through self-encoded small RNA molecules and expands our knowledge regarding the involvement of microRNAs in the host response to pathogenic infections.
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Affiliation(s)
- Yimeng Zhao
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Linyi Zhou
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Hao Zheng
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Li Gao
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Hong Cao
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Xiaoqi Li
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Shijun J Zheng
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Yongqiang Wang
- National Key Laboratory of Veterinary Public Health Security, China; Animal Epidemiology of the Ministry of Agriculture, China; College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
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Padarath K, Deroubaix A, Naicker P, Stoychev S, Kramvis A. Comparative Proteomic Analysis of Huh7 Cells Transfected with Sub-Saharan African Hepatitis B Virus (Sub)genotypes Reveals Potential Oncogenic Factors. Viruses 2024; 16:1052. [PMID: 39066215 PMCID: PMC11281506 DOI: 10.3390/v16071052] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
In sub-Saharan Africa (SSA), the (sub)genotypes A1, D3, and E of the hepatitis B virus (HBV) prevail. Individuals infected with subgenotype A1 have a 4.5-fold increased risk of HCC compared to those infected with other (sub)genotypes. The effect of (sub)genotypes on protein expression and host signalling has not been studied. Mass spectrometry was used to analyse the proteome of Huh7 cells transfected with replication-competent clones. Proteomic analysis revealed significantly differentially expressed proteins between SSA (sub)genotypes. Different (sub)genotypes have the propensity to dysregulate specific host signalling pathways. Subgenotype A1 resulted in dysregulation within the Ras pathway. Ras-associated protein, RhoC, was significantly upregulated in cells transfected with subgenotype A1 compared to those transfected with other (sub)genotypes, on both a proteomic (>1.5-fold) and mRNA level (p < 0.05). Two of the main cellular signalling pathways involving RHOC, MAPK and PI3K/Akt/mTOR, regulate cell growth, motility, and survival. Downstream signalling products of these pathways have been shown to increase MMP2 and MMP9 expression. An extracellular MMP2 and MMP9 ELISA revealed a non-significant increase in MMP2 and MMP9 in the cells transfected with A1 compared to the other (sub)genotypes (p < 0.05). The upregulated Ras-associated proteins have been implicated as oncoproteins in various cancers and could contribute to the increased hepatocarcinogenic potential of A1.
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Affiliation(s)
- Kiyasha Padarath
- Hepatitis Virus Diversity Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Science, University of Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa (A.D.)
| | - Aurélie Deroubaix
- Hepatitis Virus Diversity Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Science, University of Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa (A.D.)
- Life Sciences Imaging Facility, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa
| | - Previn Naicker
- Future Production Chemicals, Council for Scientific and Industrial Research, Pretoria 0184, South Africa;
| | - Stoyan Stoychev
- ReSyn Biosciences, Johannesburg 2000, South Africa;
- Evosep Biosystems, 5230 Odense, Denmark
| | - Anna Kramvis
- Hepatitis Virus Diversity Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Science, University of Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa (A.D.)
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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.
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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.
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Zhang L, Chen ZY, Wei XX, Li JD, Chen G. What are the changes in the hotspots and frontiers of microRNAs in hepatocellular carcinoma over the past decade? World J Clin Oncol 2024; 15:145-158. [PMID: 38292666 PMCID: PMC10823937 DOI: 10.5306/wjco.v15.i1.145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/08/2023] [Accepted: 12/28/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Emerging research suggests that microRNAs (miRNAs) play an important role in the development of hepatocellular carcinoma (HCC). A comprehensive analysis of recent research concerning miRNAs in HCC development could provide researchers with a valuable reference for further studies. AIM To make a comprehensive analysis of recent studies concerning miRNAs in HCC. METHODS All relevant publications were retrieved from the Web of Science Core Collection database. Bibliometrix software, VOSviewer software and CiteSpace software were used to visually analyze the distribution by time, countries, institutions, journals, and authors, as well as the keywords, burst keywords and thematic map. RESULTS A total of 9426 publications on this topic were found worldwide. According to the keywords analysis, we found that the studies of miRNAs focused on their expression level, effects, and mechanisms on the biological behaviour of HCC. Keywords bursting analysis showed that in the early years (2013-2017), "microRNA expression", "gene expression", "expression profile", "functional polymorphism", "circulating microRNA", "susceptibility" and "mir 21" started to attract attention. In the latest phase (2018-2022), the hot topics turned to "sorafenib resistance", "tumor microenvironment" and so on. CONCLUSION This study provides a comprehensive overview of the role of miRNAs in HCC development based on bibliometric analysis. The hotspots in this field focus on miRNAs expression level, effects, and mechanisms on the biological behavior of HCC. The frontiers turned to sorafenib resistance, tumor microenvironment and so on.
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Affiliation(s)
- Lu Zhang
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zu-Yuan Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Xian Wei
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jian-Di Li
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Gang Chen
- Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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Wang C, Gao XY, Han M, Jiang MC, Shi XY, Pu CW, Du X. Perilipin2 inhibits the replication of hepatitis B virus deoxyribonucleic acid by regulating autophagy under high-fat conditions. World J Virol 2023; 12:296-308. [PMID: 38187502 PMCID: PMC10768386 DOI: 10.5501/wjv.v12.i5.296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/19/2023] [Accepted: 11/30/2023] [Indexed: 12/25/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is often associated with increased lipid deposition in hepatocytes. However, when combined with non-alcoholic fatty liver disease or hyperlipidemia, it tends to have a lower HBV deoxyribonucleic acid (DNA) load. The relationship between lipid metabolism and HBV DNA replication and its underlying mechanisms are not well understood. AIM To investigate the relationship between lipid metabolism and HBV DNA replication and its underlying mechanisms. METHODS 1603 HBsAg-seropositive patients were included in the study. We first explored the relationship between patients' lipid levels, hepatic steatosis, and HBV DNA load. Also, we constructed an HBV infection combined with a hepatic steatosis cell model in vitro by fatty acid stimulation of HepG2.2.15 cells to validate the effect of lipid metabolism on HBV DNA replication in vitro. By knocking down and overexpressing Plin2, we observed whether Plin2 regulates autophagy and HBV replication. By inhibiting both Plin2 and cellular autophagy under high lipid stimulation, we examined whether the Plin2-autophagy pathway regulates HBV replication. RESULTS The results revealed that serum triglyceride levels, high-density lipoprotein levels, and hepatic steatosis ratio were significantly lower in the HBV-DNA high load group. Logistic regression analysis indicated that hepatic steatosis and serum triglyceride levels were negatively correlated with HBV-DNA load. Stratified analysis by HBeAg showed significant negative correlations between HBV-DNA load and hepatic steatosis ratio in both HBeAg-positive and HBeAg-negative groups. An in vitro cell model was developed by stimulating HepG2.2.15 cells with palmitic acid and oleic acid to study the relationship between HBV-DNA load and lipid metabolism. The results of the in vitro experiments suggested that fatty acid treatment increased lipid droplet deposition and decreased the expression of cell supernatant HBsAg, HBeAg, and HBV DNA load. Western blot and polymerase chain reaction analysis showed that fatty acid stimulation significantly induced Plin2 protein expression and inhibited the expression of hepatocyte autophagy proteins. Inhibition of Plin2 protein expression under fatty acid stimulation reversed the reduction in HBsAg and HBeAg expression and HBV DNA load induced by fatty acid stimulation and the inhibition of cellular autophagy. Knocking down Plin2 and blocking autophagy with 3-methyladenine (3-MA) inhibited HBV DNA replication. CONCLUSION In conclusion, lipid metabolism is a significant factor affecting HBV load in patients with HBV infection. The in vitro experiments established that fatty acid stimulation inhibits HBV replication via the Plin2-autophagy pathway.
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Affiliation(s)
- Chuang Wang
- Graduate School, Graduate School of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Xiao-Yun Gao
- Department of Geriatric, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Mei Han
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Meng-Chun Jiang
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
| | - Xiao-Yi Shi
- Graduate School, Graduate School of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Chun-Wen Pu
- Dalian Public Health Clinical Center, Dalian Municipal Research Institute for Public Health, Dalian 116001, Liaoning Province, China
| | - Xuan Du
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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10
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Zhao Z, Wei Z, Zheng J, Li Z, Zou H, Wen X, Li F, Wang X, Huang Q, Zeng H, Fan H, Cai X, Zhang J, Jia B, Huang A, Lu M, Lin Y. Hepatitis B virus promotes its own replication by enhancing RAB5A-mediated dual activation of endosomal and autophagic vesicle pathways. Emerg Microbes Infect 2023; 12:2261556. [PMID: 37725090 PMCID: PMC10614717 DOI: 10.1080/22221751.2023.2261556] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 08/18/2023] [Accepted: 09/17/2023] [Indexed: 09/21/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains one of the major global public health concerns, and it develop into liver fibrosis, cirrhosis, and hepatocellular carcinoma. Recent evidence suggests that endosomal and autophagic vesicles are beneficial for HBV replication. However, it has not been well elucidated how HBV exploits such intracellular vesicle systems for its replication. RAB5A, a member of small GTPase family, plays crucial roles in early endosome biogenesis and autophagy initiation. We observed that RAB5A mRNA and protein levels were significantly increased in HBV-expressing hepatoma cell lines as well as in liver tissue samples from chronic HBV-infected patients. Moreover, RAB5A silencing inhibited HBV replication and subviral particle (SVP) expression significantly in HBV-transfected and -infected hepatoma cells, whereas RAB5A overexpression increased them. Mechanistically, RAB5A increases HBV replication through enhancement of early endosome (EE) - late endosome (LE) activation by interacting with EEA1, as well as enhancing autophagy induction by interacting with VPS34. Additionally, HBV infection enhances RAB5A-mediated dual activation of EE-LE system and autophagy. Collectively, our findings highlight that HBV utilizes RAB5A-mediated dual activation of endosomal and autophagic vesicle pathways for its own replication and persistence. Therefore, RAB5A is a potential target for chronic HBV infection treatment.
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Affiliation(s)
- Zhenyu Zhao
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Zhen Wei
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jiaxin Zheng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Zhihong Li
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hecun Zou
- Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xiang Wen
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Fahong Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xueyu Wang
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Qian Huang
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Huaqing Zeng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Hui Fan
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Xuefei Cai
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Bei Jia
- Key Laboratory of Infectious and Parasitic Diseases in Chongqing, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
| | - Ailong Huang
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yong Lin
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
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11
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Cavallone D, Ornos EDB, Ricco G, Oliveri F, Coco B, Colombatto P, De Rosa L, Dalmacio LMM, Bonino F, Brunetto MR. The Circulating miRNA Profile of Chronic Hepatitis D and B Patients Is Comparable but Differs from That of Individuals with HBeAg-Negative HBV Infection. Viruses 2023; 15:2257. [PMID: 38005933 PMCID: PMC10675264 DOI: 10.3390/v15112257] [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: 10/16/2023] [Revised: 11/09/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
miRNAs circulating in whole serum and HBsAg-particles are differentially expressed in chronic hepatitis B (CHB) and HBeAg-negative-HBV infection (ENI); their profiles are unknown in chronic hepatitis D (CHD). Serum- and HBsAg-associated miRNAs were analyzed in 75 subjects of 3 well-characterized groups (CHB 25, CHD 25, ENI 25) using next-generation sequencing (NGS). Overall miRNA profiles were consonant in serum and HBsAg-particles but significantly different according to the presence of hepatitis independently of Hepatitis D Virus (HDV)-co-infection. Stringent (Bonferroni Correction < 0.001) differential expression analysis showed 39 miRNAs upregulated in CHB vs. ENI and 31 of them also in CHD vs. ENI. miRNA profiles were coincident in CHB and CHD with only miR-200a-3p upregulated in CHB. Three miRNAs (miR-625-3p, miR-142-5p, and miR-223-3p) involved in immune response were upregulated in ENI. All 3 hepatocellular miRNAs of MiR-B-Index (miR-122-5p, miR-99a-5p, miR-192-5p) were overexpressed in both CHB and CHD patients. In conclusion, CHD and CHB patients showed highly similar serum miRNA profiling that was significantly different from that of individuals with HBeAg-negative infection and without liver disease.
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Affiliation(s)
- Daniela Cavallone
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
| | - Eric David B. Ornos
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Department of Medical Microbiology, College of Medicine, University of the Philippines Manila, Pedro Gil Street, Ermita, Manila 1000, Philippines
- Fondazione Italiana Fegato (FIF), 34149 Trieste, Italy
| | - Gabriele Ricco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
| | - Laura De Rosa
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy;
- Department of Information Engineering and Computer Science, University of Trento, 38123 Trento, Italy
| | - Leslie Michelle M. Dalmacio
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Pedro Gil Street, Ermita, Manila 1000, Philippines;
| | - Ferruccio Bonino
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
| | - Maurizia Rossana Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (D.C.); (E.D.B.O.); (G.R.); (F.O.); (B.C.); (P.C.); (F.B.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
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12
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Gao H, Fan H, Xie H. miR-HCC2 suppresses hepatitis B virus replication by inhibiting the activity of the enhancer I/X promoter. Arch Virol 2023; 168:282. [PMID: 37889339 DOI: 10.1007/s00705-023-05899-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/03/2023] [Indexed: 10/28/2023]
Abstract
miR-HCC2 has been reported to markedly promote the growth, metastasis, and stemness of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Deep sequencing showed that miR-HCC2 was significantly upregulated in hepatitis B virus (HBV)-positive (HBV+) HCC tissue samples compared with HBV-negative (HBV-) HCC tissue samples. miR-HCC2 expression was further evaluated in HCC tissues and cells, and the expression of miR-HCC2 was found to be significantly higher in HBV+ HCC tissues and cells than in HBV- HCC tissues and cells, suggesting that high miR-HCC2 expression could be induced by HBV infection. To explore the relationship between miR-HCC2 and HBV, we investigated the effect of miR-HCC2 on HBV antigen expression, transcription, and replication. We found that miR-HCC2 was involved in the negative feedback regulation of HBV replication. Further mechanistic studies revealed that miR-HCC2 suppressed HBV replication by inhibiting the activity of the enhancer I/X promoter. Our study demonstrates the effect of the inhibition of miR-HCC2 on HBV gene expression and replication, which can help to illustrate the complex regulatory network involving host miRNAs and HBV.
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Affiliation(s)
- Huijie Gao
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070, China.
| | - Hongxia Fan
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070, China
| | - Hong Xie
- Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, No. 22 Qi-Xiang-Tai Road, Tianjin, 300070, China.
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13
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Pandita S, Verma A, Kumar N. Role of miRNAs in regulating virus replication. ANIMAL GENE 2023; 30:200162. [DOI: 10.1016/j.angen.2023.200162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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14
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health concerns worldwide. Autophagy, in addition to its role in cellular homeostasis and metabolism, plays an important part for the host antiviral immunity. However, viruses including SARS-CoV-2 have evolved diverse mechanisms to not only overcome autophagy's antiviral pressure but also manipulate its machinery in order to enhance viral replication and propagation. Here, we discuss our current knowledge on the impact that autophagy exerts on SARS-CoV-2 replication, as well as the different counteracting measures that this virus has developed to manipulate autophagy's complex machinery. Some of the elements regarding this interplay may become future therapeutic targets in the fight against SARS-CoV-2.
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Affiliation(s)
- Hao Zhou
- Department of Microbiology and Immunology, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhiqiang Hu
- Shandong New Hope Liuhe Agriculture and Animal Husbandry Technology Co., Ltd, Dezhou, China
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15
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Mishra AK, Hossain MM, Umar M, Sata TN, Yadav AK, Sah AK, Ismail M, Nayak B, Shalimar, Venugopal SK. DDX3-mediated miR-34 expression inhibits autophagy and HBV replication in hepatic cells. J Viral Hepat 2023; 30:327-334. [PMID: 36597176 DOI: 10.1111/jvh.13799] [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: 11/22/2022] [Accepted: 12/16/2022] [Indexed: 01/05/2023]
Abstract
HBV entry to the host cells and its successful infection depends on its ability to modulate the host restriction factors. DEAD box RNA helicase, DDX3, is shown to inhibit HBV replication. However, the exact mechanism of inhibition still remains unclear. DDX3 is involved in multitude or RNA metabolism processes including biogenesis of miRNAs. In this study, we sought to determine the mechanism involved in DDX3-mediated HBV inhibition. First, we observed that HBx protein of HBV downregulated DDX3 expression in HBV-infected cells. Overexpression of DDX3 inhibited HBx, HBsAg and total viral load, while its knockdown reversed the result in Hep G2.2.15 cells. Expression of miR-34 was downregulated in HBV-infected cells. Overexpression of pHBV1.3 further confirmed that HBV downregulates miR-34 expression. Consistent with the previous finding that DDX3 is involved in miRNA biogenesis, we observed that expression of miR-34 positively corelated with DDX3 expression. miRNA target prediction tools showed that miR-34 can target autophagy pathway which is hijacked by HBV for the benefit of its own replication. Indeed, transfection with miR-34 oligos downregulated the expression of autophagy marker proteins in HBV-expressing cells. Overexpression of DDX3 in HBV-expressing cells, downregulated expression of autophagy proteins while silencing of DDX3 reversed the results. These results led us to conclude that DDX3 upregulates miR-34 expression and thus inhibits autophagy in HBV-expressing cells while HBx helps HBV evade DDX3-mediated inhibition by downregulating DDX3 expression in HBV-infected cells.
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Affiliation(s)
- Amit Kumar Mishra
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Md Musa Hossain
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Mohd Umar
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Teja Naveen Sata
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Ajay K Yadav
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Amrendra Kumar Sah
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Md Ismail
- Lab of molecular medicine and Hepatology, FLSB, South Asian University, New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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16
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Cao B, Li J, Wang X, Ran Z, Tan J, Deng L, Hao Y. Mechanosensitive miR-99b mediates the regulatory effect of matrix stiffness on bone marrow mesenchymal stem cell fate both in vitro and in vivo. APL Bioeng 2023; 7:016106. [PMID: 36685676 PMCID: PMC9851713 DOI: 10.1063/5.0131125] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
Mechanical signals from extracellular matrix stiffness are important cues that regulate the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). However, the incorporation of BMSCs into soft hydrogels and the dominance of soft matrices for BMSC growth and differentiation limit the directed differentiation of BMSCs incorporated into hydrogels for tissue engineering, especially osteogenesis. Here, we found that the expression of miR-99b increased with increasing hydrogel stiffness and that miR-99b regulated the proliferation and differentiation of BMSCs seeded on the surface of substrates with different stiffnesses. Furthermore, miR-99b significantly promoted the migration of BMSCs in 3D hydrogels. Mechanistically, we demonstrated that matrix stiffness-sensitive miR-99b targets the mammalian target of the rapamycin signaling pathway to regulate the adipogenic and osteogenic differentiation of BMSCs. In addition, by modulating the expression of miR-99b, the osteogenic differentiation of BMSCs in soft 3D hydrogels was promoted. Consistently, the flexible BMSC-GelMA hydrogel transfected with miR-99b significantly promoted bone regeneration in the rat calvarial defect area. These results suggest that miR-99b plays a key role in the mechanotransduction and phenotypic transformation of BMSCs and may inspire new tissue engineering applications with MSCs as key components.
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Affiliation(s)
- Bojun Cao
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jiaxin Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaowen Wang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhaoyang Ran
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Jia Tan
- Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
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17
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Izzo C, Visco V, Gambardella J, Ferruzzi GJ, Rispoli A, Rusciano MR, Toni AL, Virtuoso N, Carrizzo A, Di Pietro P, Iaccarino G, Vecchione C, Ciccarelli M. Cardiovascular Implications of microRNAs in Coronavirus Disease 2019. J Pharmacol Exp Ther 2023; 384:102-108. [PMID: 35779946 DOI: 10.1124/jpet.122.001210] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 06/11/2022] [Accepted: 06/15/2022] [Indexed: 01/13/2023] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to be a global challenge due to resulting morbidity and mortality. Cardiovascular (CV) involvement is a crucial complication in coronavirus disease 2019 (COVID-19), and no strategies are available to prevent or specifically address CV events in COVID-19 patients. The identification of molecular partners contributing to CV manifestations in COVID-19 patients is crucial for providing early biomarkers, prognostic predictors, and new therapeutic targets. The current report will focus on the role of microRNAs (miRNAs) in CV complications associated with COVID-19. Indeed, miRNAs have been proposed as valuable biomarkers and predictors of both cardiac and vascular damage occurring in SARS-CoV-2 infection. SIGNIFICANCE STATEMENT: It is essential to identify the molecular mediators of coronavirus disease 2019 (COVID-19) cardiovascular (CV) complications. This report focused on the role of microRNAs in CV complications associated with COVID-19, discussing their potential use as biomarkers, prognostic predictors, and therapeutic targets.
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Affiliation(s)
- Carmine Izzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Valeria Visco
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Jessica Gambardella
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Germano Junior Ferruzzi
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Antonella Rispoli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Anna Laura Toni
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Nicola Virtuoso
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Paola Di Pietro
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Guido Iaccarino
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy (C.I., V.V., G.J.F., A.R., M.R.R., A.L.T., A.C., P.D.P., C.V., M.C.); Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy (J.G., G.I.); Department of Medicine, Einstein-Sinai Diabetes Research Center, The Fleischer Institute for Diabetes and Metabolism, Einstein Institute for Aging Research, Albert Einstein College of Medicine, New York, New York (J.G.); Cardiology Unit, University Hospital "San Giovanni di Dio e Ruggi d'Aragona," Salerno, Italy (N.V.); and Vascular Physiopathology Unit, IRCCS Neuromed, Pozzilli, Italy (A.C., C.V.)
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18
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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19
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Li F, Deng Y, Zhang S, Zhu B, Wang J, Wang J, Wang X, Zhao Z, Deng W, Mao R, Shen Z, Chen J, Broering R, Lin Y, Lu M, Zhang J. Human hepatocyte-enriched miRNA-192-3p promotes HBV replication through inhibiting Akt/mTOR signalling by targeting ZNF143 in hepatic cell lines. Emerg Microbes Infect 2022; 11:616-628. [PMID: 35109781 PMCID: PMC8865105 DOI: 10.1080/22221751.2022.2037393] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 01/05/2023]
Abstract
Previous studies have revealed multiple tissue- or cell-specific or enriched miRNA profiles. However, miRNA profiles enriched in hepatic cell types and their effect on HBV replication have not been well elucidated. In this study, primary human hepatocytes (PHHs), Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs) were prepared from liver specimens of non-HBV-infected patients. Four hepatic cell type-enriched miRNA profiles were identified from purified liver cells miRNA microarray assay. The results revealed that 12 miRNAs, including miR-122-5p and miR-192-3p were PHH-enriched; 9 miRNAs, including miR-142-5p and miR-155-5p were KC-enriched; 6 miRNAs, including miR-126-3p and miR-222-3p were LSEC-enriched; and 14 miRNAs, including miR-214-3p and miR-199a-3p were HSC-enriched. By testing the effect of 11 PHH-enriched miRNAs on HBV production, we observed that miR-192-3p had the greatest pro-virus effect in hepatic cell lines. Moreover, we further found that miR-192-3p promoted HBV replication and gene expression through inhibiting Akt/mTOR signalling by direct targeting of ZNF143 in HepG2.2.15 cells. Additionally, the serum and hepatic miR-192-3p expression levels were significantly higher in chronic hepatitis B patients than in healthy controls and serum miR-192-3p positively correlated with the serum levels of HBV DNA and HBsAg. Collectively, we identified miRNA profiles enriched in four hepatic cell types and revealed that PHH-enriched miR-192-3p promoted HBV replication through inhibiting Akt/mTOR signalling by direct targeting of ZNF143 in hepatic cell lines. Our study provides a specific perspective for the role of hepatic cell type-enriched miRNA in interaction with viral replication and various liver pathogenesis.
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Affiliation(s)
- Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yingying Deng
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Shenyan Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Beidi Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jun Wang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jinyu Wang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xueyu Wang
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhenyu Zhao
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Wanyu Deng
- Department of Biliary Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Zhongliang Shen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yong Lin
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, People’s Republic of China
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
- Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
- Department of Infectious Diseases, Jing’An Branch of Huashan Hospital, Fudan University, Shanghai, People’s Republic of China
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20
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Hardin LT, Xiao N. miRNAs: The Key Regulator of COVID-19 Disease. Int J Cell Biol 2022; 2022:1645366. [PMID: 36345541 PMCID: PMC9637033 DOI: 10.1155/2022/1645366] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 09/30/2022] [Indexed: 01/12/2024] Open
Abstract
As many parts of the world continue to fight the innumerable waves of COVID-19 infection, SARS-CoV-2 continues to sculpt its antigenic determinants to enhance its virulence and evolvability. Several vaccines were developed and used around the world, and oral antiviral medications are being developed against SARS-CoV-2. However, studies showed that the virus is mutating in line with the antibody's neutralization escape; thus, new therapeutic alternatives are solicited. We hereby review the key role that miRNAs can play as epigenetic mediators of the cross-talk between SARS-CoV-2 and the host cells. The limitations resulting from the "virus intelligence" to escape and antagonize the host miRNAs as well as the possible mechanisms that could be used in the viral evasion strategies are discussed. Lastly, we suggest new therapeutic approaches based on viral miRNAs.
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Affiliation(s)
- Leyla Tahrani Hardin
- Department of Biomedical Sciences at the Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, 94103 CA, USA
| | - Nan Xiao
- Department of Biomedical Sciences at the Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, 94103 CA, USA
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21
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Najafipour R, Mohammadi D, Estaki Z, Zarabadi K, Jalilvand M, Moghbelinejad S. Screening for differentially expressed microRNAs in BALF and blood samples of infected COVID-19 ARDS patients by small RNA deep sequencing. J Clin Lab Anal 2022; 36:e24672. [PMID: 36166345 PMCID: PMC9539155 DOI: 10.1002/jcla.24672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 01/08/2023] Open
Abstract
Background The pandemic COVID‐19 has caused a high mortality rate and poses a significant threat to the population of the entire world. Due to the novelty of this disease, the pathogenic mechanism of the disease and the host cell's response are not yet fully known, so lack of evidence prevents a definitive conclusion about treatment strategies. The current study employed a small RNA deep‐sequencing approach for screening differentially expressed microRNA (miRNA) in blood and bronchoalveolar fluid (BALF) samples of acute respiratory distress syndrome (ARDS) patients. Methods In this study, BALF and blood samples were taken from patients with ARDS (n = 5). Control samples were those with suspected lung cancer candidates for lung biopsy (n = 3). Illumina high‐throughput (HiSeq 2000) sequencing was performed to identify known and novel miRNAs differentially expressed in the blood and BALFs of ARDS patients compared with controls. Results Results showed 2234 and 8324 miRNAs were differentially expressed in blood and BALF samples, respectively. In BALF samples, miR‐282, miR‐15‐5p, miR‐4485‐3p, miR‐483‐3p, miR‐6891‐5p, miR‐200c, miR‐4463, miR‐483‐5p, and miR‐98‐5p were upregulated and miR‐15a‐5p, miR‐548c‐5p, miR‐548d‐3p, miR‐365a‐3p, miR‐3939, miR‐514‐b‐5p, miR‐513a‐3p, miR‐513a‐5p, miR‐664a‐3p, and miR‐766‐3p were downregulated. On the contrary, in blood samples miR‐15b‐5p, miR‐18a‐3p, miR‐486‐3p, miR‐486‐5p, miR‐146a‐5p, miR‐16‐2‐3p, miR‐6501‐5p, miR‐365‐3p, miR‐618, and miR‐623 were top upregulated miRNAs and miR‐21‐5p, miR‐142a‐3p, miR‐181‐a, miR‐31‐5p, miR‐99‐5p, miR‐342‐5p, miR‐183‐5p, miR‐627‐5p, and miR‐144‐3p were downregulated miRNAs. Network functional analysis for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), in ARDS patients' blood and BALF samples, showed that the target genes were more involved in activating inflammatory and apoptosis process. Conclusion Based on our results, the transcriptome profile of ARDS patients would be a valuable source for understanding molecular mechanisms of host response and developing clinical guidance on anti‐inflammatory medication.
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Affiliation(s)
- Reza Najafipour
- Genetics Research Center, The University of Social Welfare and Rehabilitation Science, Tehran, Iran
| | - Davood Mohammadi
- Department of Surgery, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zohreh Estaki
- Department of Pediatric Dentistry, School of Dentistry, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Kiana Zarabadi
- Department of Medical Genetics, School of Medicine, Tarbiat Modares University, Tehran, Iran
| | - Manijeh Jalilvand
- Research Institute for Prevention of Non-Communicable Diseases, Cellular and Molecular Research Centre, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sahar Moghbelinejad
- Research Institute for Prevention of Non-Communicable Diseases, Cellular and Molecular Research Centre, Qazvin University of Medical Sciences, Qazvin, Iran
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22
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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.
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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
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23
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Zou L, Liao M, Zhen Y, Zhu S, Chen X, Zhang J, Hao Y, Liu B. Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta Pharm Sin B 2022; 12:3743-3782. [PMID: 36213540 PMCID: PMC9532564 DOI: 10.1016/j.apsb.2022.06.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/27/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022] Open
Abstract
UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
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Affiliation(s)
- Ling Zou
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minru Liao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongqi Zhen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Yue Hao
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
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24
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Chu Q, Li J, Chen J, Yuan Z. HBV induced the discharge of intrinsic antiviral miRNAs in HBV-replicating hepatocytes via extracellular vesicles to facilitate its replication. J Gen Virol 2022; 103. [PMID: 35604380 DOI: 10.1099/jgv.0.001744] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV), which can cause chronic hepatitis B, has sophisticated machinery to establish persistent infection. Here, we report a novel mechanism whereby HBV changed miRNA packaging into extracellular vesicles (EVs) to facilitate replication. Disruption of the miRNA machinery in hepatocytes enhanced HBV replication, indicating an intrinsic miRNA-mediated antiviral state. Interference with EV release only decreased HBV replication if there was normal miRNA biogenesis, suggesting a possible link between HBV replication and EV-associated miRNAs. Microarray and qPCR analyses revealed that HBV replication changed miRNA expression in EVs. EV incubation, transfection of miRNA mimics and inhibitors, and functional pathway and network analyses showed that EV miRNAs are associated with antiviral function, suggesting that to promote survival HBV coopts EVs to excrete anti-HBV intracellular miRNAs. These data suggest a novel mechanism by which HBV maintains its replication, which has therapeutic implications.
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Affiliation(s)
- Qiaofang Chu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Jianhua Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, PR China
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25
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Ran Z, Wu S, Ma Z, Chen X, Liu J, Yang J. Advances in exosome biomarkers for cervical cancer. Cancer Med 2022; 11:4966-4978. [PMID: 35578572 PMCID: PMC9761094 DOI: 10.1002/cam4.4828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 02/03/2023] Open
Abstract
Cervical cancer (CC) ranks as the fourth most frequently diagnosed malignancy in females worldwide. Exosomes are a subclass of extracellular vesicles released by nearly all types of cells that act as cargo transport vehicles, carrying proteins, and genetic material (such as miRNAs, long noncoding RNAs, and mRNAs) derived from their parent cells may affect receiving cells and thus have emerged as key players in several biological processes, including inflammatory pathways. In this review, we concentrated on the findings of exosome investigations in CC, particularly their components. They direct the actions of CC cells by inducing surface molecules associated with various biological pathways. We summarized the current knowledge of exosomal RNAs and proteins from CC cells and discussed the feasibility of exosomes as potential biomarkers for CC. We suggest that cancer-derived exosomes promote metastasis in CC by supporting EMT, controlling the proliferation, invasion, or migration of cancer cells, as well as influencing immune escape and aiding angiogenesis. Overall, cancer-derived exosomes are critical in the progression of CC, and further studies are necessary to advance our understanding of the clinical value of exosomes in CC.
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Affiliation(s)
- Zihan Ran
- Department of ResearchShanghai University of Medicine & Health Sciences Affiliated Zhoupu HospitalShanghaiChina,Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Shaobo Wu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Zijng Ma
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Xiuwen Chen
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina,The Genius Medicine Consortium (TGMC)ShanghaiChina
| | - Jing Liu
- Inspection and Quarantine Department, The College of Medical TechnologyShanghai University of Medicine & Health SciencesShanghaiChina
| | - Jingcheng Yang
- The Genius Medicine Consortium (TGMC)ShanghaiChina,State Key Laboratory of Genetic Engineering, Human Phenome Institute, School of Life Sciences and Shanghai Cancer CenterFudan UniversityShanghaiChina,Greater Bay Area Institute of Precision MedicineGuangzhouChina
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26
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Luo W, Wang Y, Zhang T. Win or loss? Combination therapy does improve the oncolytic virus therapy to pancreatic cancer. Cancer Cell Int 2022; 22:160. [PMID: 35443724 PMCID: PMC9022249 DOI: 10.1186/s12935-022-02583-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/11/2022] [Indexed: 11/10/2022] Open
Abstract
Pancreatic cancer (PC) is a growing global burden, remaining one of the most lethal cancers of the gastrointestinal tract. Moreover, PC is resistant to various treatments such as chemotherapy, radiotherapy, and immunotherapy. New therapies are urgently needed to improve the prognosis of PC. Oncolytic virus (OV) therapy is a promising new treatment option. OV is a genetically modified virus that selectively replicates in tumor cells. It can kill tumor cells without harming normal cells. The activation of tumor-specific T-cells is a unique feature of OV-mediated therapy. However, OV-mediated mono-therapeutic efficacy remains controversial, especially for metastatic or advanced patients who require systemically deliverable therapies. Hence, combination therapies will be critical to improve the therapeutic efficacy of OV-mediated therapy and prevent tumor recurrence. This review aims to investigate novel combinatorial treatments with OV therapy and explore the inner mechanism of those combined therapies, hopefully providing a new direction for a better prognosis of PC.
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Affiliation(s)
- Wenhao Luo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China
| | - Yawen Wang
- Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Key Laboratory of Endocrinology of National Health Commission of the People's Republic of China, The Translational Medicine Center of Peking Union Medical College Hospital (PUMCH), PUMCH, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, 100730, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, 100730, China. .,Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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27
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Li J, Kemper T, Broering R, Chen J, Yuan Z, Wang X, Lu M. Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication. Front Cell Infect Microbiol 2022; 12:804011. [PMID: 35186790 PMCID: PMC8847603 DOI: 10.3389/fcimb.2022.804011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes acute and chronic liver diseases, including severe hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Interferon alpha 2a (IFNα-2a) is commonly used for treating chronic HBV infection. However, its efficacy remains relatively low. Yet, the immunological and molecular mechanisms for successful IFNα-2a treatment remain elusive. One issue is whether the application of increasing IFNα doses may modulate cellular processes and HBV replication in hepatic cells. In the present study, we focused on the interaction of IFNα signaling with other cellular signaling pathways and the consequence for HBV replication. The results showed that with the concentration of 6000 U/ml IFNα-2a treatment downregulated the activity of not only the Akt/mTOR signaling but also the AMPK signaling. Additionally, IFNα-2a treatment increased the formation of the autophagosomes by blocking autophagic degradation. Furthermore, IFNα-2a treatment inhibited the Akt/mTOR signaling and initiated autophagy under low and high glucose concentrations. In reverse, inhibition of autophagy using 3-methyladenine (3-MA) and glucose concentrations influenced the expression of IFNα-2a-induced ISG15 and IFITM1. Despite of ISGs induction, HBV replication and gene expression in HepG2.2.15 cells, a cell model with continuous HBV replication, were slightly increased at high doses of IFNα-2a. In conclusion, our study indicates that IFNα-2a treatment may interfere with multiple intracellular signaling pathways, facilitate autophagy initiation, and block autophagic degradation, thereby resulting in slightly enhanced HBV replication.
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Affiliation(s)
- Jia Li
- Insititute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Thekla Kemper
- Insititute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xueyu Wang
- Insititute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Mengji Lu, ; Xueyu Wang,
| | - Mengji Lu
- Insititute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Mengji Lu, ; Xueyu Wang,
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Bautista-Becerril B, Pérez-Dimas G, Sommerhalder-Nava PC, Hanono A, Martínez-Cisneros JA, Zarate-Maldonado B, Muñoz-Soria E, Aquino-Gálvez A, Castillejos-López M, Juárez-Cisneros A, Lopez-Gonzalez JS, Camarena A. miRNAs, from Evolutionary Junk to Possible Prognostic Markers and Therapeutic Targets in COVID-19. Viruses 2021; 14:41. [PMID: 35062245 PMCID: PMC8781105 DOI: 10.3390/v14010041] [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: 12/04/2021] [Accepted: 12/21/2021] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic has been a public health issue around the world in the last few years. Currently, there is no specific antiviral treatment to fight the disease. Thus, it is essential to highlight possible prognostic predictors that could identify patients with a high risk of developing complications. Within this framework, miRNA biomolecules play a vital role in the genetic regulation of various genes, principally, those related to the pathophysiology of the disease. Here, we review the interaction of host and viral microRNAs with molecular and cellular elements that could potentiate the main pulmonary, cardiac, renal, circulatory, and neuronal complications in COVID-19 patients. miR-26a, miR-29b, miR-21, miR-372, and miR-2392, among others, have been associated with exacerbation of the inflammatory process, increasing the risk of a cytokine storm. In addition, increased expression of miR-15b, -199a, and -491 are related to the prognosis of the disease, and miR-192 and miR-323a were identified as clinical predictors of mortality in patients admitted to the intensive care unit. Finally, we address miR-29, miR-122, miR-155, and miR-200, among others, as possible therapeutic targets. However, more studies are required to confirm these findings.
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Affiliation(s)
- Brandon Bautista-Becerril
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Guillermo Pérez-Dimas
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Paola C. Sommerhalder-Nava
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | - Alejandro Hanono
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | | | - Bárbara Zarate-Maldonado
- Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Mexico City 52786, Mexico; (P.C.S.-N.); (A.H.); (B.Z.-M.)
| | - Evangelina Muñoz-Soria
- Escuela Superior de Medicina, Departamento de Posgrado, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (G.P.-D.); (E.M.-S.)
| | - Arnoldo Aquino-Gálvez
- Laboratorio de Biología Molecular, Departamento de Fibrosis Pulmonar, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Manuel Castillejos-López
- Departamento de Epidemiología Hospitalaria e Infectología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Armida Juárez-Cisneros
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
| | - Jose S. Lopez-Gonzalez
- Laboratorio de Cáncer Pulmonar, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico;
| | - Angel Camarena
- Laboratorio HLA, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico; (B.B.-B.); (A.J.-C.)
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29
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Liu F, Liu T, Li H. Aloperine inhibits the progression of non-small-cell lung cancer through the PI3K/Akt signaling pathway. Cancer Cell Int 2021; 21:662. [PMID: 34895234 PMCID: PMC8666048 DOI: 10.1186/s12935-021-02361-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/24/2021] [Indexed: 12/24/2022] Open
Abstract
Background Lung cancer has become the leading cause of cancer-related death worldwide and non‐small‐cell lung cancer (NSCLC) accounts for approximately 85% of cases. Aloperine (ALO), an alkaloid active natural component from S. alopecuroide, has been found to exhibit anti-inflammatory, anti-tumor and anti-viral activity. However, Whether ALO exerts anti-tumor function on NSCLC remains poorly understood, and the underlying mechanisms remain unknown. Methods The CCK-8, colony formation, cell apoptosis with flow cytometry, wound healing and transwell cell invasion assays, were used to analyze the tumor progression of H1299 and A549 cells treated with ALO in vitro, and the xenograft model was constructed to assess the effect of ALO in vivo. The expression of protein was detected by Western blotting. Results ALO suppressed the cell proliferation, self-renewal, migration and invasion, induced apoptosis in A549 and H1299 cell. Furthermore, ALO significantly enhanced the level of cytochrome c in cytosol, and resulted in the dramatical increased levels of the cleaved caspase-3, caspased-9 and PARP. ALO also inhibited the expression of MMP-2 and MMP-9. Additionally, ALO also reduced p-AKT and p-mTOR to attenuate the PI3K/AKT signaling pathway. Conclusion This study unveils a rationale for ALO through PI3K/Akt signaling pathway affecting the cell progression such as cell growth, apoptosis and invasion, and ALO acts as a potential chemotherapeutic agent for NSCLC.
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Affiliation(s)
- Fujuan Liu
- Department of Pharmacy, Linyi Fourth People's Hospital, No. 121, Qianshi Ave., Linyi, 276005, Shandong, China
| | - Tao Liu
- Department of Pediatrics, Linyi Fourth People's Hospital, No. 121, Qianshi Ave., Linyi, 276005, Shandong, China
| | - Haiying Li
- Department of Ultrasound, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Rd., Jinan, 250012, Shandong, China.
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30
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Huang Q, Chen L, Bai Q, Tong T, Zhou Y, Li Z, Lu C, Chen S, Chen L. The roles of microRNAs played in lung diseases via regulating cell apoptosis. Mol Cell Biochem 2021; 476:4265-4275. [PMID: 34398353 DOI: 10.1007/s11010-021-04242-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 08/10/2021] [Indexed: 01/24/2023]
Abstract
MicroRNAs (miRNAs) are a type of endogenous non-coding short-chain RNA, which plays a crucial role in the regulation of many essential cellular functions, including cellular migration, proliferation, invasion, autophagy, oxidative stress, apoptosis, and differentiation. The lung can be damaged by pathogenic microorganisms, as well as physical or chemical factors. Research has confirmed that miRNAs and lung cell apoptosis can affect the development and progression of several lung diseases. This article reviews the role of miRNAs in the development of lung disease through regulating host cell apoptosis.
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Affiliation(s)
- Qiaoling Huang
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Li Chen
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Qinqin Bai
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Ting Tong
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - You Zhou
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Zhongyu Li
- Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Chunxue Lu
- Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China
| | - Shenghua Chen
- Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China.
| | - Lili Chen
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China.
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, College of Public Health, University of South China, 28 West Changsheng Rd, Hengyang, 421001, Hunan, China.
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Gga-miR-29a-3p suppresses avian reovirus-induced apoptosis and viral replication via targeting Caspase-3. Vet Microbiol 2021; 264:109294. [PMID: 34847454 DOI: 10.1016/j.vetmic.2021.109294] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/09/2021] [Accepted: 09/16/2021] [Indexed: 12/25/2022]
Abstract
Avian reovirus (ARV) is an important pathogen causing multiple types of clinical diseases in chickens, including viral arthritis, chronic respiratory diseases, retarded growth, and malabsorption syndrome, leading to considerable economic losses to the poultry industry across the globe. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post transcriptionally by silencing or degrading their targets, thus playing important roles in the host response to pathogenic infection. However, the role of miRNAs in host response to ARV infection is still not clear. Here, we show that infection of DF-1 cells (a chicken fibroblast cell line) with ARV markedly altered the expressions of 583 chicken miRNAs(gga-miR), and that transfection of DF-1 cells with gga-miR-29a-3p, an upregulated miRNA in ARV-infected cells, significantly suppressed ARV-induced apoptosis via directly targeting Caspase-3, retarding ARV growth in cells. In contrast, knockdown of endogenous gga-miR-29a-3p in DF-1 cells by specific miRNA inhibitor enhanced ARV-induced apoptosis and increased the content and activity of caspase-3, facilitating viral growth in cells. Consistently, inhibition of Caspase-3 activity by inhibitors decreased viral titers in cell cultures. Thus, gga-miR-29a-3p plays an important antiviral role in host response to ARV infection by suppression of apoptosis via targeting Caspase-3. This information will further our understandings of how host cells combat against ARV infection by self-encoded small RNA and increase our knowledge of the role of microRNAs in host response to pathogenic infection.
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Wang X, Wei Z, Jiang Y, Meng Z, Lu M. mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication. Virol Sin 2021; 36:1303-1314. [PMID: 34580816 PMCID: PMC8692646 DOI: 10.1007/s12250-021-00450-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 08/24/2021] [Indexed: 01/05/2023] Open
Abstract
Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that includes mTOR complex (mTORC) 1 and mTORC2. The mTOR pathway is activated in viral hepatitis, including hepatitis B virus (HBV) infection-induced hepatitis. Currently, chronic HBV infection remains one of the most serious public health issues worldwide. The unavailability of effective therapeutic strategies for HBV suggests that clarification of the pathogenesis of HBV infection is urgently required. Increasing evidence has shown that HBV infection can activate the mTOR pathway, indicating that HBV utilizes or hijacks the mTOR pathway to benefit its own replication. Therefore, the mTOR signaling pathway might be a crucial target for controlling HBV infection. Here, we summarize and discuss the latest findings from model biology research regarding the interaction between the mTOR signaling pathway and HBV replication.
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Affiliation(s)
- Xueyu Wang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany
| | - Zhiqiang Wei
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Yongfang Jiang
- Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China. .,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany.
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The Role of microRNAs in Cholangiocarcinoma. Int J Mol Sci 2021; 22:ijms22147627. [PMID: 34299246 PMCID: PMC8306241 DOI: 10.3390/ijms22147627] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/10/2021] [Accepted: 07/15/2021] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.
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34
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Wang X, Wei Z, Lan T, He Y, Cheng B, Li R, Chen H, Li F, Liu G, Jiang B, Lin Y, Lu M, Meng Z. CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. Autophagy 2021; 18:357-374. [PMID: 34190023 PMCID: PMC8942511 DOI: 10.1080/15548627.2021.1934271] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatitis B virus (HBV) particles are thought to be secreted from hepatocytes through multivesicular bodies (MVBs); however, the cellular trafficking mechanisms prior to this process remain elusive. It has been reported that CCDC88A/GIV expression, which is involved in multiple aspects of vesicular trafficking, changes dynamically at different phases of chronic HBV infection. In this study, we focused on the role of CCDC88A/GIV in HBV replication. In the liver tissues of chronically HBV-infected patients, HBV infection significantly enhanced CCDC88A/GIV expression, and increased endoplasmic reticulum (ER) stress and autophagosome formation without changing endosome formation. Additionally, colocalization of SHBsAg with early endosomes (~30.2%) far exceeded that with autophagosomes (~3.2%). In hepatoma cells, CCDC88A/GIV and its downstream proteins, DNM2 (dynamin 2; a CCDC88A/GIV effector), CLTC and RAB5A significantly enhanced HBV replication and endosome formation but inhibited autophagosome formation. Blocking endocytosis disrupted HBsAg trafficking to endosomes and caused its accumulation in the ER lumen, which triggered ER stress to initiate the unfolded protein response (UPR). Therefore, HBsAg trafficking into autophagosomes was increased, and the lysosomal activity and maturation, which was inhibited by HBV infection, were restored. Meanwhile, core particles were prevented from entering MVBs. CCDC88A/GIV and its other effector, GNAI3, decreased autophagic flux by enhancing the insulin-induced AKT-MTOR pathway, thereby inhibiting HBV antigens autophagic degradation. In conclusion, CCDC88A/GIV enhanced HBV replication by increasing endosomal trafficking and reducing autophagic degradation of HBV antigens, suggesting that CCDC88A/GIV-mediated endosomal trafficking plays an important role in HBV replication and progeny secretion.Abbreviations: ACTB: actin beta; AO: acridine orange; ATF6: activating transcription factor 6; CCDC88A/GIV: coiled-coil domain containing 88A; CLTC: clathrin heavy chain; CQ: chloroquine; DAPI: 4ʹ,6-diamidino-2-phenylindole; DNM2: dynamin 2; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; EIF2A: eukaryotic translation initiation factor 2A; FBS: fetal bovine serum; GNAI3: G protein subunit alpha i3; HBV: hepatitis B virus; HBV RIs: HBV replication intermediates; HBcAg: HBV core protein; HBsAg: HBV surface antigen; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MTOR: mechanistic target of rapamycin kinase; PDI: protein disulfide isomerase; PHH: primary human hepatocyte; pSM2: a HBV replication-competent plasmid; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA; SEM: standard error of the mean; UPR: unfolded protein response
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Affiliation(s)
- Xueyu Wang
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhiqiang Wei
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Tingyu Lan
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Yulin He
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Bin Cheng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Ruimin Li
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Hongxia Chen
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Fahong Li
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Department of Infectious Diseases,Huashan Hospital, Fudan University, Shanghai, China
| | - Guohua Liu
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Bin Jiang
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
| | - Yong Lin
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Zhongji Meng
- Institute of Biomedical Research, Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei province, China
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35
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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.
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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
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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.
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37
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Lasagna A, Zuccaro V, Sacchi P, Chiellino S, Bruno R, Pedrazzoli P. Risk of reactivation of occult hepatitis B during immunotherapy in cancer treatment: myth, reality or new horizons? Future Oncol 2021; 17:1577-1580. [PMID: 33590770 DOI: 10.2217/fon-2020-1196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Angioletta Lasagna
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy
| | - Valentina Zuccaro
- Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy
| | - Paolo Sacchi
- Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy
| | - Silvia Chiellino
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy
| | - Raffaele Bruno
- Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy.,Department of Clinical, Surgical, Diagnostic & Pediatric Sciences, University of Pavia, Viale Camillo Golgi 19, Pavia, Italy
| | - Paolo Pedrazzoli
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy.,Department of Internal Medicine & Medical Therapy, University of Pavia, Viale Camillo Golgi 19, Pavia, Italy
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38
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Hao Q, Wang P, Dutta P, Chung S, Li Q, Wang K, Li J, Cao W, Deng W, Geng Q, Schrode K, Shaheen M, Wu K, Zhu D, Chen QH, Chen G, Elshimali Y, Vadgama J, Wu Y. Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA. Cell Death Dis 2020; 11:1052. [PMID: 33311440 PMCID: PMC7733521 DOI: 10.1038/s41419-020-03235-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 08/03/2020] [Indexed: 01/12/2023]
Abstract
The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.
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Affiliation(s)
- Qiongyu Hao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Piwen Wang
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Pranabananda Dutta
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Seyung Chung
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Qun Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, 200120, Shanghai, China
| | - Kun Wang
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, 510080, Guangzhou, China
| | - Jieqing Li
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, 510080, Guangzhou, China
| | - Wei Cao
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Wenhong Deng
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
- Department of General Surgery, Renmin Hospital of Wuhan University, 430060, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, 430060, Wuhan, China
| | - Katrina Schrode
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Magda Shaheen
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Ke Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Donghui Zhu
- Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA
| | - Qiao-Hong Chen
- Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA, 93740, USA
| | - Guanglin Chen
- Department of Chemistry, California State University, Fresno, 2555 E. San Ramon Avenue, M/S SB70, Fresno, CA, 93740, USA
| | - Yahya Elshimali
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA
| | - Jay Vadgama
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
| | - Yong Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA, 90095, USA.
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Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int J Mol Sci 2020; 21:ijms21218362. [PMID: 33171811 PMCID: PMC7664704 DOI: 10.3390/ijms21218362] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer deaths globally, of which hepatocellular carcinoma (HCC) is the major subtype. Viral hepatitis B and C infections, alcohol abuse, and metabolic disorders are multiple risk factors for liver cirrhosis and HCC development. Although great therapeutic advances have been made in recent decades, the prognosis for HCC patients remains poor due to late diagnosis, chemotherapy failure, and frequent recurrence. MicroRNAs (miRNAs) are endogenous, non-coding RNAs that regulate various molecular biological phenomena by suppressing the translation of target messenger RNAs (mRNAs). miRNAs, which often become dysregulated in malignancy, control cell proliferation, migration, invasion, and development in HCC by promoting or suppressing tumors. Exploring the detailed mechanisms underlying miRNA-mediated HCC development and progression can likely improve the outcomes of patients with HCC. This review summarizes the molecular and functional roles of miRNAs in the pathogenesis of HCC. Further, it elucidates the utility of miRNAs as novel biomarkers and therapeutic targets.
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Tang H, Gao Y, Li Z, Miao Y, Huang Z, Liu X, Xie L, Li H, Wen W, Zheng Y, Su W. The noncoding and coding transcriptional landscape of the peripheral immune response in patients with COVID-19. Clin Transl Med 2020; 10:e200. [PMID: 33135345 PMCID: PMC7548099 DOI: 10.1002/ctm2.200] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND COVID-19 is currently a global pandemic, but the response of human immune system to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unclear. Noncoding RNAs serve as immune regulators and thus may play a critical role in disease progression. METHODS We performed multi-transcriptome sequencing of both noncoding RNAs and mRNAs isolated from the red blood cell depleted whole blood of moderate and severe COVID-19 patients. The functions of noncoding RNAs were validated by analyses of the expression of downstream mRNAs. We further utilized the single-cell RNA-seq data of COVID-19 patients from Wilk et al. and Chua et al. to characterize noncoding RNA functions in different cell types. RESULTS We defined four types of microRNAs with different expression tendencies that could serve as biomarkers for COVID-19 progress. We also identified miR-146a-5p, miR-21-5p, miR-142-3p, and miR-15b-5p as potential contributors to the disease pathogenesis, possibly serving as biomarkers of severe COVID-19 and as candidate therapeutic targets. In addition, the transcriptome profiles consistently suggested hyperactivation of the immune response, loss of T-cell function, and immune dysregulation in severe patients. CONCLUSIONS Collectively, these findings provide a comprehensive view of the noncoding and coding transcriptional landscape of peripheral immune cells during COVID-19, furthering our understanding and offering novel insights into COVID-19 pathogenesis.
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Affiliation(s)
- Hao Tang
- Department of Respiratory and Critical Care Medicine Changzheng HospitalSecond Military Medical UniversityShanghaiChina
- Department of Critical CareWuhan Huo Shen Shan HospitalHubeiChina
| | - Yuehan Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Zhaohuai Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Yushan Miao
- Department of Respiratory and Critical Care Medicine Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Zhaohao Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Xiuxing Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Lihui Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - He Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Wen Wen
- National Center for Liver CancerSecond Military Medical UniversityShanghaiChina
| | - Yingfeng Zheng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat‐sen UniversityGuangzhouChina
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Lin Y, Zhao Z, Huang A, Lu M. Interplay between Cellular Autophagy and Hepatitis B Virus Replication: A Systematic Review. Cells 2020; 9:2101. [PMID: 32942717 PMCID: PMC7563265 DOI: 10.3390/cells9092101] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
Autophagy, a conserved process in which cells break down and destroy old, damaged, or abnormal proteins and other substances in the cytoplasm through lysosomal degradation, occurs via autophagosome formation and aids in the maintenance of intracellular homeostasis. Autophagy is closely associated with hepatitis B virus (HBV) replication and assembly. Currently, HBV infection is still one of the most serious public health issues worldwide. The unavailability of satisfactory therapeutic strategies for chronic HBV infection indicates an urgent need to elucidate the mechanisms underlying the pathogenesis of HBV infection. Increasing evidence has shown that HBV not only possesses the ability to induce incomplete autophagy but also evades autophagic degradation, indicating that HBV utilizes or hijacks the autophagy machinery for its own replication. Therefore, autophagy might be a crucial target pathway for controlling HBV infection. The definite molecular mechanisms underlying the association between cellular autophagy and HBV replication require further clarification. In this review, we have summarized and discussed the latest findings on the interplay between autophagy and HBV replication.
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Affiliation(s)
- Yong Lin
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Zhenyu Zhao
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Ailong Huang
- Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing 400016, China; (Z.Z.); (A.H.)
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
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Wang X, Lin Y, Liu S, Zhu Y, Lu K, Broering R, Lu M. O-GlcNAcylation modulates HBV replication through regulating cellular autophagy at multiple levels. FASEB J 2020; 34:14473-14489. [PMID: 32892442 DOI: 10.1096/fj.202001168rr] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 02/05/2023]
Abstract
O-GlcNAcylation is a form of posttranslational modification, and serves various functions, including modulation of location, stability, and activity for the modified proteins. O-linked-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies the cellular proteins with O-GlcNAc moiety. Early studies reported that the decreased O-GlcNAcylation regulates cellular autophagy, a process relevant for hepatitis B virus replication (HBV) and assembly. Therefore, we addressed the question how O-GlcNAcylation regulates cellular autophagy and HBV replication. Inhibition of OGT activity with a small molecule inhibitor OSMI-1 or silencing OGT significantly enhanced HBV replication and HBsAg production in hepatoma cells and primary human hepatocytes (PHHs). Western blotting analysis showed that inhibition of O-GlcNAcylation-induced endoplasmic reticulum (ER) stress and cellular autophagy, two processes subsequently leading to enhanced HBV replication. Importantly, the numbers of autophagosomes and the levels of autophagic markers LC3-II and SQSTM1/p62 in hepatoma cells were elevated after inhibition of O-GlcNAcylation. Further analysis revealed that inhibition of O-GlcNAcylation blocked autophagosome-lysosome fusion and thereby prevented autophagic degradation of HBV virions and proteins. Moreover, OSMI-1 further promoted HBV replication by inducing autophagosome formation via inhibiting the O-GlcNAcylation of Akt and mTOR. In conclusion, decreased O-GlcNAcylation enhanced HBV replication through increasing autophagosome formation at multiple levels, including triggering ER-stress, Akt/mTOR inhibition, and blockade of autophagosome-lysosome fusion.
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Affiliation(s)
- Xueyu Wang
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Yong Lin
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing, China
| | - Shi Liu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Ying Zhu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Kefeng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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43
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Yi G, Li H, Li Y, Zhao F, Ying Z, Liu M, Zhang J, Liu X. The protective effect of soybean protein-derived peptides on apoptosis via the activation of PI3K-AKT and inhibition on apoptosis pathway. Food Sci Nutr 2020; 8:4591-4600. [PMID: 32884739 PMCID: PMC7455986 DOI: 10.1002/fsn3.1776] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 12/11/2022] Open
Abstract
Soybean protein-derived peptides (SBP) are a rich source of various bioactive peptides with multiple health benefits. However, the prospective effects of SBP on human cells are still unclear. Therefore, this article investigated the effects of small molecular weight SBP on MG132-induced apoptosis in RAW264.7 cells. SBP inhibited MG132-induced apoptosis of RAW264.7 cells in a dose-dependent manner by flow cytometry. To further study its molecular mechanisms, Western blot analysis demonstrated that SBP could activate the PI3K-AKT pathway by increasing the phosphorylation of PI3K and AKT and inhibiting apoptosis pathway by downregulating the expressions of pro-apoptotic proteins of Bim, Bax, Fas, and Fasl and promoting the expressions of anti-apoptotic proteins of Bcl-xL and Bcl-2. These results indicated the protective effect of SBP on MG132-induced apoptosis in RAW264.7 cells.
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Affiliation(s)
- Guofu Yi
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - He Li
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - You Li
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - Fen Zhao
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - Zhiwei Ying
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - Menglan Liu
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - Jian Zhang
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
| | - Xinqi Liu
- Beijing Advanced Innovation Center for Food Nutrition and Human HealthBeijing Engineering and Technology Research Center of Food AdditivesBeijing Technology and Business University (BTBU)BeijingChina
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Lin X, Dinglin X, Cao S, Zheng S, Wu C, Chen W, Li Q, Hu Q, Zheng F, Wu Z, Lin DC, Yao Y, Xu X, Xie Z, Liu Q, Yao H, Hu H. Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade. Cell Rep 2020; 31:107753. [PMID: 32521278 DOI: 10.1016/j.celrep.2020.107753] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/20/2020] [Accepted: 05/19/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenomic alterations can give rise to various tumor-promoting properties, including therapeutic resistance of cancer cells. Here, we identify an lncRNA, BDNF-AS, whose overexpression is specifically driven by a MEF2A-regulated enhancer in endocrine-resistant and triple-negative breast cancer (TNBC). High levels of BDNF-AS in breast cancer tissues not only feature endocrine resistance in hormone receptor (HR)-positive patients but also correlate with poor outcomes in both HR-positive and TNBC patients. Mechanistically, BDNF-AS acts as a molecular scaffold to promote RNH1 protein degradation via TRIM21-mediated ubiquitination of RNH1 at K225. Subsequently, BDNF-AS abolishes RNH1-regulated and RISC-mediated mTOR mRNA decay, therefore sustaining the activation of mTOR signaling. Importantly, mTOR inhibitor, but not PI3K inhibitor, could reverse tamoxifen resistance induced by the overexpression of BDNF-AS. These results point toward a master regulatory role of an enhancer-activated cascade of BDNF-AS/RNH1/TRIM21/mTOR in endocrine resistance and malignant progression of breast cancer.
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Affiliation(s)
- Xiaorong Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Diagnosis and Treatment Center of Breast Diseases, Shantou Affiliated Hospital, Sun Yat-sen University, Shantou 515031, People's Republic of China
| | - Xiaoxiao Dinglin
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Siting Cao
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510030, People's Republic of China
| | - Senyou Zheng
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Cheng Wu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510663, People's Republic of China
| | - Wenying Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Qingjian Li
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Qian Hu
- Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Fang Zheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Zhiyong Wu
- Diagnosis and Treatment Center of Breast Diseases, Shantou Affiliated Hospital, Sun Yat-sen University, Shantou 515031, People's Republic of China
| | - De-Chen Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Yandan Yao
- Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Zhi Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510663, People's Republic of China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China
| | - Herui Yao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China.
| | - Hai Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China; Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People's Republic of China.
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3,4,5-Tri-O-caffeoylquinic acid methyl ester isolated from Lonicera japonica Thunb. Flower buds facilitates hepatitis B virus replication in HepG2.2.15 cells. Food Chem Toxicol 2020; 138:111250. [PMID: 32156566 DOI: 10.1016/j.fct.2020.111250] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/05/2020] [Accepted: 03/06/2020] [Indexed: 12/26/2022]
Abstract
Caffeoylquinic acids are well known for their prominent antiviral activities. Beyond our expectations, we initially found 3,4,5-Tri-O-caffeoylquinic acid methyl ester (3,4,5-CQME) from L. japonica can facilitate HBV DNA and antigens secretion. This study aimed to investigate its underlying molecular mechanism. The results indicate that 3,4,5-CQME signally increased intracellular and secreted HBsAg levels by more than two times in HepG2.2.15 cells and HepAD38 cells. Furthermore, levels of HBeAg, HBV DNA and RNA were significantly enhanced by 3-day 3,4,5-CQME treatment; it didn't directly affect intracellular cccDNA amount, although it slightly increased cccDNA accumulation as a HBV DNA replication feedback. In addition, treatment with 3,4,5-CQME significantly induced HBx protein expression for viral replication. We utilized a phospho-antibody assay to profile the signal transduction change by 3,4,5-CQME to illuminate its molecular mechanism. The results indicate that treatment with 3,4,5-CQME activated AKT/mTOR, MAPK and NF-κB pathways verified by immunoblot. Moreover, 3,4,5-CQME upregulated the expression of nuclear transcriptional factors PGC1α and PPARα. In short, 3,4,5-CQME promotes HBV transcription and replication by upregulating HBx expression and activating HBV transcriptional regulation-related signals. As caffeoylquinic acids are widely present in traditional Chinese medicines, the risk of intaking caffeoylquinic acids-containing herbs for hepatitis B treatment requires more evaluation and further research.
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Lin Y, Wu C, Wang X, Liu S, Zhao K, Kemper T, Yu H, Li M, Zhang J, Chen M, Zhu Y, Chen X, Lu M. Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Autophagy 2020; 16:548-561. [PMID: 31204557 PMCID: PMC6999643 DOI: 10.1080/15548627.2019.1632104] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/27/2019] [Accepted: 05/27/2019] [Indexed: 12/12/2022] Open
Abstract
Glucosamine (GlcN), a dietary supplement widely utilized to promote joint health and effective in the treatment of osteoarthritis, is an effective macroautophagy/autophagy activator in vitro and in vivo. Previous studies have shown that autophagy is required for hepatitis B virus (HBV) replication and envelopment. The objective of this study was to determine whether and how GlcN affects HBV replication, using in vitro and in vivo experiments. Our data demonstrated that HBsAg production and HBV replication were significantly increased by GlcN treatment. Confocal microscopy and western blot analysis showed that the amount of autophagosomes and the levels of autophagic markers MAP1LC3/LC3-II and SQSTM1 were clearly elevated by GlcN treatment. GlcN strongly blocked autophagic degradation of HBV virions and proteins by inhibiting lysosomal acidification through its amino group. Moreover, GlcN further promoted HBV replication by inducing autophagosome formation via feedback inhibition of mechanistic target of rapamycin kinase complex 1 (MTORC1) signaling in an RRAGA (Ras related GTP binding A) GTPase-dependent manner. In vivo, GlcN application promoted HBV replication and blocked autophagic degradation in an HBV hydrodynamic injection mouse model. In addition, GlcN promoted influenza A virus, enterovirus 71, and vesicular stomatitis virus replication in vitro. In conclusion, GlcN efficiently promotes virus replication by inducing autophagic stress through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Thus, there is a potential risk of enhanced viral replication by oral GlcN intake in chronically virally infected patients.Abbreviations: ACTB: actin beta; ATG: autophagy-related; CMIA: chemiluminescence immunoassay; ConA: concanavalin A; CQ: chloroquine; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; EV71: enterovirus 71; GalN: galactosamine; GFP: green fluorescence protein; GlcN: glucosamine; GNPNAT1: glucosamine-phosphate N-acetyltransferase 1; HBP: hexosamine biosynthesis pathway; HBV: hepatitis B virus; HBcAg: hepatitis B core antigen; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis B e antigen; HBV RI: hepatitis B replicative intermediate; IAV: influenza A virus; LAMP1: lysosomal associated membrane protein 1; LAMTOR: late endosomal/lysosomal adaptor, MAPK and MTOR activator; ManN: mannosamine; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PHH: primary human hepatocyte; RAB7: RAB7A, member RAS oncogene family; RPS6KB1: ribosomal protein S6 kinase B1; RRAGA: Ras related GTP binding A; RT-PCR: reverse transcriptase polymerase chain reaction; SEM: standard error of the mean; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; UAP1: UDP-N-acetylglucosamine pyrophosphorylase 1; VSV: vesicular stomatitis virus.
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Affiliation(s)
- Yong Lin
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Chunchen Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, China
| | - Xueyu Wang
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Shi Liu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Kaitao Zhao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, China
| | - Thekla Kemper
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Haisheng Yu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Mengqi Li
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Mingzhou Chen
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Ying Zhu
- State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:ijms21041266. [PMID: 32070029 PMCID: PMC7072933 DOI: 10.3390/ijms21041266] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and occurs mainly in patients with liver cirrhosis. The mammalian target of rapamycin (mTOR) signaling pathway is involved in many hallmarks of cancer including cell growth, metabolism re-programming, proliferation and inhibition of apoptosis. The mTOR pathway is upregulated in HCC tissue samples as compared with the surrounding liver cirrhotic tissue. In addition, the activation of mTOR is more intense in the tumor edge, thus reinforcing its role in HCC proliferation and spreading. The inhibition of the mTOR pathway by currently available pharmacological compounds (i.e., sirolimus or everolimus) is able to hamper tumor progression both in vitro and in animal models. The use of mTOR inhibitors alone or in combination with other therapies is a very attractive approach, which has been extensively investigated in humans. However, results are contradictory and there is no solid evidence suggesting a true benefit in clinical practice. As a result, neither sirolimus nor everolimus are currently approved to treat HCC or to prevent tumor recurrence after curative surgery. In the present comprehensive review, we analyzed the most recent scientific evidence while providing some insights to understand the gap between experimental and clinical studies.
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Affiliation(s)
- Gustavo Ferrín
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
| | - Marta Guerrero
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Víctor Amado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Manuel Rodríguez-Perálvarez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
- Correspondence: ; Tel.: +34-617854692
| | - Manuel De la Mata
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, 14004 Córdoba, Spain; (G.F.); (M.G.); (V.A.); (M.D.l.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 14004 Córdoba, Spain
- Department of Hepatology and Liver Transplantaton, Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
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Chen T, Shao S, Li W, Liu Y, Cao Y. The circular RNA hsa-circ-0072309 plays anti-tumour roles by sponging miR-100 through the deactivation of PI3K/AKT and mTOR pathways in the renal carcinoma cell lines. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 47:3638-3648. [PMID: 31456425 DOI: 10.1080/21691401.2019.1657873] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Aims: To explore the roles and regulatory mechanisms of the circular RNA (circRNA)-hsa-circ-0072309 in CAKI-1 and ACHN cells. Methods: CAKI-1 and ACHN cells were transfected with hsa-circ-0072309 overproduction vector (circRNA) and microRNA-100 (miR-100) mimic or the corresponding controls. Cell viability was detected with the CCK-8. The protein expression levels of p53, c-Myc, cleaved-caspase-3/9, matrix metalloproteinase (MMP)-2/9, vimentin, AKT, PI3K and mTOR were individually determined through western blot. qRT-PCR was used to examine the expressions of hsa-circ-0072309 and miR-100. The apoptotic rate and the migration or invasion rates were separately determined by the annexin v-FITC/PI with a flow cytometer and modified two-chamber migration assay or millicell hanging cell culture. Results: The hsa-circ-0072309 was poorly expressed in tumor tissue. Abundant hsa-circ-0072309 induced the inhibitions of cell proliferation, migration and invasion, as well as the PI3K/AKT and the mTOR cascades but enhancement of apoptosis. circRNA stimulated the down-regulation of miR-100, which was low-expressed in tumour tissue and whose overproduction abolished the impacts of circRNA on these elements mentioned above. Conclusion: The hsa-circ-0072309 played anti-tumour roles by targeting miR-100 by blocking the PI3K/AKT and mTOR cascades in the CAKI-1 and ACHN cell lines.
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Affiliation(s)
- Tao Chen
- Department of Urology, Affiliated Hospital of Qingdao University , Qingdao , Shandong , China
| | - Shixiu Shao
- Department of Urology, Affiliated Hospital of Qingdao University , Qingdao , Shandong , China
| | - Wenxian Li
- Department of Urology, Affiliated Hospital of Qingdao University , Qingdao , Shandong , China
| | - Yong Liu
- Department of Urology, Affiliated Hospital of Qingdao University , Qingdao , Shandong , China
| | - Yanwei Cao
- Department of Urology, Affiliated Hospital of Qingdao University , Qingdao , Shandong , China
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49
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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.
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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
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50
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Lin Y, Wu C, Wang X, Kemper T, Squire A, Gunzer M, Zhang J, Chen X, Lu M. Hepatitis B virus is degraded by autophagosome-lysosome fusion mediated by Rab7 and related components. Protein Cell 2019; 10:60-66. [PMID: 29876903 PMCID: PMC6321816 DOI: 10.1007/s13238-018-0555-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Yong Lin
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45117, Essen, Germany
| | - Chunchen Wu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, 430071, China
| | - Xueyu Wang
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45117, Essen, Germany
| | - Thekla Kemper
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45117, Essen, Germany
| | - Anthony Squire
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45117, Essen, Germany
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45117, Essen, Germany
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xinwen Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Science, Wuhan, 430071, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45117, Essen, Germany.
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