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1
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Wei H, Bi Y, Liao C, Huang Y, Lian Y. Plasma microRNA-15a/16-1 serves as a non-invasive indicator of liver fibrosis severity in individuals with chronic hepatitis B. Noncoding RNA Res 2024; 9:1342-1350. [PMID: 39247146 PMCID: PMC11380177 DOI: 10.1016/j.ncrna.2024.08.004] [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: 06/21/2024] [Revised: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 09/10/2024] Open
Abstract
Background The lack of effective non-invasive diagnostic methods for liver fibrosis hinders timely treatment for chronic hepatitis B (CHB) patients, leading to the progression of advanced liver disease. Circulating microRNAs offer a non-invasive approach to fibrosis assessment. MicroRNA-15a/16-1 (miR-15a/16) was reported to be implicated in fibrosis development, but the role of plasma miR-15a/16 in liver fibrosis assessment remains poorly understood. This study explored the importance of plasma miR-15a/16 in assessing liver fibrosis severity of CHB patients. Methods Quantitative PCR was utilized to measure the levels of plasma miR-15a/16 in 435 patients with CHB and 74 healthy controls. We assessed the correlation between plasma miR-15a/16 levels and liver fibrosis and cirrhosis using Pearson correlation coefficients, multivariate linear and logistic regression models, and smooth curve fitting. Utilizing the receiver operating characteristic (ROC) curve, we examined the diagnostic potential of plasma miR-15a/16 in severe fibrosis and cirrhosis. Results Plasma levels of miR-15a/16 in patients with CHB were significantly reduced compared to those in healthy controls. In the CHB cohort, levels were notably decreased in individuals with severe fibrosis or cirrhosis compared to those without severe fibrosis or cirrhosis. Plasma miR-15a/16 levels exhibited a negative relationship with the severity of liver fibrosis, gradually decreasing as the histological fibrosis stage progressed from S0 to S4. Reduced levels of plasma miR-15a/16 were linked to an elevated risk of severe liver fibrosis (miR-15a: odds ratio [OR] = 0.243; 95 % confidence interval [CI]: 0.138, 0.427; miR-16: OR = 0.201; 95 % CI: 0.097, 0.417) and cirrhosis (miR-15a: OR = 0.153; 95 % CI: 0.079, 0.298; miR-16: OR = 0.064; 95 % CI: 0.025, 0.162). MiR-15a achieved an area under the ROC curve of 0.886 and 0.832 for detecting moderate-to-severe fibrosis (S2-S4) and cirrhosis, respectively. MiR-16 demonstrated similar diagnostic values. Conclusion Plasma miR-15a/16 levels were negatively correlated with the severity of liver fibrosis in CHB patients and could serve as a new non-invasive indicator in evaluating liver fibrosis.
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Affiliation(s)
- Huan Wei
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Chunhong Liao
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuehua Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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2
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [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: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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3
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Sartorius K, Sartorius B, Winkler C, Chuturgoon A, Shen TW, Zhao Y, An P. Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study. Int J Mol Sci 2024; 25:975. [PMID: 38256049 PMCID: PMC10815595 DOI: 10.3390/ijms25020975] [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: 11/07/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2001, South Africa
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, QLD 4102, Australia
| | - Cheryl Winkler
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
| | - Tsai-Wei Shen
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Yongmei Zhao
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Ping An
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
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4
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Ramakrishnan K, Babu S, Shaji V, Soman S, Leelamma A, Rehman N, Raju R. Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:581-597. [PMID: 38064540 DOI: 10.1089/omi.2023.0171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.
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Affiliation(s)
| | - Sreeranjini Babu
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Vineetha Shaji
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
| | - Sowmya Soman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Anila Leelamma
- Department of Biochemistry, NSS College, Nilamel, Kollam, Kerala, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), Mangalore, India
- Centre for Systems Biology and Molecular Medicine (CSBMM), Yenepoya Research Centre, Yenepoya (Deemed to be University), Deralakatte, Mangalore, Karnataka, India
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5
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Toro AU, Shukla SK, Bansal P. Emerging role of MicroRNA-Based theranostics in Hepatocellular Carcinoma. Mol Biol Rep 2023; 50:7681-7691. [PMID: 37418086 DOI: 10.1007/s11033-023-08586-z] [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: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023]
Abstract
Hepatocellular carcinoma (HCC), with its high mortality and short survival rate, continues to be one of the deadliest malignancies despite relentless efforts and several technological advances. The poor prognosis of HCC and the few available treatments are to blame for the low survival rate, which emphasizes the importance of creating new, effective diagnostic markers and innovative therapy strategies. In-depth research is being done on the potent biomarker miRNAs, a special class of non-coding RNA and has shown encouraging results in the early identification and treatment of HCC in order to find more viable and successful therapeutics for the disease. It is beyond dispute that miRNAs control cell differentiation, proliferation, and survival and, depending on the genes they target, can either promote tumorigenesis or suppress it. Given the vital role miRNAs play in the biological system and their potential to serve as ground-breaking treatments for HCC, more study is required to fully examine their theranostic potential.
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Affiliation(s)
- Abdulhakim Umar Toro
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India
| | - Sudheesh K Shukla
- Department of Biomedical Engineering, Shobhit institute of Engineering and Technology (Deemed to-be-University), Modipuram, Meerut, 250110, India.
| | - Parveen Bansal
- University Centre of Excellence in Research, Baba Farid University of Health Sciences, Faridkot, 151203, India.
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6
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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7
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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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8
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Ishaq Y, Ikram A, Alzahrani B, Khurshid S. The Role of miRNAs, circRNAs and Their Interactions in Development and Progression of Hepatocellular Carcinoma: An Insilico Approach. Genes (Basel) 2022; 14:genes14010013. [PMID: 36672755 PMCID: PMC9858589 DOI: 10.3390/genes14010013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/06/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of malignant tumor. miRNAs are noncoding RNAs and their differential expression patterns are observed in HCC-induced by alcoholism, HBV and HCV infections. By acting as a competing endogenous RNA (ceRNA), circRNA regulates the miRNA function, indirectly controlling the gene expression and leading to HCC progression. In the present study, data mining was performed to screen out all miRNAs and circRNA involved in alcohol, HBV or HCV-induced HCC with statistically significant (≤0.05%) expression levels reported in various studies. Further, the interaction of miRNAs and circRNA was also investigated to explore their role in HCC due to various causative agents. Together, these study data provide a deeper understanding of the circRNA-miRNA regulatory mechanisms in HCC. These screened circRNA, miRNA and their interactions can be used as prognostic biomarkers or therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore 54000, Pakistan
- Correspondence:
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka 42421, Saudi Arabia
| | - Sana Khurshid
- Department of Molecular Biology, Virtual University of Pakistan, 1-Davis Road, Lahore 54000, Pakistan
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9
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Zhang C, Dai D, Zhang W, Yang W, Guo Y, Wei Q. Role of m6A RNA methylation in the development of hepatitis B virus-associated hepatocellular carcinoma. J Gastroenterol Hepatol 2022; 37:2039-2050. [PMID: 36066844 DOI: 10.1111/jgh.15999] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 05/10/2022] [Accepted: 09/03/2022] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy that can be developed from hepatitis B and cirrhosis. Many pathophysiological alterations, including hepatitis B virus (HBV) DNA integration, oxidative stress, cytokine release, telomerase homeostasis, mitochondrial damage, epigenetic modification, and tumor microenvironment, are involved in the biological process from hepatitis B to cirrhosis and HCC. N6-methyladenosine (m6A), as an epitranscriptomic modification of RNAs, can regulate the stability, splicing, degradation, transcription, and translation of downstream target RNAs in HBV and liver cancer cells. m6A regulators (writers, erasers, and readers) play an important role in the pathogenesis of HBV-associated HCC by regulating cell proliferation, apoptosis, migration, autophagy, differentiation, inflammation, angiogenesis, and tumor microenvironment. This review summarizes the current progress of m6A methylation in the molecular mechanisms, biological functions, and potential clinical implications of HBV-associated HCC.
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Affiliation(s)
- Cheng Zhang
- Department of Medical Oncology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.,Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dongjun Dai
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wangjian Zhang
- School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenjun Yang
- Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Yinglu Guo
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qichun Wei
- Department of Radiation Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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10
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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11
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Letafati A, Najafi S, Mottahedi M, Karimzadeh M, Shahini A, Garousi S, Abbasi-Kolli M, Sadri Nahand J, Tamehri Zadeh SS, Hamblin MR, Rahimian N, Taghizadieh M, Mirzaei H. MicroRNA let-7 and viral infections: focus on mechanisms of action. Cell Mol Biol Lett 2022; 27:14. [PMID: 35164678 PMCID: PMC8853298 DOI: 10.1186/s11658-022-00317-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.
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Affiliation(s)
- Arash Letafati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Najafi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehran Mottahedi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Karimzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahini
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Setareh Garousi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028 South Africa
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
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12
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Tsuge M. The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection. Liver Int 2021; 41:2836-2848. [PMID: 34559952 DOI: 10.1111/liv.15065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface-, hepatitis B core-, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next-generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV-associated hepatocarcinogenesis are discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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13
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Cui D, Li W, Jiang D, Wu J, Xie J, Wu Y. Advances in Multi-Omics Applications in HBV-Associated Hepatocellular Carcinoma. Front Med (Lausanne) 2021; 8:754709. [PMID: 34660653 PMCID: PMC8514776 DOI: 10.3389/fmed.2021.754709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/31/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) specifically infects liver cells, leading to progressive liver cirrhosis and significantly increasing the risk of hepatocellular carcinoma (HCC). The maturity of sequencing technology, improvement in bioinformatics data analysis and progress of omics technologies had improved research efficiency. The occurrence and progression of HCC are affected by multisystem and multilevel pathological changes. With the application of single-omics technologies, including genomics, transcriptomics, metabolomics and proteomics in tissue and body fluid samples, and even the novel development of multi-omics analysis on a single-cell platform, HBV-associated HCC changes can be better analyzed. The review summarizes the application of single omics and combined analysis of multi-omics data in HBV-associated HCC and proposes the importance of multi-omics analysis in the type of HCC, which provide the possibility for the precise diagnosis and therapy of HBV-associated HCC.
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Affiliation(s)
- Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Li
- Center of Research Laboratory, The First People's Hospital of Lianyungang, Lianyungang, China
| | - Daixi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Jue Xie
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yingping Wu
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
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14
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Zhu M, Liang Z, Pan J, Zhang X, Xue R, Cao G, Hu X, Gong C. Hepatocellular carcinoma progression mediated by hepatitis B virus-encoded circRNA HBV_circ_1 through interaction with CDK1. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 25:668-682. [PMID: 34589285 PMCID: PMC8463320 DOI: 10.1016/j.omtn.2021.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 08/10/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) produces circular RNA (circRNA), whose functions have not yet been clearly elucidated. In this study, a novel circRNA HBV_circ_1 produced by HBV was identified in HBV-positive HepG2.2.15 cells and HBV-related hepatocellular carcinoma (HCC) tissue (HCCT). Microarray analysis of 68 HCCT samples showed that HBV_circ_1 abundance was significantly higher than that in paracancerous tissues. In addition, survival rate of HBV_circ_1-positive patients was significantly lower compared with HBV_circ_1-negative patients. Transient expression indicated that HBV_circ_1 enhanced cell proliferation, migration, and invasion and inhibited apoptosis in vitro. Furthermore, ectopical HBV_circ_1 expression increased tumor size in vivo. HBV_circ_1 was confirmed to interact with cyclin-dependent kinase 1 (CDK1) to regulate cell proliferation. These results suggest that HCC progression may be promoted by interaction of HBV_circ_1 with CDK1. Our data not only showed a novel clue to understand carcinogenesis and progress of HBV-related HCC but also provided a new target for the development of therapeutic drugs.
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Affiliation(s)
- Min Zhu
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Zi Liang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Jun Pan
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Xing Zhang
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Renyu Xue
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Guangli Cao
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Xiaolong Hu
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
| | - Chengliang Gong
- School of Biology & Basic Medical Science, Soochow University, Suzhou 215123, China
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15
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Ghosh S, Chakraborty A, Banerjee S. Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis. Front Microbiol 2021; 12:678537. [PMID: 34526974 PMCID: PMC8435854 DOI: 10.3389/fmicb.2021.678537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.
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Affiliation(s)
| | | | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
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16
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Bousali M, Papatheodoridis G, Paraskevis D, Karamitros T. Hepatitis B Virus DNA Integration, Chronic Infections and Hepatocellular Carcinoma. Microorganisms 2021; 9:1787. [PMID: 34442866 PMCID: PMC8398950 DOI: 10.3390/microorganisms9081787] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/13/2021] [Accepted: 08/18/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) is an Old World virus with a high mutation rate, which puts its origins in Africa alongside the origins of Homo sapiens, and is a member of the Hepadnaviridae family that is characterized by a unique viral replication cycle. It targets human hepatocytes and can lead to chronic HBV infection either after acute infection via horizontal transmission usually during infancy or childhood or via maternal-fetal transmission. HBV has been found in ~85% of HBV-related Hepatocellular Carcinomas (HCC), and it can integrate the whole or part of its genome into the host genomic DNA. The molecular mechanisms involved in the HBV DNA integration is not yet clear; thus, multiple models have been described with respect to either the relaxed-circular DNA (rcDNA) or the double-stranded linear DNA (dslDNA) of HBV. Various genes have been found to be affected by HBV DNA integration, including cell-proliferation-related genes, oncogenes and long non-coding RNA genes (lincRNAs). The present review summarizes the advances in the research of HBV DNA integration, focusing on the evolutionary and molecular side of the integration events along with the arising clinical aspects in the light of WHO's commitment to eliminate HBV and viral hepatitis by 2030.
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Affiliation(s)
- Maria Bousali
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - George Papatheodoridis
- Department of Gastroenterology, “Laiko” General Hospital of Athens, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitrios Paraskevis
- Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Laboratory of Medical Microbiology, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
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17
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Sekiba K, Otsuka M, Koike K. Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver. Semin Liver Dis 2021; 41:142-149. [PMID: 33984871 DOI: 10.1055/s-0041-1723033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
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Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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18
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Abo-Al-Ela HG. The emerging regulatory roles of noncoding RNAs in immune function of fish: MicroRNAs versus long noncoding RNAs. Mol Genet Genomics 2021; 296:765-781. [PMID: 33904988 DOI: 10.1007/s00438-021-01786-x] [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] [Received: 11/19/2020] [Accepted: 04/12/2021] [Indexed: 02/06/2023]
Abstract
The genome could be considered as raw data expressed in proteins and various types of noncoding RNAs (ncRNAs). However, a large portion of the genome is dedicated to ncRNAs, which in turn represent a considerable amount of the transcriptome. ncRNAs are modulated on levels of type and amount whenever any physiological process occurs or as a response to external modulators. ncRNAs, typically forming complexes with other partners, are key molecules that influence diverse cellular processes. Based on the knowledge of mammalian biology, ncRNAs are known to regulate and control diverse trafficking pathways and cellular activities. Long noncoding RNAs (lncRNAs) notably have diverse and more regulatory roles than microRNAs. Expanding these studies on fish has derived the same conclusion with relevance to other species, including invertebrates, explored the potentials to harness such types of RNA to further understand the biology of such organisms, and opened gates for applying recent technologies, such as RNA interference and delivering micromolecules as microRNAs to living cells and possibly to target organs. These technologies should improve aquaculture productivity and fish health, as well as help understand fish biology.
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Affiliation(s)
- Haitham G Abo-Al-Ela
- Genetics and Biotechnology, Department of Aquaculture, Faculty of Fish Resources, Suez University, 43518, Suez, Egypt.
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19
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Jia H, Yu F, Li B, Gao Z. Actin-binding protein Anillin promotes the progression of gastric cancer in vitro and in mice. J Clin Lab Anal 2021; 35:e23635. [PMID: 33089886 PMCID: PMC7891526 DOI: 10.1002/jcla.23635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/30/2020] [Accepted: 10/03/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND To detect the expression levels of actin-binding protein anillin (ANLN) in human gastric cancer (GC) tissues and explore the possible involvement of ANLN in GC cell proliferation, migration, and invasion. METHODS The bioinformation analysis was performed in TCGA database to explore the expression of ANLN in human GC tissues and the difference of ANLN expression between multiple types of cancers. IHC assays and clinical pathological analysis were performed to confirm ANLN expression and its correlation with clinical features of GC patients. Colony formation, CCK-8, wound closure, and transwell assays were performed to detect its effects on GC cell proliferation, migration, and invasion in vitro. Tumor growth was also measured using a xenograft animal model. RESULTS We found the high expression of ANLN in human GC tissues based on the results from TCGA database and IHC staining. We further noticed ANLN depletion resulted in the inhibition of GC cell proliferation, migration, and invasion. Our data further confirmed that ANLN contributed to tumor growth of GC cells in vivo. CONCLUSIONS We confirmed the involvement of ANLN in GC progression and thought ANLN could serve as a promising therapeutic target for GC.
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Affiliation(s)
- Huanxia Jia
- School of MedicineXuchang UniversityXuchangChina
| | - Fang Yu
- School of MedicineXuchang UniversityXuchangChina
| | - Baoyu Li
- Department of General SurgeryThe Secondary Hospital of Tianjin Medical UniversityTianjinChina
| | - Zhenya Gao
- School of MedicineXuchang UniversityXuchangChina
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20
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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21
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Duraisamy GS, Bhosale D, Lipenská I, Huvarova I, Růžek D, Windisch MP, Miller AD. Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going? Viruses 2020; 12:v12090998. [PMID: 32906840 PMCID: PMC7552065 DOI: 10.3390/v12090998] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether.
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Affiliation(s)
- Ganesh Selvaraj Duraisamy
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Dattatry Bhosale
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Lipenská
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Huvarova
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Daniel Růžek
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005 České Budějovice, Czech Republic
| | - Marc P. Windisch
- Applied Molecular Virology Laboratory, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea;
- Division of Bio-Medical Science and Technology, University of Science and Technology, Daejeon 305-350, Korea
| | - Andrew D. Miller
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemědělská 1, Černá Pole, CZ-61300 Brno, Czech Republic
- KP Therapeutics (Europe) s.r.o., Purkyňova 649/127, CZ-61200 Brno, Czech Republic
- Correspondence:
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22
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Xia Y, Guo H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Res 2020; 180:104824. [PMID: 32450266 PMCID: PMC7387223 DOI: 10.1016/j.antiviral.2020.104824] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/03/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide with about 257 million individuals chronically infected. Current therapies can effectively control HBV replication and slow down disease progress, but cannot cure HBV infection. Upon infection, HBV establishes a pool of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. The cccDNA exists as a minichromosome and resists to antivirals, thus a therapeutic eradication of cccDNA from the infected cells remains unattainable. In this review, we summarize the state of knowledge on the mechanisms underlying cccDNA formation and regulation, and discuss the possible strategies that may contribute to the eradication of HBV through targeting cccDNA.
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Affiliation(s)
- Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
| | - Haitao Guo
- UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
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23
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Sartorius K, Swadling L, An P, Makarova J, Winkler C, Chuturgoon A, Kramvis A. The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways. Viruses 2020; 12:v12070746. [PMID: 32664401 PMCID: PMC7412373 DOI: 10.3390/v12070746] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
- UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
- Correspondence:
| | - Leo Swadling
- Division of Infection and Immunity, University College London, London WC1E6BT, UK;
| | - Ping An
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Julia Makarova
- National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia;
| | - Cheryl Winkler
- Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA; (P.A.); (C.W.)
| | - Anil Chuturgoon
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa;
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa;
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Ochi M, Otsuka M, Maruyama R, Koike K. HBx increases EGFR expression by inhibiting miR129-5p function. Biochem Biophys Res Commun 2020; 529:198-203. [PMID: 32703411 DOI: 10.1016/j.bbrc.2020.06.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/04/2020] [Indexed: 12/29/2022]
Abstract
Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy.
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Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Reo Maruyama
- Project for Cancer Epigenomics, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
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25
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Bandopadhyay M, Bharadwaj M. Exosomal miRNAs in hepatitis B virus related liver disease: a new hope for biomarker. Gut Pathog 2020; 12:23. [PMID: 32346400 PMCID: PMC7183117 DOI: 10.1186/s13099-020-00353-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/31/2020] [Indexed: 02/06/2023] Open
Abstract
The World Health Organisation, in its 2019 progress report on HIV, viral hepatitis and STDs indicates that 257 million people are afflicted with chronic HBV infections, of which, 1 million patients lose their lives every year due to HBV related chronic liver diseases including serious complications such as liver cirrhosis and hepatocellular carcinoma. The course of HBV infection and associated liver injury depend on several host factors, genetic variability of the virus, and the host viral interplay. The challenge of medical science is the early diagnosis/identification of the potential for development of fatal complications like liver cirrhosis and HCC so that timely medical intervention can improve the chances of survival. Currently, neither the vaccination regime nor the diagnostic methods are completely effective as reflected in the high number of annual deaths. It is evident from numerous publications that microRNAs (miRNAs) are the critical regulators of gene expression and various cellular processes like proliferation, development, differentiation, apoptosis and tumorigenesis. Expressions of these diminutive RNAs are significantly affected in cancerous tissues as a result of numerous genomic and epigenetic modifications. Exosomes are membrane-derived vesicles (30–100 nm) secreted by normal as well as malignant cells, and are present in all body fluids. They are recognized as critical molecules in intercellular communication between cells through horizontal transfer of information via their cargo, which includes selective proteins, mRNAs and miRNAs. Exosomal miRNAs are transferred to recipient cells where they can regulate target gene expression. This provides an insight into the elementary biology of cancer progression and therefore the development of therapeutic approaches. This concise review outlines various on-going research on miRNA mediated regulation of HBV pathogenesis with special emphasis on association of exosomal miRNA in advanced stage liver disease like hepatocellular carcinoma. This review also discusses the possible use of exosomal miRNAs as biomarkers in the early detection of HCC and liver cirrhosis.
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Affiliation(s)
- Manikankana Bandopadhyay
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
| | - Mausumi Bharadwaj
- Molecular Genetics and Biochemistry, National Institute of Cancer Prevention and Research (NICPR), Indian Council of Medical Research (ICMR), Noida, Uttar Pradesh 201301 India
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26
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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27
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Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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28
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Lian YF, Huang YL, Wang JL, Deng MH, Xia TL, Zeng MS, Chen MS, Wang HB, Huang YH. Anillin is required for tumor growth and regulated by miR-15a/miR-16-1 in HBV-related hepatocellular carcinoma. Aging (Albany NY) 2019; 10:1884-1901. [PMID: 30103211 PMCID: PMC6128427 DOI: 10.18632/aging.101510] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 07/27/2018] [Indexed: 12/26/2022]
Abstract
Anillin (ANLN) is an actin-binding protein essential for assembly of cleavage furrow during cytokinesis. Although reportedly overexpressed in various human cancers, its role in hepatocellular carcinoma (HCC) is unclear. To address this issue, we confirmed that in 436 liver samples obtained from surgically removed HCC tissues, higher ANLN expression was detected in tumor tissues than in adjacent non-tumor tissues of HCC as measured by immunohistochemistry, quantitative real-time PCR and western blotting. Correlation and Kaplan-Meier analysis revealed that patients with higher ANLN expression were associated with worse clinical outcomes and a shorter survival time, respectively. Moreover, ANLN inhibition resulted in growth restraint, reduced colony formation, and a lower sphere number in suspension culture. Mechanistically, ANLN deficiency induced an increasing number of multinucleated cells along with the activation of apoptosis signaling and DNA damage checkpoints. Furthermore, HBV infection increased ANLN expression by inhibiting the expression of microRNA (miR)-15a and miR-16-1, both of which were identified as ANLN upstream repressors by targeting its 3’ untranslated region. Thus, we conclude that ANLN promotes tumor growth by ways of decreased apoptosis and DNA damage. Expression level of ANLN significantly influences the survival probability of HCC patients and may represent a promising prognostic biomarker.
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Affiliation(s)
- Yi-Fan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan-Lin Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jia-Liang Wang
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mei-Hai Deng
- Department of Hepatobiliary Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tian-Liang Xia
- State Key Laboratory of Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Min-Shan Chen
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hong-Bo Wang
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yue-Hua Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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29
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Wu Y, Wen J, Xiao W, Zhang B. Pregenomic RNA: How to assist the management of chronic hepatitis B? Rev Med Virol 2019; 29:e2051. [PMID: 31074177 DOI: 10.1002/rmv.2051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/31/2019] [Accepted: 04/01/2019] [Indexed: 12/17/2022]
Abstract
Pregenomic RNA (pgRNA) is an emerging serological marker for chronic hepatitis B virus (HBV) infection. While pgRNA is principally the template for viral proteins and viral DNAs, additional novel functions for the serum pgRNA have recently been described. These results extend for pgRNA a regulatory function in the viral life cycle and potentially a role in pathogenesis. Here, we review the diverse roles of pgRNA in HBV replication and pathogenesis, emphasizing how the unique structure of this RNA is key to its various functions. We focus in particular on the role of HBV pgRNA in guiding antiviral therapy including nucleot(s)ide analog interruption and role as a marker of cure with new curative therapies. We also briefly allude to the emerging niche for new direct-acting or indirect-acting antivirals targeting pgRNA.
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Affiliation(s)
- Yongbin Wu
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jian Wen
- Department of Hematology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Weiwei Xiao
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Bao Zhang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
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30
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Fu L, Fu X, Mo J, Li X, Li R, Peng S. miR-146a-5p enhances hepatitis B virus replication through autophagy to promote aggravation of chronic hepatitis B. IUBMB Life 2019; 71:1336-1346. [PMID: 31018043 DOI: 10.1002/iub.2044] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 12/20/2022]
Abstract
The objective of this study was to investigate the mechanism by which miR-146a-5p mediated autophagy and hepatitis B virus (HBV) replication. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the mRNA expression levels of miR-146a-5p and X-linked inhibitor of apoptosis (XIAP) and HBV DNA and RNA. The protein expression levels of XIAP, IκB-α, murine double minute 2 oncoprotein (MDM2) and p53, the phosphorylation of p65, and the conversion of light chain 3 (LC3)-I to LC3-II were detected by Western blotting. The expression levels of XIAP, HBV-related pro-inflammatory cytokines, and serum markers were detected by enzyme-linked immunosorbent assay (ELISA). miR-146a-5p was highly expressed in patients with chronic hepatitis B (CHB) and HBV-expressing hepatocytes. HBV core protein (HBc) and HBV X protein (HBx) were responsible for its effects on miR-146a-5p expression through the nuclear factor-κB pathway. Furthermore, the miR-146a-5p inhibitor suppressed autophagic response and HBV replication as well as MDM2/p53 expression. Luciferase reporter assay confirmed that XIAP was a direct target of miR-146a-5p. We therefore demonstrated that miR-146a-5p mediated positive feedback loop by regulating autophagy-induced HBV replication via targeting the XIAP-mediated MDM2/p53 axis. © 2019 IUBMB Life, 71(9):1336-1346, 2019.
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Affiliation(s)
- Lei Fu
- Department of Infectious Diseases, Key Laboratory of Hunan Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoyu Fu
- Department of Infectious Diseases, Key Laboratory of Hunan Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Juan Mo
- Department of Infectious Diseases, Key Laboratory of Hunan Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaomei Li
- Department of Infectious Diseases, Key Laboratory of Hunan Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ronghua Li
- Department of Nuclear Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shifang Peng
- Department of Infectious Diseases, Key Laboratory of Hunan Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan, China
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31
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Tian JH, Liu WD, Zhang ZY, Tang LH, Li D, Tian ZJ, Lin SW, Li YJ. Influence of miR-520e-mediated MAPK signalling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2. J Viral Hepat 2019; 26:496-505. [PMID: 30521133 DOI: 10.1111/jvh.13048] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/09/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022]
Abstract
We determined the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EPH receptor A2 (EphA2) in HBV-positive HCC tissues and cells were detected, and we studied the impact of miR-520e and the EphA2 receptor in cellular and murine HBV replication models. We find that MiR-520e was upregulated and EphA2 was downregulated in HBV-positive HCC tissues and cells. MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but was dose-dependently elevated after interfering with HBx. Additionally, miR-520e mimic and si-EphA2 groups were reduced in association with increases in HBV DNA content, HBsAg and HBeAg levels, cell proliferation and were enhanced in the expressions of EphA2, p-p38MAPK/p38MAPK, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2)/ERK1/2 and cell apoptosis. Furthermore, si-EphA2 reversed the promotion effect of miR-520e inhibitor on HBV replication and tumour cell growth. Upregulating miR-520e in rAAV8-1.3HBV-infected mouse resulted in reduced EphA2 in liver tissues and HBV DNA content in serum. We find that MiR-520e was decreased in HBV-positive HCC, while overexpression of miR-520e blocked p38MAPK and ERK1/2 signalling pathways by an inhibitory effect on EphA2 and ultimately reduced HBV replication and inhibited tumour cell growth. These data indicate a role for miR-520e in the regulation of HBV replication.
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Affiliation(s)
- Jing-Hui Tian
- Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, China.,School of Public Health, Taishan Medical University, Taian, China
| | - Wen-Dong Liu
- Department of Blood Transfusion, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Zhi-Yong Zhang
- Clinical Laboratory, Dezhou People's Hospital, Dezhou, China
| | - Li-Hua Tang
- Department of Blood Transfusion, Tai'an City Central Hospital, Tai'an, China
| | - Dong Li
- School of Public Health, Taishan Medical University, Taian, China
| | - Zhao-Ju Tian
- School of Public Health, Taishan Medical University, Taian, China
| | - Shao-Wei Lin
- School of Public Health, Taishan Medical University, Taian, China
| | - Ying-Jie Li
- Department of Health Examination, Qilu Hospital, Shandong University, Jinan, China
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32
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Sadri Nahand J, Bokharaei-Salim F, Salmaninejad A, Nesaei A, Mohajeri F, Moshtzan A, Tabibzadeh A, Karimzadeh M, Moghoofei M, Marjani A, Yaghoubi S, Keyvani H. microRNAs: Key players in virus-associated hepatocellular carcinoma. J Cell Physiol 2018; 234:12188-12225. [PMID: 30536673 DOI: 10.1002/jcp.27956] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 11/19/2018] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as one of the major health problems worldwide. Pathological analysis indicated that a variety of risk factors including genetical (i.e., alteration of tumor suppressors and oncogenes) and environmental factors (i.e., viruses) are involved in beginning and development of HCC. The understanding of these risk factors could guide scientists and clinicians to design effective therapeutic options in HCC treatment. Various viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) via targeting several cellular and molecular pathways involved in HCC pathogenesis. Among various cellular and molecular targets, microRNAs (miRNAs) have appeared as key players in HCC progression. miRNAs are short noncoding RNAs which could play important roles as oncogenes or tumor suppressors in several malignancies such as HCC. Deregulation of many miRNAs (i.e., miR-222, miR-25, miR-92a, miR-1, let-7f, and miR-21) could be associated with different stages of HCC. Besides miRNAs, exosomes are other particles which are involved in HCC pathogenesis via targeting different cargos, such as DNAs, RNAs, miRNAs, and proteins. In this review, we summarize the current knowledge of the role of miRNAs and exosomes as important players in HCC pathogenesis. Moreover, we highlighted HCV- and HBV-related miRNAs which led to HCC progression.
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Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Arash Salmaninejad
- Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran.,Department of Medical Genetics, Medical Genetics Research Center, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abolfazl Nesaei
- Department of Basic Sciences, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Fatemeh Mohajeri
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Azadeh Moshtzan
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Arezo Marjani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Shoeleh Yaghoubi
- Department of Infectious Disease, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Hossein Keyvani
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
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Sagnelli E, Potenza N, Onorato L, Sagnelli C, Coppola N, Russo A. Micro-RNAs in hepatitis B virus-related chronic liver diseases and hepatocellular carcinoma. World J Hepatol 2018; 10:558-570. [PMID: 30310534 PMCID: PMC6177563 DOI: 10.4254/wjh.v10.i9.558] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/24/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression at the post-transcriptional level by affecting both the stability and translation of complementary mRNAs. Several studies have shown that miRNAs are important regulators in the conflicting efforts between the virus (to manipulate the host for its successful propagation) and the host (to inhibit the virus), culminating in either the elimination of the virus or its persistence. An increasing number of studies report a role of miRNAs in hepatitis B virus (HBV) replication and pathogenesis. In fact, HBV is able to modulate different host miRNAs, particularly through the transcriptional transactivator HBx protein and, conversely, different cellular miRNAs can regulate HBV gene expression and replication by a direct binding to HBV transcripts or indirectly targeting host factors. The present review will discuss the role of miRNAs in the pathogenesis of HBV-related diseases and their role as a biomarker in the management of patients with HBV-related disease and as therapeutic targets.
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Affiliation(s)
- Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicoletta Potenza
- DISTABIF, University of Campania “Luigi Vanvitelli”, Naples 80100, Italy
| | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples 80135, Italy
| | - Aniello Russo
- DISTABIF, University of Campania “Luigi Vanvitelli”, Naples 80100, Italy
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34
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Screening of microRNAs for a repressor of hepatitis B virus replication. Oncotarget 2018; 9:29857-29868. [PMID: 30042818 PMCID: PMC6057454 DOI: 10.18632/oncotarget.25557] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 05/13/2018] [Indexed: 12/21/2022] Open
Abstract
Background Hepatitis B virus (HBV) infection is a leading cause of persistent liver diseases, cirrhosis and hepatocellular carcinoma (HCC) worldwide. Since deregulation of microRNA (miRNA) expression by HBV infection contributes to enhanced viral replication and pathogenesis, modulation of miRNA activity can be a novel therapeutic approach towards HBV eradication. As the effects of the vast majority of miRNAs on HBV replication have not been empirically investigated, here, we aim to identify novel therapeutic targets that have a strong antiviral effect on HBV. Methods HepG2-hNTCP-C4 cells were infected with HBV, and then were individually transfected with the library mimics of 2048 miRNAs. To assess the amount of intracellular and extracellular DNA and HBsAg, qPCR and ELISA were performed respectively. Results From miRNA library screening, we identified 39 miRNAs as candidate repressors of HBV replication. Among them, 9 miRNAs, including miR-204, strongly decreased both HBV DNA and HBsAg in culture supernatant of HepG2-hNTCP-C4 cells. Furthermore, we also showed that inhibition of Rab22a, one of the targets of miR-204, also suppressed intracellular and extracellular HBV DNA expression in HepG2.2.15.7 cells. Conclusions Our findings contribute to the understanding of the roles of miRNAs underlying HBV replication and show the possibility of developing a novel strategy for miRNA-mediated HBV treatment.
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35
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Sekiba K, Otsuka M, Ohno M, Yamagami M, Kishikawa T, Suzuki T, Ishibashi R, Seimiya T, Tanaka E, Koike K. Hepatitis B virus pathogenesis: Fresh insights into hepatitis B virus RNA. World J Gastroenterol 2018; 24:2261-2268. [PMID: 29881235 PMCID: PMC5989240 DOI: 10.3748/wjg.v24.i21.2261] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is still a worldwide health concern. While divergent factors are involved in its pathogenesis, it is now clear that HBV RNAs, principally templates for viral proteins and viral DNAs, have diverse biological functions involved in HBV pathogenesis. These functions include viral replication, hepatic fibrosis and hepatocarcinogenesis. Depending on the sequence similarities, HBV RNAs may act as sponges for host miRNAs and may deregulate miRNA functions, possibly leading to pathological consequences. Some parts of the HBV RNA molecule may function as viral-derived miRNA, which regulates viral replication. HBV DNA can integrate into the host genomic DNA and produce novel viral-host fusion RNA, which may have pathological functions. To date, elimination of HBV-derived covalently closed circular DNA has not been achieved. However, RNA transcription silencing may be an alternative practical approach to treat HBV-induced pathogenesis. A full understanding of HBV RNA transcription and the biological functions of HBV RNA may open a new avenue for the development of novel HBV therapeutics.
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Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Mari Yamagami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Eri Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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36
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The Role of miRNAs in Virus-Mediated Oncogenesis. Int J Mol Sci 2018; 19:ijms19041217. [PMID: 29673190 PMCID: PMC5979478 DOI: 10.3390/ijms19041217] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 04/12/2018] [Accepted: 04/13/2018] [Indexed: 12/16/2022] Open
Abstract
To date, viruses are reported to be responsible for more than 15% of all tumors worldwide. The oncogenesis could be influenced directly by the activity of viral oncoproteins or by the chronic infection or inflammation. The group of human oncoviruses includes Epstein–Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human herpesvirus 8 (HHV-8) or polyomaviruses, and transregulating retroviruses such as HIV or HTLV-1. Most of these viruses express short noncoding RNAs called miRNAs to regulate their own gene expression or to influence host gene expression and thus contribute to the carcinogenic processes. In this review, we will focus on oncogenic viruses and summarize the role of both types of miRNAs, viral as well as host’s, in the oncogenesis.
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Drury RE, O'Connor D, Pollard AJ. The Clinical Application of MicroRNAs in Infectious Disease. Front Immunol 2017; 8:1182. [PMID: 28993774 PMCID: PMC5622146 DOI: 10.3389/fimmu.2017.01182] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/06/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are short single-stranded non-coding RNA sequences that posttranscriptionally regulate up to 60% of protein encoding genes. Evidence is emerging that miRNAs are key mediators of the host response to infection, predominantly by regulating proteins involved in innate and adaptive immune pathways. miRNAs can govern the cellular tropism of some viruses, are implicated in the resistance of some individuals to infections like HIV, and are associated with impaired vaccine response in older people. Not surprisingly, pathogens have evolved ways to undermine the effects of miRNAs on immunity. Recognition of this has led to new experimental treatments, RG-101 and Miravirsen—hepatitis C treatments which target host miRNA. miRNAs are being investigated as novel infection biomarkers, and they are being used to design attenuated vaccines, e.g., against Dengue virus. This comprehensive review synthesizes current knowledge of miRNA in host response to infection with emphasis on potential clinical applications, along with an evaluation of the challenges still to be overcome.
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Affiliation(s)
- Ruth E Drury
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
| | - Daniel O'Connor
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
| | - Andrew J Pollard
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
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38
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Yu X, Zheng H, Chan MTV, Wu WKK. MicroRNAs: new players in cataract. Am J Transl Res 2017; 9:3896-3903. [PMID: 28979668 PMCID: PMC5622237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/15/2016] [Indexed: 06/07/2023]
Abstract
Cataract is the most common cause of blindness worldwide. Multiple factors such as aging, eye injury, diabetes mellitus, ultraviolet exposure, drug use and other ocular diseases are etiologically linked to cataractogenesis. Due to a rapid increase in aging population, age-related cataract has become the leading cause of blindness. Therefore, it is urgent to understand the molecular mechanism underlying cataractogenesis. MicroRNAs (miRNAs) are a group of endogenous, small noncoding RNAs that regulate gene expression at the post-translational level through binding with the 3'-untranslated regions of target mRNAs. Studies have shown that miRNAs play important roles in multiple cellular functions, including apoptosis, cell proliferation, senescence and stress response. Deregulated expression of miRNAs is also linked to the pathogenesis of many diseases, including ocular diseases. In our review, we focus on miRNAs that are involved in cataract development and discuss their potential applications as novel diagnostic markers and therapeutic targets.
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Affiliation(s)
- Xin Yu
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100042, China
| | - Heyi Zheng
- Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100042, China
| | - Matthew TV Chan
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong KongHong Kong, China
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong KongHong Kong, China
- State Key Laboratory of Digestive Disease, LKS Institute of Health Sciences, The Chinese University of Hong KongHong Kong, China
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39
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Pan J, Tong S, Tang J. Alteration of microRNA profiles by a novel inhibitor of human La protein in HBV-transformed human hepatoma cells. J Med Virol 2017; 90:255-262. [PMID: 28885699 PMCID: PMC5763324 DOI: 10.1002/jmv.24941] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 08/23/2017] [Indexed: 12/22/2022]
Abstract
A pyrazolopyridine HBSC11 was previously identified as a novel inhibitor of human La protein with anti‐hepatitis B virus (HBV) activity. However, the underlying mechanism(s) of HBV inhibition by HBSC11 remains unclear. This study aimed to examine the regulation of microRNA (miRNA) by HBSC11 in HBV‐transformed human hepatoma HepG2.2.15 cells using microarray and quantitative real‐time PCR. Target genes of the differentially expressed miRNAs were predicted and subjected to bioinformatics analysis. Results showed that HBSC11 significantly upregulated the expression of miR‐3912‐5p, miR‐6793‐5p, and miR‐7159‐5p in HepG2.2.15 cells. Target genes of the three miRNAs were mainly involved in the regulation of nucleic acid‐templated transcription, negative regulation of gene expression, nucleic acid binding transcription factor activity and regulation of phosphorylation. In addition, target genes were enriched in certain regulatory pathways related to HBV infection and HBV‐associated disease progression, such as the transforming growth factor (TGF)‐β, Wnt, and p53 signaling. Our study demonstrates the involvement of miR‐3912‐5p, miR‐6793‐5p, and miR‐7159‐5p and the potential modulation of specific pathways (TGF‐β, Wnt, and p53 signaling) in HBSC11‐mediated inhibition of HBV replication. This study provides insight into the molecular mechanism of the action of HBSC11 against HBV infection and will support the development of antiviral drugs targeting La protein.
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Affiliation(s)
- Jiaqian Pan
- Department of Clinical Pharmacy, Shanghai General Hospital of Nanjing Medical University, Shanghai, China.,Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuangmei Tong
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Tang
- Department of Clinical Pharmacy, Shanghai General Hospital of Nanjing Medical University, Shanghai, China.,Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Expression Profiling of Cellular MicroRNA in Asymptomatic HBsAg Carriers and Chronic Hepatitis B Patients. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6484835. [PMID: 28913356 PMCID: PMC5587942 DOI: 10.1155/2017/6484835] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 05/31/2017] [Accepted: 06/22/2017] [Indexed: 12/13/2022]
Abstract
Background MicroRNAs (miRNAs) may serve as potential molecular markers to predict liver injury resulting from chronic hepatitis B (CHB). In the present study, we want to study the expression profile and clinical significance of miRNAs at different stages of CHB virus infection. Methods Using miRNA microarray, we investigated the global expression profiles of cellular miRNA in asymptomatic hepatitis B antigen carriers (ASCs) and CHB patients, compared with healthy controls (HCs). Results We identified 79 and 203 differentially expressed miRNAs in the peripheral blood mononuclear cells of ASCs and CHB patients compared to HCs, respectively. Some of these miRNAs were common to ASCs and CHB patients, but another set of miRNAs that showed differential expression between ASCs and CHB patients was also identified. Gene ontology and pathway enrichment analysis showed that the target genes of the identified miRNAs played a role in important biological functions, such as learning or memory, cell-cell adherens junction, ion channel inhibitor activity, TGF-beta signaling pathway, and p53 signaling pathway. Conclusion We identified some significant differentially expressed miRNA in different phases of HBV infection, which might serve as biomarkers or therapeutic targets in the future.
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Wang Z, Wu Z, Huang P. The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein. Oncol Rep 2017. [DOI: 10.3892/or.2017.5716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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42
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Xu W, Yu J, Wong VWS. Mechanism and prediction of HCC development in HBV infection. Best Pract Res Clin Gastroenterol 2017; 31:291-298. [PMID: 28774411 DOI: 10.1016/j.bpg.2017.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/28/2017] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains one of the leading causes of hepatocellular carcinoma (HCC) globally. Over the past few decades, the risk factors of HCC in patients with chronic hepatitis B have been well characterized, and can be divided into host and viral factors. A few groups have also derived and validated HCC prediction scores based on these risk factors. In general, the scores have high negative predictive value in identifying a low risk group who may not need HCC surveillance in the next 3-5 years. The scores have been tested originally in Asian patients, and results on their performance in the Caucasian population are conflicting. Furthermore, new research has identified genetic factors and new virological markers (e.g. hepatitis B surface antigen and core-related antigen levels) for HCC, but they are yet to be applied in routine clinical practice.
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Affiliation(s)
- Weiqi Xu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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43
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Hepatitis B Virus-Encoded MicroRNA Controls Viral Replication. J Virol 2017; 91:JVI.01919-16. [PMID: 28148795 DOI: 10.1128/jvi.01919-16] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/23/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small, single-stranded, noncoding, functional RNAs. Hepatitis B virus (HBV) is an enveloped DNA virus with virions and subviral forms of particles that lack a core. It was not known whether HBV encodes miRNAs. Here, we identified an HBV-encoded miRNA (called HBV-miR-3) by deep sequencing and Northern blotting. HBV-miR-3 is located at nucleotides (nt) 373 to 393 of the HBV genome and was generated from 3.5-kb, 2.4-kb, and 2.1-kb HBV in a classic miRNA biogenesis (Drosha-Dicer-dependent) manner. HBV-miR-3 was highly expressed in hepatoma cell lines with an integrated HBV genome and HBV+ hepatoma tumors. In patients with HBV infection, HBV-miR-3 was released into the circulation by exosomes and HBV virions, and HBV-miR-3 expression had a positive correlation with HBV titers in the sera of patients in the acute phase of HBV infection. More interestingly, we found that HBV-miR-3 represses HBsAg, HBeAg, and replication of HBV. HBV-miR-3 targets the unique site of the HBV 3.5-kb transcript to specifically reduce HBc protein expression, levels of pregenomic RNA (pgRNA), and HBV replication intermediate (HBV-RI) generation but does not affect the HBV DNA polymerase level, thus suppressing HBV virion production (replication). This may explain the low levels of HBV virion generation with abundant subviral particles lacking core during HBV replication, which may contribute to the development of persistent infection in patients. Taken together, our findings shed light on novel mechanisms by which HBV-encoded miRNA controls the process of self-replication by regulating HBV transcript during infection.IMPORTANCE Hepatitis B is a liver infection caused by the hepatitis B virus (HBV) that can become a long-term, chronic infection and lead to cirrhosis or liver cancer. HBV is a small DNA virus that belongs to the hepadnavirus family, with virions and subviral forms of particles that lack a core. MicroRNA (miRNA), a small (∼22-nt) noncoding RNA, was recently found to be an important regulator of gene expression. We found that HBV encodes miRNA (HBV-miR-3). More importantly, we revealed that HBV-miR-3 targets its transcripts to attenuate HBV replication. This may contribute to explaining how HBV infection leads to mild damage in liver cells and the subsequent establishment/maintenance of persistent infection. Our findings highlight a mechanism by which HBV-encoded miRNA controls the process of self-replication by regulating the virus itself during infection and might provide new biomarkers for diagnosis and treatment of hepatitis B.
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Deng W, Zhang X, Ma Z, Lin Y, Lu M. MicroRNA-125b-5p mediates post-transcriptional regulation of hepatitis B virus replication via the LIN28B/let-7 axis. RNA Biol 2017; 14:1389-1398. [PMID: 28267418 DOI: 10.1080/15476286.2017.1293770] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
MicroRNAs (miRNAs) are able to modulate hepatitis B virus (HBV) replication and play an important role in the pathogenesis of HBV infection. Recently, we have identified that serum miR-125b-5p levels correlated with HBV DNA levels and liver necroinflammation. In the present study, we addressed how miR-125b-5p regulated HBV replication at the different steps, inclduing viral transcription, assembly, and virion production and investigated the underlying mechanisms. We found that miR-125b-5p overexpression increased HBV replication without altering HBV transcription. This is the first demonstration of post-transcriptional miRNA regulation of HBV replication. In contrast, transfection of miR-125b-5p inhibitor resulted in downregulation of HBV replication in hepatoma cells. Further, miR-125b-5p inhibited the phosphorylation of retinoblastoma protein and blocked cell cycle progression at the G1/S phase in hepatoma cell lines. Our results indicate that certain miRNAs are able to arrest the cell cycle at G1 phase and may increase HBV replication. RNA sequencing revealed several liver-specific metabolic pathways regulated by miR-125b-5p, which was also found to suppress LIN28B and induce let-7 family members. Additional data demonstrated that miR-125b-5p targeted the LIN28B/let-7 axis to stimulate HBV replication at a post-transcriptional step.
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Affiliation(s)
- Wanyu Deng
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany.,b College of Life Science, Shangrao Normal University , Shangrao , China
| | - Xiaoyong Zhang
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Zhiyong Ma
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Yong Lin
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Mengji Lu
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
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Guerrieri F, Belloni L, D'Andrea D, Pediconi N, Le Pera L, Testoni B, Scisciani C, Floriot O, Zoulim F, Tramontano A, Levrero M. Genome-wide identification of direct HBx genomic targets. BMC Genomics 2017; 18:184. [PMID: 28212627 PMCID: PMC5316204 DOI: 10.1186/s12864-017-3561-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 02/07/2017] [Indexed: 02/08/2023] Open
Abstract
Background The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3561-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francesca Guerrieri
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy
| | - Laura Belloni
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy
| | - Daniel D'Andrea
- Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy
| | - Natalia Pediconi
- Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, Rome, 00161, Italy
| | - Loredana Le Pera
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy.,Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy
| | - Barbara Testoni
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Cecilia Scisciani
- Department of Internal Medicine - DMISM, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy
| | - Oceane Floriot
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Fabien Zoulim
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Anna Tramontano
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy.,Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy.,Istituto Pasteur Fondazione Cenci Bolognetti, Viale Regina Elena 291, Rome, 00161, Italy
| | - Massimo Levrero
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy. .,INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France. .,Department of Internal Medicine - DMISM, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy. .,Cancer Research Center of Lyon (CRCL) - INSERM U1052, 151 cours Albert Thomas, 69424, Lyon Cedex 03, France.
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Zhang B, Han S, Feng B, Chu X, Chen L, Wang R. Hepatitis B virus X protein-mediated non-coding RNA aberrations in the development of human hepatocellular carcinoma. Exp Mol Med 2017; 49:e293. [PMID: 28186085 PMCID: PMC5336563 DOI: 10.1038/emm.2016.177] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 11/03/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has an important role in the development of human hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV-encoded X protein (HBx) can induce both genetic alterations in tumor suppressor genes and oncogenes, as well as epigenetic aberrations in HCC pathogens. Non-coding RNAs (ncRNAs) mainly include microRNAs and long non-coding RNAs (lncRNAs). Although ncRNAs cannot code proteins, growing evidence has shown that they have various important biological functions in cell proliferation, cell cycle control, anti-apoptosis, epithelial–mesenchymal transition, tumor invasion and metastasis. This review summarizes the current knowledge regarding the mechanisms and emerging roles of ncRNAs in the pathogenesis of HBV-related HCC. Accumulated data have shown that ncRNAs regulated by HBx have a crucial role in HBV-associated hepatocarcinogenesis. The findings of these studies will contribute to more clinical applications of HBV-related ncRNAs as potential diagnostic markers or as molecular therapeutic targets to prevent and treat HBV-related HCC.
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Affiliation(s)
- Bei Zhang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Siqi Han
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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Najib A, Kim MS, Kim KH. Viral hemorrhagic septicemia virus (VHSV) infection-mediated sequential changes in microRNAs profile of Epithelioma papulosum cyprini (EPC) cells. FISH & SHELLFISH IMMUNOLOGY 2017; 61:93-99. [PMID: 28007485 DOI: 10.1016/j.fsi.2016.12.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 12/08/2016] [Accepted: 12/15/2016] [Indexed: 06/06/2023]
Abstract
MicroRNAs are small non-coding RNAs and are involved in the regulation of wide biological processes. Viral hemorrhagic septicemia virus (VHSV) is the causative agent of viral hemorrhagic septicemia (VHS) disease causing a heavy loss in aquaculture farms. In this study, we tried to explore the effect of VHSV infection on microRNAs profile of Epithelioma papulosum cyprini (EPC) cells at different points of time (0, 3, 12, 24, and 48 h post infection). A total of 355 conserved microRNAs and 3 novel microRNAs were identified, and among them, 103 microRNAs were differentially expressed. The number of differentially expressed microRNAs was highly increased at 24 h.p.i compared to 3 h.p.i and 12 h.p.i., suggesting that EPC cells might not actively respond to VHSV infection at an early infection period, which can allow viruses to transcript and translate their genes enough to produce viral particles that can infect to another cells. Among the differentially expressed microRNAs, 2 miRNAs (miR-735 and miR-738) that were reported only in fish species were highly upregulated, and based on the target prediction, they could regulate several immune pathways. Furthermore, the present results showed the upregulation of representative immune regulating microRNAs such as miR-146a, miR-155, and miR-99. The target prediction of differentially expressed miRNAs, GO, and KEGG pathways analysis revealed that several biological processes and different pathways were affected by the viral infection. The present dynamical changing patterns of differentially expressed microRNAs in response to the progression of VHSV infection suggest that microRNA profile that was analyzed at one time point cannot provide enough information for the interpretation of the disease mechanism. Considering the wide and complex interactions between microRNAs and genes expression, the present results provide the basis for the understanding of VHSV infection-mediated cellular responses and for future investigations on the development of possible control measures.
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Affiliation(s)
- Abdellaoui Najib
- Department of Aquatic Life Medicine, Pukyong National University, Busan 48513, Republic of Korea
| | - Min Sun Kim
- Graduate School of Integrated Bioindustry, Sejong University, Seoul 05006, Republic of Korea
| | - Ki Hong Kim
- Department of Aquatic Life Medicine, Pukyong National University, Busan 48513, Republic of Korea.
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48
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Murakami Y, Kawada N. MicroRNAs in hepatic pathophysiology. Hepatol Res 2017; 47:60-69. [PMID: 27101519 DOI: 10.1111/hepr.12730] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/26/2016] [Accepted: 04/15/2016] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are a group of small non-coding RNAs that range in length from 20 to 25 nucleotides. MicroRNAs are specific for multiple cellular functions, including cell generation, differentiation, multiplication, carcinogenesis, and apoptosis. Many researchers have recently reported that the aberrant expression of miRNAs in hepatic tissue was related to the pathogenesis of liver disease, including viral hepatitis, hepatocellular carcinoma, and fatty liver disease. Multiple studies have proposed that an analysis of circulating miRNAs may be useful for diagnosing etiologies or staging the progression of liver disease, as well as for therapeutic purposes, for example, nucleic acid therapy. This review summarizes and discusses recent advances in the knowledge of miRNAs for chronic liver diseases, with special interest in viral hepatitis, liver fibrosis, and biomarkers.
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Affiliation(s)
- Yoshiki Murakami
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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49
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The role of microRNAs in hepatocyte metabolism and hepatitis B virus replication. Virol Sin 2016; 31:472-479. [PMID: 28063013 DOI: 10.1007/s12250-016-3924-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 12/22/2016] [Indexed: 02/07/2023] Open
Abstract
Though efficient vaccines against hepatitis B virus (HBV) and antiviral therapies are available, chronic HBV infection is still a global health problem. The process of HBV infection and HBV life cycle are extensively studied in last decades, however, the mechanisms of HBV-induced alterations of host cell metabolisms and host factors involved in modulating of viral replication are not fully understood. Thus, it is an important issue to examine these specific HBV-host interactions for development of novel strategies for antiviral therapies. Recently, microRNAs (miRNAs), a class of post-transcriptional regulatory small RNA, seem to be the relevant fine tuning factors of various cellular activities and pathways, including cell growth, metabolism, and viral replication. In this review, we summarize the up to date knowledge concerning the virus-host interactions and emphasizing on the role of miRNAs in regulation of HBV replication and host cell metabolism.
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50
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Deng M, Hou J, Hu J, Wang S, Chen M, Chen L, Ju Y, Li C, Meng S. Hepatitis B virus mRNAs functionally sequester let-7a and enhance hepatocellular carcinoma. Cancer Lett 2016; 383:62-72. [PMID: 27693636 DOI: 10.1016/j.canlet.2016.09.028] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 09/21/2016] [Accepted: 09/21/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection induces hepatocarcinogenesis and malignant progression, yet global effects of the redundant viral mRNAs produced during infection are unexplored. Here, microRNA (miRNA) target prediction and whole genome expression analysis revealed that HBV pre-C/C mRNA leads to upregulation of multiple let-7a targeted genes. A let-7a complementary region from nt 86 to 108 in the HBV genome was then identified in HBV pre-C/C, pre-S, and S mRNAs. The let-7a sequestration effect by HBV mRNAs was observed under transfection and virus infection, which is dependent on the let-7a response sequence. Moreover, we found reduced AGO2 binding, as well as functional mRNA and protein de-repression of let-7a targets (e.g., c-myc, K-RAS, and CCR7), upon viral mRNA expression. Let-7a levels in the liver were significantly decreased in hepatocellular carcinoma (HCC) patients with HBV infection and were negatively correlated with intrahepatic pre-S2 mRNA levels. Finally, both in vitro and in vivo studies demonstrated that let-7a inhibition by HBV mRNAs resulted in enhanced HCC cell colony formation and tumor growth, providing evidence of the oncogenic potential of HBV mRNAs.
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Affiliation(s)
- Mengmeng Deng
- School of Life Sciences, University of Science and Technology of China, Hefei, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Junwei Hou
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Jun Hu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Shuo Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Mi Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Lizhao Chen
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Ying Ju
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China
| | - Changfei Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
| | - Songdong Meng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
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