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Mansour RM, Abdel Mageed SS, Abulsoud AI, Sayed GA, Lutfy RH, Awad FA, Sadek MM, Shaker AAS, Mohammed OA, Abdel-Reheim MA, Elimam H, Doghish AS. From fatty liver to fibrosis: the impact of miRNAs on NAFLD and NASH. Funct Integr Genomics 2025; 25:30. [PMID: 39888504 DOI: 10.1007/s10142-025-01544-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.
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Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Mohamed M Sadek
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abanoub A S Shaker
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
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Ismail M, Fadul MM, Taha R, Siddig O, Elhafiz M, Yousef BA, Jiang Z, Zhang L, Sun L. Dynamic role of exosomal long non-coding RNA in liver diseases: pathogenesis and diagnostic aspects. Hepatol Int 2024; 18:1715-1730. [PMID: 39306594 DOI: 10.1007/s12072-024-10722-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/15/2024] [Indexed: 12/11/2024]
Abstract
BACKGROUND Liver disease has emerged as a significant health concern, characterized by high rates of morbidity and mortality. Circulating exosomes have garnered attention as important mediators of intercellular communication, harboring protein and stable mRNAs, microRNAs, and long non-coding RNAs (lncRNA). This review highlights the involvement of exosomal lncRNA in the pathogenesis and diagnosis of various liver diseases. Notably, exosomal lncRNAs exhibit therapeutic potential as targets for conditions including hepatic carcinoma, hepatic fibrosis, and hepatic viral infections. METHOD An online screening process was employed to identify studies investigating the association between exosomal lncRNA and various liver diseases. RESULT Our study revealed a diverse array of lncRNAs carried by exosomes, including H19, Linc-ROR, VLDLR, MALAT1, DANCR, HEIH, ENSG00000248932.1, ENST00000457302.2, ZSCAN16-AS1, and others, exhibiting varied levels across different liver diseases compared to normal liver tissue. These exosomal-derived lncRNAs are increasingly recognized as pivotal biomarkers for diagnosing and prognosticating liver diseases, supported by emerging evidence. However, the precise mechanisms underlying the involvement of certain exosomal lncRNAs remain incompletely understood. Furthermore, the combined analysis of serum exosomes using ENSG00000258332.1, LINC00635, and serum AFP may serve as novel and valuable biomarker for HCC. Clinically, exosomal ATB expression is upregulated in HCC, while exosomal HEIH and RP11-513I15.6 have shown potential for distinguishing HCC related to HCV infection. CONCLUSION The lack of reliable biomarkers for liver diseases, coupled with the high specificity and sensitivity of exosomal lncRNA and its non-invasive detection, promotes exploring their role in pathogenesis and biomarker for diagnosis, prognosis, and response to treatment liver diseases.
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Affiliation(s)
- Mohammed Ismail
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Missaa M Fadul
- Department of Pharmacology, Faculty of Medicine and Health Science, Dongola University, Dongola, Sudan
| | - Reham Taha
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Orwa Siddig
- Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Muhanad Elhafiz
- Department of Pharmacology, Faculty of Pharmacy, Omdurman Islamic University, Khartoum, Sudan
| | - Bashir A Yousef
- Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, Khartoum, Sudan
| | - Zhenzhou Jiang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
| | - Luyong Zhang
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
- Centre for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
| | - Lixin Sun
- Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
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Shinde PP, Chitkara D, Mittal A. Downregulation of microRNA-29b in cancer and fibrosis: molecular insights and clinical implications. Drug Discov Today 2024; 29:104190. [PMID: 39322175 DOI: 10.1016/j.drudis.2024.104190] [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: 05/18/2024] [Revised: 09/04/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
MicroRNA-29b (miR-29b) is known for its therapeutic potential as an antifibrotic and anticancer agent. In fibrotic conditions, miR-29b inhibits fibrogenesis by downregulating crucial regulators such as collagens, extracellular matrix proteins and the transforming growth factor-β pathway. Similarly, in cancer, it acts as a tumor suppressor by downregulating various oncogenes and signaling pathways involved in cancer progression, such as Wnt-β-catenin, p38-mitogen-activated protein kinase and nuclear factor-κB. However, the upregulation of these pathways suppresses miR-29b, contributing to fibrosis and cancer development. Preclinical research and clinical trials have shown that delivering exogenous miR-29b mimics can restore its expression, attenuating tumorigenesis and fibrogenesis. This review discusses miR-29b's potential and its possible therapeutic development for cancer and fibrotic disorders.
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Affiliation(s)
- Pratik Pramod Shinde
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India
| | - Deepak Chitkara
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India
| | - Anupama Mittal
- Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani, Rajasthan 333 031, India.
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4
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Moretti V, Romeo S, Valenti L. The contribution of genetics and epigenetics to MAFLD susceptibility. Hepatol Int 2024; 18:848-860. [PMID: 38662298 PMCID: PMC11450136 DOI: 10.1007/s12072-024-10667-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/25/2024] [Indexed: 04/26/2024]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.
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Affiliation(s)
- Vittoria Moretti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Via F Sforza 35, 20122, Milan, Italy.
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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Goncalves BDS, Meadows A, Pereira DG, Puri R, Pillai SS. Insight into the Inter-Organ Crosstalk and Prognostic Role of Liver-Derived MicroRNAs in Metabolic Disease Progression. Biomedicines 2023; 11:1597. [PMID: 37371692 PMCID: PMC10295788 DOI: 10.3390/biomedicines11061597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 06/29/2023] Open
Abstract
Dysfunctional hepatic metabolism has been linked to numerous diseases, including non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide, which can progress to hepatic fibrosis, and is closely associated with insulin resistance and cardiovascular diseases. In addition, the liver secretes a wide array of metabolites, biomolecules, and microRNAs (miRNAs) and many of these secreted factors exert significant effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the involvement of liver-derived miRNAs in biological processes with an emphasis on delineating the communication between the liver and other tissues associated with metabolic disease progression. Furthermore, the review identifies the primary molecular targets by which miRNAs act. These consolidated findings from numerous studies provide insight into the underlying mechanism of various metabolic disease progression and suggest the possibility of using circulatory miRNAs as prognostic predictors and therapeutic targets for improving clinical intervention strategies.
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Affiliation(s)
- Bruno de Souza Goncalves
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Avery Meadows
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Duane G Pereira
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Raghav Puri
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
| | - Sneha S Pillai
- Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
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Lingas EC. Hematological Abnormalities in Cirrhosis: A Narrative Review. Cureus 2023; 15:e39239. [PMID: 37337504 PMCID: PMC10277171 DOI: 10.7759/cureus.39239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 06/21/2023] Open
Abstract
Liver cirrhosis remains a major public health issue. Liver fibrosis leading to cirrhosis is the terminal stage of various chronic liver diseases. Inflammatory cytokines are involved in the pathogenesis. Patients with cirrhosis often have hematological abnormalities, such as anemia and thrombocytopenia, which have multifactorial etiologies. Anemia in cirrhosis could be related to bleeding leading to iron deficiency anemia or other nutritional anemia such as vitamin B12 and folate deficiency. The pathophysiology of thrombocytopenia in liver cirrhosis has been postulated to range from splenic sequestration to bone marrow suppression from toxic agents, such as alcohol. It often complicates management due to the risk of bleeding with severely low platelets. This review aimed to highlight pathogenesis of liver cirrhosis, hematological abnormalities in liver cirrhosis, and their clinical significance.
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Sahu R, Goswami S, Narahari Sastry G, Rawal RK. The Preventive and Therapeutic Potential of the Flavonoids in Liver Cirrhosis: Current and Future Perspectives. Chem Biodivers 2023; 20:e202201029. [PMID: 36703592 DOI: 10.1002/cbdv.202201029] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) may vary from moderately mild non-alcohol fatty liver (NAFL) towards the malignant variant known as non-alcoholic steatohepatitis (NASH), which is marked by fatty liver inflammation and may progress to liver cirrhosis (LC), liver cancer, fibrosis, or liver failure. Flavonoids can protect the liver from toxins through their anti-inflammatory, antioxidant, anti-cancer, and antifibrogenic pharmacological activities. Furthermore, flavonoids protect against LC by regulation of hepatic stellate cells (HSCs) trans-differentiation, inhibiting growth factors like TGF-β and platelets-derived growth factor (PDGF), vascular epithelial growth factor (VEGF), viral infections like hepatitis-B, C and D viruses (HBV, HCV & HDV), autoimmune-induced, alcohol-induced, metabolic disorder-induced, causing by apoptosis, and regulating MAPK pathways. These flavonoids may be explored in the future as a therapeutic solution for hepatic diseases.
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Affiliation(s)
- Rakesh Sahu
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - Sourav Goswami
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India
| | - G Narahari Sastry
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
| | - Ravindra K Rawal
- Natural Product Chemistry Group, Chemical Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, 785006, Assam, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201 002, Uttar Pradesh, India
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8
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Identification of Liver Fibrosis-Related MicroRNAs in Human Primary Hepatic Stellate Cells Using High-Throughput Sequencing. Genes (Basel) 2022; 13:genes13122201. [PMID: 36553468 PMCID: PMC9778123 DOI: 10.3390/genes13122201] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) participate in hepatic stellate cell (HSC) activation, which drives liver fibrosis initiation and progression. We aimed to identify novel hepatic fibrosis targets using miRNA sequencing (miRNA-seq) of human primary HSCs. Surgically resected liver tissues were used to extract HSCs. Based on next-generation sequencing, miRNA-seq was performed on four pairs of HSCs before and after in vitro culture. Additionally, we compared our data with open access miRNA-seq data derived from fourteen cirrhotic and nine healthy liver tissues. Selected miRNAs associated with fibrosis were verified by quantitative real-time PCR. Target mRNAs of differentially expressed (DE) miRNAs were predicted to construct co-expression networks. We identified 230 DEmiRNAs (118 upregulated and 112 downregulated) upon HSC activation. Of the 17 miRNAs with the most significant differences in expression, liver disease-related miRNAs included miR-758-3p, miR-493-5p, miR-409-3p, miR-31-5p, miR-1268a, and miR-381-3p, which might play roles in hepatic fibrosis. Moreover, let-7g-5p, miR-107, miR-122-5p, miR-127-3p, miR-139-5p, miR-148a-3p, miR-194-5p, miR-215-5p, miR-26a-5p, miR-340-5p, miR-451a, and miR-99a-5p were common between our data and the publicly available sequencing data. A co-expression network comprising 1891 matched miRNA-mRNA pairs representing 138 DEmiRNAs and 1414 DEmRNAs was constructed. MiR-1268a and miR-665, possessing the richest target DEmRNAs, may be vital in HSC activation. The targeted genes were involved in collagen metabolism, extracellular matrix structural constituent, cytoskeletal protein binding, and cell adhesion. The miRNAs we identified may provide a basis and reference for the selection of diagnostic and therapeutic targets for hepatic fibrosis.
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Enge AM, Sprenger H, Braeuning A, Hessel-Pras S. Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells. Foods 2022; 11:foods11040532. [PMID: 35206009 PMCID: PMC8871147 DOI: 10.3390/foods11040532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 12/14/2022] Open
Abstract
1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells.
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10
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Zhao X, Ji Z, Xuan R, Wang A, Li Q, Zhao Y, Chao T, Wang J. Characterization of the microRNA Expression Profiles in the Goat Kid Liver. Front Genet 2022; 12:794157. [PMID: 35082837 PMCID: PMC8784682 DOI: 10.3389/fgene.2021.794157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
The liver is the largest digestive gland in goats with an important role in early metabolic function development. MicroRNAs (miRNA) are crucial for regulating the development and metabolism in the goat liver. In the study, we sequenced the miRNAs in the liver tissues of the goat kid to further research their regulation roles in early liver development. The liver tissues were procured at 5-time points from the Laiwu black goats of 1 day (D1), 2 weeks (W2), 4 weeks (W4), 8 weeks (W8), and 12 weeks (W12) after birth, respectively with five goats per time point, for a total of 25 goats. Our study identified 214 differential expression miRNAs, and the expression patterns of 15 randomly selected miRNAs were examined among all five age groups. The Gene ontology annotation results showed that differential expression miRNA (DE miRNA) target genes were significantly enriched in the fatty acid synthase activity, toxin metabolic process, cell surface, and antibiotic metabolic process. The KEGG analysis result was significantly enriched in steroid hormone synthesis and retinol metabolism pathways. Further miRNA-mRNA regulation network analysis reveals 9 differently expressed miRNA with important regulation roles. Overall, the DE miRNAs were mainly involved in liver development, lipid metabolism, toxin related metabolism-related biological process, and pathways. Our results provide new information about the molecular mechanisms and pathways in the goat kid liver development.
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Affiliation(s)
- Xiaodong Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Zhibin Ji
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Rong Xuan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Aili Wang
- Shandong Peninsula Engineering Research Center of Comprehensive Brine Utilization, Weifang University of Science and Technology, Shouguang, China
| | - Qing Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Yilin Zhao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Tianle Chao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Jianmin Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
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Zaafan MA, Abdelhamid AM. Dasatinib ameliorates thioacetamide-induced liver fibrosis: modulation of miR-378 and miR-17 and their linked Wnt/β-catenin and TGF-β/smads pathways. J Enzyme Inhib Med Chem 2021; 37:118-124. [PMID: 34894966 PMCID: PMC8667920 DOI: 10.1080/14756366.2021.1995379] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-β/smads and Wnt/β-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/β-catenin and TGF-β/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibitor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regulated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/β-catenin and TGF-β/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs.
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Affiliation(s)
- Mai A Zaafan
- Faculty of Pharmacy, Pharmacology and Toxicology Department, October University for Modern Sciences and Arts (MSA), Dokki, Egypt
| | - Amr M Abdelhamid
- Faculty of Pharmacy, Biochemistry Department, October University for Modern Sciences and Arts (MSA), Dokki, Egypt
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12
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Abdelhamid AM, Selim A, Zaafan MA. The Hepatoprotective Effect of Piperine Against Thioacetamide-Induced Liver Fibrosis in Mice: The Involvement of miR-17 and TGF-β/Smads Pathways. Front Mol Biosci 2021; 8:754098. [PMID: 34778375 PMCID: PMC8585739 DOI: 10.3389/fmolb.2021.754098] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/13/2021] [Indexed: 01/14/2023] Open
Abstract
Liver fibrosis is characterized by a series of events including activation of quiescent hepatic stellate cells (HSCs) into proinflammatory, contractile, and fibrogenic myofibroblasts, which is the primary trigger for the fibrogenesis process. HSC activation involves many signaling pathways such as the TGF-β/smads pathway. Specific microRNAs have been identified to play a crucial role in the activation of HSCs via various signaling pathways. Piperine has recently been studied as a promising anti-fibrotic agent against pancreatic fibrosis through altering the TGF-β1/Smad pathway. Hence, the current study evaluated the beneficial effects of piperine in thioacetamide-induced liver fibrosis in mice through the modulation of miRNA-17 and TGF-β/smads pathways. Mice were allocated into three groups randomly. Thioacetamide was used to induce liver fibrosis for 6 weeks. Starting from the fourth week of the experiment, mice were treated with piperine daily for 21 days. Piperine treatment resulted in a significant downregulation of miRNA-17 expression, leading to the restoration of smad-7 accompanied with marked inhibition of TGF-β/smads signaling with further suppression of the activated HSCs and collagen deposition in the hepatocytes. In conclusion, piperine has the potential to be a promising therapeutic drug for the treatment of liver fibrosis through inhibiting the TGF-β/smads pathway.
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Affiliation(s)
- Amr M Abdelhamid
- Biochemistry Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October City, Egypt
| | - Ayman Selim
- Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October City, Egypt
| | - Mai A Zaafan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6th of October City, Egypt
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Momen-Heravi F, Catalano D, Talis A, Szabo G, Bala S. Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 25:155-167. [PMID: 34458001 PMCID: PMC8368790 DOI: 10.1016/j.omtn.2021.05.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.
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Affiliation(s)
- Fatemeh Momen-Heravi
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Catalano
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Austin Talis
- Cancer Biology and Immunology Laboratory, College of Dental Medicine, Columbia University Irving Medical Center, New York, NY, USA
- Division of Periodontics, Section of Oral, Diagnostic, and Rehabilitation Sciences, Columbia University College of Dental Medicine, New York, NY, USA
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
- KASA BIO, 10405 Old Alabama Road Connector, Suite 201, Alpharetta, GA 30022, USA
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14
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Gong X, Wang X, Zhou F. Liver microRNA-29b-3p positively correlates with relative enhancement values of magnetic resonance imaging and represses liver fibrosis. J Biochem 2021; 168:603-609. [PMID: 32653922 DOI: 10.1093/jb/mvaa074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
This study aims to identify potential microRNAs (miRNAs) contribute to liver fibrosis progression and investigate how the miRNA is involved. We recruited totally 58 patients. Magnetic resonance imaging was employed to detect fibrosis. Classification of liver fibrosis was carried out by Ishak scoring system. Cell viability was tested using cell counting kit-8. Measurements of mRNA and protein expressions were conducted using real-time quantitative polymerase chain reaction and western blotting. Luciferase reporter assay was recruited for determination of miR-29b-3p targets. We found that relative enhancement (RE) values were reduced with the increases in fibrosis stages and was negatively associated with Ishak scores. In comparison with patients without liver fibrosis, miR-29b-3p level was remarkably reduced in those with liver fibrosis. Its level was found to be positively associated with RE values. Transforming growth factor beta 1 (TGF-β1)-induced hepatic stellate cell (HSC) activation significantly decreased miR-29b-3p expression. However, miR-29b-3p overexpression repressed TGF-β1-induced collagen I protein and alpha-smooth muscle actin (α-SMA) expression. As expected, its overexpression also reduced cell viability. We found that miR-29b-3p directly bind to signal transducer and activator of transcription 3 (STAT3) and suppressed its expression. Our study demonstrates that low expression of miR-29b-3p may contribute to the progression of liver fibrosis by suppressing STAT3.
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Affiliation(s)
- Xijun Gong
- Department of Radiology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui, China
| | - Xiaolin Wang
- Department of Pathology, the First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, Anhui, China
| | - Fangfang Zhou
- Department of Radiology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230000, Anhui, China
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15
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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16
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Complexation with Random Methyl-β-Cyclodextrin and (2-Hidroxypropyl)-β-Cyclodextrin Enhances In Vivo Anti-Fibrotic and Anti-Inflammatory Effects of Chrysin via the Inhibition of NF-κB and TGF-β1/Smad Signaling Pathways and Modulation of Hepatic Pro/Anti-Fibrotic miRNA. Int J Mol Sci 2021; 22:ijms22041869. [PMID: 33668543 PMCID: PMC7917810 DOI: 10.3390/ijms22041869] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 01/24/2021] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chrysin (CHR) is a natural flavonoid with a wide range of pharmacological activities, including hepatoprotection, but poor water solubility. By including water-soluble hydroxypropyl (HPBCD) and randomly methylated (RAMEB) β-cyclodextrin, we aimed to increase its biodisponibility and the effectiveness of the antifibrotic effects of chrysin at oral administration. Liver fibrosis in mice was induced in 7 weeks by CCl4 i.p. administration, and afterwards treated with 50 mg/kg of CHR-HPBCD, CHR-RAMEB, and free chrysin. CCl4 administration increased hepatic inflammation (which was augmented by the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor (TNF)-α, and interleukin 6 (IL-6) and induced fibrosis, as determined using histopathology and electron microscopy. These results were also confirmed by the upregulation of Collagen I (Col I) and matrix metalloproteinase (MMP) expression, which led to extracellular fibrotic matrix proliferation. Moreover, the immunopositivity of alpha-smooth muscle actin (a-SMA) in the CCl4 group was evidence of hepatic stellate cell (HSC) activation. The main profibrotic pathway was activated, as confirmed by an increase in the transforming growth factor- β1 (TGF-β1) and Smad 2/3 expression, while Smad 7 expression was decreased. Treatment with CHR–HPBCD and CHR–RAMEB considerably reduced liver injury, attenuated inflammation, and decreased extracellular liver collagen deposits. CHR–RAMEB was determined to be the most active antifibrotic complex. We conclude that both nanocomplexes exert anti-inflammatory effects and antifibrotic effects in a considerably stronger manner than for free chrysin administration.
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17
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Li B, Liu J, Xin X, Zhang L, Zhou J, Xia C, Zhu W, Yu H. MiR-34c promotes hepatic stellate cell activation and Liver Fibrogenesis by suppressing ACSL1 expression. Int J Med Sci 2021; 18:615-625. [PMID: 33437196 PMCID: PMC7797556 DOI: 10.7150/ijms.51589] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/02/2020] [Indexed: 12/19/2022] Open
Abstract
Normally, there are multiple microRNAs involved in the pathogenesis of liver fibrosis. In our work, we aimed at identifying the role of miR-34c in the hepatic stellate cell (HSC) activation and liver fibrosis and its potential mechanism. Our results have shown that during natural activation of HSC, the level of miR-34c was increased significantly whereas acyl-CoA synthetase long-chain family member-1(ACSL1), which is a key enzyme can affect fatty acid(FA) synthesis, was decreased. A double fluorescence reporter assay further confirmed that ACSL1 is a direct target gene of miR-34c. Moreover, the inhibition of miR-34C can attenuate the synthesis of collagen in HSC-T6. In our rescue assay, ACSL1 expression was 1.49-fold higher compared to normal control cells which were transfected with the miR-34c inhibitor in a stable low expression ACSL1 cell line. While at the same time, α-SMA and Col1α expression decreased by 18.22% and 2.58%, respectively. Moreover, we performed an in vivo model using dimethylnitrosamine (DMN) in conjunction with the miR-34c agomir, combined with the treatment of DMN and the miR-34c agomir can increase liver fibrosis. Meanwhile, the degree of hepatic fibrosis was increased and lipid droplets reduced dramatically in rats and HSC-T6 cell treated with miR-34c mimics alone compared to untreated groups. Our results indicate that miR-34c plays an essential role in liver fibrosis by targeting ACSL1 closely associated with lipid droplets, and it might be used as a potential therapeutic target.
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Affiliation(s)
- Binbin Li
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Jiaxuan Liu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Xuan Xin
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
- Department of Pathology, No. 960 Hospital of People' Liberation Army, Jinan 250031, China
| | - Lifen Zhang
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Jiaming Zhou
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
- Department of Pathological Anatomy, Nantong University, Nantong 226001, China
| | - Chunyan Xia
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Weijian Zhu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
| | - Hongyu Yu
- Department of Pathology, Changzheng Hospital, Navy Medical University (Second Military Medical University), Shanghai 200003, China
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18
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Riaz F, Li D. Non-coding RNA Associated Competitive Endogenous RNA Regulatory Network: Novel Therapeutic Approach in Liver Fibrosis. Curr Gene Ther 2020; 19:305-317. [PMID: 31696817 DOI: 10.2174/1566523219666191107113046] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/21/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022]
Abstract
Liver fibrosis or scarring is the most common pathological feature caused by chronic liver injury, and is widely considered one of the primary causes of morbidity and mortality. It is primarily characterised by hepatic stellate cells (HSC) activation and excessive extracellular matrix (ECM) protein deposition. Overwhelming evidence suggests that the dysregulation of several noncoding RNAs (ncRNAs), mainly long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) contributes to the activation of HSC and progression of liver fibrosis. These ncRNAs not only bind to their target genes for the development and regression of liver fibrosis but also act as competing endogenous RNAs (ceRNAs) by sponging with miRNAs to form signaling cascades. Among these signaling cascades, lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA are critical modulators for the initiation, progression, and regression of liver fibrosis. Thus, targeting these interacting ncRNA cascades can serve as a novel and potential therapeutic target for inhibition of HSC activation and prevention and regression of liver fibrosis.
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Affiliation(s)
- Farooq Riaz
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.,Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi 710061, China
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19
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miR-7-5p Promotes Hepatic Stellate Cell Activation by Targeting Fibroblast Growth Factor Receptor 4. Gastroenterol Res Pract 2020; 2020:5346573. [PMID: 32587612 PMCID: PMC7303738 DOI: 10.1155/2020/5346573] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 05/14/2020] [Indexed: 12/14/2022] Open
Abstract
Aims Fibroblast growth factor receptor 4 (FGFR4) is a key mediator that protects the liver from chronic injury. MicroRNA-7 (miR-7) is a tumor suppressor and associated with lipid homeostasis in the liver. This study was designed to examine the role of the miR-7-5p/FGFR4 axis in liver fibrogenesis. Methods TargetScan was employed to predict microRNAs that targeted FGFR4 on the 3'-untranslated region (3'-UTR). miR-7-5p and FGFR4 expression in pathological liver tissues and LX-2 cells was determined using qRT-PCR and an immunoblotting assay. A dual-luciferase assay was conducted to validate the target prediction. A Cell Counting Lit-8 assay was performed to assess the proliferation ability of LX-2 cells. Hydroxyproline content in LX-2 cells was measured using a hydroxyproline assay. The expression of hepatic stellate cell (HSC) activation markers was examined using qRT-PCR and an immunoblotting assay. Results FGFR4 was a putative target of miR-7-5p. In LX-2 cells, miR-7-5p targeted FGFR4 by binding to 3'-UTR. FGFR4 was downregulated, but miR-7-5p was markedly enhanced in the liver samples as the degree of liver fibrosis rose. miR-7-5p was negatively associated with FGFR4 expression in liver tissues. The miR-7-5p inhibitor blocked the lipopolysaccharide-induced proliferation and activation of LX-2 cells, and FGFR4 overexpression inhibited LX-2 cell proliferation and activation triggered by miR-7-5p. Conclusion miR-7-5p promotes HSC proliferation and activation by downregulating FGFR4.
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20
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Ji D, Wang Q, Zhao Q, Tong H, Yu M, Wang M, Lu T, Jiang C. Co-delivery of miR-29b and germacrone based on cyclic RGD-modified nanoparticles for liver fibrosis therapy. J Nanobiotechnology 2020; 18:86. [PMID: 32513194 PMCID: PMC7281922 DOI: 10.1186/s12951-020-00645-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatic stellate cells (HSCs) were activated and secreted excessive amounts of extracellular matrix (ECM) proteins during pathogenetic progress of liver fibrosis. Germacrone (GMO) and miR-29b can play an important role in inhibiting growth of HSCs and production of type I collagen. GMO and miR-29b were co-encapsulated into nanoparticles (NPs) based on poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-PLGA). Then, NPs were modified with cyclic RGD peptides (cRGDfK). cRGDfK is an effective ligand to bind integrin αvβ3 and increase the targeting ability for fibrotic liver. GMO- and miR-29b-loaded NPs exhibited great cytotoxicity to activated HSCs and significantly inhibited production of type I collagen. Liver fibrosis model of mice was induced by administration of carbon tetrachloride. Great targeting ability was achieved in liver fibrotic mice treated with cRGD-modified NPs. Significant ant-fibrotic effects have been presented based on hematoxylin and eosin (H&E), Masson and Sirius Red staining results of liver tissues collected from mice treated with drug-loaded NPs. All these results indicate GMO- and miR-29b-loaded cRGD-modified NPs have the potential for clinical use to treat liver fibrosis.
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Affiliation(s)
- De Ji
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Qiaohan Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qi Zhao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, China.,Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, 325035, China
| | - Huangjin Tong
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China
| | - Mengting Yu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Meng Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Tulin Lu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Chengxi Jiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, China. .,Biomedical Collaborative Innovation Center of Zhejiang, Wenzhou, 325035, China.
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21
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Chiabotto G, Camussi G, Bruno S. Role of ncRNAs in modulation of liver fibrosis by extracellular vesicles. ACTA ACUST UNITED AC 2020. [DOI: 10.1186/s41544-020-00050-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
AbstractExtracellular vesicles (EVs) are small membrane vesicles carrying bioactive lipids, proteins and nucleic acids of the cell of origin. In particular, EVs carry non-coding RNAs (ncRNAs) and the vesicle membrane may protect them from degradation. Once released within the extracellular space, EVs can transfer their cargo, including ncRNAs, to neighboring or distant cells, thus inducing phenotypical and functional changes that may be relevant in several physio-pathological conditions. This review provides an overview of the role of EV-carried ncRNAs in the modulation of liver fibrosis. In particular, we focused on EV-associated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) involved into the development of liver fibrosis and on the potential use of EV-associated ncRNAs as diagnostic and prognostic biomarkers of liver fibrosis.
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22
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Liang H, Wang X, Si C, Duan Y, Chen B, Liang H, Yang D. Downregulation of miR‑141 deactivates hepatic stellate cells by targeting the PTEN/AKT/mTOR pathway. Int J Mol Med 2020; 46:406-414. [PMID: 32319536 DOI: 10.3892/ijmm.2020.4578] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 03/27/2020] [Indexed: 01/18/2023] Open
Abstract
The activation of hepatic stellate cells (HSCs) caused by stimulating factors or fibrogenic cytokines is the critical stage of liver fibrosis. Recent studies have demonstrated the influence of microRNAs (miRNAs or miRs) on HSC activation and transformation; however, the function and underlying mechanisms of miRNAs in HSC activation have not yet been completely clarified. In the present study, transforming growth factor β1 (TGF‑β1) was used to treat human HSC lines (HSC‑T6 and LX2 cells) to simulate the activation of HSCs in vivo and whether the expression of miRNAs in HSCs was affected by TGF‑β1 treatment was examined using a miRNA microarray. It was observed that miR‑141 was one of the most upregulated miRNAs during HSC activation. Functional analyses revealed that miR‑141 knockdown suppressed the viability of HSCs and inhibited the expression levels of pro‑fibrotic markers. In addition, phosphatase and tensin homolog (PTEN), a well‑known suppressor of the AKT/mammalian target of rapamycin (mTOR) pathway, was found to be directly targeted by miR‑141 in HSCs. More importantly, the knockdown of PTEN markedly reversed the suppressive effects of miR‑141 inhibition on the viability of and the expression levels of pro‑fibrotic markers during HSC activation. Finally, it was observed that the downregulation of miR‑141 blocked the TGF‑β1‑induced activation of the AKT/mTOR pathway in HSCs. On the whole, the findings of the present study indicate that miR‑141 inhibition suppresses HSC activation via the AKT/mTOR pathway by targeting PTEN, highlighting that miR‑141 may serve as a novel therapeutic target for liver fibrosis.
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Affiliation(s)
- Haijun Liang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Xinwei Wang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Changyun Si
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yuxiu Duan
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Baoxin Chen
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Haixia Liang
- Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Daokun Yang
- Department of Infectious Disease, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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23
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Chen L, Huang W, Wang L, Zhang Z, Zhang F, Zheng S, Kong D. The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism. Expert Rev Gastroenterol Hepatol 2020; 14:259-270. [PMID: 32124651 DOI: 10.1080/17474124.2020.1736042] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Introduction: Epigenetic modification is a type of gene expression and regulation that does not involve changes in DNA sequences. An increasing number of studies have proven that epigenetic modifications play an important role in the occurrence and progression of liver diseases through the gene regulation and protein expressions of hepatocellular lipid metabolism, inflammatory reaction, cell proliferation, and activation, etc.Areas covered: In this study, we elaborated and analyzed the underlying functional mechanism of epigenetic modification in alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), liver fibrosis (LF), viral hepatitis, hepatocellular carcinoma (HCC), and research progress of recent years.Expert opinion: The further understanding of epigenetic mechanisms that can regulate gene expression and cell phenotype leads to new insights in epigenetic control of chronic liver disease. Currently, hepatologists are exploring the role of DNA methylation, histone/chromatin modification, and non-coding RNA in specific liver pathology. These findings have led to advances in direct epigenetic biomarker testing of patient tissue or body fluid specimens, as well as quantitative analysis. Based on these findings, drug validation of some targets involved in the epigenetic mechanism of liver disease is gradually being carried out clinically.
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Affiliation(s)
- Liping Chen
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Weifang Huang
- Department of Pharmacology, School of Integral Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zili Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shizhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Desong Kong
- Chinese Medicine Modernization and Big Data Research Center, Nanjing Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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24
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Ye L, Yu Y, Zhao Y. Icariin-induced miR-875-5p attenuates epithelial-mesenchymal transition by targeting hedgehog signaling in liver fibrosis. J Gastroenterol Hepatol 2020; 35:482-491. [PMID: 31617598 DOI: 10.1111/jgh.14875] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/18/2019] [Accepted: 09/23/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatic fibrosis is the final endpoint for most chronic liver diseases and remains a significant public health problem worldwide. Icariin, a naturally occurring flavonol glucoside, has been reported to exhibit protective effects on liver injury and alleviate liver fibrosis. However, the underlying detail molecular mechanism is not fully revealed. METHODS Mouse primary hepatic stellate cells (HSCs) and carbon tetrachloride (CCL4 )-induced liver fibrosis model in mice were used as in vitro and in vivo models in this study. The expression levels of miR-875-5p were detected by quantitative reverse transcription-PCR. The validation of the direct target of miR-875-5p was through dual-luciferase reporter assay and western blotting assay. The cell proliferation and cell mobility were determined using MTT assay and Transwell migration assay, respectively. RESULTS We found that icariin inhibited epithelial-mesenchymal transition and collagen protein section of HSCs. Icariin exerted hepatoprotective effects on mice model of CCL4 -induced liver fibrosis. Our further results revealed that miR-875-5p was downregulated in human cirrhosis tissues and activated murine HSCs. Icariin induced miR-875-5p upregulation and subsequently decreased glioma-associated oncogene homolog 1 (GLI1) expression through direct binding to the three prime untranslated region of GLI1 mRNA. CONCLUSION Our study highlighted the potential therapeutic application of icariin for liver fibrosis management.
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Affiliation(s)
- Lei Ye
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Zhejiang, China
| | - Yaping Yu
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Zhejiang, China
| | - Yanping Zhao
- First Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Zhejiang, China
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25
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Li L, Ran J, Li L, Chen G, Zhang S, Wang Y. Gli3 is a novel downstream target of miR‑200a with an anti‑fibrotic role for progression of liver fibrosis in vivo and in vitro. Mol Med Rep 2020; 21:1861-1871. [PMID: 32319630 PMCID: PMC7057771 DOI: 10.3892/mmr.2020.10997] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 07/09/2019] [Indexed: 12/11/2022] Open
Abstract
GLI family zinc finger 3 (Gli3), as the upstream transcriptional activator of hedgehog signaling, has previously been demonstrated to participate in the process of liver fibrosis. The present study aimed to investigate the potential functions of microRNA (miR)‑200a and Gli3 in the progression of liver fibrosis. The expression levels of miR‑200a and Gli3 in cells and tissues were determined by PCR and western blotting; the interaction of Gli3 and miR‑200a was evaluated by bioinformatics analysis and dual‑luciferase reporter assay. miR‑200a was significantly reduced in serum samples from clinical patients, liver tissues of a carbon tetrachloride (CCl4)‑induced rat model and activated LX2 cells. The expression of α‑smooth muscle actin (α‑SMA) and albumin at the mRNA and protein levels was increased and decreased in LX2 cells, respectively. However, the expression levels of α‑SMA and albumin were reversed and Gli3 expression was markedly decreased in LX2 cells when transfected with miR‑200a mimics. In addition, the dual‑-luciferase reporter assay confirmed the target interaction between miR‑200a and Gli3. Finally, following the administration of miR‑200a mimics to CCl4‑induced rats, it was revealed that the alterations of α‑SMA, albumin and Gli3 presented a similar trend to that in LX2 cells with miR‑200a mimics transfection. Taken together, these results indicated that downregulation of miR‑200a might enhance the formation of liver fibrosis, probably by targeting Gli3, and elevated miR‑200a may attenuate the progression of liver fibrosis by suppressing Gli3. These findings suggested that miR‑200a may function as a novel anti‑fibrotic agent in liver fibrosis via inhibition of the expression of Gli3.
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Affiliation(s)
- Li Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Jianghua Ran
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Lan Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Gang Chen
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Shengning Zhang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Yingjia Wang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
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Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development. Cells 2020; 9:cells9020461. [PMID: 32085494 PMCID: PMC7072785 DOI: 10.3390/cells9020461] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/10/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.
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Yang J, Tao Q, Zhou Y, Chen Q, Li L, Hu S, Liu Y, Zhang Y, Shu J, Zhang X, Zhang L, Zhang L. MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway. Eur J Pharmacol 2020; 871:172927. [PMID: 31962101 DOI: 10.1016/j.ejphar.2020.172927] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/12/2020] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is caused by a sustained wound healing response to chronic liver injury, and the activation of insubstantial hepatic stellate cells (HSCs) is the key process involved. The progression of liver fibrosis may be attenuated by suppressing activation and proliferation of the HSCs. MicroRNA (miRNA) have emerged as major players in governing fundamental biological processes through multiple mechanisms MiR-708 is known to inhibit the development of hepatocellular carcinoma. However, whether miR-708 can function as a transcriptional regulator in liver fibrosis remains unclear. Our study demonstrated that miR-708 expression was inhibited in fibrotic liver tissues and in activated HSCs, accompanied by an increase of the Zinc finger E-box binding homeobox 1 (ZEB1) level. Besides, overexpression of miR-708 and silencing of ZEB1 inhibited the activation and proliferation of LX-2 cells. While knockdown of miR-708 or overexpression of ZEB1 showed reversed results. Further, dual luciferase reporter assays showed that miR-708 directly targeted ZEB1 in vitro. Interestingly, ZEB1 was found to be involved in HSCs by regulating Wnt/β-catenin signaling pathway. Together, our data showed that miR-708 may be a potential therapeutic target in liver fibrosis therapy.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qing Tao
- Department of Pathogen Biology, Anhui Medical University, China
| | - Yiwen Zhou
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qingfeng Chen
- Clinic Medical College of Anhui Medical University, Hefei, 230032, China
| | - Liangyun Li
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Shuang Hu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yumin Liu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yu Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Jinling Shu
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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Nasser MZ, Zayed NA, Mohamed AM, Attia D, Esmat G, Khairy A. Circulating microRNAs (miR-21, miR-223, miR-885-5p) along the clinical spectrum of HCV-related chronic liver disease in Egyptian patients. Arab J Gastroenterol 2019; 20:198-204. [PMID: 31806407 DOI: 10.1016/j.ajg.2019.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 11/23/2019] [Accepted: 11/24/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND STUDY AIMS MicroRNAs (miRNAs), small single stranded RNAs, function in the post-transcriptional regulation of gene expression and incorporated in pathogenesis of HCV related chronic liver disease. This study was designed to evaluate the significance of serum miR-21, miR-223, and miR-885-5p as biomarkers in various clinicopathological stages of HCV related chronic liver disease. PATIENTS AND METHODS Serum miR-21, miR-223, and miR-885-5p were quantified by quantitative RT PCR in 60 patients with HCV-related liver disease (presumably genotype 4), in addition to 25 healthy controls. HCV patients were classified into: chronic non-cirrhotic HCV (n = 15), HCV related liver cirrhosis (n = 15), and hepatocellular carcinoma (HCC) (n = 30). RESULTS Serum levels of miR-885-5p in cirrhotic patients ± HCC (n = 45) were significantly higher than the non-cirrhotic patients (n = 15); p = 0.007 and healthy control; p = 0.001. However, no such significance was detected between HCC and non-HCC HCV patients; p = 0.12. Serum miRNA-885-5p was able to discriminate cirrhosis ± HCC from healthy controls using ROC analysis; AUC 0.85, 87% sensitivity and 80% specificity. On the other hand, HCC patients had significantly higher serum miR-2 1evels than non-HCC patients (non-cirrhotic and cirrhotic groups, n = 30); p = 0.048 and the control group; p = 0.002. ROC could differentiate HCC from control group; AUC 0.89, 80% sensitivity, 80% specificity. Both serum bilirubin and albumin showed significant weak correlation with miRNA-885-5p (r = 0.42, p = 0.001) and (r = -0.27, p = 0.04), respectively but no such correlation was observed with serum miRNA-21. In contrast, miRNA-223 showed no significant difference across the studied groups. CONCLUSION Along the spectrum of HCV-related chronic liver disease, miR-885-5p could be a potential marker for advanced liver damage while miR-21 could be a helpful diagnostic marker for HCC.
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Affiliation(s)
- Mona Zaky Nasser
- Clinical Pathology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Naglaa Ali Zayed
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Dina Attia
- Department of Gastroenterology, Hepatology and Endemic Medicine, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Gamal Esmat
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Khairy
- Endemic Medicine and Hepatology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
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Animal Models of Hepatocellular Carcinoma Prevention. Cancers (Basel) 2019; 11:cancers11111792. [PMID: 31739536 PMCID: PMC6895981 DOI: 10.3390/cancers11111792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/08/2019] [Accepted: 11/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context.
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Ren S, Chen J, Wang Q, Li X, Xu Y, Zhang X, Mu Y, Zhang H, Huang S, Liu P. MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis. Hepatol Int 2019; 13:814-825. [PMID: 31643031 PMCID: PMC7400990 DOI: 10.1007/s12072-019-09993-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/28/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND MicroRNAs have added a new dimension to our understanding of liver cirrhosis (LC) and associated processes like the activation of hepatic stellate cells (HSCs). METHODS Serum samples were collected from 40 LC patients and 30 healthy donors. CCl4-induced LC mouse model in vivo and in vitro human HSC LX-2 and murine HSC JS-1 cells were researched. RESULTS The levels of serum microRNA (miR)-744 is inversely correlated with the severity of LC and is a reliable biomarker of LC. In CCl4-induced LC model, the abundance of miR-744 was reduced in both sera and livers compared with sham controls. Importantly, increasing miR-744 abundance with synthetic miR-744 Agomir alleviated liver fibrosis, a critical component of LC, while reducing miR-744 with Antagomir exacerbated it. To elucidate molecular mechanism underlying the suppressive role of miR-744 in LC, we observed that miR-744 and transforming growth factor β1 (TGFβ1) are inversely correlated in LC patients' sera as well as sera/livers from CCl4-induced LC mice. We demonstrated that miR-744 Agomir downregulated the expression of TGFβ1 and further confirmed that TGFβ1 mRNA was a bona fide miR-744 target in HSCs. Moreover, miR-744 Agomir reduced the degree of F-actin formation and cell proliferation while miR-744 Antagomir promoted these events, suggesting that miR-744 is a negative regulator of HSC activation. CONCLUSIONS MiR-744-led suppression in HSC activation is most likely through TGFβ1 because exogenous TGFβ1 nearly negated miR-744 Agomir's action. This study suggests that reduction of miR-744 is a reliable biomarker for LC and miR-744/TGFβ1 relationship is a key regulator of LC.
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Affiliation(s)
- Shuang Ren
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
- Traditional Chinese Medicine Department, First Affiliated Hospital of China Medical University, Shenyang, 201203, Liaoning, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qinglan Wang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xuewei Li
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Xu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiao Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shuang Huang
- Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, 32611, USA.
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Priyanka SH, Syam Das S, Nair SS, Rauf AA, Indira M. All trans retinoic acid modulates TNF-α and CYP2E1 pathways and enhances regression of ethanol-induced fibrosis markers in hepatocytes and HSCs in abstaining rodent model. Arch Physiol Biochem 2019; 125:302-310. [PMID: 29592769 DOI: 10.1080/13813455.2018.1455712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Context: Our previous studies showed that all trans retinoic acid (ATRA) ameliorates alcohol-induced toxicity. Hence, we evaluated the efficacy of ATRA and abstention in the regression of alcohol-induced hepatotoxicity. Materials and methods: After ethanol administration to rats for 90 days, the regression of alcohol-induced toxicity was studied by supplementing ATRA at a dose of 100 μg/kg body weight for 30 days. It was also compared with animals in abstention. Results and discussion: Ethanol administration enhanced oxidative stress, activated HSCs and increased collagen deposition. All these alterations were reversed to a certain extent by ATRA supplementation. Conclusions: ATRA had better efficacy than just abstention in reducing ethanol-induced toxicity. The mechanism might be downregulation of CYP2E1, leading to reduced oxidative stress in the hepatocytes and thus impeding NFκB activation, cytokine production, activation of HSC and resulting in the reduction of inflammation and remodelling of fibrosis by modulating MMP and TIMP.
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Affiliation(s)
- S H Priyanka
- a Department of Biochemistry, University of Kerala , Thiruvananthapuram , India
| | - S Syam Das
- a Department of Biochemistry, University of Kerala , Thiruvananthapuram , India
| | - Saritha S Nair
- a Department of Biochemistry, University of Kerala , Thiruvananthapuram , India
| | - Arun A Rauf
- a Department of Biochemistry, University of Kerala , Thiruvananthapuram , India
| | - M Indira
- a Department of Biochemistry, University of Kerala , Thiruvananthapuram , India
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Zhu S, Wang T, Luo F, Li H, Jia Q, He T, Wu H, Zou T. Astaxanthin inhibits proliferation and induces apoptosis of LX‑2 cells by regulating the miR‑29b/Bcl‑2 pathway. Mol Med Rep 2019; 19:3537-3547. [PMID: 30896849 PMCID: PMC6471391 DOI: 10.3892/mmr.2019.10025] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to investigate the role of microRNAs (miRNAs/miRs) in the anti-fibrotic effect of astaxanthin (AST), using the human hepatic stellate cell (HSC) line LX-2 as the research model. LX-2 cells were treated with various concentrations of AST (10, 20 and 40 µM) for 24 or 48 h. miR-29b was selected based on existing literature, and its targeting gene B cell lymphoma (Bcl)-2 was predicted by TargetScan and miRanda databases for further analysis. Interactions between miR-29b and Bcl-2 in the AST treated LX-2 cells were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. MTT analysis was used to analyze cell viability. Overexpression of miR-29b decreased the expression of Bcl-2 in AST-treated LX-2 cells, and silencing of it had the opposite effect. Additionally, Annexin V-fluorescein isothiocyanate/propidium iodide double staining and flow cytometry were used to evaluate the cell apoptosis, and overexpression of miR-29b increased cell apoptosis rates in AST-treated LX-2 cells; however, silencing of it had the opposite effect. RT-qPCR and western blotting demonstrated that AST induced LX-2 cells apoptosis which may be by regulating miR-29b, as indicated by inhibited Bcl-2 expression levels and elevated Bax and Caspase-3 expression levels. These results highlight an important role of miR-29b in the AST modulating LX-2 cells proliferation and apoptosis and implicate a potential mechanism of miR-29b and AST preventing liver fibrosis.
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Affiliation(s)
- Shanshan Zhu
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Tao Wang
- Department of Surgery, The Third Affiliated Hospital of Guangdong Medical University, Longjiang Hospital of Shunde District, Foshan, Guangdong 528318, P.R. China
| | - Fei Luo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Huawen Li
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Qing Jia
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Taiping He
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Hongfu Wu
- School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Tangbin Zou
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Musaddaq G, Shahzad N, Ashraf MA, Arshad MI. Circulating liver-specific microRNAs as noninvasive diagnostic biomarkers of hepatic diseases in human. Biomarkers 2019; 24:103-109. [PMID: 30252499 DOI: 10.1080/1354750x.2018.1528631] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 09/22/2018] [Indexed: 02/08/2023]
Abstract
CONTEXT Hepatitis is an endemic disease worldwide leading to chronic and debilitating cancers. The viral agents and hepatotoxic substances lead to damage of hepatocytes and release of damage associated molecules in circulation. The lack of timely and rapid diagnosis of hepatitis results in chronic disease. OBJECTIVE The present review aimed to describe regulation, release and functions of microRNAs (miR) during human liver pathology and insights into their promising use as noninvasive biomarkers of hepatitis. METHODS Comprehensive data were collected from PubMed, ScienceDirect and the Web of Science databases utilizing the keywords "biomarkers", "microRNAs" and "hepatic diseases". RESULTS The miRs are readily released in the body fluids and blood during HBV/HCV associated hepatitis as well as metabolic, alcoholic, drug induced and autoimmune hepatitis. The liver-specific microRNAs including miR-122, miR-130, miR-183, miR-196, miR-209 and miR-96 are potential indicators of liver injury (mainly via apoptosis, necrosis and necroptosis) or hepatitis with their varied expression during acute/fulminant, chronic, liver fibrosis/cirrhosis and hepato-cellular carcinoma. CONCLUSIONS The liver-specific miRs can be used as rapid and noninvasive biomarkers of hepatitis to discern different stages of hepatitis. Blocking or stimulating pathways associated with miR regulation in liver could unveil novel therapeutic strategies in the management of liver diseases. Clinical significance Liver specific microRNAs interact with cellular proteins and signaling molecules to regulate the expression of various genes controlling biological processes. The circulatory level of liver specific microRNAs is indicator of severity of HBV and HCV infections as well as prognostic and therapeutic candidates. The expression of liver specific microRNAs is strongly associated with infectious, drug-induced, hepatotoxic, nonalcoholic steatohepatitis and nonalcoholic fatty liver diseases.
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Affiliation(s)
- Ghulam Musaddaq
- a Institute of Microbiology, University of Agriculture , Faisalabad , Pakistan
| | - Naveed Shahzad
- b School of Biological Sciences (SBS), University of the Punjab , Lahore , Pakistan
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Wang P, Lei S, Wang X, Xu W, Hu P, Chen F, Zhang X, Yin C, Xie W. MicroRNA-134 deactivates hepatic stellate cells by targeting TGF-β activated kinase 1-binding protein 1. Biochem Cell Biol 2019; 97:505-512. [PMID: 30645141 DOI: 10.1139/bcb-2018-0211] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Aberrant expression of microRNAs is associated with liver fibrogenesis. We previously found that microRNA-134 (miR-134) expression was reduced in fibrosis-based hepatocarcinogenesis induced by diethylinitrosamine. Herein we investigate the role and mechanisms of miR-134 in hepatic fibrosis. Our data show that miR-134 expression is reduced in rat hepatic fibrogenesis induced by carbontetrachloride, bile duct ligation, and dimethylnitrosamine, as well as in activated hepatic stellate cells (HSCs). Moreover, miR-134 inhibited HSC proliferation, and decreased the expression of smooth muscle actin and collagen I in HSCs, whereas the miR-134 inhibitor increased HSC activation. MiR-134 also negatively regulated transforming growth factor-β-activated kinase 1-binding protein 1 (TAB1) expression in both human and rat HSCs by directly binding to its 3' untranslated region. Importantly, TAB1 expression was significantly elevated during liver fibrogenesis and HSC activation. Knockdown of TAB1 inhibited the proliferation and fibrogenic behavior of HSCs, and significantly reduced the effect of the miR-134 inhibitor on HSC proliferation. Collectively, these data suggest that miR-134 inhibits the activation of HSCs via directly targeting TAB1, and the restoration of miR-134 or targeting TAB1 is of clinical significance in the treatment of liver fibrosis.
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Affiliation(s)
- Peiqin Wang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Shujuan Lei
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xiaohang Wang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Wenping Xu
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Pingfang Hu
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Fei Chen
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xin Zhang
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Chuan Yin
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Weifen Xie
- Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.,Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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Abstract
MicroRNAs (miRNA) are small non-coding RNAs (∼22 nt in length) that are known as potent master regulators of eukaryotic gene expression. miRNAs have been shown to play a critical role in cancer pathogenesis, and the misregulation of miRNAs is a well-known feature of cancer. In recent years, miR-29 has emerged as a critical miRNA in various cancers, and it has been shown to regulate multiple oncogenic processes, including epigenetics, proteostasis, metabolism, proliferation, apoptosis, metastasis, fibrosis, angiogenesis, and immunomodulation. Although miR-29 has been thoroughly documented as a tumor suppressor in the majority of studies, some controversy remains with conflicting reports of miR-29 as an oncogene. In this review, we provide a systematic overview of miR-29's functional role in various mechanisms of cancer and introspection on the contradictory roles of miR-29.
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36
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Ma L, Ma J, Ou HL. MicroRNA‑219 overexpression serves a protective role during liver fibrosis by targeting tumor growth factor β receptor 2. Mol Med Rep 2018; 19:1543-1550. [PMID: 30592264 PMCID: PMC6390038 DOI: 10.3892/mmr.2018.9787] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 11/05/2018] [Indexed: 12/11/2022] Open
Abstract
Progressive liver fibrosis is the primary cause of liver cirrhosis and hepatocellular carcinoma, and leads to considerable morbidity and mortality. Recent studies have demonstrated that microRNAs (miRNAs or miRs) are associated with fibrotic processes in liver disorders, although the exact role of miR-219 remains unclear and the relevant mechanisms remain to be completely understood. To the best of our knowledge, the present study was the first to demonstrate the functional implications of miR-219 expression during liver fibrosis. The present study reported that miR-219 exhibited significantly reduced expression in serum from patients and that its expression was negatively associated with clinical stage. It was also demonstrated that miR-219 attenuated angiotensin II-induced expression of pro-fibrotic markers, including α-smooth muscle actin, atlastin GTPase 1 and collagen. Additionally, a CCl4-induced mouse liver injury model was used to demonstrate that miR-219 strongly suppressed liver fibrosis in vivo. Furthermore, the present study identified tumor growth factor β receptor 2 (TGFBR2) as a direct target gene of miR-219. In conclusion, the results of the present study revealed that miR-219 may regulate pro-fibrotic markers by directly targeting the TGFBR2 gene and the miR-219/TGFBR2 signaling pathway may be a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Li Ma
- Department of Liver Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Jian Ma
- Department of Endocrinology, The People's Hospital of Fenghua District, Ningbo, Zhejiang 315500, P.R. China
| | - Hong-Liang Ou
- Department of Liver Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China
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37
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Yang J, Lu Y, Yang P, Chen Q, Wang Y, Ding Q, Xu T, Li X, Li C, Huang C, Meng X, Li J, Zhang L, Wang X. MicroRNA-145 induces the senescence of activated hepatic stellate cells through the activation of p53 pathway by ZEB2. J Cell Physiol 2018; 234:7587-7599. [PMID: 30479019 DOI: 10.1002/jcp.27521] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 09/10/2018] [Indexed: 12/11/2022]
Abstract
Activation of quiescent hepatic stellate cells (HSCs) is the major event in liver fibrosis, along with enhancement of cell proliferation and overproduction of extracellular matrix. Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. The p53, a guardian of the genome is associated with liver fibrosis, has been shown to regulate HSCs senescence. In this study, we report that microRNA-145 (miR-145) and p53 were downregulated in vivo and in vitro, concomitant with the enhanced expression of zinc finger E-box binding homeobox 2 (ZEB2). In addition, overexpression of miR-145 and p53 led to upregulation of the number of senescence-associated β-galactosidase-positive HSCs and the expression of senescence markers p16 and p21, along with the reduced abundance of HSC activation markers α-smooth muscle actin and type I collagen in activated HSCs. Furthermore, silencing of ZEB2 promoted senescence of activated HSCs. Moreover, we also demonstrated that miR-145 specifically targeted the 3'-untranslated regions of ZEB2. In vitro promoter regulation studies show that ZEB2 could bind to the E-box of the p53 promoter as well as inhibit its promoter activity and thus suppress the expression of p53, which in turn repressed activated HSCs senescence. Taken together, our results describe a novel miR-145-ZEB2-p53 regulatory line might participate in the senescence of activated HSCs and might carry potential therapeutic targets for restraining liver fibrosis.
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Affiliation(s)
- Junfa Yang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Yuchen Lu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Peipei Yang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Qingfeng Chen
- Department of Clinical Medicine, Clinic Medical College of Anhui Medical University, Hefei, China
| | - Yang Wang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Qi Ding
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Tao Xu
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Xiaofeng Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Changyao Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Cheng Huang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Xiaoming Meng
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Jun Li
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China
| | - Xiao Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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MicroRNA Expression in Focal Nodular Hyperplasia in Comparison with Cirrhosis and Hepatocellular Carcinoma. Pathol Oncol Res 2018; 25:1103-1109. [PMID: 30411298 DOI: 10.1007/s12253-018-0528-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023]
Abstract
The liver disease focal nodular hyperplasia (FNH) has several histological features that resemble hepatic cirrhosis. Since cirrhosis may develop further into hepatocellular carcinoma (HCC) contrary to FNH, the aim of the present study was to identify microRNAs (miRNA), which, by their altered expression levels, may be associated with the benign, tumor-like nature of FNH. Altogether 106 surgically removed formalin-fixed paraffin-embedded liver samples were selected, including 22 FNH, 45 cirrhosis, 24 HCC and 15 normal liver tissues. Etiology of the cases of cirrhosis and HCC includes hepatitis C and alcoholism and the HCC cases developed in cirrhotic livers. Relative expression levels of 14 miRNAs were determined using TaqMan MicroRNA Assays. In comparison to normal liver, the levels of miR-34a and miR-224 were elevated not only in FNH but also in cirrhosis and HCC, while the expression of miR-17-5p, miR-18a and miR-210 was decreased in FNH. Further, the levels of miR-21 and miR-222 were increased in cirrhosis and HCC but were decreased in FNH and the expression of miR-17-5p, miR-18a, miR-195 and miR-210 was decreased in FNH as compared with cirrhosis and/or HCC. In conclusion, the elevation of miR-34a and miR-224 may be associated with both benign and malignant proliferative processes, nevertheless the increased expression of oncomiRs miR-21 and miR-222 in cirrhosis and HCC but not in FNH may be related to malignant processes of the liver. The decreased levels of miR-18a, miR-195 and miR-210 may further differentiate FNH from cirrhosis, reflecting the different pathogenesis of these two entities contrary to some histologically similar features.
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Yi S, Qin X, Luo X, Zhang Y, Liu Z, Zhu L. Identification of miRNAs associated with the mechanical response of hepatic stellate cells by miRNA microarray analysis. Exp Ther Med 2018; 16:1707-1714. [PMID: 30186391 PMCID: PMC6122293 DOI: 10.3892/etm.2018.6384] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 06/04/2018] [Indexed: 12/16/2022] Open
Abstract
It has been suggested that hepatic stellate cells (HSCs) could be used in the regulation of liver microcirculation and portal hypertension. The effects of tensile strain on the microRNA (miRNA) profile of HSCs are largely unknown. In this study, we aimed to explore the changes of miRNA expression in tensile strain-treated HSCs. The purity and activation of HSCs were determined by immunofluorescence staining with antibody against desmin and a-SMA, respectively. miRNA profile analysis was performed on HSCs with and without tensile strain treatment (n=3) using microarray analysis. We identified 6 significantly differentially expressed miRNAs (DEMs), including 1 downregulated (rno-miR-125b-2-3p) and 5 upregulated (rno-miR-1224, rho-miR-188-5p, rho-miR-211-3p, rho-miR-3584-5p and rho-miR-466b-5p), which were validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) experiments. Further analysis of the DEMs revealed that many important biological processes and signal pathways were triggered in tensile strain-treated HSCs. These include the signal transduction mechanisms associated with protein binding, apoptosis, proliferation, and the FoxO and Wnt signaling pathways. In conclusion, this study presents the specific DEMs in tensile strain-treated HSCs. Our study provide novel miRNA-based information that may enhance our understanding of the pathophysiological processes leading to portal hypertension.
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Affiliation(s)
- Suhong Yi
- Department of Gastroenterology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.,Department of Gastroenterology, Xinyu People's Hospital, Xinyu, Jiangxi 338000, P.R. China
| | - Xia Qin
- Department of Gastroenterology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.,Shanghai University of Medicine and Health Sciences, Shanghai 200003, P.R. China
| | - Xu Luo
- Department of Gastroenterology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Yi Zhang
- Department of Gastroenterology, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Zhijun Liu
- Department of Gastroenterology, Xinyu People's Hospital, Xinyu, Jiangxi 338000, P.R. China
| | - Liang Zhu
- Department of Gastroenterology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
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40
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Yang J, Liu Q, Cao S, Xu T, Li X, Zhou D, Pan L, Li C, Huang C, Meng X, Zhang L, Wang X. MicroRNA-145 Increases the Apoptosis of Activated Hepatic Stellate Cells Induced by TRAIL through NF-κB Signaling Pathway. Front Pharmacol 2018; 8:980. [PMID: 29375381 PMCID: PMC5770373 DOI: 10.3389/fphar.2017.00980] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 12/21/2017] [Indexed: 12/18/2022] Open
Abstract
During the liver fibrosis recovery stage tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can effectively induce apoptosis of activated hepatic stellate cells (HSCs). Normal hepatic stellate cells are resistant to TRAIL cytotoxicity. Therefore, enhancing the sensitivity of TRAIL-induced apoptosis of HSCs may be useful to treat hepatic fibrogenesis. Here, we demonstrated that miR-145 and TRAIL were down-regulated in both liver fibrosis tissue samples and transforming growth factor-β1 induced HSCs, concomitant with increased the expression of ZEB2. In addition, we found that mimics-mediated over-expression of miR-145 led to resistance to the ZEB2 expression and up-regulation of the TRAIL-induced apoptosis after treatment of LX-2 cells with TRAIL. Furthermore, ZEB2-siRNA transfected LX-2 cells showed the increased sensitivity to TRAIL-induced apoptosis. Whereas, opposite results were obtained in miR-145-inhibitor group or ZEB2 plasmid group. Moreover, miR-145 regulated ZEB2 gene expression by specifically interacting with the 3′-UTR of ZEB2 mRNA to inhibit the expression of ZEB2. Further studies showed that the over-expression of ZEB2 could inhibit TRAIL-induced apoptosis via inhibiting nuclear factor-κB (NF-κB) signaling pathway in LX-2 cells. Collectively, our data suggest that up-regulation of miR-145 can down-regulate ZEB2 expression, consequently promoting TRAIL-induced apoptosis in LX-2 cells through NF-κB signaling pathway, which facilitates the resolution of liver fibrosis.
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Affiliation(s)
- Junfa Yang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Qingxue Liu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Shiyang Cao
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Tao Xu
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaofeng Li
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Dandan Zhou
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Linxin Pan
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Changyao Li
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Cheng Huang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiaoming Meng
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiao Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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41
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Xiang T, Zhang S, Cheng N, Ge S, Wen J, Xiao J, Wu X. Oxidored-nitro domain-containing protein 1 promotes liver fibrosis by activating the Wnt/β-catenin signaling pathway in vitro. Mol Med Rep 2017; 16:5050-5054. [PMID: 28791396 DOI: 10.3892/mmr.2017.7165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 05/26/2017] [Indexed: 11/06/2022] Open
Abstract
Hepatic fibrosis is a characteristic of various types of chronic liver diseases, and may further develop into liver cirrhosis and liver cancer. Oxidored‑nitro domain‑containing protein 1 (NOR1) expression levels are greater in hepatitis, cirrhosis and hepatocellular carcinoma samples compared with from normal liver samples. However, the importance of NOR1 in liver fibrosis remains to be elucidated. The present study aimed to investigate the effect of NOR1 on the proliferation and matrix expression of human hepatic stellate cells (HSCs) in vitro. Additionally, the molecular mechanisms underlying the role of NOR1 in the activation of HSCs was investigated. The present study determined that transforming growth factor β1 (TGF‑β1) may induce NOR1 expression in HSCs in a dose‑dependent manner, as determined by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. NOR1‑small hairpin (sh)RNA was transfected into TGF‑β1‑treated HSCs to knock down NOR1. The MTT assay revealed that TGF‑β1‑induced cell proliferation was significantly inhibited in the NOR1‑shRNA group. In addition, NOR1 knockdown significantly inhibited TGF‑β1‑induced protein expression of fibrosis indexes, including collagen 1, 3 and α‑smooth muscle actin (α‑SMA). Subsequently, NOR1‑pcDNA3.1 was transfected into HSCs to overexpress NOR1. It was revealed that NOR1 overexpression may activate the Wnt/β‑catenin pathway in HSCs. The gain‑of function experiments demonstrated that NOR1 overexpression promoted cell proliferation and the expression of fibrosis indexes; however, these effects may be attenuated by dickkopf‑1, an inhibitor of the Wnt/β‑catenin signaling pathway. In conclusion, the present study demonstrated that NOR1 activates HSCs and contributes to liver fibrosis in vitro and this effect was achieved through the activation of the Wnt/β‑catenin pathway. Therefore, the current study may provide a novel target for the treatment of chronic liver diseases.
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Affiliation(s)
- Tianxin Xiang
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shouhua Zhang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Na Cheng
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Shanfei Ge
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jiangxiong Wen
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Juhua Xiao
- Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaoping Wu
- Department of Infectious Disease, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Elemeery MN, Badr AN, Mohamed MA, Ghareeb DA. Validation of a serum microRNA panel as biomarkers for early diagnosis of hepatocellular carcinoma post-hepatitis C infection in Egyptian patients. World J Gastroenterol 2017; 23:3864-3875. [PMID: 28638226 PMCID: PMC5467072 DOI: 10.3748/wjg.v23.i21.3864] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/18/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prospective importance of serum micro (mi)RNAs (miR-125b, miR-138b, miR-1269, miR-214-5p, miR-494, miR375 and miR-145) as early biomarkers for the diagnosis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
METHODS Two-hundred and fifty HCV4a patients, 224 HCV4a-HCC patients, and 84 healthy controls were enrolled in the study. Expression levels of miR214-5p, miR-125b, miR-1269 and miR-375 were quantified using quantitative real-time PCR.
RESULTS Expression of the selected miRNAs in serum was significantly lower in HCC patients than in the healthy controls, except for miR-1269 and miR-494. There was a significant difference between HCC and HCV patients, in particular for HCC and late stage fibrosis, rather than HCV patients and early fibrosis. It is obvious that miR-1269 was significantly upregulated in HCC cases compared to hepatic fibrosis cases. Each miRNA can show HCC progression. Multivariate logistic regression analysis indicated that the tested panel of miRNAs (miR214-5p, miR-125b, miR-1269 and miR-375) represent accurate and specific indictors of HCC development.
CONCLUSION This study presents a panel of miRNAs with strong power as putative diagnostic and prognostic biomarkers for HCV-induced HCC. Moreover, miR-214-5p and miR-1269 could be considered as early biomarkers for tracking the progress of liver fibrosis to HCC.
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Zhu HT, Liu RB, Liang YY, Hasan AME, Wang HY, Shao Q, Zhang ZC, Wang J, He CY, Wang F, Shao JY. Serum microRNA profiles as diagnostic biomarkers for HBV-positive hepatocellular carcinoma. Liver Int 2017; 37:888-896. [PMID: 28061012 DOI: 10.1111/liv.13356] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 12/30/2016] [Accepted: 12/31/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The discovery of effective and reliable biomarkers to detect hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) at an early stage may improve the survival of HCC. The aim of this study was to establish serum microRNA (miRNA) profiles as diagnostic biomarkers for HBV-positive HCC. METHODS We used deep sequencing to screen serum miRNAs in a discovery cohort (n=100). Quantitative polymerase chain reaction (qPCR) assays were then applied to evaluate the expression of selected miRNAs. A diagnostic 2-miRNA panel was established by a logistic regression model using a training cohort (n=182). The predicted probability of being detected as HCC was used to construct the receiver operating characteristic (ROC) curve. Area under the ROC curve (AUC) was used to assess the diagnostic performance of the selected miRNA panel. RESULTS The predicted probability of being detected as HCC by the 2-miRNA panel was calculated by: logit P=-2.988 + 1.299 × miR-27b-3p + 1.245 × miR-192-5p. These results were further confirmed in a validation cohort (n=246).The miRNA panel provided a high diagnostic accuracy of HCC (AUC=0.842, P<.0001 for training set; AUC=0.836, P<.0001 for validation set respectively). In addition, the miRNA panel showed better prediction of HCC diagnosis than did alpha-foetoprotein (AFP). The miRNA panel also differentiated HCC from healthy (AUC=0.823, P<.0001), and cirrhosis patients (AUC=0.859, P<.0001) respectively. CONCLUSIONS Differentially expressed serum miRNAs may have considerable clinical value in HCC diagnosis, and be particularly helpful for AFP-negative HCC.
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Affiliation(s)
- Hao-Tu Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Rong-Bin Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ya-Yong Liang
- Department of paediatrics, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Abdulbaqi M E Hasan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hai-Yun Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiong Shao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zi-Chen Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jing Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Cai-Yun He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jian-Yong Shao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
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Abstract
Liver fibrosis arises because prolonged injury combined with excessive scar deposition within hepatic parenchyma arising from overactive wound healing response mediated by activated myofibroblasts. Fibrosis is the common end point for any type of chronic liver injury including alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cholestatic liver diseases. Although genetic influences are important, it is epigenetic mechanisms that have been shown to orchestrate many aspects of fibrogenesis in the liver. New discoveries in the field are leading toward the development of epigenetic biomarkers and targeted therapies. This review considers epigenetic mechanisms as well as recent advances in epigenetic programming in the context of hepatic fibrosis.
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Key Words
- CLD, chronic liver disease
- Chronic Liver Disease
- CpG, cytosine-phospho-guanine
- DNA Methylation
- DNMT, DNA methyltransferase
- Epigenetics
- HDAC, histone deacetylase
- HSC, hepatic stellate cell
- Histone Modifications
- Liver Fibrosis
- NAFLD, nonalcoholic fatty liver disease
- PPAR, peroxisome proliferator activated receptor
- TET, Ten Eleven Translocation
- miRNA, microRNA
- ncRNA, non-coding RNA
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Affiliation(s)
| | - Jelena Mann
- Correspondence Address correspondence to: Jelena Mann, PhD, Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH United Kingdom. fax: +44-191-208-0723.Institute of Cellular MedicineFaculty of Medical Sciences4th FloorWilliam Leech BuildingNewcastle UniversityFramlington PlaceNewcastle upon TyneNE2 4HH United Kingdom
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Rogler CE, Matarlo JS, Kosmyna B, Fulop D, Rogler LE. Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice. Gene Expr 2017; 17:99-114. [PMID: 27938504 PMCID: PMC8751183 DOI: 10.3727/105221616x693891] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
MicroRNAs (miRNAs) regulate cell fate selection and cellular differentiation. miRNAs of the miR23b polycistron (miR-23b, miR-27b, and miR-24) target components of the TGF-β signaling pathway and affect murine bile ductular and hepatocyte cell fate selection in vitro. Here we show that miR-23b polycistron miRNAs directly target murine Smad4, which is required for TGF-β signaling. Injection of antagomirs against these miRNAs directly into E16.5 murine fetuses caused increased cytokeratin expression in sinusoids and primitive ductular elements throughout the parenchyma of newborn mice. Similar antagomir injection in newborn mice increased bile ductular differentiation in the liver periphery and reduced hepatocyte proliferation. Antagomir injection in newborn Alb/TGF-β1 transgenic mice that develop fibrosis inhibited the development of fibrosis, and injection of older mice caused the resolution of existing fibrosis. Furthermore, murine stellate cell activation, including ColA1 and ACTA2 expression, is regulated by miR-23b cluster miRNAs. In summary, knockdown of miR-23b cluster miRNAs in fetal and newborn liver promotes bile duct differentiation and can block or revert TGF-β-induced liver fibrosis that is dependent on stellate cell activation. These data may find practical application in the highly needed development of therapies for the treatment of fibrosis.
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Affiliation(s)
- Charles E. Rogler
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joe S. Matarlo
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Brian Kosmyna
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Daniel Fulop
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Leslie E. Rogler
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Chen R, Wu JC, Liu T, Qu Y, Lu LG, Xu MY. MicroRNA profile analysis in the liver fibrotic tissues of chronic hepatitis B patients. J Dig Dis 2017; 18:115-124. [PMID: 28127890 DOI: 10.1111/1751-2980.12452] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 01/16/2017] [Accepted: 01/24/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We aimed to identify the features of microRNA (miRNA) at different fibrotic stages in patients with hepatitis B virus (HBV)-related liver fibrosis. METHODS Liver tissues were collected from 40 chronic hepatitis B (CHB) patients at fibrotic stages S0-4. Microarrays of miRNAs and genomic informatics analysis were performed. RESULTS In total, 105 miRNAs were differentially expressed in fibrotic tissues (S1-4 groups) compared with no fibrotic tissues (S0 group; P < 0.05). Combined with three classifications, 17 differential miRNAs were found to be closely related to fibrotic stages (over twofold change and P < 0.05). Five miRNAs had a signature that correlated with serum biochemical parameters and liver inflammatory grades. The receiver operating characteristic (ROC) curve showed that six miRNAs performed excellently in the diagnosis of liver fibrosis, with the area under the ROC curve (AUROC) over 0.8; among them hsa-miR-214-3p had the highest AUROC (0.867). Gene ontology functions of differential miRNAs mainly involved in the cellular and developmental processes, localization, biological regulation, binding, transcriptional regulator and organelle. We also found that 23 novel signaling pathways were dysregulated in the liver fibrosis. CONCLUSIONS MiRNA profile signature, including 17 differential miRNAs and 23 dysregulated signaling pathways, was associated with liver fibrosis. Hepatic inflammatory grades were correlated with the differential miRNA. Some miRNAs can be used for the diagnosis of liver fibrosis.
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Affiliation(s)
- Rong Chen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Cheng Wu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Liu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ying Qu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun Gen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ming Yi Xu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Men R, Wen M, Zhao M, Dan X, Yang Z, Wu W, Wang MH, Liu X, Yang L. MircoRNA-145 promotes activation of hepatic stellate cells via targeting krüppel-like factor 4. Sci Rep 2017; 7:40468. [PMID: 28091538 PMCID: PMC5238405 DOI: 10.1038/srep40468] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Accepted: 12/06/2016] [Indexed: 02/05/2023] Open
Abstract
Krüppel-like Factor 4 (KLF4), a target gene of miR-145, can negatively regulate lung fibrosis. However, the potential role of KLF4 and miR-145 in hepatic stellate cells (HSCs) activation or in hepatic fibrosis keeps unclear. This study aims to characterize miR-145 and KLF4 in activated HSCs and liver cirrhotic, and the underlying molecular basis. miR-145 was significantly up-regulated, while KLF4 was dramatically down-regulated during the activation of rat primary HSCs and TGF-βtreated HSCs. Furthermore, miR-145 mimics induced and inhibition of miR-145 reduced α-SMA and COL-I expression in primary HSCs. Additionally, the mRNA and protein levels of KLF4 in the liver of cirrhotic patients and rats were significantly down-regulated. α-SMA and COL-I were increased after inhibition of KLF4 by specific shRNA in primary HSCs. Forced KLF4 expression led to a reduction of α-SMA and COL-I expression in HSCs. miR-145 promotes HSC activation and liver fibrosis by targeting KLF4.
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Affiliation(s)
- Ruoting Men
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China
- Department of Biostatistics, JC school of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, China
| | - Maoyao Wen
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingyue Zhao
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuelian Dan
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zongze Yang
- Creation and Management of a Tumour Bank, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China
| | - Wenchao Wu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Maggie Haitian Wang
- Department of Biostatistics, JC school of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, China
| | - Xiaojing Liu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Li Yang
- Division of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu 610041, China
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Kota J, Hancock J, Kwon J, Korc M. Pancreatic cancer: Stroma and its current and emerging targeted therapies. Cancer Lett 2017; 391:38-49. [PMID: 28093284 DOI: 10.1016/j.canlet.2016.12.035] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 12/22/2016] [Accepted: 12/23/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies with a 5-year survival rate of 8%. Dense, fibrotic stroma associated with pancreatic tumors is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Targeting stroma is considered as a potential therapeutic strategy to improve anti-cancer drug efficacy and patient survival. Although numerous stromal depletion therapies have reached the clinic, they add little to overall survival and are often associated with toxicity. Furthermore, increasing evidence suggests the anti-tumor properties of stroma. Its complete ablation enhanced tumor progression and reduced survival. Consequently, efforts are now focused on developing stromal-targeted therapies that normalize the reactive stroma and avoid the extremes: stromal abundance vs. complete depletion. In this review, we summarized the state of current and emerging anti-stromal targeted therapies, with major emphasis on the role of miRNAs in PDAC stroma and their potential use as novel therapeutic agents to modulate PDAC tumor-stromal interactions.
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Affiliation(s)
- Janaiah Kota
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
| | - Julie Hancock
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Jason Kwon
- Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA
| | - Murray Korc
- The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA; Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA; Department of Medicine, IUSM, Indianapolis, IN, USA
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Yu F, Chen B, Dong P, Zheng J. HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis. Mol Ther 2017; 25:205-217. [PMID: 28129115 PMCID: PMC5363197 DOI: 10.1016/j.ymthe.2016.10.015] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 10/27/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
Homeobox transcript antisense RNA (HOTAIR), as a long intergenic non-coding RNA (lincRNA), is upregulated in various cancers and involved in diverse cellular functions. However, its role in liver fibrosis is unclear. In this study, HOTAIR expression was upregulated in hepatic stellate cells (HSCs) in vivo and in vitro during liver fibrosis. HOTAIR knockdown suppressed HSC activation including α-smooth muscle actin (α-SMA) and typeIcollagen in vitro and in vivo. Both HSC proliferation and cell cycle were inhibited by HOTAIR knockdown. Notably, inhibition of HOTAIR led to an increase in PTEN, associated with the loss of DNA methylation. miR-29b-mediated control of PTEN methylation was involved in the effects of HOTAIR knockdown. HOTAIR was confirmed a target of miR-29b and lack of the miR-29b binding site in HOTAIR prevented the suppression of miR-29b, suggesting HOTAIR contributes to PTEN expression downregulation via sponging miR-29b. Interestingly, increased HOTAIR was also observed in hepatocytes during liver fibrosis. Loss of HOTAIR additionally led to the increase in PTEN and the reduction in typeIcollagen in hepatocytes. Collectively, we demonstrate that HOTAIR downregulates miR-29b expression and attenuates its control on epigenetic regulation, leading to enhanced PTEN methylation, which contributes to the progression of liver fibrosis.
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Affiliation(s)
- Fujun Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Gastroenterology, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 201600, China; Department of Gastroenterology, Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China
| | - Bicheng Chen
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Peihong Dong
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
| | - Jianjian Zheng
- Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
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Rosenbloom J, Macarak E, Piera-Velazquez S, Jimenez SA. Human Fibrotic Diseases: Current Challenges in Fibrosis Research. Methods Mol Biol 2017; 1627:1-23. [PMID: 28836191 DOI: 10.1007/978-1-4939-7113-8_1] [Citation(s) in RCA: 109] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Human fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals, the incomplete knowledge of the fibrotic process pathogenesis, the marked heterogeneity in their etiology and clinical manifestations, the absence of appropriate and fully validated biomarkers, and, most importantly, the current void of effective disease-modifying therapeutic agents. The fibrotic disorders encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis (SSc), sclerodermatous graft vs. host disease, and nephrogenic systemic fibrosis, as well as numerous organ-specific disorders including radiation-induced fibrosis and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse and in several instances have remained elusive, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrotic tissue in affected organs causing their dysfunction and ultimate failure. Despite the remarkable heterogeneity in the etiologic mechanisms responsible for the development of fibrotic diseases and in their clinical manifestations, numerous studies have identified activated myofibroblasts as the common cellular element ultimately responsible for the replacement of normal tissues with nonfunctional fibrotic tissue. Critical signaling cascades, initiated primarily by transforming growth factor-β (TGF-β), but also involving numerous cytokines and signaling molecules which stimulate profibrotic reactions in myofibroblasts, offer potential therapeutic targets. Here, we briefly review the current knowledge of the molecular mechanisms involved in the development of tissue fibrosis and point out some of the most important challenges to research in the fibrotic diseases and to the development of effective therapeutic approaches for this often fatal group of disorders. Efforts to further clarify the complex pathogenetic mechanisms of the fibrotic process should be encouraged to attain the elusive goal of developing effective therapies for these serious, untreatable, and often fatal disorders.
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Affiliation(s)
- Joel Rosenbloom
- The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Edward Macarak
- The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sonsoles Piera-Velazquez
- The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sergio A Jimenez
- The Joan and Joel Rosenbloom Center for Fibrotic Diseases and The Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
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