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Ullah K, Hossain A, Cao M, Xue L, Wang Y. Target miRNA identification for the LPL gene in large yellow croaker (Larimichthys crocea). Sci Rep 2025; 15:4164. [PMID: 39905090 PMCID: PMC11794633 DOI: 10.1038/s41598-024-82988-2] [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: 07/03/2024] [Accepted: 12/10/2024] [Indexed: 02/06/2025] Open
Abstract
MicroRNA (miRNA), a conservatively evolved single-stranded non-coding RNA, exerts pivotal control over the appearance of target genes and several biological processes. This study conducted a comprehensive screening of candidate microRNAs (miRNAs) associated with Lipoprotein Lipase (LPL) in the large yellow croaker (Larimichthys crocea), utilizing sophisticated bioinformatics techniques across the species' muscular and hepatic tissues. The bioinformatics analysis facilitated the compilation and examination of miRNA datasets specific to these tissues. The investigation culminated in the identification of miR-84a and miR-1231-5p as key miRNAs that modulate fat hydrolysis, highlighting their potential roles in lipid metabolism. Subsequent in-depth analysis further implicated these miRNAs, along with miR-891a, as prospective targets of LPL, suggesting their integral involvement in the regulation of this critical enzyme. Validation of these bioinformatics predictions was conducted through the construction of double luciferase reporters concealing the LPL 3' untranslated region (3'UTR), substantiating that miR-84a and miR-1231-5p can modulate LPL expression via the LPL 3'UTR. Conversely, miR-891a was not concerned with this regulatory mechanism. Site-directed mutagenesis experiments elucidated the specificity of the interaction sequences. Quantitative PCR assays suggested that miR-84a and miR-1231-5p might influence LPL expression during the starvation phase, intimating the regulatory role of miRNA in fatty acid metabolism within hepatic and muscular tissue under starvation. These findings offer a nuanced understanding of LPL's molecular functionality under stress conditions in fish, emphasizing the regulatory dynamics of miRNA during metabolic stress.
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Affiliation(s)
- Kalim Ullah
- College of Marine Science, Ningbo University, 169 Qixing South Road, Meishan Bonded Port, Ningbo, 315832, Zhejiang, People's Republic of China
| | - Aslam Hossain
- College of Marine Science, Ningbo University, 169 Qixing South Road, Meishan Bonded Port, Ningbo, 315832, Zhejiang, People's Republic of China
| | - Mingyue Cao
- College of Marine Science, Ningbo University, 169 Qixing South Road, Meishan Bonded Port, Ningbo, 315832, Zhejiang, People's Republic of China
| | - Liangyi Xue
- College of Marine Science, Ningbo University, 169 Qixing South Road, Meishan Bonded Port, Ningbo, 315832, Zhejiang, People's Republic of China.
| | - Yajun Wang
- College of Marine Science, Ningbo University, 169 Qixing South Road, Meishan Bonded Port, Ningbo, 315832, Zhejiang, People's Republic of China.
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Agustiningsih A, Rasyak MR, Turyadi, Jayanti S, Sukowati C. The oncogenic role of hepatitis B virus X gene in hepatocarcinogenesis: recent updates. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:120-134. [PMID: 38464387 PMCID: PMC10918233 DOI: 10.37349/etat.2024.00209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 11/21/2023] [Indexed: 03/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers with high mortality rate. Among its various etiological factors, one of the major risk factors for HCC is a chronic infection of hepatitis B virus (HBV). HBV X protein (HBx) has been identified to play an important role in the HBV-induced HCC pathogenesis since it may interfere with several key regulators of many cellular processes. HBx localization within the cells may be beneficial to HBx multiple functions at different phases of HBV infection and associated hepatocarcinogenesis. HBx as a regulatory protein modulates cellular transcription, molecular signal transduction, cell cycle, apoptosis, autophagy, protein degradation pathways, and host genetic stability via interaction with various factors, including its association with various non-coding RNAs. A better understanding on the regulatory mechanism of HBx on various characteristics of HCC would provide an overall picture of HBV-associated HCC. This article addresses recent data on HBx role in the HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Muhammad Rezki Rasyak
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Turyadi
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy
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Ezzat WM, Amr KS, Tawfeek S, Elbatae H, Bayomi EA, Heiba A, Elhosary Y. Serum MicroRNA profiles in chronic hepatitis C Egyptian patients before and after combined sofosbuvir and daclatasvir treatment. BMC Infect Dis 2024; 24:67. [PMID: 38195397 PMCID: PMC10775543 DOI: 10.1186/s12879-023-08016-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 01/18/2023] [Indexed: 01/11/2024] Open
Abstract
BACKGROUND MicroRNAs (miR) are small sequence of nucleotides that can affect multiple genes involved in the hepatitis C virus (HCV) life cycle and disease development. The purpose of the present study was to investigate the clinical significance of serum microRNA profiles in a cohort of Egyptian patients with chronic HCV infection before and after combined sofosbuvir and daclatasvir treatment, as well as to gain a better understanding of the exact interaction mechanism in HCV transcriptional activity via differentially expressed miRNAs. For 12 weeks, 50 patients were eligible for and received sofosbuvir (400 mg daily) and daclatasvir (60 mg daily) treatment. Each patient's blood was obtained twice: once before therapy began and again three months afterwards. RESULTS The current study found that serum levels of circulating miR-122, miR-221, miR-23a, miR-125, miR-217, miR-224, and miR-181a were high in HCV pre-treatment patients, but after 12 weeks of direct-acting antiviral (DAAs) treatment, there was a statistically significant reduction in expression levels of miR-122, miR-221, miR-23a, miR-125, miR-217, and miR-224 (p < 0.001). There is no statistical significance for miR-181a. CONCLUSION The key differentially expressed microRNAs before and after the direct-acting antiviral (DAA) regimen were connected to the dynamics of chronic HCV infection, suggesting their potential as predictive biomarkers for HCV clearance after sofosbuvir and daclatasvir therapy.
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Affiliation(s)
- Wafaa M Ezzat
- Internal Medicine Department, National Research Centre, Cairo, Egypt
| | - Khalda S Amr
- Medical Molecular Genetics Department, National Research Centre, El-Buhouth St., Dokki, 12622, Cairo, Egypt.
| | - Salwa Tawfeek
- Internal Medicine Department, National Research Centre, Cairo, Egypt
| | - Hassan Elbatae
- Tropical Medicine Department, Kafr Elsheikh University, Kafr Elsheikh, Egypt
| | - Eman A Bayomi
- Medical Molecular Genetics Department, National Research Centre, El-Buhouth St., Dokki, 12622, Cairo, Egypt
| | - Ahmed Heiba
- Internal Medicine Department, National Research Centre, Cairo, Egypt
| | - Yasser Elhosary
- Internal Medicine Department, National Research Centre, Cairo, Egypt
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Shams F, Azeem A, Shams A, Tawab A, Rehman S, Tariq S, Latief N, Ijaz B. Flavonoid rich extract of Trigonella foenum-graecum leaves ameliorate liver fibrosis. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.102046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Yan LR, Liu AR, Jiang LY, Wang BG. Non-coding RNA and hepatitis B virus-related hepatocellular carcinoma: A bibliometric analysis and systematic review. Front Med (Lausanne) 2022; 9:995943. [PMID: 36203765 PMCID: PMC9530602 DOI: 10.3389/fmed.2022.995943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Objectives A bibliometric analysis for non-coding RNA and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) was performed to describe international research status and visualize the research scope and emerging trends over the last two decades on this topic. Materials and methods Research data of non-coding RNA and HBV-related HCC were retrieved and extracted from the Web of Science Core Collection (WoSCC) database from 1 January 2003 to 13 June 2022 and then analyzed by means of bibliometric methods. A total of 1,036 articles published in this field were assessed for specific characteristics, including the year of publication, journal, author, institution, country/region, references, and keywords. VOSviewer was employed to perform co-authorship, co-occurrence, and co-citation analyses accompanied by constructing a visual network. Results Overall, 1,036 reports on non-coding RNA and HBV-related HCC from 2003 to 2022 were retrieved from WoSCC. The publication has gradually increased during the last two decades with 324 journals involved. Most research records (748 publications and 23,184 citations) were concentrated in China. A co-occurrence cluster analysis for the top 100 keywords was performed and four clusters were generated: (1) non-coding RNA as a molecular marker for the diagnosis and prognosis of HBV-related HCC; (2) dysregulation of non-coding RNA by hepatitis B virus X protein (HBx); (3) non-coding RNA affecting the biological behaviors of HBV-related HCC; and (4) epidemiological study for the effects of non-coding RNA on the risk of HBV-related HCC. Conclusion The publications and citations involved in non-coding RNA and HBV-related HCC have increased over the last two decades associated with many countries, institutions, and authors. Our study revealed current development trends, global cooperation models, basic knowledge, research hotspots, and emerging frontiers in this field.
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Affiliation(s)
- Li-rong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Ao-ran Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Li-yue Jiang
- Tangdu Hospital of the Fourth Military Medical University, Xi’an, China
| | - Ben-gang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
- Department of Hepatobiliary Surgery, Institute of General Surgery, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Ben-gang Wang,
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Parvanak M, Mostafavi-Pour Z, Soleimani M, Atashi A, Arefian E, Esmaeili E. Mir-122 upregulation and let-7f downregulation combination: The effects on hepatic differentiation of hiPSCs on the PCL-Gel-HA nanofibrous scaffold. J Cell Mol Med 2022; 26:5235-5245. [PMID: 36098216 PMCID: PMC9575133 DOI: 10.1111/jcmm.17552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 06/24/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Cell therapy and tissue engineering as promising candidates for the liver transplantation dilemma are of special interest. Induced pluripotent stem cells (iPSCs) are one of the best sources in this field, but their differentiation methods to hepatocytes have remained challenging. We transduced human iPSCs (hiPSCs) with miR-122 and off-let-7f (hiPSCsmiR-122 + off-let-7f ) to evaluate how they can differentiate hiPSCs to hepatocyte-like cells (HLCs) without any extrinsic growth factor. Additionally, we studied the effect of Poly ɛ-caprolactone-gelatin-hyaluronic acid (PCL-Gel-HA) nanofibrous scaffold as an extracellular matrix (ECM) simulator on differentiation improvement. Definitive endoderm markers (FOXA2 and SOX17), as well as hepatic markers (AFP, Albumin, CK18, HNF4α) expression, were significantly higher in hiPSCsmiR-122 + off-let-7f derived HLCs (hiPSCs-HLCs) compared to the control group (miR-scramble transduced hiPSCs: hiPSCsscramble ). hiPSCs-HLCs indicated hepatocyte morphological characteristics and positive immunostaining for AFP, Albumin and HNF4α. Albumin and urea secretion were significantly higher in hiPSCs-HLCs than hiPSCsscramble . Comparing these markers in the PCL-Gel-HA group with the tissue culture plate (TCP) group revealed that PCL-Gel-HA could improve differentiation towards HLCs significantly. Regarding our results, these microRNAs can be used to differentiate hiPSCs to the functional hepatocytes for disease modelling, drug screening and cell-based therapy in future studies.
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Affiliation(s)
- Maliheh Parvanak
- Biochemistry Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zohreh Mostafavi-Pour
- Biochemistry Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,Autophagy Research Center, Shiraz University of Medicel Sciences, Shiraz, Iran
| | - Masoud Soleimani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Atashi
- Stem cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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Lima RVC, Stefano JT, Malta FDM, Pinho JRR, Carrilho FJ, Arrese M, Oliveira CP. Ability of a Combined FIB4/miRNA181a Score to Predict Significant Liver Fibrosis in NAFLD Patients. Biomedicines 2021; 9:1751. [PMID: 34944567 PMCID: PMC8698380 DOI: 10.3390/biomedicines9121751] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 12/12/2022] Open
Abstract
Liver biopsy is the gold standard for assessing fibrosis, but there is a need to seek non-invasive biomarkers for this purpose. The aim of this study was to evaluate the correlation between the serum levels of the microRNAs miR-21, miR-29a, miR-122, miR-155 and miR-181a and the phenotypic expression of NAFLD. A cross-sectional study was carried out on 108 NAFLD patients diagnosed by liver biopsy. FIB-4 and NAFLD fibrosis scores were calculated. The comparison between the distributions of microRNA values according to the presence or absence of histological fibrosis (F2-F4) was performed. A multivariate logistic regression analysis was performed to build a score for predicting fibrosis using FIB-4 and Ln (miR-181a) as independent variables. Only miR-181a showed a statistical difference between patients with significant liver fibrosis (>F2) and those without (F0-F1) (p = 0.017). FIB-4 revealed an AUC on the ROC curve of 0.667 to predict clinically significant fibrosis (F2-F4). When assessed using the score in association with Ln (miR-181a), there was an improvement in the ROC curve, with an AUC of 0.71. miR-181a can be used as a non-invasive method of predicting fibrosis in NAFLD, and an association with FIB-4 has the potential to increase the accuracy of each method alone.
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Affiliation(s)
- Rodrigo Vieira Costa Lima
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
| | - José Tadeu Stefano
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
| | - Fernanda de Mello Malta
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
| | - João Renato Rebello Pinho
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
| | - Flair José Carrilho
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 833-0024, Chile;
- Centro de Envejecimiento y Regeneracion (CARE), Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Católica de Chile, Santiago 833-0024, Chile
| | - Claudia P. Oliveira
- Laboratório de Gastroenterologia Clínica e Experimental LIM-07, Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas HCFMUSP, Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, SP, Brazil; (R.V.C.L.); (J.T.S.); (F.d.M.M.); (J.R.R.P.); (F.J.C.)
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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Shafaati M, Jamalidoust M, Kargar M, Arefian E, Kafilzadeh F. Downregulation of hepatitis C virus replication by miR-196a using lentiviral vectors. Microbiol Immunol 2021; 65:161-170. [PMID: 33470443 DOI: 10.1111/1348-0421.12875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 11/25/2020] [Accepted: 01/08/2021] [Indexed: 11/29/2022]
Abstract
Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis and hepatocellular carcinoma. Cellular microRNAs (miRNAs) directly modulate the viral infectivity and indirectly through targeting virus-related host factors. They play an essential role in the progression of different stages of HCV infection. The roles of miR-196 family in HCV infection and hepatocellular carcinoma progression remain poorly understood. Using ViTa databases, miR-196a as a high-score miRNA targeting the NS5 A region of HCV genome was selected. Using dual luciferase assay and an established cell-cultured HCV (HCVcc) system, the effect of miR-196a on HCV genome was assessed. In silico analysis demonstrated the significant role of miR-196a in the downregulation of HCV replication. Using dual luciferase assay, the liver-specific miR-196a and NS5 A gene binding was confirmed. To assess the experimental role of miR-196a, an HCVcc system was established in the Huh 7.5 cell lines. The HCV-RNA 1b derived from an infected patient was transfected into Huh 7.5 cells containing miR-196a lentiviral vectors (Huh 7.5/miR-196a), mocks (Huh 7.5/mock vector), and naïve Huh 7.5 cells. The rate of reduction of the HCV genome replication was assessed using relative real-time PCR assay. These results represent miR-196a overexpression and its roles in regulating HCV genome replication. However, miR-196a may inhibit HCV replication and accelerate the early stages of apoptosis. Overexpression of miR-196a in Huh 7.5 replicon cell is a potential new strategy to prevent hepatitis C infection. The results of this study suggest that miR-196a directly downregulates HCV replication and may serve as a new antiviral therapy.
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Affiliation(s)
- Maryam Shafaati
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Marzieh Jamalidoust
- Department of Virology, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Kargar
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Farshid Kafilzadeh
- Department of Microbiology, Faculty of Sciences, Jahrom Branch, Islamic Azad University, Jahrom, Iran
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Yang C, Nan B, Ye H, Yan H, Wang M, Yuan Y. MiR-193b-5p protects BRL-3A cells from acrylamide-induced cell cycle arrest by targeting FoxO3. Food Chem Toxicol 2021; 150:112059. [PMID: 33582169 DOI: 10.1016/j.fct.2021.112059] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/16/2021] [Accepted: 02/08/2021] [Indexed: 12/25/2022]
Abstract
Acrylamide (AA), an important by-product of the Maillard reaction, has been reported to be genotoxic and carcinogenic. The present study employed miRNAs to investigate the toxic mechanism of AA and their role against AA toxicity. Deep sequencing of small RNA libraries was performed and miR-193b-5p was applied for further study. AA significantly reduced the level of miR-193b-5p and its ectopic expression promoted cell cycle G1/S transition and cell proliferation by upregulating the cyclin-dependent kinase regulator Cyclin D1 and downregulating the cyclin-dependent kinase inhibitor p21, while miR-193b-5p inhibitor led to the opposite results. Dual luciferase assay demonstrated miR-193b-5p regulated the expression of FoxO3 by directly targeting the FoxO3 3'-untranslated region (3'-UTR). Knockdown of FoxO3 induced cell cycle G1/S transition and cell proliferation, which was suppressed by the inhibition of miR-193b-5p but promoted by miR-193b-5p mimics. MiR-193b-5p inhibitor strengthened the effect of FoxO3, contrary to the effect of miR-193b-5p mimics. In conclusion, miR-193b-5p acted as a regulator of cell cycle G1/S transition and cell proliferation by targeting FoxO3 to mediate the expression of p21 and Cyclin D1.
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Affiliation(s)
- Chaoyue Yang
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China
| | - Bo Nan
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China
| | - Haiqing Ye
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China
| | - Haiyang Yan
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China
| | - Minghua Wang
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China
| | - Yuan Yuan
- College of Food Science and Engineering, Jilin University, Changchun, 130062, China.
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Garcia Garcia de Paredes A, Manicardi N, Tellez L, Ibañez L, Royo F, Bermejo J, Blanco C, Fondevila C, Fernandez Lanza V, Garcia-Bermejo L, Falcon-Perez JM, Bañares R, Gracia-Sancho J, Albillos A. Molecular Profiling of Decompensated Cirrhosis by a Novel MicroRNA Signature. Hepatol Commun 2021; 5:309-322. [PMID: 33553977 PMCID: PMC7850302 DOI: 10.1002/hep4.1642] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/27/2020] [Accepted: 10/23/2020] [Indexed: 02/04/2023] Open
Abstract
Noninvasive staging of decompensated cirrhosis is an unmet clinical need. The aims of this study were to characterize and validate a novel microRNA (miRNA) signature to stage decompensated cirrhosis and predict the portal pressure and systolic cardiac response to nonselective beta-blockers (NSBBs). Serum samples from patients with decompensated cirrhosis (n = 36) and healthy controls (n = 36) were tested for a novel signature of five miRNAs (miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p) identified in the secretome of primary human hepatocytes and for three miRNAs (miR-192-5p, miR-34a-5p, and miR-29a-5p) previously discovered as biomarkers of chronic liver disease. All patients had ascites, which was refractory in 18 (50%), and were placed on NSBBs for variceal bleeding prophylaxis. In all patients, serum miRNAs, hepatic venous pressure gradient, and an echocardiogram study were performed before and 1 month after NSBBs. Patients with cirrhosis had lower serum levels of miR-429, miR-885-5p, miR-181b-5p, miR-122-5p, miR-192-5p, and miR-29a-5p (P < 0.05). Baseline serum miR-452-5p and miR-429 levels were lower in NSBB responders (P = 0.006). miR-181b-5p levels were greater in refractory ascites than in diuretic-sensitive ascites (P = 0.008) and correlated with serum creatinine. miR-452-5p and miR-885-5p were inversely correlated with baseline systemic vascular resistance (ρ = -0.46, P = 0.007; and ρ = -0.41, P = 0.01, respectively) and with diminished systolic contractility (ρ = -0.55, P = 0.02; and ρ = -0.55, P = 0.02, respectively) in patients with refractory ascites after NSBBs. Conclusion: Analysis of a miRNA signature in serum discriminates between patients with decompensated cirrhosis who show more severe systemic circulatory dysfunction and compromised systolic function after beta-blockade and those more likely to benefit from NSBBs.
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Affiliation(s)
- Ana Garcia Garcia de Paredes
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain
| | - Nicolo Manicardi
- Liver Vascular Biology Research GroupAugust Pi i Sunyer Biomedical Research InstituteBarcelonaSpain
| | - Luis Tellez
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Luis Ibañez
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Gastroenterology and Hepatology DepartmentHospital Universitario Gregorio MarañonInstituto de Investigacion Sanitaria Gregorio Marañon (IiSGM)Universidad Complutense de MadridMadridSpain
| | - Felix Royo
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Exosomes LaboratoryCenter for Cooperative Research in BioscienciesBasque Research and Technology Alliance DerioDerioSpain
| | - Javier Bermejo
- Cardiology DepartmentHospital Universitario Gregorio MarañonIiSGMUniversidad Complutense de MadridMadridSpain
| | | | - Constantino Fondevila
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Liver Surgery and Transplantation UnitHospital ClinicBarcelonaSpain
| | | | | | - Juan Manuel Falcon-Perez
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Exosomes LaboratoryCenter for Cooperative Research in BioscienciesBasque Research and Technology Alliance DerioDerioSpain.,IKERBASQUE-Basque Foundation for ScienceBilbaoSpain
| | - Rafael Bañares
- Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain.,Gastroenterology and Hepatology DepartmentHospital Universitario Gregorio MarañonInstituto de Investigacion Sanitaria Gregorio Marañon (IiSGM)Universidad Complutense de MadridMadridSpain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research GroupAugust Pi i Sunyer Biomedical Research InstituteBarcelonaSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
| | - Agustin Albillos
- Gastroenterology and Hepatology DepartmentHospital Universitario Ramon y CajalInstituto Ramon y Cajal de Investigacion Biosanitaria (IRYCIS)Universidad de AlcalaMadridSpain.,Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y DigestivasInstituto de Salud Carlos IIIMadridSpain
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12
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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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13
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Mukiibi R, Johnston D, Vinsky M, Fitzsimmons C, Stothard P, Waters SM, Li C. Bovine hepatic miRNAome profiling and differential miRNA expression analyses between beef steers with divergent feed efficiency phenotypes. Sci Rep 2020; 10:19309. [PMID: 33168877 PMCID: PMC7653039 DOI: 10.1038/s41598-020-73885-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small RNA molecules involved in regulation of multiple biological processes through modulating expression of their target genes. Here we employed RNAseq to profile liver tissue miRNAome of 60 steers from Angus, Charolais, and Kinsella Composite (KC) populations. Of these animals, 36 animals (n = 12 for each breed) were utilized to identify differentially expressed (DE) miRNAs between animals with high (n = 6) or low (n = 6) phenotypic values of residual feed intake (RFI), a common measurement of feed efficiency. At a threshold of fold-change > 1.5 and P-value < 0.05, we detected 12 (7 up- and 5 downregulated in low-RFI animals), 18 (12 up- and 6 downregulated), and 13 (8 up- and 5 downregulated) DE miRNAs for Angus, Charolais, and KC steers, respectively. Most of the DE miRNAs were breed specific, with bta-miR-449a and bta-miR-AB-2 being differentially expressed in all three breeds. The predicted target genes of the identified DE miRNA are mainly involved in cell cycle, cell death and survival, cell signaling, cellular growth and proliferation, protein trafficking, cell morphology, cell-to-cell signaling and interaction, cellular development, molecular transport, post-translational modification, as well as nutrient metabolism (lipids, carbohydrates, protein and amino acid). Our results provide insights into the bovine hepatic miRNAome and their potential roles in molecular regulation of RFI in beef cattle.
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Affiliation(s)
- Robert Mukiibi
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada
| | - Dayle Johnston
- Animal and Bioscience Research Department, Teagasc, Grange, Dunsany, County Meath, Ireland
| | - Michael Vinsky
- Lacombe Research and Development Centre, Lacombe, Agriculture and Agri-Food Canada, Alberta, T4L 1W1, Canada
| | - Carolyn Fitzsimmons
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada
- Lacombe Research and Development Centre, Lacombe, Agriculture and Agri-Food Canada, Alberta, T4L 1W1, Canada
| | - Paul Stothard
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada
| | - Sinéad M Waters
- Animal and Bioscience Research Department, Teagasc, Grange, Dunsany, County Meath, Ireland.
| | - Changxi Li
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, T6G 2P5, Canada.
- Lacombe Research and Development Centre, Lacombe, Agriculture and Agri-Food Canada, Alberta, T4L 1W1, Canada.
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14
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MicroRNA-499 rs3746444 polymorphism in Egyptian children with biliary atresia. Clin Exp Hepatol 2020; 6:263-269. [PMID: 33145433 PMCID: PMC7592094 DOI: 10.5114/ceh.2020.99526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 07/06/2020] [Indexed: 11/17/2022] Open
Abstract
Aim of the study We aimed to evaluate the association of microRNA-499 rs3746444 polymorphism and biliary atresia (BA) risk and its correlation with clinic-pathologic features of BA. Material and methods This study was performed on 300 Egyptian children (100 BA cases, 100 cases with cholestatic liver diseases other than BA and 100 healthy controls). Routine laboratory investigations, clinical examination and abdominal ultrasound were done. All infants were genotyped for miR-499 single nucleotide polymorphisms (SNPs) (rs3746444 A>G) by real-time polymerase chain reaction (PCR) fluorescence detection on a Rotor Gene Real Time PCR System (QIAGEN, GmbH) using fluorescent labeled probes. Results The AG genotype was the most prevalent genotype of miR-499 rs3746444 among the studied groups. A significantly higher frequency of the rs3746444 G allele was found in the BA cases than the other groups (odds ratio = 1.62). This polymorphism was also correlated with the degree of fibrosis in BA cases (p < 0.05). The miR-499 rs3746444 polymorphism (GG genotype) was significantly associated with severe form of BA and bad prognosis after the Kasai operation (p < 0.05). miR-499 rs3746444 polymorphism had no effect on the clinic-pathological features or the liver function status in the non-BA group. Conclusions There is an association between the miR-499 SNP genotypes and the occurrence of BA. The variant allele G is the predominant allele in the BA group and is associated with severe liver inflammation and bad prognosis after the Kasai operation.
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15
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miR-125b acts as anti-fibrotic therapeutic target through regulating Gli3 in vivo and in vitro. Ann Hepatol 2020; 18:825-832. [PMID: 31548167 DOI: 10.1016/j.aohep.2019.06.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 06/03/2019] [Accepted: 03/26/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Liver fibrosis is a major characteristic of most chronic liver diseases which leads to accumulation of extracellular matrix (ECM) proteins. Hedgehog (Hh) pathway activated by Gli genes participated in the pathogenesis of liver fibrosis. However, the regulatory role of miR-125b in liver fibrosis via targeting Gli genes remains unknown. MATERIALS AND METHODS RT-qPCR and western blot were employed to the expression levels of mRNA and protein, respectively. The fibrosis level of liver tissue was determined by Masson's trichrome staining. The interaction between miR-125b and Gli3 was tested by luciferase reporter assay. In addition, LX2 cells were activated and CCl4-induced rat model was used in this study. RESULTS miR-125b was significantly declined in serum samples of the clinical liver fibrosis patient, activated LX2 cells and the liver tissues of the CCl4-induced rat model. Furthermore, in cellular level, the alpha-smooth muscle actin (α-SMA) and Albumin expressions were ascending and descending in LX2 cells, respectively, with the decline of miR-125b. However, when transfecting with miR-125b mimic, the expressions of α-SMA and Albumin was reversed and Gli3 expression was notably repressed in LX2 cells. The target interaction between miR-125b and Gli3 was determined by dual-luciferase assays. It was further discovered that the changes of α-SMA, Albumin, and Gli3 were similar to the expression trend in LX2 cells with miR-125b mimic transfection. CONCLUSION These results suggested that miR-125b might be protective against liver fibrosis via regulating Gli3 and it might be a promising target in the development of novel therapies to treat pathological fibrotic disorders.
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16
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Smith M, Zuckerman M, Kandanearatchi A, Thompson R, Davenport M. Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study. Access Microbiol 2020; 2:acmi000127. [PMID: 32974591 PMCID: PMC7497833 DOI: 10.1099/acmi.0.000127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/24/2020] [Indexed: 12/11/2022] Open
Abstract
Biliary atresia (BA) is a progressive disease affecting infants resulting in inflammatory obliteration and fibrosis of the extra- and intra-hepatic biliary tree. BA may be grouped into type 1 isolated; type 2 syndromic, where other congenital malformations may be present; type 3 cystic BA, where there is cyst formation within an otherwise obliterated biliary tree; and cytomegalovirus-associated BA. The cause of BA is unclear, with immune dysregulation, inflammation and infection, particularly with cytomegalovirus (CMV), all implicated. In this study a total of 50/67 samples were tested for CMV DNA using quantitative real-time PCR. Ten liver tissue and 8 bile samples from 10 patients representing the range of BA types were also analysed by next-generation sequencing. CMV DNA was found in 8/50 (16 %) patients and a total of 265 differentially expressed microRNAs were identified. No statistically significant differences between the various types of BA were found. However, differences were identified in the expression patterns of 110 microRNAs in bile and liver tissue samples (P<0.05). A small number of bacterial and viral sequences were found, although their relevance to BA remains to be determined. No direct evidence of viral causes of BA were found, although clear evidence of microRNAs associated with hepatocyte and cholangiocyte differentiation together with fibrosis and inflammation were identified. These include miR-30 and the miR-23 cluster (liver and bile duct development) and miR-29, miR-483, miR-181, miR-199 and miR-200 (inflammation and fibrosis).
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Affiliation(s)
- Melvyn Smith
- Viapath Analytics, South London Specialist Virology Centre, Denmark Hill, London
| | - Mark Zuckerman
- Viapath Analytics, South London Specialist Virology Centre, Denmark Hill, London
| | | | - Richard Thompson
- Institute of Liver Studies and Paediatric Liver Services, Denmark Hill, London
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS
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17
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Cheng X, Chen M, Liu Z. MicroRNA-294 Promotes Cell Proliferation, Migration and Invasion in SMMC-7721 Hepatoma Carcinoma Cells by Activating the JNK/ERK Signaling Pathway. Am J Med Sci 2020; 359:365-371. [PMID: 32498943 DOI: 10.1016/j.amjms.2020.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 12/25/2019] [Accepted: 03/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND It has been reported that miR-294 is highly expressed in hepatocellular carcinoma (HCC) tissues and cells. However, the potential role of miR-294 in the pathogenesis of HCC remains unclear. This study aimed to explore the role of miR-294 in HCC and the potential mechanism involved in this process. MATERIALS AND METHODS Reverse transcription polymerase chain reaction was performed to determine the expression of miR-294 in HCC tissues and cell lines. Following the overexpression or knockdown of miR-294, the proliferation, migration, and invasion abilities of cells were determined using Cell Counting Kit-8 (CCK-8), wound healing and transwell assays, respectively. The phosphorylation of JNK and ERK was determined through western blotting. Furthermore, HCC cells were treated with JNK inhibitor SP600125 or ERK inhibitor U0126 and transfected with miR-294 mimics or negative control. Subsequently, the phosphorylation of JNK and ERK was evaluated and the proliferation, migration and invasion abilities of HCC cells were also determined. RESULTS The expression of miR-294 was significantly increased in HCC tissues and cell lines. Following the overexpression of miR-294, proliferation, migration, and invasion were promoted in the SSMC-7721 cell line, and the phosphorylation of JNK and ERK was increased, while silencing of miR-294 led to the opposite result. Use of the JNK or ERK inhibitor to treat SSMC-7721 cells transfected with miR-294 mimics decreased the phosphorylation of JNK and ERK and inhibited the proliferation, migration and invasion abilities of cells. CONCLUSIONS miR-294 is important for the development of HCC in terms of the biological activities of cells, and may be a novel therapeutic target for HCC.
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Affiliation(s)
- Xianping Cheng
- Department of Oncology, Anhui No. 2 Provincial People's Hospital, Anhui Province, China.
| | - Mo Chen
- Department of Oncology, Anhui No. 2 Provincial People's Hospital, Anhui Province, China
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18
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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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19
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Hochreuter MY, Altıntaş A, Garde C, Emanuelli B, Kahn CR, Zierath JR, Vienberg S, Barrès R. Identification of two microRNA nodes as potential cooperative modulators of liver metabolism. Hepatol Res 2019; 49:1451-1465. [PMID: 31408567 PMCID: PMC6972499 DOI: 10.1111/hepr.13419] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 07/03/2019] [Accepted: 07/02/2019] [Indexed: 12/19/2022]
Abstract
AIM Hepatic insulin resistance is a hallmark of type 2 diabetes and non-alcoholic fatty liver disease. Dysregulation of microRNA (miRNA) expression in insulin-resistant livers might coordinate impaired hepatic metabolic function. Here, we aimed to discover miRNAs and their downstream targets involved in hepatic insulin resistance. METHODS We determined miRNA expression profiles by small RNA sequencing of two mouse models of impaired hepatic insulin action: high-fat diet-induced obesity and liver-specific insulin receptor knockout. Conversely, we assessed the hepatic miRNA expression profile after treatment with the antidiabetic hormone, fibroblast growth factor 21 (FGF21). Ontology analysis of predicted miRNA gene targets was performed to identify regulated gene pathways. Target enrichment analysis and miRNA mimic overexpression in vitro were used to identify unified protein targets of nodes of regulated miRNAs. RESULTS We identified an array of miRNA species regulated by impaired liver insulin action or after fibroblast growth factor 21 treatment. Ontology analysis of predicted miRNA gene targets identified pathways controlling hepatic energy metabolism and insulin sensitivity. We identified a node of two miRNAs downregulated in the livers of liver-specific insulin receptor knockout mice, miR-883b and miR-205, which positively regulate the expression of transcription factor zinc finger E-box-binding homeobox 1 (ZBED1). We found another node of two miRNAs upregulated in the livers of fibroblast growth factor 21-treated mice, miR-155-3p and miR-1968-5p, which canonically downregulates the caveola component, polymerase I and transcript release factor (PTRF), a gene previously implicated in hepatic energy metabolism. CONCLUSIONS This study identifies two nodes of coregulated miRNAs that might coordinately control hepatic energy metabolism in states of insulin resistance.
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Affiliation(s)
- Mette Yde Hochreuter
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Ali Altıntaş
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Christian Garde
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Brice Emanuelli
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - C. Ronald Kahn
- Section of Integrative Physiology and MetabolismJoslin Diabetes Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Juleen R. Zierath
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark,Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden,Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | | | - Romain Barrès
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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20
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The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
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21
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Ghazy AA, Osman EM, Rashwan EA, Gaballah AH, Mostafa H, Tawfik S. Relation between microRNA-21, transforming growth factor β and response to treatment among chronic hepatitis C patients. J Med Virol 2019; 91:2166-2173. [PMID: 31368531 DOI: 10.1002/jmv.25559] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/25/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Persistence of hepatitis C virus (HCV) infection and response to antiviral therapy has been shown to be associated with inappropriate levels of cytokines and microRNAs (miRNAs). miRNA levels have been reported to fluctuate during treatment. Thus they could be useful predictors for responses to treatment among HCV infected patients, thereby reducing ineffective treatments. AIM The current study aimed to investigate the relation between miRNA-21 expression profiles, transforming growth factor β (TGF-β) serum levels and response to treatment with the new direct antiviral drugs (sofosbuvir + daclatasvir ± ribavirin), among HCV infected Egyptian patients. SUBJECTS AND METHODS This prospective study was conducted on 50 HCV infected patients (before and after treatment) and 20 healthy volunteers. miRNA expression profiles were determined by real-time polymerase chain reaction and TGF-β1 serum levels were measured by using enzyme-linked immunosorbent assay. RESULTS There was a significant increase in serum albumin, platelets count and a significant decrease in liver enzymes, serum bilirubin, and prothrombin time after treatment. Significant reduction of viral load among HCV patients after receiving the treatment was reported. Concomitantly, there was an increase in the relative quantity of miRNA-21 (P = .001*) and serum levels of TGF-β1 ( P = .337) among HCV patients after receiving treatment. CONCLUSION Nearly all responders to direct antiviral drugs showed increased levels of both miRNA-21 and TGF-β1. This may indicate an interplay between TGF-β1 and miRNA-21 during remission or progression of viral infection. Thus miRNA-21 could be used as promising serum biomarker, for assessment of antiviral treatment efficacy and improvement of fibrosis among chronically infected HCV patients.
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Affiliation(s)
- Amany A Ghazy
- Microbiology and Medical Immunology Unit, Pathology Departments, College of Medicine, Jouf University, Sakaka, Saudi Arabia.,Department of Microbiology & Medical Immunology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Eman M Osman
- Department of Immunology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Eman A Rashwan
- Department of Immunology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Ahmed H Gaballah
- Department of Microbiology, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Hanan Mostafa
- Department of Internal Medicine, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Salwa Tawfik
- Department of Internal Medicine, National Research Center, Cairo, Egypt
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22
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Lin X, Xiaoqin H, Jiayu C, Li F, Yue L, Ximing X. Long non-coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen-activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma. Hepatol Res 2019; 49:902-918. [PMID: 30945380 DOI: 10.1111/hepr.13344] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/26/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023]
Abstract
AIM The expression of microRNA143HG (miR143HG) was significantly downregulated in hepatocellular carcinoma (HCC) tissues by bioinformatics analysis. This study aimed to determine the role of miR143HG in HCC cell proliferation and metastasis. METHODS Fifty patients with HCC were divided into two groups based on median miR143HG expression levels. The correlation between miR143HG expression and prognosis, and the correlations between miR143HG expression and the patients' clinicopathological characteristics were evaluated based on the two groups. Gain-of-function and loss-of-function measurements of miR143HG were carried out to verify the biological function of miR143HG by Cell Counting Kit-8, EdU, Transwell, and western blotting assays and flow cytometric analysis. The underlying mechanism was explored by quantitative real-time polymerase chain reaction of miRNA (miR-155-5p and miR-26b-5p), luciferase reporter assay, western blotting of Wnt signaling pathway-related proteins (β-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), ZEB1, and E-cadherin), mitogen-activated protein kinase (MAPK) signaling pathway-related proteins (extracellular signal-regulated kinase [ERK]1/2, p-ERK1/2, c-Jun N-terminal kinase (JNK), p-JNK, P38, and p-P38), and immunofluorescence staining of β-catenin. RESULTS miR143HG expression was markedly downregulated in HCC tissues and cells. Its expression was associated with the presence or absence of portal vein tumor thrombus, hepatitis B virus infection, relapse and metastasis, and Barcelona Clinic Liver Cancer stage. Additionally, miR143HG expression predicted a good prognosis and acted as an independent prognostic factor in HCC for overall survival. Overexpression of miR143HG suppressed HCC cell proliferation and metastasis, and induced cell cycle arrest and apoptosis. Consistently, the depletion of miR143HG resulted in the opposite phenomenon of the aforementioned results. miR143HG inhibits miR-155 expression; miR-155 directly targets APC, which is a negative regulator of the Wnt/β-catenin pathway, so miR143HG can act on the Wnt pathway. miR143HG was further found to reduce the expression of β-catenin and block the nuclear accumulation of β-catenin, ultimately inhibiting the activation of the Wnt pathway. It inhibits the expression of Wnt downstream target gene ZEB1, and then E-cadherin expression is increased and cell motility is inhibited. Furthermore, miR143HG exerts its antiproliferative function by influencing the MAPK signaling pathway and then inducing G2 /M arrest in cells. CONCLUSION This study showed that miR143HG plays critical roles in the development and progression of HCC by suppressing the MAPK and Wnt signaling pathways.
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Affiliation(s)
- Xiong Lin
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - He Xiaoqin
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Chen Jiayu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fan Li
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Yue
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xu Ximing
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
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23
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Chen X, Zhu X, Wei Z, Lv Q. Integrated mRNA‐Seq and miRNA‐Seq analysis of PLCγ2‐overexpressing hepatocarcinoma cells and identification of the associated miRNA‐mRNA network. J Cell Biochem 2019; 120:19878-19890. [DOI: 10.1002/jcb.29294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 06/27/2019] [Indexed: 01/04/2023]
Affiliation(s)
- Xiaoguang Chen
- Animal Science and Technology School Henan University of Science and Technology Luoyang China
| | - Xuemin Zhu
- Animal Science and Technology School Henan University of Science and Technology Luoyang China
| | - Zhiguo Wei
- Animal Science and Technology School Henan University of Science and Technology Luoyang China
| | - Qiongxia Lv
- Animal Science and Technology School Henan University of Science and Technology Luoyang China
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24
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Fang QH, Shen QL, Li JJ, Yang Y, Guo JJ, Cheng Y, Zhou HC, Niu WY, Chen LM, Li CJ, Sun B. Inhibition of microRNA-124a attenuates non-alcoholic fatty liver disease through upregulation of adipose triglyceride lipase and the effect of liraglutide intervention. Hepatol Res 2019; 49:743-757. [PMID: 30861258 DOI: 10.1111/hepr.13330] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 02/23/2019] [Accepted: 03/05/2019] [Indexed: 12/19/2022]
Abstract
AIM Glucagon-like peptide-1 receptor agonists (GLP-1Ras) have been reported to prevent non-alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP-1Ra liraglutide on NAFLD in terms of miRNAs. METHODS MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet-fed mice. The luciferase reporter assay was carried out to validate the cross-talk between adipose triglyceride lipase (ATGL) and miR-124a. MicroRNA-124a mimics and inhibitor plasmids were transfected to study the role of miR-124a in palmitate-treated normal human liver cell line (HL-7702). Liraglutide treatment was used to observe the effect of GLP-1Ra on the miR-124a/ATGL pathway. RESULTS Expression of ATGL decreased and miR-124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR-124a interacted with the 3'-untranslated region of ATGL mRNA and induced its degradation. MicroRNA-124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR-124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. CONCLUSIONS MicroRNA-124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR-124a knockdown can reverse this trend, suggesting that miR-124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR-124a/ATGL/Sirt1 pathway.
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Affiliation(s)
- Qian-Hua Fang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Qi-Ling Shen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Jin-Jin Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Yang Yang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Juan-Juan Guo
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Ying Cheng
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Han-Chi Zhou
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Wen-Yan Niu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Li-Ming Chen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Chun-Jun Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin, China
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Li L, Zhang L, Zhao X, Cao J, Li J, Chu G. Downregulation of miR-152 contributes to the progression of liver fibrosis via targeting Gli3 in vivo and in vitro. Exp Ther Med 2019; 18:425-434. [PMID: 31258681 PMCID: PMC6566101 DOI: 10.3892/etm.2019.7595] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 01/24/2019] [Indexed: 12/13/2022] Open
Abstract
The Gli family is known to be required for the activation of hedgehog signalling, which participates in the pathogenesis of liver fibrosis. The aim of the present study was to identify the association between microRNA (miR)-152 and GLI family zinc finger 3 (Gli3) and their roles in liver fibrosis. In a carbon tetrachloride (CCl4)-treated rat model, fibrogenesis-associated indexes, including hydroxyproline content, collagen deposition, and α-smooth muscle actin (α-SMA) and albumin expression, were examined in in vivo and in vitro models. The expression of miR-152 and Gli3 in cells and tissues was determined by reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction of Gli3 and miR-152 was evaluated by bioinformatical analysis and a dual-luciferase reporter assay. The results demonstrated that miR-152 was significantly downregulated in serum samples from clinical patients, liver tissues from CCl4-treated rats and activated LX2 cells. Furthermore, at the cellular level, the mRNA and protein expression levels of α-SMA and albumin were increased and decreased, respectively, in LX2 cells. Nevertheless, following transfection with an miR-152 mimic, the expression levels of α-SMA and albumin were reversed, and Gli3 expression was notably decreased in LX2 cells. Additionally, the target interaction between miR-152 and Gli3 was demonstrated. Finally, an miR-152 mimic was introduced into the rat model and additionally demonstrated that the changes in α-SMA, albumin and Gli3 expression levels were similar to the expression pattern in LX2 cells following miR-152 mimic transfection. These data provided insight into the potential function of miR-152 as an anti-fibrotic therapy through the modulation 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
| | - Lei Zhang
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Xiongqi Zhao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Jun Cao
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Jingfeng Li
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
| | - Guang Chu
- Department of Hepatobiliary Surgery, First People's Hospital of Kunming City, Kunming, Yunnan 650034, P.R. China
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26
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Tsuchiya A, Ogawa M, Watanabe T, Takeuchi S, Kojima Y, Watanabe Y, Kimura N, Hayashi K, Yokoyama J, Terai S. Diverse perspectives to address for the future treatment of heterogeneous hepatocellular carcinoma. Heliyon 2019; 5:e01325. [PMID: 30911692 PMCID: PMC6416651 DOI: 10.1016/j.heliyon.2019.e01325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/05/2018] [Accepted: 03/04/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinomas (HCCs), which often arise from chronic liver damage, have poor conditional 5-year survival and are recognized as heterogeneous tumors. Considering the heterogeneity of HCCs, diverse perspectives need to be addressed for treating such tumors, besides the findings of conventional imaging modalities and tumor markers. Data from the latest technologies, such as liquid biopsy, and the detection of the presence of cancer cells with stem/progenitor cell markers, gene mutations and diverse pathways, crosstalk with immune cells and cancer-associated fibroblasts, and mechanisms of epithelial–mesenchymal transition provide diverse lines of information. Integration of these data with clinical data might be necessary to develop effective therapies for precision medicine. Here, we review several aspects of dealing with the complexity of heterogeneous HCCs.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takayuki Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yuichi Kojima
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kazunao Hayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Junji Yokoyama
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
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Wu J, Huang J, Kuang S, Chen J, Li X, Chen B, Wang J, Cheng D, Shuai X. Synergistic MicroRNA Therapy in Liver Fibrotic Rat Using MRI-Visible Nanocarrier Targeting Hepatic Stellate Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1801809. [PMID: 30886803 PMCID: PMC6402399 DOI: 10.1002/advs.201801809] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 12/10/2018] [Indexed: 05/02/2023]
Abstract
Liver fibrosis, as one of the leading causes of liver-related morbidity and mortality, has no Food and Drug Administration (FDA)-approved antifibrotic therapy yet. Although microRNA-29b (miRNA-29b) and microRNA-122 (miRNA-122) have great potential in treating liver fibrosis via regulating profibrotic genes in hepatic stellate cells (HSCs), it is still a challenge to achieve a HSC-targeted and meanwhile noninvasively trackable delivery of miRNAs in vivo. Herein, a pH-sensitive and vitamin A (VA)-conjugated copolymer VA-polyethylene glycol-polyethyleneimine-poly(N-(N',N'-diisopropylaminoethyl)-co-benzylamino) aspartamide (T-PBP) is synthesized and assembled into superparamagnetic iron oxide (SPIO)-decorated cationic micelle for miRNA delivery. The T-PBP micelle efficiently transports the miRNA-29b and miRNA-122 to HSC in a magnetic resonance imaging-visible manner, resulting in a synergistic antifibrosis effect via downregulating the expression of fibrosis-related genes, including collagen type I alpha 1, α-smooth muscle actin, and tissue inhibitor of metalloproteinase 1. Consequently, the HSC-targeted combination therapy with miRNA-29b and miRNA-122 demonstrates a prominent antifibrotic efficacy in terms of improving liver function and relieving hepatic fibrosis.
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Affiliation(s)
- Jun Wu
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Jinsheng Huang
- PCFM Lab of Ministry of EducationSchool of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhou510275China
| | - Sichi Kuang
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Jingbiao Chen
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Xiaoxia Li
- PCFM Lab of Ministry of EducationSchool of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhou510275China
| | - Bin Chen
- Department of Orthopaedics and TraumatologyNanfang HospitalSouthern Medical UniversityGuangzhou510515China
| | - Jin Wang
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
| | - Du Cheng
- PCFM Lab of Ministry of EducationSchool of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhou510275China
| | - Xintao Shuai
- The Third Affiliated HospitalSun Yat‐sen UniversityGuangzhou510630China
- PCFM Lab of Ministry of EducationSchool of Materials Science and EngineeringSun Yat‐sen UniversityGuangzhou510275China
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28
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Assessment of serum level of MiRNAs before and after treatment with sofosbuvir in Egyptian patients with chronic HCV infection. Meta Gene 2018. [DOI: 10.1016/j.mgene.2018.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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29
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Chen QQ, Zhang C, Qin MQ, Li J, Wang H, Xu DX, Wang JQ. Inositol-Requiring Enzyme 1 Alpha Endoribonuclease Specific Inhibitor STF-083010 Alleviates Carbon Tetrachloride Induced Liver Injury and Liver Fibrosis in Mice. Front Pharmacol 2018; 9:1344. [PMID: 30538632 PMCID: PMC6277551 DOI: 10.3389/fphar.2018.01344] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/31/2018] [Indexed: 12/12/2022] Open
Abstract
Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.
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Affiliation(s)
- Qian-Qian Chen
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Cheng Zhang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Ming-Qiang Qin
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Jian Li
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - De-Xiang Xu
- Department of Toxicology, Anhui Medical University, Hefei, China
| | - Jian-Qing Wang
- The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China.,The Second Affiliated Hospital, 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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Anti-fibrotic impact of Carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-β1/EMT track. Sci Rep 2018; 8:14327. [PMID: 30254303 PMCID: PMC6156520 DOI: 10.1038/s41598-018-32309-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 08/30/2018] [Indexed: 12/15/2022] Open
Abstract
Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective β-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl4 (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl4 + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor β1 (TGF-β1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-β1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.
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32
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Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity. Cytokine 2018; 124:154542. [PMID: 30241896 DOI: 10.1016/j.cyto.2018.09.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/01/2018] [Accepted: 09/07/2018] [Indexed: 12/15/2022]
Abstract
In their quiescent state, Hepatic stellate cells (HSCs), are present in the sub-endothelial space of Disse and have minimal interaction with immune cells. However, upon activation following injury, HSCs directly or indirectly interact with various immune cells that enter the space of Disse and thereby regulate diverse hepatic function and immune physiology. Other than the normal physiological functions of HSCs such as hepatic homeostasis, maturation and differentiation, they also participate in hepatic inflammation by releasing a battery of inflammatory cytokines and chemokines and interacting with other liver cells. Here, we have reviewed the role of HSC in the pathogenesis of liver inflammation and some infectious diseases in order to understand how the interplay between immune cells and HSCs regulates the overall outcome and disease pathology.
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miRNA-221 and miRNA-222 are promising biomarkers for progression of liver fibrosis in HCV Egyptian patients. Virus Res 2018; 253:135-139. [PMID: 29932949 DOI: 10.1016/j.virusres.2018.06.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 06/17/2018] [Accepted: 06/18/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Current methodologies used to determine the progression of hepatic fibrosis rely heavily on liver biopsy, a dangerous and invasive procedure, with semi-subjective analysis of the results of the biopsy. Thus, a new approach is immensely needed for monitoring the progression of liver fibrosis in Hepatitis C virus (HCV) patients. AIM OF WORK The purpose of this study was to find highly specific and sensitive miRNA biomarkers that can be used to detect different stages of liver fibrosis. METHODOLOGY The study consisted of 42 cases of chronic hepatitis C (CHC) with early-stage fibrosis, 45 cases of CHC with late-stage fibrosis, and 40 healthy subjects with no CHC or fibrosis as controls. Expression patterns of 5 miRNAs (miR-16, miR-146a, miR-214-5p, miR-221, and miR-222) were analyzed in each group using TaqMan real-time PCR. RESULTS Serum levels of miRNA-16, miRNA-146a, miRNA-221, and miRNA-222 were all significantly up-regulated in early and late stages of liver fibrosis. miRNA-222 had the highest sensitivity and specificity values in early and late fibrosis. miRNA-221 had the second highest sensitivity and specificity with the late-stage fibrosis group. Furthermore, miRNA-221 showed significant positive correlations with both miRNA-16 and miRNA-146a in the early- and late-stage fibrosis groups, with the early stage having a stronger correlation. CONCLUSIONS The results indicated that miRNA-16, miRNA-146a, miRNA-221, and miRNA-222 can be used to detect the presence of liver fibrosis. The high sensitivity and specificity of miRNA-222 and miRNA-221 in late-stage fibrosis indicate promising prognostic biomarkers for HCV-induced liver fibrosis.
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Steviol, a natural product inhibits proliferation of the gastrointestinal cancer cells intensively. Oncotarget 2018; 9:26299-26308. [PMID: 29899860 PMCID: PMC5995179 DOI: 10.18632/oncotarget.25233] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 03/24/2018] [Indexed: 12/19/2022] Open
Abstract
New anticancer agents with lower toxicity have been always urged because of drug resistance associated with overused chemotherapy agents. In this study, steviol, a colonic metabolite of natural sweetener and also a component in leaves of stevia rebaudiana bertoni, was found to possess intensive anticancer activity on the human gastrointestinal cancer cells. Steviol inhibited six human gastrointestinal cancer cells intensively as 5-fluorouracil did at 100 μg/mL. The inhibition mechanism follows mitochondrial apoptotic pathway that was evidenced by increase of Bax/Bcl-2 ratio, activation of p21 and p53; and caspase 3-independent mechanism was also involved. These results are consistent with the miRNA expression analysis. The most regulated miRNAs in the steviol treated gastrointestinal cancer cells were miR-203a-3p (log2 =1.32) and miR-6088 (log2 =-2.54) in HCT-116, miR-1268b (log2 =19.85) and miR-23c (log2 =-2.05) in MKN-45. In view of the metabolic characteristics of steviol and its cytotoxicity on the cancer cells, steviol could be a chemotherapy agent potentially for cancer treatment.
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Ringelhan M, McKeating JA, Protzer U. Viral hepatitis and liver cancer. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0274. [PMID: 28893941 PMCID: PMC5597741 DOI: 10.1098/rstb.2016.0274] [Citation(s) in RCA: 227] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors. This article is part of the themed issue ‘Human oncogenic viruses’.
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Affiliation(s)
- Marc Ringelhan
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Muenchen, Germany.,Department of Internal Medicine II, University Hopsital rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675 Muenchen, Germany.,German Center for Infection Research (DZIF), partner site Munich
| | - Jane A McKeating
- Institute for Advanced Science, Technical University of Munich, Muenchen, Germany .,Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Trogerstrasse 30, 81675 Muenchen, Germany .,German Center for Infection Research (DZIF), partner site Munich.,Institute for Advanced Science, Technical University of Munich, Muenchen, Germany
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Wang F, Wang J, Ju L, Chen L, Cai W, Yang J. Diagnostic and prognostic potential of serum miR-132/212 cluster in patients with hepatocellular carcinoma. Ann Clin Biochem 2018; 55:576-582. [PMID: 29357677 DOI: 10.1177/0004563218755815] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background It has been reported that both of the miR-132/212 (micro-RNA) cluster members, miR-132 and miR-212, are downregulated in hepatocellular carcinoma. Nevertheless, the expression pattern and clinical utility of serum miR-132/212 in hepatocellular carcinoma are still unknown. Methods In this study, serum concentrations of miR-132 and miR-212 were measured in 80 hepatocellular carcinoma patients, 51 controls with chronic liver diseases and 42 healthy volunteers by using quantitative real-time polymerase chain reaction. Results In hepatocellular carcinoma patients, serum concentrations of miR-132 and miR-212 were significantly reduced and strongly correlated (r = 0.603, p < 0.001). Receiver operator characteristic analyses showed that serum miR-132 and miR-212 might have a potential role in the diagnosis of hepatocellular carcinoma. Moreover, the combination of serum miR-132, miR-212 and alpha-fetoprotein improved the diagnostic efficiency for hepatocellular carcinoma, especially in sensitivity and negative predictive value. Serum miR-132 was associated with tumour differentiation degree ( p = 0.021) and tumour-node-metastasis stage ( p = 0.002); serum miR-212 correlated with tumour size ( p = 0.023) and tumour-node-metastasis stage ( p = 0.007). Kaplan-Meier analyses indicated poorer overall survival in hepatocellular carcinoma patients with lower serum concentrations of miR-132 ( p < 0.001) and miR-212 ( p = 0.005). Conclusions Our results suggest that both components of the miR-132/212 cluster have potential roles as non-invasive serum biomarkers for diagnosis and prognosis of hepatocellular carcinoma.
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Affiliation(s)
- Feng Wang
- 1 Department of Clinical Laboratory, Affiliated Hospital of Nantong University, Nantong, China.,2 Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.,*These authors contributed equally to this work
| | - Jun Wang
- 3 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Nanjing University, Nanjing, China.,*These authors contributed equally to this work
| | - Linlin Ju
- 4 Department of Gastroenterology and Clinical Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Lin Chen
- 2 Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.,4 Department of Gastroenterology and Clinical Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Weihua Cai
- 4 Department of Gastroenterology and Clinical Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Jialin Yang
- 2 Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
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Role of circulatory microRNAs in the pathogenesis of hepatitis C virus. Virusdisease 2017; 28:360-367. [PMID: 29291226 DOI: 10.1007/s13337-017-0407-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022] Open
Abstract
Hepatitis C virus (HCV) is associated with one of the major health problem in world that ultimate results in the liver cirrhosis and leads to carcinoma of hepatocellular components round the world. More than 185 million people were found to be infected with HCV. MicroRNAs are small oligonucleotide RNA having 18-22 nucleotides. Circulating mi-RNAs regulate the replication of HCV and HCV-induced liver fibrosis and HCC. By comparing the expression profiles of mi-RNAs of normal individuals with HCV infected patients, aberrant changes in expression of different mi-RNAs have been observed so it can be predicted that these mi-RNAs are associated with and play a central role in the hepatitis C infection and diseases associated with it. This review demonstrates the major role of circulatory microRNAs in the HCV and HCV associated ailments.
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Recent Advances in the Pathogenesis of Hepatitis C Virus-Related Non-Alcoholic Fatty Liver Disease and Its Impact on Patients Cured of Hepatitis C. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s11901-017-0370-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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MicroRNA-195 Activates Hepatic Stellate Cells In Vitro by Targeting Smad7. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1945631. [PMID: 28929107 PMCID: PMC5591989 DOI: 10.1155/2017/1945631] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 07/03/2017] [Accepted: 07/26/2017] [Indexed: 12/16/2022]
Abstract
Background and Aim Aberrant activation of the TGF-β1/Smad pathway contributes to the activation of hepatic stellate cells (HSCs). MicroRNA-195 has been shown to regulate the activation of HSCs. The aim of this study was to investigate the role of miRNA-195 in HSCs activation. Methods A liver fibrotic rat model induced by diethylnitrosamine was established. Dual luciferase reporter assays were performed to verify that Smad7 was the target of miRNA-195. The expression levels of miR-195, Smad7, and α-SMA in HSC-T6 transfected, respectively, with miR-195 mimic, inhibitor, or control were measured by qRT-PCR. The protein expression of Smad7 was detected by Western blot analysis. Results Enhanced miR-195 and decreased Smad7 were observed in diethylnitrosamine-induced liver fibrotic rats (P < 0.05). Dual luciferase reporter assays showed that the miR-195 mimic significantly suppressed the luciferase activity of a reporter plasmid carrying the binding site of miR-195 on the 3′UTR of Smad7 (P < 0.05). The miR-195 mimics activated HSCs, further elevated miR-195 and α-SMA (P < 0.01), and reduced the Smad7 level (P < 0.05). The miR-195 inhibitors blocked the activation of HSCs, reduced the expression of miR-195 and α-SMA (P < 0.01), and upregulated the expression of Smad7 (P < 0.05). Conclusion Collectively, we demonstrated that miRNA-195 activated HSCs by targeting Smad7.
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Yu J, Zhang W, Qian H, Tang H, Lin W, Lu B. SOCS1 regulates hepatic regenerative response and provides prognostic makers for acute obstructive cholangitis. Sci Rep 2017; 7:9482. [PMID: 28842621 PMCID: PMC5573403 DOI: 10.1038/s41598-017-09865-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 07/31/2017] [Indexed: 12/31/2022] Open
Abstract
Acute obstructive cholangitis (AOC) is a common and severe infectious diseases that occurs in an obstructed biliary system. The suppressors of cytokine signaling (SOCS) family include well-known negative regulators of cytokine receptor signaling. However, few studies have been conducted to determine their function in AOC. In this study, we showed that SOCS1 expression aberrantly changed and was associated with AOC prognosis in rat models. Decreased SOCS1 expression enhances regenerative response after biliary drainage (BD) resulting from AOC by upregulating hepatocyte growth factor (HGF) signaling. To detect SOCS1 expression in the liver less invasively and to predict the prognosis for AOC after BD, miR-221 and miR-222 were investigated. Ectopic SOCS1 expression indirectly decreases miR-221/222 expression through Met in vitro. An inverse correlation between SOCS1 expression and miR-221/222 expression in liver tissue or in serum was verified in rats. Serum from AOC patients showed that lower expression of circulating miR-221/222 after endoscopic nasobiliary drainage was associated with delayed restoration of liver function. Our results showed that SOCS1 regulates hepatic regenerative response, and indirectly detecting downstream molecules, such as miR-221/222, may provide prognostic makers for AOC.
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Affiliation(s)
- Jianhua Yu
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Weiguang Zhang
- Department of Molecular Medicine and Clinical Laboratory, Shaoxing Second Hospital, Shaoxing, China
| | - Hongwei Qian
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Haijun Tang
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Weiguo Lin
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Baochun Lu
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China.
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Nishimura T, Tamizu E, Uno S, Uwamino Y, Fujiwara H, Nishio K, Nakano Y, Shiono H, Namkoong H, Hoshino Y, Iwata S, Hasegawa N. hsa-miR-346 is a potential serum biomarker of Mycobacterium avium complex pulmonary disease activity. J Infect Chemother 2017; 23:703-708. [PMID: 28827075 DOI: 10.1016/j.jiac.2017.07.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 07/20/2017] [Accepted: 07/31/2017] [Indexed: 12/11/2022]
Abstract
MicroRNA (miRNA) has been recently recognized as a biomarker of various diseases; however, there are no known miRNAs associated with Mycobacterium avium complex (MAC) pulmonary disease. In addition, there are no known biomarkers to precisely reflect disease activity after the diagnosis of MAC pulmonary disease. Thus, we sought to identify a miRNA which is a candidate biomarker of MAC pulmonary disease activity. Serum hsa-miR-346 concentrations of 16 patients with M. avium pulmonary disease were significantly higher than those of 16 healthy controls (p = 0.047). The secretion of hsa-miR-346 increased in a multiplicity of infection-dependent manner in M. avium-infected macrophages. Serum hsa-miR-346 levels of 5 patients with bacterial conversion at the end of follow-up were significantly lower than those at the beginning of the follow-up (p = 0.043). In addition, the longitudinal change in serum hsa-miR-346 concentration correlated with bacterial load in 2 patients with M. avium pulmonary disease. Based on our results, it is supposed that MAC-infected macrophages in pulmonary lesions produce hsa-miR-346, which is then secreted into the bloodstream. The magnitude of this process could be quantitatively controlled by the bacterial load, suggesting that serum hsa-miR-346 is a potentially useful biomarker of MAC pulmonary disease activity.
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Affiliation(s)
| | - Eiko Tamizu
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Japan
| | - Shunsuke Uno
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Japan
| | - Yoshifumi Uwamino
- Department of Laboratory Medicine, Keio University School of Medicine, Japan
| | - Hiroshi Fujiwara
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Japan
| | - Kazumi Nishio
- Department of Pulmonary Medicine, Kawasaki Municipal Ida Hospital, Japan
| | - Yasushi Nakano
- Department of Pulmonary Medicine, Kawasaki Municipal Ida Hospital, Japan
| | - Hirofumi Shiono
- Medical Business Development Division, Nikon Corporation, Japan
| | - Ho Namkoong
- Department of Pulmonary Medicine, Eiju General Hospital, Japan
| | - Yoshihiko Hoshino
- Leprosy Research Center, National Institute of Infectious Diseases, Japan
| | - Satoshi Iwata
- Department of Infectious Diseases, Keio University School of Medicine, Japan
| | - Naoki Hasegawa
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Japan.
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Uemura R, Murakami Y, Hashimoto A, Sawada A, Otani K, Taira K, Hosomi S, Nagami Y, Tanaka F, Kamata N, Yamagami H, Tanigawa T, Watanabe T, Taguchi YH, Fujiwara Y. Expression of Serum Exosomal and Esophageal MicroRNA in Rat Reflux Esophagitis. Int J Mol Sci 2017; 18:1611. [PMID: 28757556 PMCID: PMC5578003 DOI: 10.3390/ijms18081611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 07/18/2017] [Accepted: 07/20/2017] [Indexed: 12/16/2022] Open
Abstract
Gastroesophageal reflux disease (GERD) is a common upper gastrointestinal disease. However, the role of exosomal microRNAs (miRNAs) and esophageal miRNAs in GERD has not been studied. A rat model of acid reflux esophagitis was used to establish a novel diagnosis marker for GERD and examine dynamics of miRNA expression in GERD. Rats were sacrificed 3 (acute phase), 7 (sub-acute phase) and 21 days (chronic phase) after induction of esophagitis. Exosomes were extracted from serum, and the expression patterns of serum miRNAs were analyzed. Four upregulated miRNAs (miR-29a-3p, 128-3p, 223-3p and 3473) were identified by microarray analysis. The expression levels of exosomal miR-29a-3p were significantly higher in the chronic phase of reflux esophagitis compared with controls, and increased expression of miR-29a-3p was specific to chronic reflux esophagitis. Esophageal miR-223-3p expression was higher compared with controls, and gradually decreased from acute to chronic phase in esophagitis. In conclusion, exosomal miR-29a-3p and esophageal miR-223-3p might play roles in GERD.
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Affiliation(s)
- Risa Uemura
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Atsushi Hashimoto
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Akinari Sawada
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Hirokazu Yamagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
| | - Y-H Taguchi
- Department of Physics, Chuo University, Tokyo 112-8551, Japan.
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
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Shi BM, Lu W, Ji K, Wang YF, Xiao S, Wang XY. Study on the value of serum miR-106b for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 2017; 23:3713-3720. [PMID: 28611524 PMCID: PMC5449428 DOI: 10.3748/wjg.v23.i20.3713] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 03/07/2017] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the incidence of hepatocellular carcinoma (HCC) in a population that underwent health checkups and had high serum miR-106b levels. METHODS A total of 335 subjects who underwent checkups in the Digestive and Liver Disease Department of our hospital were randomly selected. RT-PCR was used to detect the level of miR-106b in serum samples. Laboratory and imaging examinations were carried out to confirm the HCC diagnosis in patients who had a > 2-fold change in miR-106b levels. Ultrasound-guided biopsy was also used for HCC diagnosis when necessary. On this basis, the clinical data of these subjects, including history of hepatitis virus infection, obesity, long-term history of alcohol use and stage of HCC, were collected. Then, the impact of these factors on the level of miR-106b in serum was analyzed. Furthermore, receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic efficacy of miR-106b for HCC. RESULTS A total of 35 subjects had abnormal serum miR-106b levels, of which 20 subjects were diagnosed with HCC. t-test revealed that the difference in serum miR-106b level in terms of sex, age, history of hepatitis virus infection, obesity and long-term history of alcohol use was not statistically significant. However, serum miR-106b levels in patients with advanced HCC (stage III/IV) was higher than in patients with early HCC (stage I/II), and the difference was statistically significant (P = 0.000). Moreover, the ROC curve revealed that the area under the curve value for miR-106b was 0.885, which shows that serum miR-106b level has a certain clinical value for HCC diagnosis. CONCLUSION The random sampling survey shows that serum miR-106b level is a valuable diagnostic marker for HCC. However, the diagnostic threshold value needs to be further researched.
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Dkhil MA, Al-Quraishy SA, Abdel-Baki AAS, Delic D, Wunderlich F. Differential miRNA Expression in the Liver of Balb/c Mice Protected by Vaccination during Crisis of Plasmodium chabaudi Blood-Stage Malaria. Front Microbiol 2017; 7:2155. [PMID: 28123381 PMCID: PMC5225092 DOI: 10.3389/fmicb.2016.02155] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/21/2016] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs are increasingly recognized as epigenetic regulators for outcome of diverse infectious diseases and vaccination efficacy, but little information referring to this exists for malaria. This study investigates possible effects of both protective vaccination and P. chabaudi malaria on the miRNome of the liver as an effector against blood-stage malaria using miRNA microarrays and quantitative PCR. Plasmodium chabaudi blood-stage malaria takes a lethal outcome in female Balb/c mice, but a self-healing course after immunization with a non-infectious blood-stage vaccine. The liver robustly expresses 71 miRNA species at varying levels, among which 65 miRNA species respond to malaria evidenced as steadily increasing or decreasing expressions reaching highest or lowest levels toward the end of the crisis phase on day 11 p.i. in lethal malaria. Protective vaccination does not affect constitutive miRNA expression, but leads to significant (p < 0.05) changes in the expression of 41 miRNA species, however evidenced only during crisis. In vaccination-induced self-healing infections, 18 miRNA-species are up- and 14 miRNA-species are down-regulated by more than 50% during crisis in relation to non-vaccinated mice. Vaccination-induced self-healing and survival of otherwise lethal infections of P. chabaudi activate epigenetic miRNA-regulated remodeling processes in the liver manifesting themselves during crisis. Especially, liver regeneration is accelerated as suggested by upregulation of let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-26a, miR-122-5p, miR30a, miR27a, and mir-29a, whereas the up-regulated expression of miR-142-3p by more than 100% is compatible with the view of enhanced hepatic erythropoiesis, possibly at expense of megakaryopoiesis, during crisis of P. chabaudi blood-stage malaria.
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Affiliation(s)
- Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud UniversityRiyadh, Saudi Arabia; Department of Zoology and Entomology, Faculty of Science, Helwan UniversityCairo, Egypt
| | - Saleh A Al-Quraishy
- Department of Zoology, College of Science, King Saud University Riyadh, Saudi Arabia
| | - Abdel-Azeem S Abdel-Baki
- Department of Zoology, College of Science, King Saud UniversityRiyadh, Saudi Arabia; Department of Zoology, Faculty of Science, Beni-Suef UniversityBeni-Suef, Egypt
| | - Denis Delic
- Boehringer-Ingelheim Pharma Biberach, Germany
| | - Frank Wunderlich
- Department of Biology, Heinrich-Heine-University Duesseldorf, Germany
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Sanjay S, Girish C. Role of miRNA and its potential as a novel diagnostic biomarker in drug-induced liver injury. Eur J Clin Pharmacol 2016; 73:399-407. [PMID: 28028586 DOI: 10.1007/s00228-016-2183-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 12/16/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE MicroRNAs (miRNA or miR) are the most abundant and stable class of small RNA. Unlike the typical RNA molecules present in the cell, they do not encode proteins but can control translation. and Hhence, they are found to play a major role in the regulation of cellular processes. miRNAs have been shown to differentially regulate various genes, and the expression levels of some miRNAs changes several fold in liver and serum, during drug- induced toxicity. This review summarises some of the latest findings about the biological functions of miRNA and its potential use as diagnostic biomarkers in drug- induced liver injury. METHODS The information presented in this article is taken from published literature, both original work and reviews on mechanisms of drug- induced liver injury, miRNA in liver pathophysiology, and studies exploring the use of miRNA as biomarker in drug- induced liver injury. Literature search was done using search engines:- PUBMED, Google scholar, and relevant journal sites. RESULTS AND CONCLUSIONS Recent research provides insight into the ability of miRNA to regulate various pathways in diseased and nondiseased states of liver. They also lay a foundation for development of diagnostic tests utilizing the potential of miRNAs that can not only be used for early detection of DILI but also to differentiate between different types of DILI. More studies on biological functions of miRNA and standardisation of protocol between research laboratories can lead to further advancement in this field. Considering the therapeutic and diagnostic potential of miRNA, the major challenge would be to integrate these findings to clinical settings where it can be used for the treatment of cases with DILI.
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Affiliation(s)
- Sukumaran Sanjay
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Chandrashekaran Girish
- Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.
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