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Han X, Liu Z, Cui M, Lin J, Li Y, Qin H, Sheng J, Zhang X. FGA influences invasion and metastasis of hepatocellular carcinoma through the PI3K/AKT pathway. Aging (Albany NY) 2024; 16:12806-12819. [PMID: 39227068 PMCID: PMC11501378 DOI: 10.18632/aging.206011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 06/03/2024] [Indexed: 09/05/2024]
Abstract
Fibrinogen is an important plasma protein composed of three polypeptide chains, fibrinogen alpha (FGA), beta, and gamma. Apart from being an inflammation regulator, fibrinogen also plays a role in tumor progression. Liver cancer usually has a poor prognosis, with chronic hepatitis being the main cause of liver cirrhosis and hepatocellular carcinoma (HCC). FGA serves as a serological marker for chronic hepatitis, but its relationship with liver cancer remains unclear. Through bioinformatics analysis and agarose gel electrophoresis, we found that FGA was downregulated in HCC and correlated with tumor stage and grade. By constructing both FGA gene knockout and overexpression cell models, we demonstrated that overexpressing FGA inhibited migration and invasion of liver cancer cells through Transwell migration/invasion and wound healing assays. Western blotting experiments showed that FGA overexpression increased the expression of the epithelial-mesenchymal transition marker protein E-cadherin while decreasing N-cadherin and slug protein expression. In addition, FGA knockout activated the PI3K/AKT pathway. In a mouse model of metastatic tumors, overexpression of FGA restricted the spread of tumor cells. In conclusion, FGA exhibits an inhibitory effect on tumor metastasis, providing new insights for the treatment of advanced HCC metastatic tumors.
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Affiliation(s)
- Xi Han
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Zefeng Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Jie Lin
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Yongzhi Li
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Hanjiao Qin
- Department of Radiotherapy, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Jiyao Sheng
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
| | - Xuewen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Second Hospital of Jilin University, Changchun, Jilin 130041, China
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Vallianou I, Dafou D, Vassilaki N, Mavromara P, Hadzopoulou-Cladaras M. Hepatitis C virus suppresses Hepatocyte Nuclear Factor 4 alpha, a key regulator of hepatocellular carcinoma. Int J Biochem Cell Biol 2016; 78:315-326. [PMID: 27477312 DOI: 10.1016/j.biocel.2016.07.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/20/2016] [Accepted: 07/26/2016] [Indexed: 12/18/2022]
Abstract
Hepatitis C Virus (HCV) infection presents with a disturbed lipid profile and can evolve to hepatic steatosis and hepatocellular carcinoma (HCC). Hepatocyte Nuclear Factor 4 alpha (HNF4α) is the most abundant transcription factor in the liver, a key regulator of hepatic lipid metabolism and a critical determinant of Epithelial to Mesenchymal Transition and hepatic development. We have previously shown that transient inhibition of HNF4α initiates transformation of immortalized hepatocytes through a feedback loop consisting of miR-24, IL6 receptor (IL6R), STAT3, miR-124 and miR-629, suggesting a central role of HNF4α in HCC. However, the role of HNF4α in Hepatitis C Virus (HCV)-related hepatocarcinoma has not been evaluated and remains controversial. In this study, we provide strong evidence suggesting that HCV downregulates HNF4α expression at both transcriptional and translational levels. The observed decrease of HNF4α expression correlated with the downregulation of its downstream targets, HNF1α and MTP. Ectopic overexpression of HCV proteins also exhibited an inhibitory effect on HNF4α levels. The inhibition of HNF4α expression by HCV appeared to be mediated at transcriptional level as HCV proteins suppressed HNF4α gene promoter activity. HCV also up-regulated IL6R, activated STAT3 protein phosphorylation and altered the expression of acute phase genes. Furthermore, as HCV triggered the loss of HNF4α a consequent change of miR-24, miR-629 or miR-124 was observed. Our findings demonstrated that HCV-related HCC could be mediated through HNF4α-microRNA deregulation implying a possible role of HNF4α in HCV hepatocarcinogenesis. HCV inhibition of HNF4α could be sustained to promote HCC.
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Affiliation(s)
- Ioanna Vallianou
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitra Dafou
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Niki Vassilaki
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Penelope Mavromara
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Margarita Hadzopoulou-Cladaras
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Song B, Shu Y, Xu YN, Fu P. Plasma fibrinogen lever and risk of coronary heart disease among Chinese population: a systematic review and meta-analysis. Int J Clin Exp Med 2015; 8:13195-13202. [PMID: 26550243 PMCID: PMC4612928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 06/26/2015] [Indexed: 06/05/2023]
Abstract
Coronary heart disease (CHD) remains the leading causes of death and disability for men and women in most developed countries. It may soon become the leading cause of death in developing countries. Several studies have examined the role of fibrinogen levels in the prediction of atherosclerosis and CHD events. The aim of this study was to explore the effects of plasma fibrinogen levels in Chinese patients with CHD and to examine the relationship of fibrinogen. We performed this meta-analysis of prospective studies of plasma fibrinogen level in relation to CHD risk in electronic database of Medline, EMBase, the Cochrane Library and CNKI (China National Knowledge Infrastructure). Plasma fibrinogen levels were calculated by mean difference with 95% confidence intervals (CI) in patients with CHD and related controls without CHD. The selected 23 studies included 2984 CHD cases and 2279 controls. Our results found that plasma fibrinogen levels of patients were significantly higher than control group (P<0.0001). The predicted odds ratio (OR) for a 1 g/L higher plasma fibrinogen level was 0.94 (95% CI=0.78-1.10). Furthermore, fibrinogen levels were slightly related to age-related CHD patients. The plasma fibrinogen lever was correlated with CHD in the Chinese population, and may be a risk factor and predictor of CHD. Further studies assessing any causal relevance of fibrinogen levels to disease are required.
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Affiliation(s)
- Bin Song
- Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan UniversityChengdu 610041, China
| | - Ying Shu
- Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan UniversityChengdu 610041, China
| | - Yuan Ning Xu
- Department of Internal Medicine, Division of Cardiology, West China Hospital of Sichuan UniversityChengdu 610041, China
| | - Ping Fu
- Department of Internal Medicine, Division of Nephrology, West China Hospital of Sichuan UniversityChengdu 610041, China
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4
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Lim T. Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? Hepat Med 2014; 6:113-8. [PMID: 25506251 PMCID: PMC4259863 DOI: 10.2147/hmer.s60083] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy.
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Affiliation(s)
- Tr Lim
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, UK
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5
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Foka P, Dimitriadis A, Kyratzopoulou E, Giannimaras DA, Sarno S, Simos G, Georgopoulou U, Mamalaki A. A complex signaling network involving protein kinase CK2 is required for hepatitis C virus core protein-mediated modulation of the iron-regulatory hepcidin gene expression. Cell Mol Life Sci 2014; 71:4243-58. [PMID: 24718935 PMCID: PMC11114079 DOI: 10.1007/s00018-014-1621-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 02/25/2014] [Accepted: 03/24/2014] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is associated with hepatic iron overload and elevated serum iron that correlate to poor antiviral responses. Hepcidin (HAMP), a 25-aa cysteine-rich liver-specific peptide, controls iron homeostasis. Its expression is up-regulated in inflammation and iron excess. HCV-mediated hepcidin regulation remains controversial. Chronic HCV patients possess relatively low hepcidin levels; however, elevated HAMP mRNA has been reported in HCV core transgenic mice and HCV replicon-expressing cells. We investigated the effect of HCV core protein on HAMP gene expression and delineated the complex interplay of molecular mechanisms involved. HCV core protein up-regulated HAMP promoter activity, mRNA, and secreted protein levels. Enhanced promoter activity was abolished by co-transfections of core with HAMP promoter constructs containing mutated/deleted BMP and STAT binding sites. Dominant negative constructs, pharmacological inhibitors, and silencing experiments against STAT3 and SMAD4 confirmed the participation of both pathways in HAMP gene regulation by core protein. STAT3 and SMAD4 expression levels were found increased in the presence of HCV core, which orchestrated SMAD4 translocation into the nucleus and STAT3 phosphorylation. To further understand the mechanisms governing the core effect, the role of the JAK/STAT-activating kinase CK2 was investigated. A CK2-dominant negative construct, a CK2-specific inhibitor, and RNAi interference abrogated the core-induced increase on HAMP promoter activity, mRNA, and protein levels, while CK2 acted in synergy with core to significantly enhance HAMP gene expression. Therefore, HCV core up-regulates HAMP gene transcription via a complex signaling network that requires both SMAD/BMP and STAT3 pathways and CK2 involvement.
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Affiliation(s)
- Pelagia Foka
- Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece
- Laboratory of Molecular Virology, Hellenic Pasteur Institute, Athens, Greece
| | - Alexios Dimitriadis
- Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece
| | - Eleni Kyratzopoulou
- Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece
| | - Dionysios A. Giannimaras
- Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece
| | - Stefania Sarno
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - George Simos
- Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Urania Georgopoulou
- Laboratory of Molecular Virology, Hellenic Pasteur Institute, Athens, Greece
| | - Avgi Mamalaki
- Laboratory of Molecular Biology and Immunobiotechnology, Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece
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Kwon YC, Ray RB, Ray R. Hepatitis C virus infection: establishment of chronicity and liver disease progression. EXCLI JOURNAL 2014; 13:977-96. [PMID: 26417315 PMCID: PMC4464452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/14/2014] [Indexed: 11/16/2022]
Abstract
Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV related end stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these ob-servations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression.
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Affiliation(s)
- Young-Chan Kwon
- Department of Internal Medicine, Saint Louis University, Missouri
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Missouri
| | - Ranjit Ray
- Department of Internal Medicine, Saint Louis University, Missouri,Department of Molecular Microbiology & Immunology, Saint Louis University, Missouri,*To whom correspondence should be addressed: Ranjit Ray, Division of Infectious Diseases, Allergy & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd, 8th Floor, St. Louis, MO 63104, USA, E-mail:
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The association of toll-like receptor 4 polymorphism with hepatitis C virus infection in Saudi Arabian patients. BIOMED RESEARCH INTERNATIONAL 2014; 2014:357062. [PMID: 25177689 PMCID: PMC4142570 DOI: 10.1155/2014/357062] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 07/09/2014] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) is a single stranded RNA virus. It affects millions of people worldwide and is considered as a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. A recent study reported that TLR4 gene polymorphisms are good prognostic predictors and are associated with protection from liver fibrosis among Caucasians. This study aims to investigate the implication of genetic polymorphisms of TLR4 gene on the HCV infection in Saudi Arabian patients. Two SNPs in the TLR4 gene, rs4986790 (A/G) and rs4986791 (C/T), were genotyped in 450 HCV patients and 600 uninfected controls. The association analysis confirmed that both SNPs showed a significant difference in their distribution between HCV-infected patients and uninfected control subjects (P < 0.0001; OR = 0.404, 95% CI = 0.281-0.581) and (P < 0.0001; OR = 0.298, 95% CI = 0.201-0.443), respectively. More importantly, haplotype analysis revealed that four haplotypes, AC, GT, GC, and AT (rs4986790, rs4986791), were significantly associated with HCV infection when compared with control subjects. One haplotype AC was more prominently found when chronic HCV-infected patients were compared with cirrhosis/HCC patients (frequency = 94.7% and P = 0.04). Both TLR4 SNPs under investigation were found to be significantly implicated with HCV-infection among Saudi Arabian population.
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8
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Fierro NA, Gonzalez-Aldaco K, Torres-Valadez R, Martinez-Lopez E, Roman S, Panduro A. Immunologic, metabolic and genetic factors in hepatitis C virus infection. World J Gastroenterol 2014; 20:3443-3456. [PMID: 24707127 PMCID: PMC3974511 DOI: 10.3748/wjg.v20.i13.3443] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/16/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
The mechanisms that regulate disease progression during hepatitis C virus (HCV) infection and the response to treatment are not clearly identified. Numerous studies have demonstrated that a strong host immune response against HCV favors HCV clearance. In addition, genetic factors and metabolic machinery, particularly cholesterol modulation, are involved in HCV infection. It is likely that the interplay between all of these factors contributes to the outcome of HCV infection. In recent years, the world has experienced its largest epidemic of obesity. Mexico and the United States are the leading sufferers from this epidemic at the global level. Obesity is associated with the development of numerous pathologies including hypercholesterolemia which is one of the eight most important risk factors for mortality in Mexico. This may be related to the course of HCV infection in this population. Here, we focus on the urgent need to study the progression of HCV infection in relation to ethnic characteristics. Discoveries are discussed that hold promise in identifying immune, metabolic and genetic factors that, in conjunction, could be therapeutic targets or predictors of the progression of HCV infection.
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Ferrín G, Ranchal I, Llamoza C, Rodríguez-Perálvarez ML, Romero-Ruiz A, Aguilar-Melero P, López-Cillero P, Briceño J, Muntané J, Montero-Álvarez JL, De la Mata M. Identification of candidate biomarkers for hepatocellular carcinoma in plasma of HCV-infected cirrhotic patients by 2-D DIGE. Liver Int 2014; 34:438-446. [PMID: 23944848 DOI: 10.1111/liv.12277] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 06/23/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND The current methods available for screening and detecting hepatocellular carcinoma (HCC) have insufficient sensitivity and specificity, and only a low percentage of diagnosis of small tumours is based on these assays. Because HCC is usually asymptomatic at potentially curative stages, identification of biomarkers for the early detection of HCC is essential to improve patient survival. AIM The aim of this study was to identify candidate markers for HCC development in the plasma from hepatitis C virus (HCV)-infected cirrhotic patients. METHODS We compared protein expression profiles of plasma samples from HCV-infected cirrhotic patients with and without HCC, using two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analysed statistically using Decyder™ software, and verified by western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS In the plasma of HCV-infected HCC patients, we observed decreased expression of complement component 9, ficolin-3 (FCN3), serum amyloid P component (SAP), fibrinogen-gamma and immunoglobulin gamma-1 chain, and increased expression of vitronectin (VTN) and galectin-3 binding protein (G3BP) by DIGE analysis. ELISA confirmed DIGE results for VTN and G3BP but not for SAP or FCN3 in a larger patient population. CONCLUSIONS The proteins VTN and SAP are candidate biomarkers for HCC development in HCV-infected cirrhotic patients.
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Affiliation(s)
- Gustavo Ferrín
- Maimónides Institute for Biomedical Research in Córdoba (IMBIC), Reina Sofía University Hospital, University of Córdoba, Córdoba, Spain; Networked Biomedical Research Center, Hepatic and Digestive Diseases (CIBERehd), Barcelona, Spain
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Hepatitis C virus impairs natural killer cell-mediated augmentation of complement synthesis. J Virol 2013; 88:2564-71. [PMID: 24352446 DOI: 10.1128/jvi.02988-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
UNLABELLED Natural killer (NK) cells and the complement system play critical roles in the first line of defense against pathogens. The synthesis of complement components C4 and C3 is transcriptionally downregulated by hepatitis C virus (HCV) core and NS5A proteins, and this negative regulation is apparent in chronically HCV-infected patients. In this study, we have examined the potential contribution of an NK cell line as a model in regulating complement synthesis. Coculture of NK cells (NK3.3) with human hepatoma cells (Huh7.5) expressing HCV core or NS5A protein led to a significant increase in C4 and C3 complement synthesis via enhanced specific transcription factors. Reestablishment of complement protein expression was found to be mediated by direct interaction between NKG2D on NK cells and the hepatocyte protein major histocompatibility complex class I-related chains A and B (MICA/B) and not to be associated with specific cytokine signaling events. On the other hand, C4 and C3 synthesis remained impaired in a coculture of NK cells and Huh7.5 cells infected with cell culture-grown HCV. The association between these two cell types through NKG2D and MICA/B was examined further, with MICA/B expression in HCV-infected hepatocytes found to remain inhibited during coculture. Further experiments revealed that the HCV NS2 and NS5B proteins are responsible for the HCV-associated decrease in MICA/B. These results suggest that HCV disables a key receptor ligand in infected hepatoma cells, thereby inhibiting the ability of infected cells to respond to stimuli from NK cells to positively regulate complement synthesis. IMPORTANCE The complement system contributes to the protection of the host from virus infection. However, the involvement of complement in viral hepatitis has not been well documented. Whether NK cells affect complement component expression in HCV-infected hepatocytes remains unknown. Here, we have shown how HCV subverts the ability of NK cells to positively mediate complement protein expression.
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Shrivastava S, Mukherjee A, Ray R, Ray RB. Hepatitis C virus induces interleukin-1β (IL-1β)/IL-18 in circulatory and resident liver macrophages. J Virol 2013; 87:12284-90. [PMID: 24006444 PMCID: PMC3807883 DOI: 10.1128/jvi.01962-13] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV)-mediated chronic liver disease is a global health problem, and inflammation is believed to be an important player in disease pathogenesis. HCV infection often leads to severe fibrosis/cirrhosis and hepatocellular carcinoma, although the mechanisms for advancement of disease are not fully understood. The proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 have critical roles in establishment of inflammation. In this study, we examined induction of IL-1β/IL-18 secretion following HCV infection. Our results demonstrated that monocyte-derived human macrophages (THP-1) incubated with cell culture-grown HCV enhance the secretion of IL-1β/IL-18 into culture supernatants. A similar cytokine release was also observed for peripheral blood mononuclear cell (PBMC)-derived primary human macrophages and Kupffer cells (liver-resident macrophages) upon incubation with HCV. THP-1 cells incubated with HCV led to caspase-1 activation and release of proinflammatory cytokines. Subsequent studies demonstrated that HCV induces pro-IL-1β and pro-IL-18 synthesis via the NF-κB signaling pathway in macrophages. Furthermore, introduction of HCV viroporin p7 RNA into THP-1 cells was sufficient to cause IL-1β secretion. Together, our results suggested that human macrophages exposed to HCV induce IL-1β and IL-18 secretion, which may play a role in hepatic inflammation.
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Affiliation(s)
| | | | - Ranjit Ray
- Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
| | - Ratna B. Ray
- Departments of Pathology
- Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
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12
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Lee J. Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2013; 17:375-83. [PMID: 24227937 PMCID: PMC3823949 DOI: 10.4196/kjpp.2013.17.5.375] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 09/21/2013] [Accepted: 09/23/2013] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.
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Affiliation(s)
- Jinhwa Lee
- Department of Clinical Lab Science, School of Health Science, Dongseo University, Busan 617-716, Korea
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13
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Abstract
Capsid proteins are obligatory components of infectious virions. Their primary structural function is to protect viral genomes during entry and exit from host cells. Evidence suggests that these proteins can also modulate the activity and specificity of viral replication complexes. More recently, it has become apparent that they play critical roles at the virus–host interface. Here, we discuss how capsid proteins of RNA viruses interact with key host cell proteins and pathways to modulate cell physiology in order to benefit virus replication. Capsid–host cell interactions may also have implications for viral disease. Understanding how capsids regulate virus–host interactions may lead to the development of novel antiviral therapies based on targeting the activities of cellular proteins.
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Affiliation(s)
- Steven Willows
- Department of Cell Biology, University of Alberta, 5–14 Medical Sciences Building, Edmonton, T6G 2H7, Canada
| | - Shangmei Hou
- Department of Cell Biology, University of Alberta, 5–14 Medical Sciences Building, Edmonton, T6G 2H7, Canada
| | - Tom C Hobman
- Department of Li Ka Shing Institute of Virology, University of Alberta, 5–14 Medical Sciences Building, Edmonton, T6G 2H7, Canada
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Oguz A, Atay AE, Tas A, Seven G, Koruk M. Predictive role of acute phase reactants in the response to therapy in patients with chronic hepatitis C virus infection. Gut Liver 2012; 7:82-8. [PMID: 23424009 PMCID: PMC3572325 DOI: 10.5009/gnl.2013.7.1.82] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 05/23/2012] [Accepted: 06/20/2012] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Biochemical parameters and acute-phase proteins (APPs) may provide complementary data in patients with chronic hepatitis C (CHC). We aimed to evaluate the predictive role of APPs in the response to antiviral therapy. METHODS Forty-five patients underwent antiviral therapy. Serum ferritin, C-reactive protein (CRP), transferrin, albumin, alpha-1 acid glycoprotein (A1AG), and alpha-2 macroglobulin (A2MG) levels were examined at the initial evaluation and at the 4th, 12th, and 48th weeks. HCV RNA levels were examined at the initial evaluation and at the 12th and 48th weeks. RESULTS Ferritin, transferrin, A1AG, and A2MG levels were significantly higher in the patient group (p<0.05). CRP, ferritin, A1AG, and A2MG levels were significantly increased from baseline to the 4th week (p<0.05). The responders and nonresponders to antiviral therapy had insignificantly but remarkably different levels of CRP, ferritin, transferrin, A1AG, A2MG, and alanine aminotransferase (ALT) both at the initial evaluation and at the 12th week. CONCLUSIONS Variations in ferritin, A1AG, A2MG, albumin, CRP, and transferrin levels are not alternatives to virological and biochemical parameters for predicting an early response to therapy in patients with CHC. However, the investigation of ALT levels and hepatitis C virus RNA in combination with acute-phase reactants may provide supplementary data for evaluating responses to antiviral therapy.
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Affiliation(s)
- Ayten Oguz
- Department of Internal Medicine, Gaziantep University Faculty of Medicine, Gaziantep, Turkey
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Fafi-Kremer S, Fauvelle C, Felmlee DJ, Zeisel MB, Lepiller Q, Fofana I, Heydmann L, Stoll-Keller F, Baumert TF. Neutralizing antibodies and pathogenesis of hepatitis C virus infection. Viruses 2012. [PMID: 23202451 PMCID: PMC3497039 DOI: 10.3390/v4102016] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.
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Affiliation(s)
- Samira Fafi-Kremer
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Catherine Fauvelle
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
| | - Daniel J. Felmlee
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
| | - Mirjam B. Zeisel
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
| | - Quentin Lepiller
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Isabel Fofana
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
| | - Laura Heydmann
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
| | - Françoise Stoll-Keller
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Thomas F. Baumert
- Inserm, U748, Strasbourg, France ; (S.F.-K.); (C.F.); (D.J.F.); (M.B.Z.); (Q.L.); (I.F.); (L.H.); (F.S.-K.)
- Université de Strasbourg, Strasbourg, France
- Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Author to whom correspondence should be addressed; ; Tel.: +33 3 68 85 37 03; Fax: +33 3 68 85 37 50
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16
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Kim H, Mazumdar B, Bose SK, Meyer K, Di Bisceglie AM, Hoft DF, Ray R. Hepatitis C virus-mediated inhibition of cathepsin S increases invariant-chain expression on hepatocyte surface. J Virol 2012; 86:9919-28. [PMID: 22761382 PMCID: PMC3446550 DOI: 10.1128/jvi.00388-12] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Accepted: 06/28/2012] [Indexed: 01/05/2023] Open
Abstract
Hepatocytes are the main source of hepatitis C virus (HCV) replication and contain the maximum viral load in an infected person. Chronic HCV infection is characterized by weak cellular immune responses to viral proteins. Cathepsin S is a lysosomal cysteine protease and controls HLA-DR-antigen complex presentation through the degradation of the invariant chain. In this study, we examined the effect of HCV proteins on cathepsin S expression and found it to be markedly decreased in dendritic cells (DCs) exposed to HCV or in hepatocytes expressing HCV proteins. The downregulation of cathepsin S was mediated by HCV core and NS5A proteins involving inhibition of the transcription factors interferon regulatory factor 1 (IRF-1) and upstream stimulatory factor 1 (USF-1) in gamma interferon (IFN-γ)-treated hepatocytes. Inhibition of cathepsin S by HCV proteins increased cell surface expression of the invariant chain. In addition, hepatocytes stably transfected with HCV core or NS5A inhibited HLA-DR expression. Together, these results suggested that HCV has an inhibitory role on cathepsin S-mediated major histocompatibility complex (MHC) class II maturation, which may contribute to weak immunogenicity of viral antigens in chronically infected humans.
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Affiliation(s)
| | | | - Sandip K. Bose
- Departments of Internal Medicine
- Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, Missouri, USA
| | | | - Adrian M. Di Bisceglie
- Departments of Internal Medicine
- Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, Missouri, USA
| | - Daniel F. Hoft
- Departments of Internal Medicine
- Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, Missouri, USA
| | - Ranjit Ray
- Departments of Internal Medicine
- Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, Missouri, USA
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17
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Hassan M, Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O. Hepatitis C virus-host interactions: Etiopathogenesis and therapeutic strategies. World J Exp Med 2012; 2:7-25. [PMID: 24520529 PMCID: PMC3905577 DOI: 10.5493/wjem.v2.i2.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2012] [Revised: 04/16/2012] [Accepted: 04/18/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a significant health problem facing the world. This virus infects more than 170 million people worldwide and is considered the major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Although the sexual behavior is considered as a high risk factor for HCV infection, the transmission of HCV infection through sexual means, is less frequently. Currently, the available treatment for patients with chronic HCV infection is interferon based therapies alone or in combination with ribavirin and protease inhibitors. Although a sustained virological response of patients to the applied therapy, a great portion of patients did not show any response. HCV infection is mostly associated with progressive liver diseases including fibrosis, cirrhosis and hepatocellular carcinoma. Although the focus of many patients and clinicians is sometimes limited to that problem, the natural history of HCV infection (HCV) is also associated with the development of several extrahepatic manifestations including dermatologic, rheumatologic, neurologic, and nephrologic complications, diabetes, arterial hypertension, autoantibodies and cryglobulins. Despite the notion that HCV-mediated extrahepatic manifestations are credible, the mechanism of their modulation is not fully described in detail. Therefore, the understanding of the molecular mechanisms of HCV-induced alteration of intracellular signal transduction pathways, during the course of HCV infection, may offer novel therapeutic targets for HCV-associated both hepatic and extrahepatic manifestations. This review will elaborate the etiopathogenesis of HCV-host interactions and summarize the current knowledge of HCV-associated diseases and their possible therapeutic strategies.
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Affiliation(s)
- Mohamed Hassan
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Denis Selimovic
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Abdelouahid El-Khattouti
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Hanan Ghozlan
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Youssef Haikel
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
| | - Ola Abdelkader
- Mohamed Hassan, Denis Selimovic, Youssef Haikel, National Institute of Health and Medical Research, U 977, Faculty of Medicine, and Dental Faculty, 11 Rue Humann, 67085 Strasbourg Cedex, France
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18
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Vassalle C. Hepatitis C virus and atherosclerosis in a close and dangerous liaison. Atherosclerosis 2012; 221:319-20. [DOI: 10.1016/j.atherosclerosis.2011.11.040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 11/30/2011] [Indexed: 01/14/2023]
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Abstract
The third component of human complement (C3) plays a central role in innate immune function as its activation is required to trigger classical as well as alternative complement pathways. In this study, we have observed that sera from patients chronically infected with hepatitis C virus (HCV) displayed significantly lower C3 levels than sera from healthy individuals. Liver biopsy specimens from the same patients also exhibited lower C3 mRNA expression than liver tissues from healthy donors. C3 mRNA level was reduced in hepatocytes upon infection with cell culture-grown HCV genotype 1a or 2a in vitro. Further analysis suggested that HCV core protein displayed a weak repression of C3 promoter activity by downregulating the transcription factor farnesoid X receptor (FXR). On the other hand, HCV NS5A protein strongly downregulated C3 promoter activity at the basal level or in the presence of interleukin-1β (IL-1β) as an inducer. In addition, the expression of the transcription factor CAAT/enhancer binding protein beta (C/EBP-β), which binds to the IL-1/IL-6 response element in the C3 promoter, was inhibited in liver biopsy specimens. Furthermore, expression of C/EBP-β was reduced in hepatocytes infected with cell culture-grown HCV, as well as in hepatocytes transfected with the NS5A genomic region of HCV. Together, these results underscore the role of HCV NS5A protein in impairing innate immune function.
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20
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Lee JW, Liao PC, Young KC, Chang CL, Chen SSL, Chang TT, Lai MD, Wang SW. Identification of hnRNPH1, NF45, and C14orf166 as Novel Host Interacting Partners of the Mature Hepatitis C Virus Core Protein. J Proteome Res 2011; 10:4522-34. [PMID: 21823664 DOI: 10.1021/pr200338d] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Jun-Wei Lee
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Pao-Chi Liao
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Kung-Chia Young
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Christina L. Chang
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Steve S. L. Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China
| | - Ting-Tsung Chang
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Department of Medicine, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Ming-Derg Lai
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
| | - Shainn-Wei Wang
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
- Division of Clinical Research, National Health Research Institutes, Tainan 70401, Taiwan, Republic of China
- Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan 70401, Taiwan, Republic of China
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21
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Banerjee A, Ray RB, Ray R. Oncogenic potential of hepatitis C virus proteins. Viruses 2010; 2:2108-2133. [PMID: 21994721 PMCID: PMC3185750 DOI: 10.3390/v2092108] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Revised: 09/23/2010] [Accepted: 09/24/2010] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today.
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Affiliation(s)
- Arup Banerjee
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ratna B. Ray
- Department of Pathology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 2nd Floor, St. Louis, MO 63104, USA; E-Mail:
| | - Ranjit Ray
- Department of Internal Medicine, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA; E-Mail:
- Molecular Microbiology & Immunology, Edward A. Doisy Research Center, 1100 S. Grand Blvd., 8th Floor, St. Louis, MO 63104, USA
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: 1-314- 977-9034; Fax: 1-314-771-3816
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22
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Hitti E, Al-Yahya S, Al-Saif M, Mohideen P, Mahmoud L, Polyak SJ, Khabar KSA. A versatile ribosomal protein promoter-based reporter system for selective assessment of RNA stability and post-transcriptional control. RNA (NEW YORK, N.Y.) 2010; 16:1245-55. [PMID: 20418359 PMCID: PMC2874176 DOI: 10.1261/rna.2026310] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Assessment of post-transcriptional control relies on use of transcriptional inhibitors and is masked by copious and cryptic transcriptional induction. We screened several cellular promoters that are constitutively active yet noninducible to external stimuli. The ribosomal protein RPS30 promoter was chosen; its TATA signal and sp1 site location were optimized. The modified promoter (RPS30M) is selective to post-transcriptional effects of AU-rich elements (ARE) in the 3'UTR, while it is not transcriptionally responsive to a wide variety of agents including pro-inflammatory cytokines and RNA-binding proteins. Specific cis-acting elements can be appended to RPS30M by a cloning-free approach to allow coupled transcriptional/post-transcriptional assessment, as demonstrated with NF-kappaB and beta-catenin/wnt signaling experiments. Moreover, efficient tetracycline-regulated RPS30M was created for quantitative assessment of the half-lives of mRNAs containing AREs. The described approach provides enhanced versatility and suitability for selective post-transcriptional assessment with or without transcriptional induction.
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Affiliation(s)
- Edward Hitti
- Program in BioMolecular Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia 11211
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