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Sánchez-Martínez C, Grueso E, Calvo-López T, Martinez-Ortega J, Ruiz A, Almendral JM. VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications. Cells 2024; 13:1815. [PMID: 39513922 PMCID: PMC11545703 DOI: 10.3390/cells13211815] [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: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.
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Affiliation(s)
- Cristina Sánchez-Martínez
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Esther Grueso
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Tania Calvo-López
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- Department of Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Jorge Martinez-Ortega
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - Ana Ruiz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - José M. Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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Duchemin NJ, Loonawat R, Yeakle K, Rosenkranz A, Bouchard MJ. Hypoxia-inducible factor affects hepatitis B virus transcripts and genome levels as well as the expression and subcellular location of the hepatitis B virus core protein. Virology 2023; 586:76-90. [PMID: 37490813 DOI: 10.1016/j.virol.2023.06.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 06/13/2023] [Accepted: 06/21/2023] [Indexed: 07/27/2023]
Abstract
Globally, a chronic-hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC). The transcription factor hypoxia-inducible factor 1 (HIF1) is often elevated in HCC, including HBV-associated HCC. Previous studies have suggested that the expression of the HIF1 subunit, HIF1α, is elevated in HBV-infected hepatocytes; however, whether HIF1 activity affects the HBV lifecycle has not been fully explored. We used a liver-derived cell line and ex vivo cultured primary hepatocytes as models to determine how HIF1 affects the HBV lifecycle. We observed that HIF1 elevates HBV RNA transcript levels, core protein levels, core protein localization to the cytoplasm, and HBV genome replication. Attenuating the transcription activity of HIF1 blocked HIF1-mediated effects on the HBV lifecycle. Our studies show that HIF1 regulates various stages of the HBV lifecycle in hepatocytes and could be a therapeutic target for blocking HBV replication and the development of HBV-associated diseases.
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Affiliation(s)
- Nicholas J Duchemin
- Molecular and Cellular Biology and Genetic Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, USA
| | - Ronak Loonawat
- Microbiology and Immunology Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, USA
| | - Kyle Yeakle
- Molecular and Cellular Biology and Genetic Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, USA
| | - Andrea Rosenkranz
- Molecular and Cellular Biology and Genetic Graduate Program, Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, USA
| | - Michael J Bouchard
- Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA.
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3
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Role of Genetic and Epigenetic Modifications in the Progression of Hepatocellular Carcinoma in Chronic HCV Patients. LIVERS 2023. [DOI: 10.3390/livers3010008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
Abstract
Globally, hepatocellular carcinoma (HCC) is a significant cause of mortality and morbidity among chronically infected HCV patients. It is established that HCV is a primary risk factor for HCC progression. The treatment of HCV infection has been transformed by the introduction of DAAs with high rates of virological clearance. The reduction in cirrhosis-related consequences, particularly HCC, is the long-term objective of DAAs therapy for HCV. Although the risk of developing HCC is decreased in HCV patients who achieve a disease-sustaining virological response, these patients are nevertheless at risk, especially those with severe fibrosis and cirrhosis. Previous studies have shown that HCV induce several mechanisms of hepatocarcinogenesis in the host’s hepatic micro- and macro-environment, which leads to HCC progression. In an HCV-altered environment, compensatory liver regeneration favors chromosomal instability and irreversible alterations, which encourage hepatocyte neoplastic transformation and the development of malignant clones. These mechanisms involve a series of genetic and epigenetic modifications including host genetic factors, dysregulation of several signaling pathways, histone, and DNA modifications including methylation and acetylation. This review highlights the genetic and epigenetic factors that lead to the development of HCC in chronic HCV-infected individuals and can be targeted for earlier HCC diagnosis and prevention.
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Hypoxia signaling in human health and diseases: implications and prospects for therapeutics. Signal Transduct Target Ther 2022; 7:218. [PMID: 35798726 PMCID: PMC9261907 DOI: 10.1038/s41392-022-01080-1] [Citation(s) in RCA: 177] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 02/07/2023] Open
Abstract
Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.
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Diao P, Jia F, Wang X, Hu X, Kimura T, Nakajima T, Aoyama T, Moriya K, Koike K, Tanaka N. Mechanisms of Steatosis-Derived Hepatocarcinogenesis: Lessons from HCV Core Gene Transgenic Mice. ENGINEERING 2021; 7:1797-1805. [DOI: 10.1016/j.eng.2021.08.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
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7
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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Almaeen AH, Alduraywish AA, Mobasher MA, Almadhi OIM, Nafeh HM, El-Metwally TH. Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients. Arch Med Sci 2021; 17:368-375. [PMID: 33747272 PMCID: PMC7959056 DOI: 10.5114/aoms.2019.91451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Hepatitis C virus (HCV) is the main cause of chronic liver disease, with calamitous complications. Its highest rate is recorded in Egypt. This study investigated whether oxidative stress, immunological chaos and cellular hypoxia are implicated in the pathophysiology of the disease. MATERIAL AND METHODS This cross-sectional study aimed to evaluate the changes in blood oxidative stress, cellular hypoxia/angiogenesis and cellular immunological biomarkers in hospital-diagnosed treatment-naïve HCV-infected Upper Egyptian chronic liver disease patients vs. healthy controls (n = 40). The consecutively included patients comprised 120 with normal serum enzymes (HCV-NE) and 130 with high serum enzymes (HCV-HE), along with 120 cirrhotic patients. RESULTS Oxidative stress biomarkers - malondialdehyde (MDA), total peroxides and oxidative stress index (OSI) - were significantly lower in controls vs. each of the patient groups. Cirrhotic patients presented the highest levels. However, total antioxidants (TAO) showed non-significant differences among the four groups. The cellular hypoxia/angiogenesis biomarkers - lactate, vascular endothelial cell growth factor (VEGF) and its soluble receptor 1 (sVEGFR1) - vs. controls were massively increased in patient groups. VEGF was lowest while sVEGFR1 was highest among cirrhotic patients. Immunological biomarkers, - granulocyte/monocyte-colony stimulating factor (GM-CSF) and total immunoglobulin G (IgG) - were massively increased in patient groups vs. controls. GM-CSF was lowest in HCV-HE and IgG was highest in cirrhotic patients. sVEGFR1 correlated with the progression towards cirrhosis. CONCLUSIONS Oxidative stress is implicated in the progress of HCV infection with marked induction of cellular hypoxia and dysfunctional angiogenesis, and a futile immunological reaction. sVEGFR1 level correlated with progression towards HCV-induced liver fibrosis.
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Affiliation(s)
| | | | - Maysa Ahmed Mobasher
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Omar I. M. Almadhi
- College of Medicine, Jouf University College of Medicine, Sakaka, Saudi Arabia
| | - Hanan M. Nafeh
- Department of Tropical Medicine and Gastroenterology, Assiut University, Faculty of Medicine, Assiut, Egypt
| | - Tarek Hassan El-Metwally
- Department of Pathology, Jouf University College of Medicine, Sakaka, Saudi Arabia
- Department of Medical Biochemistry, Assiut University, Faculty of Medicine, Assiut, Egypt
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9
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Abstract
Liver cancer is a global problem and hepatocellular carcinoma (HCC) accounts for about 85% of this cancer. In the USA, etiologies and risk factors for HCC include chronic hepatitis C virus (HCV) infection, diabetes, non-alcoholic steatohepatitis (NASH), obesity, excessive alcohol drinking, exposure to tobacco smoke, and genetic factors. Chronic HCV infection appears to be associated with about 30% of HCC. Chronic HCV infection induces multistep changes in liver, involving metabolic disorders, steatosis, cirrhosis and HCC. Liver carcinogenesis requires initiation of neoplastic clones, and progression to clinically diagnose malignancy. Tumor progression associates with profound exhaustion of tumor-antigen-specific CD8+T cells, and accumulation of PD-1hi CD8+T cells and Tregs. In this chapter, we provide a brief description of HCV and environmental/genetic factors, immune regulation, and highlight mechanisms of HCV associated HCC. We also underscore HCV treatment and recent paradigm of HCC progression, highlighted the current treatment and potential future therapeutic opportunities.
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Liu PJ, Balfe P, McKeating JA, Schilling M. Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis. Viruses 2020; 12:E1213. [PMID: 33113858 PMCID: PMC7693908 DOI: 10.3390/v12111213] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.
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11
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Herbein G, Nehme Z. Polyploid Giant Cancer Cells, a Hallmark of Oncoviruses and a New Therapeutic Challenge. Front Oncol 2020; 10:567116. [PMID: 33154944 PMCID: PMC7591763 DOI: 10.3389/fonc.2020.567116] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/11/2020] [Indexed: 12/19/2022] Open
Abstract
Tumors are renowned as intricate systems that harbor heterogeneous cancer cells with distinctly diverse molecular signatures, sizes and genomic contents. Among those various genomic clonal populations within the complex tumoral architecture are the polyploid giant cancer cells (PGCC). Although described for over a century, PGCC are increasingly being recognized for their prominent role in tumorigenesis, metastasis, therapy resistance and tumor repopulation after therapy. A shared characteristic among all tumors triggered by oncoviruses is the presence of polyploidy. Those include Human Papillomaviruses (HPV), Epstein Barr Virus (EBV), Hepatitis B and C viruses (HBV and HCV, respectively), Human T-cell lymphotropic virus-1 (HTLV-1), Kaposi's sarcoma herpesvirus (KSHV) and Merkel polyomavirus (MCPyV). Distinct viral proteins, for instance Tax for HTLV-1 or HBx for HBV have demonstrated their etiologic role in favoring the appearance of PGCC. Different intriguing biological mechanisms employed by oncogenic viruses, in addition to viruses with high oncogenic potential such as human cytomegalovirus, could support the generation of PGCC, including induction of endoreplication, inactivation of tumor suppressors, development of hypoxia, activation of cellular senescence and others. Interestingly, chemoresistance and radioresistance have been reported in the context of oncovirus-induced cancers, for example KSHV and EBV-associated lymphomas and high-risk HPV-related cervical cancer. This points toward a potential linkage between the previously mentioned players and highlights PGCC as keystone cancer cells in virally-induced tumors. Subsequently, although new therapeutic approaches are actively needed to fight PGCC, attention should also be drawn to reveal the relationship between PGCC and oncoviruses, with the ultimate goal of establishing effective therapeutic platforms for treatment of virus-associated cancers. This review discusses the presence of PGCCs in tumors induced by oncoviruses, biological mechanisms potentially favoring their appearance, as well as their consequent implication at the clinical and therapeutic level.
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Affiliation(s)
- Georges Herbein
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Department of Virology, CHRU Besancon, Besançon, France
| | - Zeina Nehme
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Faculty of Sciences, Lebanese University, Beirut, Lebanon
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12
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Vescovo T, Pagni B, Piacentini M, Fimia GM, Antonioli M. Regulation of Autophagy in Cells Infected With Oncogenic Human Viruses and Its Impact on Cancer Development. Front Cell Dev Biol 2020; 8:47. [PMID: 32181249 PMCID: PMC7059124 DOI: 10.3389/fcell.2020.00047] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/20/2020] [Indexed: 12/14/2022] Open
Abstract
About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.
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Affiliation(s)
- Tiziana Vescovo
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Benedetta Pagni
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Mauro Piacentini
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Biology, University of Rome "Tor Vergata," Rome, Italy
| | - Gian Maria Fimia
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy.,Department of Molecular Medicine, University of Rome "Sapienza," Rome, Italy
| | - Manuela Antonioli
- National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
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13
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037366. [PMID: 31501266 DOI: 10.1101/cshperspect.a037366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.,Institut Universitaire de France (IUF), 75231 Paris, France
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
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14
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Positive Effects of Ger-Gen-Chyn-Lian-Tang on Cholestatic Liver Fibrosis in Bile Duct Ligation-Challenged Mice. Int J Mol Sci 2019; 20:ijms20174181. [PMID: 31455001 PMCID: PMC6747316 DOI: 10.3390/ijms20174181] [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: 07/05/2019] [Revised: 08/12/2019] [Accepted: 08/24/2019] [Indexed: 01/22/2023] Open
Abstract
The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-β, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.
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Integration of VEGF and α-SMA Expression Improves the Prediction Accuracy of Fibrosis in Chronic Hepatitis C Liver Biopsy. Appl Immunohistochem Mol Morphol 2019; 25:261-270. [PMID: 26990742 DOI: 10.1097/pai.0000000000000299] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The progression of fibrosis in chronic hepatitis C (CHC) is a multifactorial process. The high adverse effects and the cost of standard health care increase the demand to discover new predictors for the progression of fibrosis in CHC patients. Our study aims to establish the relation between the angiogenic marker [vascular endothelial growth factor (VEGF)] and activated hepatic stellate cells (HSCs) represented by the expression of α-smooth muscle actin (α-SMA) and whether these 2 markers can be used as predictors for the progression of fibrosis in patients with CHC. MATERIALS AND METHODS Histopathologic and immunohistochemical analyses were used for examining the morphology and the expression of VEGF and α-SMA in 60 CHC biopsies procured from CHC patients. Multivariate analysis was used to correlate the protein expression with staging and grading of liver fibrosis. Cutoff values of α-SMA and VEGF were determined by the receiver operating characteristics curve. RESULTS There was a positive correlation between VEGF and HSCs expressing α-SMA (ρ=0.287, P=0.026) and both factors were correlated with the stage of fibrosis (P<0.001). Using the receiver operating characteristics curve, both VEGF (area under the curve=0.71, P<0.006) and α-SMA (area under the curve=0.82, P<0.001) were positive predictors for moderate and severe fibrosis. CONCLUSIONS This study demonstrates the relation between VEGF expression and the activated HSCs denoted by the expression of α-SMA in CHC biopsies and together can be used as a predictor for the progression of fibrosis.
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Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
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Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
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VEGF Upregulation in Viral Infections and Its Possible Therapeutic Implications. Int J Mol Sci 2018; 19:ijms19061642. [PMID: 29865171 PMCID: PMC6032371 DOI: 10.3390/ijms19061642] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 12/12/2022] Open
Abstract
Several viruses are recognized as the direct or indirect causative agents of human tumors and other severe human diseases. Vascular endothelial growth factor (VEGF) is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network. Therefore, oncogenic viruses such as Kaposi’s sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) and non-oncogenic viruses such as herpes simplex virus (HSV-1) and dengue virus, which lack their own angiogenic factors, rely on the recruitment of cellular genes for angiogenesis in tumor progression or disease pathogenesis. This review summarizes how human viruses exploit the cellular signaling machinery to upregulate the expression of VEGF and benefit from its physiological functions for their own pathogenesis. Understanding the interplay between viruses and VEGF upregulation will pave the way to design targeted and effective therapeutic approaches for viral oncogenesis and severe diseases.
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18
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Mui UN, Haley CT, Tyring SK. Viral Oncology: Molecular Biology and Pathogenesis. J Clin Med 2017; 6:E111. [PMID: 29186062 PMCID: PMC5742800 DOI: 10.3390/jcm6120111] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/17/2017] [Accepted: 11/22/2017] [Indexed: 02/06/2023] Open
Abstract
Oncoviruses are implicated in approximately 12% of all human cancers. A large number of the world's population harbors at least one of these oncoviruses, but only a small proportion of these individuals go on to develop cancer. The interplay between host and viral factors is a complex process that works together to create a microenvironment conducive to oncogenesis. In this review, the molecular biology and oncogenic pathways of established human oncoviruses will be discussed. Currently, there are seven recognized human oncoviruses, which include Epstein-Barr Virus (EBV), Human Papillomavirus (HPV), Hepatitis B and C viruses (HBV and HCV), Human T-cell lymphotropic virus-1 (HTLV-1), Human Herpesvirus-8 (HHV-8), and Merkel Cell Polyomavirus (MCPyV). Available and emerging therapies for these oncoviruses will be mentioned.
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Affiliation(s)
- Uyen Ngoc Mui
- Center for Clinical Studies, Houston, TX 77004, USA.
| | | | - Stephen K Tyring
- Center for Clinical Studies, Houston, TX 77004, USA.
- Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX 77004, USA.
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19
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Modulation of HIF-1α and STAT3 signaling contributes to anti-angiogenic effect of YC-1 in mice with liver fibrosis. Oncotarget 2017; 8:86206-86216. [PMID: 29156788 PMCID: PMC5689678 DOI: 10.18632/oncotarget.21039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/16/2017] [Indexed: 12/25/2022] Open
Abstract
Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The aim of the study was to evaluate the mechanisms of HIF-1α inhibitor, YC-1, during bile duct ligation (BDL)-induced liver fibrosis in mice. Liver fibrosis was induced in mice, and YC-1 was then given intraperitoneally (50 mg/kg) once daily following 5 days. Liver injuries mice that were treated with YC-1 showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. YC-1 treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α signaling as well as macrophage aggregation. In addition, YC-1 downregulates iNOS and COX-2 levels by inhibiting the activation of NF-κB and STAT3 phosphorylation by negative regulation the expression of SOCS1 and SOCS3 signaling. On the other hand, YC-1 decreased angiogenesis, as shown by the downregulation of hypoxia-inducible cascade genes, i.e. VEGF. YC-1 treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-βR1 expression as well as hypoxia were assessed using VEGFR1, vWF and HIF-1α immunostaining. These results suggest that multi-targeted therapies directed against angiogenesis, hypoxia, and fibrosis. Therefore, it may be suggested that YC-1 treatment may be a novel therapeutic agent for the treatment of liver disease.
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20
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Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect 2016; 22:853-861. [PMID: 27476823 DOI: 10.1016/j.cmi.2016.07.019] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/09/2016] [Accepted: 07/16/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis.
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21
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Zhu C, Zhu Q, Wang C, Zhang L, Wei F, Cai Q. Hostile takeover: Manipulation of HIF-1 signaling in pathogen-associated cancers (Review). Int J Oncol 2016; 49:1269-76. [PMID: 27499495 DOI: 10.3892/ijo.2016.3633] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/23/2016] [Indexed: 11/05/2022] Open
Abstract
Hypoxia-inducible factor (HIF)-1 is a central regulator in the adaptation process of cell response to hypoxia (low oxygen). Emerging evidence has demonstrated that HIF-1 plays an important role in the development and progression of many types of human diseases, including pathogen-associated cancers. In the present review, we summarize the recent understandings of how human pathogenic agents including viruses, bacteria and parasites deregulate cellular HIF-1 signaling pathway in their associated cancer cells, and highlight the common molecular mechanisms of HIF-1 signaling activated by these pathogenic infection, which could act as potential diagnostic markers and new therapeutic strategies against human infectious cancers.
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Affiliation(s)
- Caixia Zhu
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Qing Zhu
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Chong Wang
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Liming Zhang
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
| | - Fang Wei
- ShengYushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, P.R. China
| | - Qiliang Cai
- Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), School of Basic Medical Sciences, Fudan University, Shanghai 200032, P.R. China
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22
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Schinzari V, Barnaba V, Piconese S. Chronic hepatitis B virus and hepatitis C virus infections and cancer: synergy between viral and host factors. Clin Microbiol Infect 2015; 21:969-74. [PMID: 26163104 DOI: 10.1016/j.cmi.2015.06.026] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 06/12/2015] [Accepted: 06/16/2015] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infections represent major causes of chronic liver disease and hepatocellular carcinoma. Despite inducing shared pathological events leading to oncogenic transformation, these two viruses present profound differences in their molecular features, life cycle and interplay with host factors, which significantly differentiate the prognostic and therapeutic approach to the related diseases. In the present review, we report the main mechanisms involved in the multistep process leading from HCV/HBV infection and cancer development, discussing side-by-side the analogies and differences between the two viruses. Such events can be broadly categorized into (a) direct oncogenic effects, involving integration in the host genome (in the case of HBV) and chromosomal instability, interference with oncosuppressor pathways, induction of oxidative stress, promotion of angiogenesis, epithelial-mesenchymal transition, alterations in the epigenetic asset and interaction with non-coding RNAs; and (b) indirect activities mostly mediated by host events, including chronic inflammation sustained by peculiar cytokine networks (such as interleukin-6 and lymphotoxins), metabolic dysfunctions promoted by steatohepatitis, interplay with gut microbiota and fibrotic events (mainly in HCV infection). This scenario suggests that the integrated study of viral and host factors may lead to the successful development of novel biomarkers and targets for therapy.
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Affiliation(s)
- V Schinzari
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - V Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy.
| | - S Piconese
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
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23
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Elpek G&O. Angiogenesis and liver fibrosis. World J Hepatol 2015; 7:377-391. [PMID: 25848465 PMCID: PMC4381164 DOI: 10.4254/wjh.v7.i3.377] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/27/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.
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24
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Urbaczek AC, Ribeiro LCDA, Ximenes VF, Afonso A, Nogueira CT, Generoso WC, Alberice JV, Rudnicki M, Ferrer R, da Fonseca LM, da Costa PI. Inflammatory response of endothelial cells to hepatitis C virus recombinant envelope glycoprotein 2 protein exposure. Mem Inst Oswaldo Cruz 2014; 109:748-56. [PMID: 25317702 PMCID: PMC4238766 DOI: 10.1590/0074-0276140090] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 07/29/2014] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus (HCV) encodes approximately 10 different structural and non-structural proteins, including the envelope glycoprotein 2 (E2). HCV proteins, especially the envelope proteins, bind to cell receptors and can damage tissues. Endothelial inflammation is the most important determinant of fibrosis progression and, consequently, cirrhosis. The aim of this study was to evaluate and compare the inflammatory response of endothelial cells to two recombinant forms of the HCV E2 protein produced in different expression systems (Escherichia coli and Pichia pastoris). We observed the induction of cell death and the production of nitric oxide, hydrogen peroxide, interleukin-8 and vascular endothelial growth factor A in human umbilical vein endothelial cells (HUVECs) stimulated by the two recombinant E2 proteins. The E2-induced apoptosis of HUVECs was confirmed using the molecular marker PARP. The apoptosis rescue observed when the antioxidant N-acetylcysteine was used suggests that reactive oxygen species are involved in E2-induced apoptosis. We propose that these proteins are involved in the chronic inflammation caused by HCV.
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Affiliation(s)
- Ana Carolina Urbaczek
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | | | - Valdecir Farias Ximenes
- Departamento de Química, Faculdade de Ciências, Universidade Estadual
Paulista Julio de Mesquita Filho, Bauru, SP, Brasil
| | - Ana Afonso
- Departamento de Parasitologia Médica, Unidade de Parasitologia Médica e
Microbiologia, Instituto de Higiene e Medicina Tropcal, Universidade Nova de Lisboa,
Lisboa, Portugal
- Departamento de Morfologia e Patologia, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Camila Tita Nogueira
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Wesley Cardoso Generoso
- Departamento de Genética e Evolução, Universidade Federal de São
Carlos, São Carlos, SP, Brasil
| | - Juliana Vieira Alberice
- Grupo de Bioanalítica, Microfabricações e Separações, Departamento de
Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São
Paulo, São Carlos, SP, Brasil
| | - Martina Rudnicki
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Renila Ferrer
- Escola de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo,
SP, Brasil
| | - Luiz Marcos da Fonseca
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
| | - Paulo Inácio da Costa
- Laboratório de Imunologia Clínica, Departamento de Análises Clínicas,
Escola de Ciências Farmacêuticas, Bauru, SP, Brasil
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Li HC, Ma HC, Yang CH, Lo SY. Production and pathogenicity of hepatitis C virus core gene products. World J Gastroenterol 2014; 20:7104-7122. [PMID: 24966583 PMCID: PMC4064058 DOI: 10.3748/wjg.v20.i23.7104] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 12/05/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and its infection is also associated with insulin resistance and type 2 diabetes mellitus. HCV, belonging to the Flaviviridae family, is a small enveloped virus whose positive-stranded RNA genome encoding a polyprotein. The HCV core protein is cleaved first at residue 191 by the host signal peptidase and further cleaved by the host signal peptide peptidase at about residue 177 to generate the mature core protein (a.a. 1-177) and the cleaved peptide (a.a. 178-191). Core protein could induce insulin resistance, steatosis and even hepatocellular carcinoma through various mechanisms. The peptide (a.a. 178-191) may play a role in the immune response. The polymorphism of this peptide is associated with the cellular lipid drop accumulation, contributing to steatosis development. In addition to the conventional open reading frame (ORF), in the +1 frame, an ORF overlaps with the core protein-coding sequence and encodes the alternative reading frame proteins (ARFP or core+1). ARFP/core+1/F protein could enhance hepatocyte growth and may regulate iron metabolism. In this review, we briefly summarized the current knowledge regarding the production of different core gene products and their roles in viral pathogenesis.
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Cuninghame S, Jackson R, Zehbe I. Hypoxia-inducible factor 1 and its role in viral carcinogenesis. Virology 2014; 456-457:370-83. [PMID: 24698149 DOI: 10.1016/j.virol.2014.02.027] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/17/2014] [Accepted: 02/26/2014] [Indexed: 01/05/2023]
Abstract
The advent of modern molecular biology has allowed for the discovery of several mechanisms by which oncoviruses promote carcinogenesis. Remarkably, nearly all human oncogenic viruses increase levels of the transcription factor hypoxia-inducible factor 1 (HIF-1). In this review, we highlight HIF-1׳s significance in viral oncogenesis, while providing an in-depth analysis of its activation mechanisms by the following oncoviruses: human papillomaviruses (HPVs), hepatitis B/C viruses (HBV/HCVs), Epstein-Barr virus (EBV), Kaposi׳s sarcoma-associated herpes virus (KSHV), and human T-cell lymphotropic virus (HTLV-1). We discuss virus-induced HIF-1׳s role in transcriptional upregulation of metabolic, angiogenic, and microenvironmental factors that are integral for oncogenesis. Admittedly, conclusive evidence is lacking as to whether activation of HIF-1 target genes is necessary for malignant transformation or merely a result thereof. In addition, a complete understanding of host-virus interactions, the effect of viral genomic variation, and the clinical (and potential therapeutic) relevance of HIF-1 in viral oncogenesis warrant further investigation.
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Affiliation(s)
- Sean Cuninghame
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada
| | - Robert Jackson
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada
| | - Ingeborg Zehbe
- Probe Development & Biomarker Exploration, Thunder Bay Regional Research Institute, 980 Oliver Rd, Thunder Bay, Ont., Canada P7B 6V4; Department of Biology, Lakehead University, Thunder Bay, Ont., Canada.
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Escobedo G, Arjona-Román JL, Meléndez-Pérez R, Suárez-Álvarez K, Guzmán C, Aguirre-García J, Gutiérrez-Reyes G, Vivas O, Varela-Fascinetto G, Rodríguez-Romero A, Robles-Díaz G, Kershenobich D. Liver exhibits thermal variations according to the stage of fibrosis progression: A novel use of modulated-differential scanning calorimetry for research in hepatology. Hepatol Res 2013; 43:785-94. [PMID: 23252661 DOI: 10.1111/hepr.12026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Revised: 11/09/2012] [Accepted: 11/13/2012] [Indexed: 02/08/2023]
Abstract
AIM Liver fibrosis results in a disproportion of the hepatic composition and architecture, characterized by a progressive accumulation of fibrillar proteins at the liver parenchyma. Modulated-differential scanning calorimetry (mDSC) is an experimental methodology able to determine the specific thermal signature from any biological substance, based on the variation in heat flow and heat capacity. As these physicochemical properties are directly influenced by compositional and structural changes, we decided to study the thermal behavior of the liver during fibrosis using mDSC. METHODS Liver fibrosis was induced in rats by bile duct ligation or carbon tetrachloride administration. Degree of liver fibrosis was determined by histological examination using the Masson-trichrome stain, accompanied by hepatic expression of α-smooth muscle actin. The thermal analysis was performed in a modulated-differential scanning calorimeter using 20 mg of fresh liver mass. RESULTS The liver showed a characteristic thermal signature in control animals, which progressively differed among mild (F1), moderate (F2) and advanced (F3-F4) liver fibrosis. For heat flow, the hepatic thermal signature from F3-F4 rats exhibited significant differences when compared with F1, F2 and controls. In terms of heat capacity, liver specimens provided a specific thermal signature for each stage of disease, characterized by a transition temperature onset at 95°C for controls, whereas in F1, F2 and F3-F4 animals this temperature significantly decreased to 93°C, 84°C and 75°C, respectively. CONCLUSION Because the liver shows a differential thermal signature according to the degree of fibrosis, mDSC could be a novel tool in the study of liver fibrosis progression.
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Affiliation(s)
- Galileo Escobedo
- Unit of Experimental Medicine, General Hospital of Mexico, México D.F., México; Laboratory for Liver, Pancreas and Motility, Department of Experimental Medicine, School of Medicine, General Hospital of Mexico, México D.F., México
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Arzumanyan A, Reis HMGPV, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer 2013; 13:123-35. [PMID: 23344543 DOI: 10.1038/nrc3449] [Citation(s) in RCA: 611] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.
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Affiliation(s)
- Alla Arzumanyan
- Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA
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Fiorino S, Lorenzini S, Masetti M, Deleonardi G, Grondona AG, Silvestri T, Chili E, Del Prete P, Bacchi-Reggiani L, Cuppini A, Jovine E. Hepatitis B and C virus infections as possible risk factor for pancreatic adenocarcinoma. Med Hypotheses 2012; 79:678-97. [PMID: 22959312 DOI: 10.1016/j.mehy.2012.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2011] [Revised: 07/20/2012] [Accepted: 08/09/2012] [Indexed: 12/14/2022]
Abstract
Pancreatic adenocarcinoma (PAC) is a very aggressive and lethal cancer, with a very poor prognosis, because of absence of early symptoms, advanced stage at presentation, early metastatic dissemination and lack of both specific tests to detect its growth in the initial phases and effective systemic therapies. To date, the causes of PAC still remain largely unknown, but multiple lines of evidence from epidemiological and laboratory researches suggest that about 15-20% of all cancers are linked in some way to chronic infection, in particular it has been shown that several viruses have a role in human carcinogenesis. The purpose of this report is to discuss the hypothesis that two well-known oncogenic viruses, Human B hepatitis (HBV) and Human C hepatitis (HCV) are a possible risk factor for this cancer. Therefore, with the aim to examine the potential link between these viruses and PAC, we performed a selection of observational studies evaluating this association and we hypothesized that some pathogenetic mechanisms involved in liver carcinogenesis might be in common with pancreatic cancer development in patients with serum markers of present or past HBV and HCV infections. To date the available observational studies performed are few, heterogeneous in design as well as in end-points and with not univocal results, nevertheless they might represent the starting-point for future larger and better designed clinical trials to define this hypothesized relationship. Should these further studies confirm an association between HBV/HCV infection and PAC, screening programs might be justified in patients with active or previous hepatitis B and C viral infection.
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Affiliation(s)
- S Fiorino
- Unità Operativa di Medicina Interna, Ospedale di Budrio, Budrio, Bologna, Italy.
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