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Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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Capasso M, Cossiga V, Guarino M, Ranieri L, Morisco F. The Role of Hepatitis Viruses as Drivers of Hepatocancerogenesis. Cancers (Basel) 2024; 16:1505. [PMID: 38672587 PMCID: PMC11048534 DOI: 10.3390/cancers16081505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28-30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer.
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Affiliation(s)
| | - Valentina Cossiga
- Diseases of the Liver and Biliary System Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.G.); (L.R.); (F.M.)
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Bunz M, Eisele M, Hu D, Ritter M, Kammerloher J, Lampl S, Schindler M. CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells. Front Cell Infect Microbiol 2024; 14:1338606. [PMID: 38357447 PMCID: PMC10864554 DOI: 10.3389/fcimb.2024.1338606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024] Open
Abstract
The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout in hepatoma cells. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as a regulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might be relevant for viral persistence and chronic infection.
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Affiliation(s)
- Maximilian Bunz
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Mona Eisele
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Dan Hu
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Michael Ritter
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Julia Kammerloher
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Sandra Lampl
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Michael Schindler
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
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Chavda V, Zajac KK, Gunn JL, Balar P, Khadela A, Vaghela D, Soni S, Ashby CR, Tiwari AK. Ethnic differences in hepatocellular carcinoma prevalence and therapeutic outcomes. Cancer Rep (Hoboken) 2023; 6 Suppl 1:e1821. [PMID: 37344125 PMCID: PMC10440848 DOI: 10.1002/cnr2.1821] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/17/2023] [Accepted: 04/10/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The incidence of HCC is affected by genetic and non-genetic factors. Genetically, mutations in the genes, tumor protein P53 (TP53), catenin beta 1 (CTNNB1), AT-rich interaction domain 1A (ARIC1A), cyclin dependent kinase inhibitor 2A (CDKN2A), mannose 6-phosphate (M6P), smooth muscle action against decapentaplegic (SMAD2), retinoblastoma gene (RB1), cyclin D, antigen presenting cells (APC), AXIN1, and E-cadherin, have been shown to contribute to the occurrence of HCC. Non-genetic factors, including alcohol consumption, exposure to aflatoxin, age, gender, presence of hepatitis B (HBV), hepatitis C (HCV), and non-alcoholic fatty liver disease (NAFLD), increase the risk of HCC. RECENT FINDINGS The severity of the disease and its occurrence vary based on geographical location. Furthermore, men and minorities have been shown to be disproportionately affected by HCC, compared with women and non-minorities. Ethnicity has been reported to significantly affect tumorigenesis and clinical outcomes in patients diagnosed with HCC. Generally, differences in gene expression and/or the presence of comorbid medical diseases affect or influence the progression of HCC. Non-Caucasian HCC patients are significantly more likely to have poorer survival outcomes, compared to their Caucasian counterparts. Finally, there are a number of factors that contribute to the success rate of treatments for HCC. CONCLUSION Assessment and treatment of HCC must be consistent using evidence-based guidelines and standardized outcomes, as well as international clinical practice guidelines for global consensus. Standardizing the assessment approach and method will enable comparison and improvement of liver cancer research through collaboration between researchers, healthcare providers, and advocacy groups. In this review, we will focus on discussing epidemiological factors that result in deviations and changes in treatment approaches for HCC.
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Affiliation(s)
- Vivek Chavda
- Department of Pharmaceutics and Pharmaceutical TechnologyL M College of PharmacyAhmedabadIndia
| | - Kelsee K. Zajac
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
| | - Jenna Lynn Gunn
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
| | - Pankti Balar
- Pharmacy SectionL M College of PharmacyAhmedabadIndia
| | - Avinash Khadela
- Department of PharmacologyL M College of PharmacyAhmedabadIndia
| | - Dixa Vaghela
- Pharmacy SectionL M College of PharmacyAhmedabadIndia
| | - Shruti Soni
- PharmD SectionL M College of PharmacyAhmedabadIndia
| | - Charles R. Ashby
- Department of Pharmaceutical Sciences, College of PharmacySt. John's UniversityNew YorkNew YorkUSA
| | - Amit K. Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
- Department of Cancer Biology, College of Medicine and Life SciencesUniversity of ToledoToledoOhioUSA
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Ikram A, Rauff B, Alzahrani B, Awan FM, Obaid A, Naz A, Kakar SJ, Janjua HA. Integrated analysis to study the interplay between post-translational modifications (PTM) in hepatitis C virus proteins and hepatocellular carcinoma (HCC) development. Sci Rep 2022; 12:15648. [PMID: 36123370 PMCID: PMC9483894 DOI: 10.1038/s41598-022-19854-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 09/06/2022] [Indexed: 02/05/2023] Open
Abstract
Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly affect the generation of infectious virus particles and completion of its life cycle. In this study, we have performed comprehensive analysis of PTMs within HCV non-structural proteins (NS3/4A, NS5A and NS5B) through bioinformatics analysis to examine post-translational crosstalk between phosphorylation, palmitoylation, methylation, acetylation and ubiquitination sites in selected viral proteins. Our analysis has revealed many highly putative PTMs sites that are also conserved among major genotypes conferring the importance of these sites. We have also analysed viral 3D structures in their modified and unmodified forms to address extent and signatures of structural changes upon PTM. This study provides evidence that PTMs induce significant conformational changes and make viral proteins more stable. To find the potential role of PTMs in HCV induced HCC, docking analysis between selected viral proteins and p38-MAPK has been performed which also confirms their strong association with HCV induced HCC. The major findings proposed that PTMs at specific sites of HCV viral proteins could dysregulate specific pathways that cause the development of HCC.
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Affiliation(s)
- Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore, Pakistan.
| | - Bisma Rauff
- Department of Biomedical Engineering, UET Lahore, Narowal campus, Narowal, Pakistan
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka, Saudi Arabia
| | - Faryal Mehwish Awan
- Department of Medical Lab Technology, University of Haripur (UOH), Haripur, Pakistan
| | - Ayesha Obaid
- Department of Medical Lab Technology, University of Haripur (UOH), Haripur, Pakistan
| | - Anam Naz
- Institute of Molecular Biology and Biotechnology (IMBB), University of Lahore (UOL), Lahore, Pakistan
| | - Salik Javed Kakar
- Atta Ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Hussnain Ahmed Janjua
- Atta Ur Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
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Pisaturo M, Di Fraia A, Occhiello L, Minichini C, Starace M, Iodice V, Farella N, Stanzione M, Coppola N. Genetic Variability in Patients with HCV-Related Hepatocellular Carcinoma. Infect Drug Resist 2021; 14:5199-5208. [PMID: 34908854 PMCID: PMC8665876 DOI: 10.2147/idr.s337647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/09/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND The present paper evaluates the genetic variability of HCV in patients with hepatocellular carcinoma (HCC). METHODS Amino acid substitutions (aas) in NS3, NS5A and core regions were analyzed in 17 patients with HCC (Cases) and 13 without HCC (Controls), all naïve to DAAs. For the Cases, a sample of neoplastic liver tissue, non-neoplastic liver tissue and a serum sample were collected; for the Controls, a sample of liver tissue was collected. Sanger sequencing of three regions was performed using homemade protocols. RESULTS Phylogenetic trees showed that there was no difference in the virus populations in the three compartments analyzed for the three HCV regions in patients with HCC. Low variability and no difference between the Cases and Controls were observed in the core and NS5A regions; however, in the NS3 region, a higher variability was observed in the Cases. No difference was observed in the core region between Cases and Controls. In NS3, aa substitutions at positions 103 and 122 were more frequently found in Cases than Controls (in both cases 50% vs 9.1%, p<0.05); moreover, aas in positions 32, 44 (p=0.035 for both), 79 (p=0.008) and 121 (p=0.018) were observed in the Cases and absent in the Controls. Finally, considering the NS5A region, aa substitutions at positions 37 and 54 were more frequently identified in the Cases than the Controls, but without statistical significance. CONCLUSION These data may suggest a higher aa variability in patients with HCC than in those without, especially in the NS3 region.
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Affiliation(s)
- Mariantonietta Pisaturo
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Alessandra Di Fraia
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Laura Occhiello
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Carmine Minichini
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Mario Starace
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | | | - Nunzia Farella
- IX Infectious Disease Unit, AORN dei Colli, Naples, Italy
| | - Maria Stanzione
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
| | - Nicola Coppola
- Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania “L. Vanvitelli”, Naples, Italy
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HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development. Cancers (Basel) 2021; 13:cancers13102485. [PMID: 34069740 PMCID: PMC8161081 DOI: 10.3390/cancers13102485] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary According to the last estimate by the World Health Organization (WHO), more than 71 million individuals have chronic hepatitis C worldwide. The persistence of HCV infection leads to chronic hepatitis, which can evolve into liver cirrhosis and ultimately into hepatocellular carcinoma (HCC). Although the pathogenic mechanisms are not fully understood, it is well established that an interplay between host cell factors, including microRNAs (miRNA), and viral components exist in all the phases of the viral infection and replication. Those interactions establish a complex equilibrium between host cells and HCV and participate in multiple mechanisms characterizing hepatitis C pathogenesis. The present review aims to describe the role of HCV structural and non-structural proteins in the modulation of cellular miRNA during HCV infection and pathogenesis. Abstract Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.
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Khalid J, Umar M, Ur-Rehman T, Ali M, Khan GM. Tumor aggression among hepatitis-C related hepatocellular carcinoma patients: an observational study regarding the impact of anti-HCV therapy. Infect Agent Cancer 2020; 15:35. [PMID: 32508980 PMCID: PMC7251734 DOI: 10.1186/s13027-020-00300-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) represents a major risk factor for hepatocellular carcinoma (HCC) development and anti-HCV therapy is a significant measure to reduce the incidence of HCC, however development of HCC in HCV treated patients is an emerging clinical problem which needs to be investigated. In this study we aim to analyze association between anti-HCV therapy and tumor pattern of HCV related HCC patients. METHODS Hepatocellular Carcinoma (HCC) patients with seropositivity for hepatitis C virus (HCV) antibodies, registered at three tertiary care hospitals of Rawalpindi and Islamabad, Pakistan during August 2017 to July 2018 were enrolled. Selected patients were then segregated in two groups on the basis of their HCV treatment history i.e., "TN" (HCV Treatment Naïve i.e. having no history/medical record for treatment prior to HCC diagnosis) and "TH" (Treated for HCV infection). Aggressiveness index (AgI) scoring system was applied to determine the tumor pattern. Univariate and multivariate analysis was carried out to analyze the independent effect of anti-HCV therapy on tumor pattern. RESULTS Out of 234 consecutive HCC patients, 171 HCV-related HCC patients were enrolled in final analysis and labeled as "TN" (n = 120) and "TH" (n = 51). Tumor pattern was found to be significantly aggressive (P = 0.02) in the treated cohort with an adjusted odds of 2.47 for aggressive and 6.92 for highly aggressive tumor. Neutrophil to lymphocyte ratio (NLR) was strongly associated with highly aggressive tumor pattern (P = 0.012). Patients in TN group were found to be marginally older than those in the TH group (59.5 vs. 55 years) where mean age of the patients treated with direct acting anti-viral agents was found to be visibly lower than mean age of patients who received interferon based treatment (53.5 vs. 57 years) with significant masculine predominance (62.1 vs. 37.9%, P = 0.049). CONCLUSION We observed raised neutrophil to lymphocyte ratio and prominence of younger age with aggressive tumor biology in HCV treated HCC patients. These observations highlight the need for a longitudinal prospective study on HCV positive subjects treated with antivirals, irrespective of treatment response.
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Affiliation(s)
- Javeria Khalid
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
- Clinical Pharmacist at Shifa International Hospital Islamabad, Islamabad, Pakistan
| | - Mohammad Umar
- Center for Liver and Digestive Diseases, Holy Family Hospital, Rawalpindi Medical University, Rawalpindiand, 46300 Pakistan
| | - Tofeeq Ur-Rehman
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
| | - Mashhood Ali
- Gasteroenterology Department, Pakistan Institute of Medical Sciences (PIMS) Hospital, Islamabad, 44000 Pakistan
| | - Gul Majid Khan
- Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320 Pakistan
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Sorbo MC, Carioti L, Bellocchi MC, Antonucci F, Sforza D, Lenci I, Ciancio Manuelli M, Armenia D, De Leonardis F, Milana M, Manzia TM, Angelico M, Tisone G, Cento V, Perno CF, Ceccherini-Silberstein F. HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma. Liver Int 2019; 39:1986-1998. [PMID: 31172639 DOI: 10.1111/liv.14168] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. METHODS Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. RESULTS At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. CONCLUSIONS Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.
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Affiliation(s)
- Maria C Sorbo
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Luca Carioti
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Maria C Bellocchi
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - FrancescoPaolo Antonucci
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Daniele Sforza
- Hepatobiliary and Transplant Unit, Department of Surgery, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Ilaria Lenci
- Hepatology Unit, Department of Systems Medicine, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Matteo Ciancio Manuelli
- Hepatobiliary and Transplant Unit, Department of Surgery, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Daniele Armenia
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Francesco De Leonardis
- Hepatology Unit, Department of Systems Medicine, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Martina Milana
- Hepatology Unit, Department of Systems Medicine, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Tommaso M Manzia
- Hepatobiliary and Transplant Unit, Department of Surgery, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Mario Angelico
- Hepatology Unit, Department of Systems Medicine, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Giuseppe Tisone
- Hepatobiliary and Transplant Unit, Department of Surgery, Policlinico Tor Vergata/Tor Vergata University, Rome, Italy
| | - Valeria Cento
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo F Perno
- Chair of Virology, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
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10
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Sghaier I, Brochot E, Loueslati BY, Almawi WY. Hepatitis C virus protein interaction network for HCV clearance and association of DAA to HCC occurrence via data mining approach: A systematic review and critical analysis. Rev Med Virol 2019; 29:e2033. [PMID: 30614131 DOI: 10.1002/rmv.2033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 12/23/2022]
Abstract
HCV has been associated with a pro-inflammatory state, which predisposes to hepatocellular carcinoma (HCC). However, the different molecular mechanisms underlying the effect of HCV infection on HCC progression remain unclear. Although HCV infection illustrates the potential role of host genetics in the outcome of infectious diseases, there is no clear overview of some single nucleotide polymorphisms (SNPs) influencing spontaneous or treatment-induced HCV eradication. We studied the possible role of HCV infection in the processes of HCC initiation and performed a systematic analysis using data mining approaches to identify host polymorphisms associated with treatment response and HCC development using topological analysis of protein-proteins interactions (PPI) networks. On the basis of our analysis performed, we identified key hub proteins related to HCV-treatment response infection and to HCC development. Host genetic polymorphisms, such as inosine triphosphatase (ITPA), interferon, lambda 3 (IFNL3), Q5 interferon, lambda 4 (IFNL4), toll-like receptors (TLRs) and interferon-stimulated gene 15 (ISG-15), were identified as key genes for treatment prediction and HCC evolution. By comparing unique genes for HCV-treatment response and genes particular to HCV-HCC development, we found a common PPI network that may participate in more extensive signalling processes during anti-HCV treatment, which can play important roles in modulating the immune response to the occurrence of HCC. Data mining is an effective tool for identifying potential regulatory pathways involved in treatment response and HCC development. Our study may contribute to a better understanding of HCV immunopathogenesis and highlights the complex role of host genetics in HCV clearance.
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Affiliation(s)
- Ikram Sghaier
- University of Tunis El Manar, Biology department, Tunish, Tunisia
| | - Etienne Brochot
- Department of Virology, Amiens University Medical Centre, Amiens, France.,Virology Research Unit, EA 4294, Jules Verne University of Picardie, Amiens, France
| | - Besma Y Loueslati
- Faculty of Sciences of Tunis, department of Biology, Laboratory of Mycology, Pathologies and Biomarkers, Tunis, Tunisia
| | - Wassim Y Almawi
- University of Tunis El Manar, Biology department, Tunish, Tunisia.,School of Medicine, Nazarbayev University, Astana, Kazakhstan
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11
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Schietroma I, Scheri GC, Pinacchio C, Statzu M, Petruzziello A, Vullo V. Hepatitis C Virus and Hepatocellular Carcinoma: Pathogenetic Mechanisms and Impact of Direct-Acting Antivirals. Open Virol J 2018; 12:16-25. [PMID: 29541275 PMCID: PMC5842384 DOI: 10.2174/1874357901812010016] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 09/26/2017] [Accepted: 02/02/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Globally, between 64 and 103 million people are chronically infected with Hepatitis C virus (HCV), with more than 4.6 million people in the United States and is associated with more than 15.000 deaths annually. Chronic infection can result in cirrhosis and hepatocellular carcinoma. EXPLANATION Epidemiological studies have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC), mainly through chronic inflammation, cell deaths, and proliferation. Despite the new direct-acting antiviral drugs (DAA's) being able to clear the HCV, HCC recurrence rate in these patients is still observed. CONCLUSION In this review we highlighted some aspects that could be involved in the onset of HCV-induced HCC such as immune system, viral factors and host genetics factors.Moreover, we focused on some of the last reports about the effects of DAA's on the HCV clearance and their potential implications in HCC recurrence.
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Affiliation(s)
- Ivan Schietroma
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy
| | - Giuseppe Corano Scheri
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy
| | - Claudia Pinacchio
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy
| | - Maura Statzu
- Department of Molecular Medicine, Laboratory of Virology, “Sapienza” University of Rome, Rome, Italy
| | - Arnolfo Petruzziello
- Virology and Molecular Biology Unit, Department of Diagnostic Pathology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy
| | - Vincenzo Vullo
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy
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12
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Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017; 9:1305-1314. [PMID: 29359013 PMCID: PMC5756719 DOI: 10.4254/wjh.v9.i36.1305] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/08/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.
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Affiliation(s)
- Mohammad Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Priyanka Gupta
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Khushboo Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
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13
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Kasprzak A, Rogacki K, Adamek A, Sterzyńska K, Przybyszewska W, Seraszek-Jaros A, Helak-Łapaj C, Pyda P. Tissue expression of β-catenin and E- and N-cadherins in chronic hepatitis C and hepatocellular carcinoma. Arch Med Sci 2017; 13:1269-1280. [PMID: 29181057 PMCID: PMC5701691 DOI: 10.5114/aoms.2017.65272] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 09/26/2016] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION The role of Wnt/ β -catenin signaling pathway in HCV-associated hepatocellular carcinogenesis is still unknown. MATERIAL AND METHODS This study aimed to perform quantitative analysis of immuno- and hybridocytochemical expression of β -catenin, E- and N-cadherins and HCV proteins (C, NS3, NS5A) in long-lasting (≥ 20 years) chronic hepatitis C (CH-C) (n = 54), hepatocellular carcinoma (HCC) (n = 61), and control liver samples (n = 8). RESULTS Typical membranous expression of β -catenin in the control liver was higher than in the CH-C and HCC (p = 0.06). The mean β -catenin tissue expression in CH-C was similar to controls, and significantly higher than that of HCC (p = 0.005). E-cadherin expression was lower in CH-C than in the control (p = 0.045) and HCC (p < 0.001). In HCC both β -catenin and E-cadherin expressions were significantly lower in comparison to controls (p = 0.02, p = 0.001, respectively). Positive correlations were found between β -catenin and E-cadherin (in CH-C and HCC), β -catenin and N-cadherin (HCC), E- and N-cadherins expressions (HCC) (p < 0.05 in all cases). In CH-C the positive correlation was demonstrated between NS5A protein and β -catenin, and between the all HCV proteins (C, NS3, NS5A) and E-cadherin expression (p < 0.05 in all cases). CONCLUSIONS Alterations in cellular locations of β -catenin and E-cadherin in CH-C and HCC pointed to structural disturbances in intercellular junctions in the livers and presence of the transcriptionally inactive form of β -catenin. The reduced expression of E-cadherin in long-lasting CH-C may represent an early indicator of the epithelial-mesenchymal transition. The most important role in modulation of the Wnt/ β -catenin pathway in vivo is probably played by the NS5A viral protein.
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Affiliation(s)
- Aldona Kasprzak
- Chair and Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Karol Rogacki
- Chair and Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Agnieszka Adamek
- Chair and Department of Infectious Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Karolina Sterzyńska
- Chair and Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Wiesława Przybyszewska
- Chair and Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland
| | - Agnieszka Seraszek-Jaros
- Department of Bioinformatics and Computational Biology, Chair of Clinical Pathomorphology, Poznan University of Medical Sciences, Poznan, Poland
| | - Celina Helak-Łapaj
- Department of Bioinformatics and Computational Biology, Chair of Clinical Pathomorphology, Poznan University of Medical Sciences, Poznan, Poland
| | - Przemysław Pyda
- Chair and Department of General Surgery, Oncologic Gastroenterological Surgery and Plastic Surgery, Poznan University of Medical Sciences, Poznan, Poland
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14
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Masalova OV, Lesnova EI, Samokhvalov EI, Permyakova KY, Ivanov AV, Kochetkov SN, Kushch AA. Low-molecular-weight regulators of biogenic polyamine metabolism affect cytokine production and expression of hepatitis С virus proteins in Huh7.5 human hepatocarcinoma cells. Mol Biol 2017; 51:453-464. [DOI: 10.1134/s0026893317030128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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15
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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16
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Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 2016; 20:1-10. [PMID: 27504999 DOI: 10.1016/j.coviro.2016.07.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 07/20/2016] [Accepted: 07/20/2016] [Indexed: 12/13/2022]
Abstract
Globally, over half a billion people are persistently infected with hepatitis B (HBV) and/or hepatitis C viruses. Chronic HBV and HCV infection frequently lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Co-infections with hepatitis delta virus (HDV), a subviral satellite requiring HBV for its propagation, accelerates the progression of liver disease toward HCC. The mechanisms by which these viruses cause malignant transformation, culminating in HCC, remain incompletely understood, partially due to the lack of adequate experimental models for dissecting these complex disease processes in vivo.
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17
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Ng KJ, Tseng CW, Chang TT, Tzeng SJ, Hsieh YH, Hung TH, Huang HT, Wu SF, Tseng KC. Aspartate aminotransferase to platelet ratio index and sustained virologic response are associated with progression from hepatitis C associated liver cirrhosis to hepatocellular carcinoma after treatment with pegylated interferon plus ribavirin. Clin Interv Aging 2016; 11:1035-41. [PMID: 27536084 PMCID: PMC4976814 DOI: 10.2147/cia.s108589] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the clinically significant predictors of hepatocellular carcinoma (HCC) development among hepatitis C virus (HCV) cirrhotic patients receiving combination therapy. PATIENTS AND METHODS One hundred and five compensated cirrhosis patients who received pegylated interferon plus ribavirin between January 2005 and December 2011 were enrolled. All the patients were examined with abdominal sonography and liver biochemistry at baseline, end of treatment, and every 3-6 months posttreatment. The occurrence of HCC was evaluated every 3-6 months posttreatment. RESULTS A total of 105 patients were enrolled (mean age 58.3±10.4 years). The average follow-up time for each patient was 4.38 years (standard deviation 1.73 years; range 1.13-9.27 years). Fifteen (14.3%) patients developed HCC during follow-up period. Thirteen of them had high baseline aspartate aminotransferase to platelet ratio index (APRI) (ie, an APRI >2.0). Multivariate analysis showed that those without sustained virologic response (SVR) (hazard ratio [HR] 5.795; 95% confidence interval [CI] 1.370-24.5; P=0.017) and high APRI (HR 5.548; 95% CI 1.191-25.86; P=0.029) had a significantly higher risk of HCC occurrence. The cumulative incidence of HCC was significantly higher (P=0.009) in patients without SVR (3-year cumulative incidence 21.4%; 95% CI 7.4%-35.5%; 5-year cumulative incidence 31.1%; 95% CI 11.2%-51.1%) compared to those with SVR (3- and 5-year cumulative incidence 6.2%; 95% CI 0%-1.3%). Further, the cumulative incidence of HCC was significantly higher (P=0.006) in patients with high APRI (3-year cumulative incidence 21.8%; 95% CI 8.2%-35.3%; 5-year cumulative incidence 30.5%, 95% CI 11.8%-49.3%) compared to those with low APRI (3- and 5-year cumulative incidence 4.2%, 95% CI 0%-1.0%). CONCLUSION In HCV-infected cirrhotic patients who received combination therapy, APRI and SVR are the two major predictors of HCC development.
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Affiliation(s)
- Khai-Jing Ng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi; School of Medicine, Tzu Chi University, Hualien
| | - Chih-Wei Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi; School of Medicine, Tzu Chi University, Hualien; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei; School of Medicine, National Yang-Ming University, Taipei
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan; Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan
| | | | - Yu-Hsi Hsieh
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi; School of Medicine, Tzu Chi University, Hualien
| | - Tsung-Hsing Hung
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi; School of Medicine, Tzu Chi University, Hualien
| | - Hsiang-Ting Huang
- Department of Nursing, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi
| | - Shu-Fen Wu
- Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan
| | - Kuo-Chih Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi; School of Medicine, Tzu Chi University, Hualien
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18
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Tornesello ML, Buonaguro L, Izzo F, Buonaguro FM. Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections. Oncotarget 2016; 7:25087-25102. [PMID: 26943571 PMCID: PMC5041890 DOI: 10.18632/oncotarget.7837] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 02/20/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches.
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Affiliation(s)
- Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Luigi Buonaguro
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Francesco Izzo
- Hepato-Biliary Surgery Department, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
| | - Franco M. Buonaguro
- Molecular Biology and Viral Oncology Unit, Department of Research, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy
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19
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Masalova OV, Lesnova EI, Permyakova KY, Samokhvalov EI, Ivanov AV, Kochetkov SN, Kushch AA. Effect of Hepatitis C virus proteins on the production of proinflammatory and profibrotic cytokines in Huh7.5 human hepatoma cells. Mol Biol 2016; 50:422-430. [DOI: 10.1134/s0026893316020163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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20
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Han B, Dvory-Sobol H, Greenstein A, McCarville JF, Hung M, Liu X, Miller MD, Mo H. Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate. J Virol Methods 2015; 225:76-86. [PMID: 26391876 DOI: 10.1016/j.jviromet.2015.09.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 09/01/2015] [Accepted: 09/06/2015] [Indexed: 02/06/2023]
Abstract
The hepatitis C virus (HCV) NS3/4A protease is a key target of efforts to develop direct-acting antiviral inhibitors for treatment of chronic HCV infection. In vitro analyses of the effects of NS3/4A mutations and polymorphisms on protease inhibitor (PI) susceptibility are essential to nonclinical and clinical compound characterization, but can be hampered by time and technical limitations of current in vitro methods using replicon or purified protein systems. We have developed a fast and simple method utilizing full-length NS3/4A protease inducibly expressed in Escherichia coli cells. Minimally processed E. coli whole cell lysate was used for analyzing NS3/4A protease activity and inhibition by antiviral compounds. Assay conditions were optimized to develop a reproducible assay that can be used for efficient analysis of NS3 protease mutants with poor replication capacity in the replicon system. IC50 fold-changes for NS3 mutants relative to their wild-types generated by this NS3 assay are comparable to those observed in the replicon system, with an R(2) of 0.82 for the values obtained by the two methods. In addition, we demonstrate that this assay can be successfully used for population and clonal phenotyping of patient samples and characterization of PIs against the NS3/4A protease from HCV genotypes 1-6.
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Affiliation(s)
- Bin Han
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
| | | | | | | | - Magdeleine Hung
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
| | - Xiaohong Liu
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
| | | | - Hongmei Mo
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
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21
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Al-Kubaisy WAAQ, Obaid KJ, Noor NAM, Ibrahim NSBN, Al-Azawi AAK. Hepatitis C virus prevalence and genotyping among hepatocellular carcinoma patients in Baghdad. Asian Pac J Cancer Prev 2015; 15:7725-30. [PMID: 25292053 DOI: 10.7314/apjcp.2014.15.18.7725] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause for cancer death in the world, now being especially linked to chronic hepatitis C virus (HCV) infection. This case-control study consisting of 65 HCC patients and 82 patients with other malignant tumours as controls was conducted to determine the association of HCV markers with HCC. Serum of each participant was obtained for detection of HCV Ab and RNA by DNA enzyme immunoassay (DEIA). Twenty six per cent (26.0%) of HCC patients had positive anti-HCV which was significantly greater than the control group (p=0.001). HCC patients significantly have a risk of exposure to HCV infection almost 3 times than the control group (OR=2.87, 95% C.I=1.1-7). Anti-HCV seropositive rate was significantly (p=0.03) higher among old age HCC patients and increases with age. Males with HCC significantly showed to have more than 9 times risk of exposure to HCV infection (OR=9.375, 95 % CI=1.299-67.647) than females. HCV-RNA seropositive rate was (70.8%) significantly higher among HCC patients compared to (22.2%) the control group (p=0.019). The most prevalent genotype (as a single or mixed pattern of infection) was HCV- 1b. This study detected a significantly higher HCV seropositive rate of antibodies and RNA in HCC patients.
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22
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Au TH, Destache CJ, Vivekanandan R. Hepatitis C therapy: Looking toward interferon-sparing regimens. J Am Pharm Assoc (2003) 2015; 55:e72-84; quiz e85-6. [DOI: 10.1331/japha.2015.15508] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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Wu JQ, Saksena MM, Soriano V, Vispo E, Saksena NK. Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs. Virol J 2015; 12:4. [PMID: 25623235 PMCID: PMC4312599 DOI: 10.1186/s12985-014-0236-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 12/30/2014] [Indexed: 01/01/2023] Open
Abstract
Background Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups. Methods Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection. Results Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively. Conclusions Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation. Electronic supplementary material The online version of this article (doi:10.1186/s12985-014-0236-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jing Qin Wu
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, Newcastle, NSW, 2308, Australia.
| | - Monica Miranda Saksena
- Herpes Virus Pathogenesis Lab, Center for Virus Research, Westmead Millennium Institute, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.
| | - Vincent Soriano
- Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain.
| | - Eugenia Vispo
- Department of Infectious Diseases, Hospital Carlos III, Sinesio Delgado 10, 28029, Madrid, Spain.
| | - Nitin K Saksena
- Retroviral Genetics Division, Center for Virus Research, Westmead Millennium Institute & Westmead Hospital, University of Sydney, Westmead, Sydney, NSW, 2145, Australia.
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Dubois-Pot-Schneider H, Fekir K, Coulouarn C, Glaise D, Aninat C, Jarnouen K, Le Guével R, Kubo T, Ishida S, Morel F, Corlu A. Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells. Hepatology 2014; 60:2077-2090. [PMID: 25098666 DOI: 10.1002/hep.27353] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 08/01/2014] [Indexed: 01/05/2023]
Abstract
UNLABELLED Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and resistance to therapies. Recent studies have reported that HCC may be derived not only from adult hepatocytes and hepatoblasts but also hepatic stem/progenitors. In this context, HepaRG cells may represent a suitable cellular model to study stem/progenitor cancer cells and the retrodifferentiation of tumor-derived hepatocyte-like cells. Indeed, they differentiate into hepatocyte- and biliary-like cells. Moreover, tumor-derived HepaRG hepatocyte-like cells (HepaRG-tdHep) differentiate into both hepatocyte- and biliary-like cells through a hepatic progenitor. In this study we report the mechanisms and molecular effectors involved in the retrodifferentiation of HepaRG-tdHep into bipotent progenitors. Gene expression profiling was used to identify genomic changes during the retrodifferentiation of HepaRG-tdHep into progenitors. We demonstrated that gene expression signatures related to a poor-prognosis HCC subclass, proliferative progenitors, or embryonic stem cells were significantly enriched in HepaRG progenitors derived from HepaRG-tdHep. HepaRG-tdHep retrodifferentiation is mediated by crosstalk between transforming growth factor beta 1 (TGFβ1) and inflammatory cytokine pathways (e.g., tumor necrosis factor alpha [TNFα] and interleukin 6 [IL6]). Signatures related to TNFα, IL6, and TGFβ activation pathways are induced within the first hour of retrodifferentiation. Moreover, specific activation or inhibition of these signaling pathways allowed us to determine that TNFα and IL6 contribute to the loss of hepatic-specific marker expression and that TGFβ1 induces an epithelial-to-mesenchymal transition of HepaRG-tdHep. Interestingly, the retrodifferentiation process is blocked by the histone deacetylase inhibitor trichostatin A, opening new therapeutic opportunities. CONCLUSION Cancer progenitor cells (or metastasis progenitors) may derive from tumor-derived hepatocyte-like cells in an inflammatory environment that is frequently associated with HCC.
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Affiliation(s)
- Hélène Dubois-Pot-Schneider
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033, Rennes, France; Université de Rennes 1, F-35043, Rennes, France
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Hassan M, Selimovic D, El-Khattouti A, Soell M, Ghozlan H, Haikel Y, Abdelkader O, Megahed M. Hepatitis C virus-mediated angiogenesis: Molecular mechanisms and therapeutic strategies. World J Gastroenterol 2014; 20:15467-15475. [PMID: 25400432 PMCID: PMC4229513 DOI: 10.3748/wjg.v20.i42.15467] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis is an essential process for organ growth and repair. Thus, an imbalance in this process can lead to several diseases including malignancy. Angiogenesis is a critical step in vascular remodeling, tissue damage and wound healing besides being required for invasive tumor growth and metastasis. Because angiogenesis sets an important point in the control of tumor progression, its inhibition is considered a valuable therapeutic approach for tumor treatment. Chronic liver disease including hepatitis C virus (HCV) infection is one of the main cause for the development of hepatic angiogenesis and thereby plays a critical role in the modulation of hepatic angiogenesis that finally leads to hepatocellular carcinoma progression and invasion. Thus, understanding of the molecular mechanisms of HCV-mediated hepatic angiogenesis will help design a therapeutic protocol for the intervention of HCV-mediated angiogenesis and subsequently its outcome. In this review, we will focus on the molecular mechanisms of HCV-mediated hepatic angiogenesis and the related signaling pathways that can be target for current and under development therapeutic approaches.
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Herzer K, Gerken G, Hofmann TG. Hepatitis C-associated liver carcinogenesis: Role of PML nuclear bodies. World J Gastroenterol 2014; 20:12367-12371. [PMID: 25253937 PMCID: PMC4168070 DOI: 10.3748/wjg.v20.i35.12367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/31/2013] [Accepted: 07/25/2014] [Indexed: 02/06/2023] Open
Abstract
Successful escape from immune response characterises chronic hepatitis C virus (HCV) infection, which results in persistence of infection in about 80% of the patients. The deleterious consequences are cirrhosis and hepatocellular carcinoma. HCV accounts the most frequent cause for hepatocellular carcinoma (HCC) and liver transplantation (LT) in the western world. The underlying molecular mechanisms how HCV promotes tumor development are largely unknown. There is some in vitro and in vivo evidence that HCV interferes with the tumor suppressor PML and may thereby importantly contribute to the HCV-associated pathogenesis with respect to the development of HCC. The tumor suppressor protein “promyelocytic leukemia” (PML) has been implicated in the regulation of important cellular processes like differentiation and apoptosis. In cancer biology, PML and its associated nuclear bodies (NBs) have initially attracted intense interest due to its role in the pathogenesis of acute promyelocytic leukemia (APL). More recently, loss of PML has been implicated in human cancers of various histologic origins. Moreover, number and intensity of PML-NBs increase in response to interferons (IFNs) and there is evidence that PML-NBs may represent preferential targets in viral infections. Thus, PML could not only play a role in the mechanisms of the antiviral action of IFNs but may also be involved in a direct oncogenic effect of the HCV on hepatocytes. This review aims to summarise current knowledge about HCV-related liver carcinogenesis and to discuss a potential role of the nuclear body protein PML for this this hard-to-treat cancer.
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Interaction of Hepatitis C Viral Proteins with Cellular Oncoproteins in the Induction of Liver Cancer. ACTA ACUST UNITED AC 2014. [DOI: 10.1155/2014/351407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Hepatitis C virus infection is a major health problem all over the world. A large proportion of patients infected by HCV develop liver cirrhosis or cancer. However, the mechanism(s) remain to be elucidated. Since HCV does not carry any known oncogene, it is thought that interaction between virally encoded proteins and host proteins is responsible for carcinogenesis. Many crucial interactions between HCV-encoded proteins and host proteins have been reported. In this review we focus on the interaction of viral proteins with important regulators of cell cycle—oncoproteins YB-1, p53, and cyclin D1—which play a major role in cell proliferation, apoptosis, DNA repair, and genomic stability. Genetic variants of HCV accumulate in patients and alter these interactions of host cell proteins. It is a battle between the virus and host and the final outcome depends on the winner; if the host succeeds in clearing the virus the patient may not develop serious liver diseases. On the other hand, if the virus dominates by evolving quasispecies which code for altered proteins that interact differently with host proteins, or induce mutations in host protooncogenes, then the patient may develop liver cirrhosis and/or liver cancer.
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Using Proteomics to Unravel the Mysterious Steps of the HBV-Life-Cycle. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 806:453-81. [PMID: 24952197 DOI: 10.1007/978-3-319-06068-2_22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Testino G, Borro P. Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis. World J Hepatol 2013; 5:521-527. [PMID: 24179611 PMCID: PMC3812454 DOI: 10.4254/wjh.v5.i10.521] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 09/18/2013] [Indexed: 02/06/2023] Open
Abstract
Interferon (IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma (HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus (HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer. Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated (PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.
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Tornesello ML, Buonaguro L, Tatangelo F, Botti G, Izzo F, Buonaguro FM. Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics 2013; 102:74-83. [PMID: 23583669 DOI: 10.1016/j.ygeno.2013.04.001] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 03/28/2013] [Accepted: 04/03/2013] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Hepatocarcinogenesis is a multistep process mainly associated with persistent infection with hepatitis B (HBV) or C (HCV) viruses and always involving the accumulation of genetic alterations over decades of chronic liver disease. Mutations in TP53 and CTNNB1 genes are considered the cancer drivers for HCC development with variable frequencies depending on the etiology. Here we present a comprehensive review evaluating somatic mutations in TP53 and CTNNB1 genes in HBV- and HCV-related HCCs. Moreover, we report the mutational analysis of TP53 (exons 4-9) and CTNNB1 (exon 3) as well as PIK3CA (exon 9) genes in HCC from Southern Italy. The overall mutation frequency of TP53 and CTNNB1 was 33.3%, while hotspot variations in PIK3CA were completely absent. CTNNB1 mutations were significantly associated with young age (P=0.019) and moderately/poorly differentiated HCV-related HCC (P=0.015). The extended analysis of genetic alterations will help to identify molecular markers for liver cancer prevention, diagnosis and treatment of HBV and HCV-associated liver cancer.
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Affiliation(s)
- Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Department of Experimental Oncology, National Cancer Institute, Fond. Pascale, Naples, Italy.
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