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Lei W, Zhou K, Lei Y, Li Q, Zhu H. Pathogenesis and Systemic Treatment of Hepatocellular Carcinoma: Current Status and Prospects. Mol Cancer Ther 2025; 24:692-708. [PMID: 39417575 DOI: 10.1158/1535-7163.mct-24-0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/14/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Hepatocellular carcinoma (HCC) remains one of the major threats to human health worldwide. The emergence of systemic therapeutic options has greatly improved the prognosis of patients with HCC, particularly those with advanced stages of the disease. In this review, we discussed the pathogenesis of HCC, genetic alterations associated with the development of HCC, and alterations in the tumor immune microenvironment. Then, important indicators and emerging technologies related to the diagnosis of HCC are summarized. Also, we reviewed the major advances in treatments for HCC, offering insights into future prospects for next-generation managements.
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Affiliation(s)
- Wanting Lei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kexun Zhou
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Lei
- College of Liberal Arts, Neijiang Normal University, Neijiang, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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2
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Gupta J, Mohammed MH, Alghazali T, Uthirapathy S, R R, Thakur V, Kaur M, Naidu KS, Kubaev A, Al-Mukhtar MM. Inflammasomes and autophagy in cancer: unlocking targeted therapies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04184-x. [PMID: 40310530 DOI: 10.1007/s00210-025-04184-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/13/2025] [Indexed: 05/02/2025]
Abstract
This study clarifies the interaction between autophagy and inflammasome within the cancer framework. The inflammasome generates pro-inflammatory cytokines to direct the immune response to pathogens and cellular stressors. Autophagy maintains cellular homeostasis and can either promote or inhibit cancer. These pathways interact to affect tumorigenesis, immune responses, and therapy. Autophagy controls inflammasome activity by affecting cancer pathogenesis and tumor microenvironment inflammation, highlighting novel cancer therapeutic approaches. Recent studies indicate that modulating autophagy and inflammasome pathways can boost anti-cancer immunity, reduce drug-resistance, and improve therapeutic efficacy. Recent studies indicate modulating inflammasome and autophagy pathways can augment anti-cancer immunity, mitigate therapy resistance, and improve treatment efficacy. Cancer research relies on understanding the inflammasome-autophagy relationship to develop targeted therapies that enhance anti-tumor efficacy and reduce inflammatory symptoms. Customized therapies may improve outcomes based on autophagy gene variations and inflammasome polymorphisms. This study investigates autophagy pathways and the inflammasome in tumor immunopathogenesis, cytokine function, and cancer therapeutic strategies, highlighting their significance in cancer biology and treatment.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Pin Code 281406, U.P., India.
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-Maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Roopashree R
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Vishal Thakur
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Manpreet Kaur
- Department of Pharmacy, Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra, Pradesh- 531162, India
| | - Aziz Kubaev
- Department of Maxillofacial Surgery, Samarkand State Medical University, 18 Amir Temur Street, 140100, Samarkand, Uzbekistan
| | - Mahmoud Mussleh Al-Mukhtar
- Anesthesia Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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Ishaq Y, Rauff B, Alzahrani B, Ikram A, Javed H, Abdullah I, Mujtaba G. Bioinformatics and Experimental Insights Into miR-182, hsa_circ_0070269, and circ-102,166 as Therapeutic Targets for HCV-Associated HCC. Cancer Rep (Hoboken) 2024; 7:e70049. [PMID: 39617640 PMCID: PMC11608829 DOI: 10.1002/cnr2.70049] [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: 05/09/2024] [Revised: 09/28/2024] [Accepted: 10/03/2024] [Indexed: 01/05/2025] Open
Abstract
AIMS Hepatocellular carcinoma (HCC) is a type of malignant tumor and the sixth leading cause of death worldwide. It is caused by HBV, HCV infection, and alcohol consumption. MicroRNAs are typically small, non-coding RNAs that are involved in the regulation of mRNA expression. Recent studies revealed miRNAs' regulatory roles in liver cancer, linked to risk factors like HCV, HBV infection, alcoholism, drug use, and auto-immune hepatic disorders. Circular RNAs also belong to the class of non-coding RNAs; they act as ceRNAs to regulate miRNA expression and regulate different oncogenic pathways in HCC progression. This study aimed to check the hsa_circ_0070269, circ-102,166 (hsa_circ_0004913), and miR-182 expression in HCV induced HCC patients. METHODS Data analysis was used to find out studies related to the role of hsa_circ_0070269, circ-102,166, and miR-182 in HCC; miR-182 targeted genes, their role in different diseases; and miR-182 interactions with hsa_circ_0070269 and circ-102,166 in the HCC. It was revealed that the hsa_circ_0070269, circ-102,166, and miR-182 correlations in HCV induced HCC have not been explored yet. Therefore, to validate data from literature mining, expression analysis of dysregulated hsa_circ_0070269, circ-102,166, and miR-182 was performed in HCV induced HCC patients using RT-PCR. RESULTS It was found that miR-182 was significantly upregulated and acts as an oncomiRNA in HCV induced HCC, and hsa_circ_0070269 and circ-102,166 were downregulated in HCV induced HCC. We have identified that miR-182 relative expression level was significantly high (p < 0.0029), while has_circ_0070269 (p < 0.002) and circ-102,166 (p < 0.002) were significantly downregulated in HCV-HCC patients as compared to expression in healthy individuals. CONCLUSION Our data revealed that miR-182 acts as an oncomiRNA in HCC development. Hsa_circ_0070269 and circ-102,166 are highly expressed in healthy controls compared to HCV induced HCC patients, can sponge miR-182 expression by acting as tumor suppressors, and can be used as biomarkers and targets for HCC treatment.
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Affiliation(s)
- Yasmeen Ishaq
- Institute of Molecular Biology and Biotechnology (IMBB)University of Lahore (UOL)LahorePakistan
| | - Bisma Rauff
- Department of Biomedical EngineeringUET LahoreNarowalPakistan
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical SciencesJouf UniversitySakakaSaudi Arabia
| | - Aqsa Ikram
- Institute of Molecular Biology and Biotechnology (IMBB)University of Lahore (UOL)LahorePakistan
| | - Hasnain Javed
- Provincial Public Health reference lab LahorePunjab AIDS Control ProgramLahorePakistan
| | - Imran Abdullah
- Institute of Nuclear Medicine & Oncology (INMOL) Cancer HospitalLahorePakistan
| | - Ghulam Mujtaba
- Institute of Nuclear Medicine & Oncology (INMOL) Cancer HospitalLahorePakistan
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4
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Liu H, Zhang J, Rao Y, Jin S, Zhang C, Bai D. Intratumoral microbiota: an emerging force in diagnosing and treating hepatocellular carcinoma. Med Oncol 2024; 41:300. [PMID: 39453562 DOI: 10.1007/s12032-024-02545-9] [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: 09/12/2024] [Accepted: 10/17/2024] [Indexed: 10/26/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer in the world and its incidence and mortality are increasing year by year, frequently diagnosed at an advanced stage. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited efficacy, so new diagnostic and treatment strategies are urgently needed. Recent research has discovered that intratumoral microbiota significantly influences the development, progression, and metastasis of HCC by modulating inflammation, immune responses, and cellular signaling pathways. Intratumoral microbiota contributes to the pathologic process of HCC by influencing the tumor microenvironment and altering the function of immune system. This article reviews the mechanism of intratumoral microbiota in HCC and anticipates the future possibilities of intratumoral microbiota-based therapeutic strategies for HCC management. This emerging field provides fresh insights into early diagnosis and personalized approaches for HCC while holding substantial clinical application potential to improve patient outcomes and tailor interventions to individual tumor profiles.
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Affiliation(s)
- Huanxiang Liu
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Jiahao Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Yuye Rao
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China.
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China.
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Echevarria-Lima J, Moles R. Monocyte and Macrophage Functions in Oncogenic Viral Infections. Viruses 2024; 16:1612. [PMID: 39459945 PMCID: PMC11512331 DOI: 10.3390/v16101612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Monocytes and macrophages are part of innate immunity and constitute the first line of defense against pathogens. Bone marrow-derived monocytes circulate in the bloodstream for one to three days and then typically migrate into tissues, where they differentiate into macrophages. Circulatory monocytes represent 5% of the nucleated cells in normal adult blood. Following differentiation, macrophages are distributed into various tissues and organs to take residence and maintain body homeostasis. Emerging evidence has highlighted the critical role of monocytes/macrophages in oncogenic viral infections, mainly their crucial functions in viral persistence and disease progression. These findings open opportunities to target innate immunity in the context of oncogenic viruses and to explore their potential as immunotherapies.
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Affiliation(s)
- Juliana Echevarria-Lima
- Laboratório de Imunologia Básica e Aplicada, Department of Immunology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil;
| | - Ramona Moles
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Center for Immunology and Microbial Research, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Gedallovich SM, Kwo PY. Reply to correspondence on "Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy". Clin Mol Hepatol 2024; 30:1050-1052. [PMID: 38993076 PMCID: PMC11540377 DOI: 10.3350/cmh.2024.0546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/13/2024] Open
Affiliation(s)
- Seren M. Gedallovich
- Division of Gastroenterology and Hepatology, Stanford University Medical School, Stanford, CA, USA
| | - Paul Y. Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical School, Stanford, CA, USA
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Tran CS, Kersten J, Yan J, Breinig M, Huth T, Poth T, Colasanti O, Riedl T, Faure-Dupuy S, Diehl S, Verhoye L, Li TF, Lingemann M, Schult P, Ahlén G, Frelin L, Kühnel F, Vondran FWR, Breuhahn K, Meuleman P, Heikenwälder M, Schirmacher P, Bartenschlager R, Laketa V, Roessler S, Tschaharganeh DF, Sällberg M, Lohmann V. Phosphatidylinositol 4-Kinase III Alpha Governs Cytoskeletal Organization for Invasiveness of Liver Cancer Cells. Gastroenterology 2024; 167:522-537. [PMID: 38636680 DOI: 10.1053/j.gastro.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 03/06/2024] [Accepted: 04/03/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND & AIMS High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process. METHODS Several hepatic cell culture and mouse models were used to study the functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing, and PI4KIIIα-specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. RESULTS High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased phosphorylation of paxillin and cofilin. This led to morphologic alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver-specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. CONCLUSIONS PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to the progression of liver cancer and identify promising targets for therapeutic intervention.
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Affiliation(s)
- Cong Si Tran
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Julia Kersten
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Jingyi Yan
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Clinical Microbiology, Karolinska University Hospital, Huddinge, Sweden
| | - Marco Breinig
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thorben Huth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Tanja Poth
- Center for Model System and Comparative Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Ombretta Colasanti
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Tobias Riedl
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany; Université Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Stefan Diehl
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium
| | - Teng-Feng Li
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Marit Lingemann
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Philipp Schult
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Gustaf Ahlén
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Clinical Microbiology, Karolinska University Hospital, Huddinge, Sweden
| | - Lars Frelin
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Clinical Microbiology, Karolinska University Hospital, Huddinge, Sweden
| | - Florian Kühnel
- Department of Gastroenterology, Hepatology, Infectiology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian W R Vondran
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover, Hannover, Germany
| | - Kai Breuhahn
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany; The M3 Research Institute, Medical Faculty Tübingen, Tübingen, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Ralf Bartenschlager
- DZIF, Partner Site Heidelberg, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis, DKFZ, Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Vibor Laketa
- DZIF, Partner Site Heidelberg, Heidelberg, Germany; Department of Infectious Diseases, Virology, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ) and Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Matti Sällberg
- Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Clinical Microbiology, Karolinska University Hospital, Huddinge, Sweden
| | - Volker Lohmann
- Department of Infectious Diseases, Molecular Virology, Section Virus-Host Interactions, Center for Integrative Infectious Disease Research, Heidelberg University, Medical Faculty Heidelberg, Heidelberg, Germany; DZIF, Partner Site Heidelberg, Heidelberg, Germany.
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Huang DQ, Hoang JK, Kamal R, Tsai PC, Toyoda H, Yeh ML, Yasuda S, Leong J, Maeda M, Huang CF, Won Jun D, Ishigami M, Tanaka Y, Uojima H, Ogawa E, Abe H, Hsu YC, Tseng CH, Alsudaney M, Yang JD, Yoshimaru Y, Suzuki T, Liu JK, Landis C, Dai CY, Huang JF, Chuang WL, Schwartz M, Dan YY, Esquivel C, Bonham A, Yu ML, Nguyen MH. Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma. J Clin Oncol 2024; 42:790-799. [PMID: 38175991 DOI: 10.1200/jco.23.00757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 08/31/2023] [Accepted: 10/17/2023] [Indexed: 01/06/2024] Open
Abstract
PURPOSE There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. METHODS This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). RESULTS The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). CONCLUSION Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.
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Affiliation(s)
- Daniel Q Huang
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - Joseph K Hoang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA
| | - Rubayet Kamal
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA
- Meharry Medical College, Nashville, TN
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Satoshi Yasuda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Jennifer Leong
- Henry D. Janowitz Division of Gastroenterology, Mt. Sinai Health System, New York, NY
| | - Mayumi Maeda
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroshi Abe
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Chiba, Japan
| | - Yao-Chun Hsu
- Division of Gastroenterology of Hepatology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Cheng-Hao Tseng
- Division of Gastroenterology of Hepatology, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Manaf Alsudaney
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Yoko Yoshimaru
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Takanori Suzuki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | - Charles Landis
- Division of Gastroenterology, Kaiser Permanente, Seattle, WA
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Myron Schwartz
- Recanati-Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
| | - Carlos Esquivel
- Department of Surgery, Stanford University Medical Center, Palo Alto, CA
| | - Andrew Bonham
- Department of Surgery, Stanford University Medical Center, Palo Alto, CA
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Hepatitis Research Center, College of Medicine and Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA
- Department of Epidemiology and Population Health, Stanford University, Palo Alto, CA
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Kim JI, Lee J, Choi GH, Lee MW, Park DA, Yoo JJ. Comparison of Surgical Resection and Radiofrequency Ablation in Elderly Patients with Hepatocellular Carcinoma. Dig Dis Sci 2024; 69:1055-1067. [PMID: 38300416 DOI: 10.1007/s10620-023-08245-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/02/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND/AIMS The aim of this study was to examine whether the efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are comparable for hepatocellular carcinoma (HCC) less than 3 cm in elderly individuals aged 65 years or older. METHODS We used the National Health Insurance Service claims data in Korea, which was linked with liver cancer stage data from the Central Cancer Registry of the National Cancer Center, as well as death data from the National Statistical Office. Out of the 9213 registrants, we focused on 141 patients who underwent SR and 225 patients who underwent RFA when they were 65 years or older. To ensure comparability, a 1:1 propensity score (PS) matching was conducted. RESULTS The SR group had lower performance status and better liver function compared to the RFA group. Tumor diameter was larger in the SR group than in the RFA group (2.1 cm vs. 1.7 cm), and the proportion of stage II cases was higher (62.4% vs. 33.8%). After PS matching, the mortality rate in the RFA group did not significantly differ from the SR group (HR 1.33, 95% CI 0.86-2.06, P = 0.19). Also, liver related mortality was similar between the SR and RFA group after matching (log rank P = 0.13). However, recurrence free survival was significantly longer in the SR group than RFA group before and after matching (log rank P = 0.03). CONCLUSION In patients aged 65 years or older with resectable HCC, RFA demonstrates a therapeutic effect comparable to SR.
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Affiliation(s)
- Jun Il Kim
- Department of Gastroenterology and Hepatology, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea
| | - Jayoun Lee
- Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency (NECA), 173 Toegye-ro, Jung-gu, Seoul, 04554, Republic of Korea
| | - Gi Hong Choi
- Department of General Surgery, Yonsei University School of Medicine, Cheonan, Republic of Korea
| | - Min Woo Lee
- Department of Radiology, Samgsung Medical Cente, Sungkyunkwan University, Seoul, Republic of Korea
| | - Dong Ah Park
- Division of Healthcare Technology Assessment Research, National Evidence-Based Healthcare Collaborating Agency (NECA), 173 Toegye-ro, Jung-gu, Seoul, 04554, Republic of Korea
| | - Jeong-Ju Yoo
- Department of Gastroenterology and Hepatology, Soonchunhyang University School of Medicine, Bucheon, Republic of Korea.
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang Bucheon Hospital, 170 Jomaruro Wonmigu, Bucheonsi, Gyeonggido, 14584, Republic of Korea.
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10
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Liu Y, Kim ES, Guo H. Hepatitis B virus-related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures. J Med Virol 2024; 96:e29485. [PMID: 38377167 PMCID: PMC10916714 DOI: 10.1002/jmv.29485] [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: 01/12/2024] [Revised: 02/08/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024]
Abstract
Emerging evidence supports a high prevalence of cancer type-specific microbiota residing within tumor tissues. The intratumoral microbiome in hepatocellular carcinoma (HCC), especially in viral (hepatitis B virus [HBV]/hepatitis C virus [HCV]) HCC, has not been well characterized for their existence, composition, distribution, and biological functions. We report herein a finding of specific microbial signature in viral HCC as compared to non-HBV/non-HCV (NBNC) HCC. However, the significantly diverse tumor microbiome was only observed in HBV-related HCC, and Cutibacterium was identified as the representative taxa biomarker. Biological function of the unique tumor microbiota in modulating tumor microenvironment (TME) was characterized by using formalin-fixed paraffin-embedded (FFPE) tissue-based multiplex immunofluorescence histochemistry (mIFH) allowing simultaneous in situ detection of the liver cancer cells surrounded with high/low density of microbiota, and the infiltrating immune cells. In HBV_HCC, the intratumoral microbiota are positively associated with increased tumor-infiltrating CD8+ T lymphocytes, but not the CD56+ NK cells. Two subtypes of myeloid-derived suppressor cells (MDSCs): monocytic MDSCs and polymorphonuclear MDSCs, were also found to be positively correlated with the intratumoral microbiota in HBV_HCC, indicating an inhibitory role of these microbial species in antitumor immunity and the contribution to the liver TME in combination of chronic viral hepatitis during HCC development.
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Affiliation(s)
- Yuanjie Liu
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Microbiome Facility, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
| | - Elena S. Kim
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
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11
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Song JJ, Chobrutskiy A, Chobrutskiy BI, Cios KJ, Huda TI, Eakins RA, Diaz MJ, Blanck G. Chemical Complementarity of Tumor Resident, Adaptive Immune Receptor CDR3s and Previously Defined Hepatitis C Virus Epitopes Correlates with Improved Outcomes in Hepatocellular Carcinoma. Viral Immunol 2023; 36:669-677. [PMID: 38052065 DOI: 10.1089/vim.2023.0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023] Open
Abstract
To better understand how adaptive immune receptors (IRs) in hepatocellular carcinoma (HCC) microenvironments are related to disease outcomes, we employed a chemical complementarity scoring algorithm to quantify electrostatic complementarity between HCC tumor TRB or IGH complementarity-determining region 3 (CDR3) amino acid (AA) sequences and previously characterized hepatitis C virus (HCV) epitopes. High electrostatic complementarity between HCC-resident CDR3s and 12 HCV epitopes was associated with greater survival probabilities, as indicated by two distinct HCC IR CDR3 datasets. Two of the HCV epitopes, HCV*71871 (TRB) and HCV*13458 (IGH), were also determined to represent significantly larger electrostatic CDR3-HCV epitope complementarity in HCV-positive HCC cases, compared with HCV-negative HCC cases, with the CDR3s representing yet a third, independent HCC dataset. Overall, the results indicated the utility of CDR3 AA sequences as biomarkers for HCC patient stratification and as potential guides for the development of therapeutic reagents.
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Affiliation(s)
- Joanna J Song
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Andrea Chobrutskiy
- Department of Pediatrics, Oregon Health and Science University Hospital, Portland, Oregon, USA
| | - Boris I Chobrutskiy
- Department of Internal Medicine, Oregon Health and Science University Hospital, Portland, Oregon, USA
| | - Konrad J Cios
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Taha I Huda
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Rachel A Eakins
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Michael J Diaz
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - George Blanck
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
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12
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Pernigoni N, Guo C, Gallagher L, Yuan W, Colucci M, Troiani M, Liu L, Maraccani L, Guccini I, Migliorini D, de Bono J, Alimonti A. The potential role of the microbiota in prostate cancer pathogenesis and treatment. Nat Rev Urol 2023; 20:706-718. [PMID: 37491512 DOI: 10.1038/s41585-023-00795-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2023] [Indexed: 07/27/2023]
Abstract
The human body hosts a complex and dynamic population of trillions of microorganisms - the microbiota - which influences the body in homeostasis and disease, including cancer. Several epidemiological studies have associated specific urinary and gut microbial species with increased risk of prostate cancer; however, causal mechanistic data remain elusive. Studies have associated bacterial generation of genotoxins with the occurrence of TMPRSS2-ERG gene fusions, a common, early oncogenic event during prostate carcinogenesis. A subsequent study demonstrated the role of the gut microbiota in prostate cancer endocrine resistance, which occurs, at least partially, through the generation of androgenic steroids fuelling oncogenic signalling via the androgen receptor. These studies present mechanistic evidence of how the host microbiota might be implicated in prostate carcinogenesis and tumour progression. Importantly, these findings also reveal potential avenues for the detection and treatment of prostate cancer through the profiling and modulation of the host microbiota. The latter could involve approaches such as the use of faecal microbiota transplantation, prebiotics, probiotics, postbiotics or antibiotics, which can be used independently or combined with existing treatments to reverse therapeutic resistance and improve clinical outcomes in patients with prostate cancer.
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Affiliation(s)
- Nicolò Pernigoni
- Institute of Oncology Research, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Christina Guo
- Institute of Cancer Research, London, UK
- Royal Marsden Hospital, London, UK
| | | | - Wei Yuan
- Institute of Cancer Research, London, UK
| | - Manuel Colucci
- Institute of Oncology Research, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Martina Troiani
- Institute of Oncology Research, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Lei Liu
- Institute of Oncology Research, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
| | - Luisa Maraccani
- Institute of Oncology Research, Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine, Padova, Italy
| | - Ilaria Guccini
- Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
| | - Denis Migliorini
- Department of Oncology, Geneva University Hospitals, Geneva, Switzerland
- Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland
- Swiss Cancer Center Léman, Lausanne and Geneva, Geneva, Switzerland
- AGORA Cancer Research Center, Lausanne, Switzerland
| | - Johann de Bono
- Institute of Cancer Research, London, UK
- Royal Marsden Hospital, London, UK
| | - Andrea Alimonti
- Institute of Oncology Research, Bellinzona, Switzerland.
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
- Veneto Institute of Molecular Medicine, Padova, Italy.
- Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland.
- Department of Medicine, University of Padova, Padova, Italy.
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
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13
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El-Khobar KE, Tay E, Diefenbach E, Gloss BS, George J, Douglas MW. Polo-like kinase-1 mediates hepatitis C virus-induced cell migration, a drug target for liver cancer. Life Sci Alliance 2023; 6:e202201630. [PMID: 37648284 PMCID: PMC10468647 DOI: 10.26508/lsa.202201630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/04/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Polo-like kinase 1 (PLK1) is a regulator of cell mitosis and cytoskeletal dynamics. PLK1 overexpression in liver cancer is associated with tumour progression, metastasis, and vascular invasion. Hepatitis C virus (HCV) NS5A protein stimulates PLK1-mediated phosphorylation of host proteins, so we hypothesised that HCV-PLK1 interactions might be a mechanism for HCV-induced liver cancer. We used a HCV cell-culture model (Jc1) to investigate the effects of virus infection on the cytoskeleton. In HCV-infected cells, a novel posttranslational modification in β-actin was observed with phosphorylation at Ser239. Using in silico and in vitro approaches, we identified PLK1 as the mediating kinase. In functional experiments with a phosphomimetic mutant form of β-actin, Ser239 phosphorylation influences β-actin polymerization and distribution, resulting in increased cell motility. The changes were prevented by treating cells with the PLK1 inhibitor volasertib. In HCV-infected hepatocytes, increased cell motility contributes to cancer cell migration, invasion, and metastasis. PLK1 is an important mediator of these effects and early treatment with PLK1 inhibitors may prevent or reduce HCC progression, particularly in people with HCV-induced HCC.
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Affiliation(s)
- Korri E El-Khobar
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
- Eijkman Institute for Molecular Biology, Jakarta, Indonesia
| | - Enoch Tay
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Eve Diefenbach
- Protein Core Facility, Westmead Institute for Medical Research, Westmead, Australia
| | - Brian S Gloss
- Westmead Research Hub, Westmead Institute for Medical Research, Westmead, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
| | - Mark W Douglas
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney at Westmead Hospital, Westmead, Australia
- Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, University of Sydney at Westmead Hospital, Westmead, Australia
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14
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Elbahrawy A, Atalla H, Mahmoud AA, Eliwa A, Alsawak A, Alboraie M, Madian A, Alashker A, Mostafa S, Alwassief A, Aly HH. Prediction and surveillance of de novo HCC in patients with compensated advanced chronic liver disease after hepatitis C virus eradication with direct antiviral agents. FRONTIERS IN VIROLOGY 2023; 3. [DOI: 10.3389/fviro.2023.1227317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The risk of hepatocellular carcinoma (HCC) diminishes in patients with hepatitis C virus (HCV)-related advanced chronic liver disease after virological cure. However, despite viral clearance, HCV-induced epigenetic alterations, immune dysregulations, and hepatic parenchymal injuries remain, contributing to de novo HCC occurrence. While HCC incidence is low (0.45 – 0.5%) in patients with advanced fibrosis (F3), the presence of liver cirrhosis and clinically significant portal hypertension increases the HCC risk. The cost-effectiveness of lifelong HCC surveillance in patients with compensated advanced chronic liver disease (cACLD) has sparked debate, raising questions about the most reliable noninvasive tests and stratification models for predicting HCC in patients with sustained virological response (SVR). Furthermore, identifying cACLD patients who may not require long-term HCC surveillance after SVR remains crucial. Several HCC risk stratification scores have been suggested for patients with cACLD, and emerging evidence supports individualized care based on personalized risk assessments. This review focuses on revising the pretreatment and posttreatment predictors of HCC, as well as the indications for HCC surveillance in cACLD patients treated with direct-acting antivirals.
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15
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Minarovits J. Human tumor viruses: induction of three-dimensional alterations in the host genome structure. Front Microbiol 2023; 14:1280210. [PMID: 37928671 PMCID: PMC10620758 DOI: 10.3389/fmicb.2023.1280210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 09/21/2023] [Indexed: 11/07/2023] Open
Abstract
Certain viruses called tumor viruses or oncoviruses are capable to change the gene expression pattern of distinct human or animal cell types in tissue culture, resulting in uncontrolled proliferation as well as a change in the social behavior of the infected cells: the oncovirus-transformed, immortalized cells are capable to form malignant neoplasms in suitable animal models. At present, seven human viruses are categorized as causative agents of distinct human malignancies. The genomes of human tumor viruses, typically encode viral oncoproteins and non- translated viral RNAs that affect the gene expression pattern of their target cells or induce genetic and epigenetic alterations contributing to oncogenesis. Recently, the application of chromatin conformation capture technologies and three-dimensional (3D) molecular imaging techniques revealed how the gene products or genomes of certain human tumor viruses interact with and induce alterations in the 3D host genome structure. This Mini Review aims to cover selected aspects of these developments. The papers, discussed briefly, describe how insertion of a novel viral binding site for the 3D genome organizer cellular protein CCCTC-binding factor (CTCF) into the DNA of T cells infected by human T-cell lymphotropic virus type 1 (HTLV-1) may contribute to lymphomagenesis, as well as how integration of high risk human papillomavirus genome into the host cell DNA may facilitate cervical carcinogenesis. Recent results regarding the interactions of cellular genomes with the episomal, chromatinized DNA genomes of oncogenic human herpesvirus, Epstein-Barr virus (EBV) will also be summarized, similarly to available data regarding contacts formed by episomal or integrated hepatitis B virus (HBV) DNA with host chromatin. Finally, a putative mechanism of hepatitis C virus (HCV) induced chromatin alterations will be presented, which may solve the riddle, how a cytoplasmic RNA virus without a viral oncogene could induce malingnant transfrormation of hepatocytes.
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Affiliation(s)
- Janos Minarovits
- Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, Szeged, Hungary
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16
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Suresh D, Srinivas AN, Prashant A, Harikumar KB, Kumar DP. Therapeutic options in hepatocellular carcinoma: a comprehensive review. Clin Exp Med 2023; 23:1901-1916. [PMID: 36780119 DOI: 10.1007/s10238-023-01014-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/27/2023] [Indexed: 02/14/2023]
Abstract
Hepatocellular carcinoma (HCC) is a chronic liver disease that is highly fatal if not detected and treated early. The incidence and death rate of HCC have been increasing in recent decades despite the measures taken for preventive screening and effective diagnostic and treatment strategies. The pathophysiology of HCC is multifactorial and highly complex owing to its molecular and immune heterogeneity, and thus the gap in knowledge still precludes making choices between viable therapeutic options and also the development of effective regimens. The treatment of HCC demands multidisciplinary approaches and primarily depends on tumor stage, hepatic functional reserve, and response to treatment by patients. Although curative treatments are limited but critical in the early stages of cancer, there are numerous palliative treatments available for patients with intermediate and advanced-stage HCC. In recent times, the use of combination therapy has succeeded over the use of monotherapy in the treatment of HCC by achieving effective tumor suppression, increasing survival rate, decreasing toxicity, and also aiding in overcoming drug resistance. This work focuses on reviewing the current and emerging treatment strategies for HCC.
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Affiliation(s)
- Diwakar Suresh
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Akshatha N Srinivas
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Akila Prashant
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, India
| | - Divya P Kumar
- Department of Biochemistry, CEMR, JSS Medical College, JSS Academy of Higher Education and Research, SS Nagar, Mysuru, 570015, India.
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17
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Alawyia B, Constantinou C. Hepatocellular Carcinoma: a Narrative Review on Current Knowledge and Future Prospects. Curr Treat Options Oncol 2023; 24:711-724. [PMID: 37103744 DOI: 10.1007/s11864-023-01098-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 04/28/2023]
Abstract
OPINION STATEMENT Hepatocellular carcinoma is the fourth leading cause of cancer-related deaths worldwide and its associated mortality rate is expected to rise within the next decade. The incidence rate of hepatocellular carcinoma varies significantly across countries and the latter can be attributed to the differences in risk factors that are prevalent across different countries. Some of the risk factors associated with hepatocellular carcinoma include hepatitis B and C infections, non-alcoholic fatty liver disease, and alcoholic liver disease. Regardless of the underlying aetiology, the end result is liver fibrosis and cirrhosis that ultimately progress into carcinoma. The treatment and management of hepatocellular carcinoma is complicated by treatment resistance and high tumor recurrence rates. Early stages of hepatocellular carcinoma are treated with liver resection and other forms of surgical therapy. Advanced stages of hepatocellular carcinoma can be treated with chemotherapy, immunotherapy, and the use of oncolytic viruses and these treatment options can be combined with nanotechnology to improve efficacy and reduce side effects. Moreover, chemotherapy and immunotherapy can be combined to further improve treatment efficacy and overcome resistance. Despite the treatment options available, the high mortality rates provide evidence that current treatment options for advanced-stage hepatocellular carcinoma are not achieving the desired therapeutic goals. Various clinical trials are ongoing to improve treatment efficacy, reduce recurrence rates, and ultimately prolong survival. This narrative review aims to provide an update on our current knowledge and future direction of research on hepatocellular carcinoma.
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Affiliation(s)
- Basil Alawyia
- University of Nicosia Medical School, Nicosia, Cyprus
| | - Constantina Constantinou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, P.O. Box 24005, 21 Ilia Papakyriakou, 2414 Engomi, CY-1700, Nicosia, Cyprus.
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18
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Cheung CCL, Seah YHJ, Fang J, Orpilla NHC, Lau MC, Lim CJ, Lim X, Lee JNLW, Lim JCT, Lim S, Cheng Q, Toh HC, Choo SP, Lee SY, Lee JJX, Liu J, Lim TKH, Tai D, Yeong J. Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma. Front Immunol 2023; 14:1150985. [PMID: 37342338 PMCID: PMC10277502 DOI: 10.3389/fimmu.2023.1150985] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/04/2023] [Indexed: 06/22/2023] Open
Abstract
Introduction Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. Methods HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. Results Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3+ and LAG-3+CD8+ cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3+ cell proportion to the total CD8+ cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8+ cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3+CD8+ cell proportion was significantly associated with responses to ICB regardless of viral status. Conclusion Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.
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Affiliation(s)
- Chun Chau Lawrence Cheung
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Yong Hock Justin Seah
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juntao Fang
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | - Mai Chan Lau
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Chun Jye Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Xinru Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Justina Nadia Li Wen Lee
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Jeffrey Chun Tatt Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Sherlly Lim
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
| | - Qing Cheng
- Duke-NUS Medical School, Singapore, Singapore
- Center of Statistical Research, School of Statistics, Southwestern University of Finance and Economics, Chengdu, Sichuan, China
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Suat Ying Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joycelyn Jie Xin Lee
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Jin Liu
- Duke-NUS Medical School, Singapore, Singapore
| | - Tony Kiat Hon Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - David Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joe Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
- Singapore Immunology Network (SIgN), Agency of Science, Technology, and Research (A*STAR), Singapore, Singapore
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19
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Ismael MK, Qaddoori YB, Shaban MN, AL-Rubaii BAL. The Immunohistochemical Staining of Vimentin and E-Cadherin in Bladder Cancer Patients Infected with Hepatitis C Virus. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2023; 17:1009-1016. [DOI: 10.22207/jpam.17.2.30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The invasion and spread of cancer cells are two of the most notable characteristics of malignant tumors. Recent studies suggest that the epithelial-mesenchymal transition (EMT) has been linked to this significant occurrence. It is linked to the absence of the epithelial brow and the presence of mesenchymal facial hair. The aims of the present study were to explore the immunohistochemical staining of vimentin and E-cadherin ex vivo as EMT markers and assess their potential as predictive biomarkers for transitional cell cancer (TCC). In this study, 55 paraffin-embedded biopsies from TCC patients and 10 autopsies that appeared to be normal were included. Immunohistochemistry was used to produce patterns of vimentin and E-cadherin expression. When compared to female patients, the expression of E-cadherin and vimentin significantly increased with increasing age in male patients (> 50 years). In contrast to the considerable rise in vimentin expression in higher grades and stages of the tumor, E-cadherin expression was significantly reduced with tumor stage and grade. The findings of this study reveal that elevated vimentin and reduced E-cadherin are important indicators associated with a poor prognosis for TCC.
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Kouroumalis E, Tsomidis I, Voumvouraki A. Pathogenesis of Hepatocellular Carcinoma: The Interplay of Apoptosis and Autophagy. Biomedicines 2023; 11:1166. [PMID: 37189787 PMCID: PMC10135776 DOI: 10.3390/biomedicines11041166] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/09/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is a multifactorial process that has not yet been fully investigated. Autophagy and apoptosis are two important cellular pathways that are critical for cell survival or death. The balance between apoptosis and autophagy regulates liver cell turnover and maintains intracellular homeostasis. However, the balance is often dysregulated in many cancers, including HCC. Autophagy and apoptosis pathways may be either independent or parallel or one may influence the other. Autophagy may either inhibit or promote apoptosis, thus regulating the fate of the liver cancer cells. In this review, a concise overview of the pathogenesis of HCC is presented, with emphasis on new developments, including the role of endoplasmic reticulum stress, the implication of microRNAs and the role of gut microbiota. The characteristics of HCC associated with a specific liver disease are also described and a brief description of autophagy and apoptosis is provided. The role of autophagy and apoptosis in the initiation, progress and metastatic potential is reviewed and the experimental evidence indicating an interplay between the two is extensively analyzed. The role of ferroptosis, a recently described specific pathway of regulated cell death, is presented. Finally, the potential therapeutic implications of autophagy and apoptosis in drug resistance are examined.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, PAGNI University Hospital, University of Crete School of Medicine, 71500 Heraklion, Crete, Greece
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Central Macedonia, Greece
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21
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Tskhomelidze I, Shadaker S, Kuchuloria T, Gvinjilia L, Butsashvili M, Nasrullah M, Gabunia T, Gamkrelidze A, Getia V, Sharvadze L, Tsertsvadze T, Zarqua J, Tsanava S, Handanagic S, Armstrong PA, Averhoff F, Vickerman P, Walker JG. Economic evaluation of the Hepatitis C virus elimination program in the country of Georgia, 2015 to 2017. Liver Int 2023; 43:558-568. [PMID: 36129625 PMCID: PMC10227952 DOI: 10.1111/liv.15431] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 08/02/2022] [Accepted: 09/20/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS In 2015, the country of Georgia launched an elimination program aiming to reduce the prevalence of Hepatitis C virus (HCV) infection by 90% from 5.4% prevalence (~150 000 people). During the first 2.5 years of the program, 770 832 people were screened, 48 575 were diagnosed with active HCV infection, and 41 483 patients were treated with direct-acting antiviral (DAA)-based regimens, with a >95% cure rate. METHODS We modelled the incremental cost-effectiveness ratio (ICER) of HCV screening, diagnosis and treatment between April 2015 and November 2017 compared to no treatment, in terms of cost per quality-adjusted life year (QALY) gained in 2017 US dollars, with a 3% discount rate over 25 years. We compared the ICER to willingness-to-pay (WTP) thresholds of US$4357 (GDP) and US$871 (opportunity cost) per QALY gained. RESULTS The average cost of screening, HCV viremia testing, and treatment per patient treated was $386 to the provider, $225 to the patient and $1042 for generic DAAs. At 3% discount, 0.57 QALYs were gained per patient treated. The ICER from the perspective of the provider including generic DAAs was $2285 per QALY gained, which is cost-effective at the $4357 WTP threshold, while if patient costs are included, it is just above the threshold at $4398/QALY. All other scenarios examined in sensitivity analyses remain cost-effective except for assuming a shorter time horizon to the end of 2025 or including the list price DAA cost. Reducing or excluding DAA costs reduced the ICER below the opportunity-cost WTP threshold. CONCLUSIONS The Georgian HCV elimination program provides valuable evidence that national programs for scaling up HCV screening and treatment for achieving HCV elimination can be cost-effective.
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Affiliation(s)
- Irina Tskhomelidze
- Task Force for Global Health, Tbilisi, Georgia
- Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
| | - Shaun Shadaker
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, USA
| | | | | | | | - Muazzam Nasrullah
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, USA
| | - Tamar Gabunia
- Ministry of Internally Displaced Persons from the Occupied Territories, Labour Health and Social Affairs of Georgia, Tbilisi, Georgia
| | | | - Vladimer Getia
- National Center for Disease Control and Public Health, Tbilisi, Georgia
| | | | - Tengiz Tsertsvadze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, Tbilisi, Georgia
| | | | - Shota Tsanava
- National Center for Disease Control and Public Health, Tbilisi, Georgia
| | - Senad Handanagic
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, USA
| | - Paige A. Armstrong
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, USA
| | - Francisco Averhoff
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, USA
| | - Peter Vickerman
- Population Health Sciences, University of Bristol, Bristol, UK
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22
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Goncharova IA, Zarubin AA, Babushkina NP, Koroleva IA, Nazarenko MS. Changes in DNA methylation profile in liver tissue during progression of HCV-induced fibrosis to hepatocellular carcinoma. Vavilovskii Zhurnal Genet Selektsii 2023; 27:72-82. [PMID: 36923478 PMCID: PMC10009477 DOI: 10.18699/vjgb-23-10] [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: 10/18/2022] [Revised: 12/08/2022] [Accepted: 12/15/2022] [Indexed: 03/11/2023] Open
Abstract
In this study we compared methylation levels of 27,578 CpG sites between paired samples of the tumor and surrounding liver tissues with various degrees of damage (fibrosis, cirrhosis) in HCV-induced hepatocellular carcinoma (HCC) patients, as well as between tumor and normal tissue in non-viral HCC patients, using GSE73003 and GSE37988 data from GEODataSets (https://www.ncbi.nlm.nih.gov/). A significantly lower number of differentially methylated sites (DMS) were found between HCC of non-viral etiology and normal liver tissue, as well as between HCC and fibrosis (32 and 40), than between HCC and cirrhosis (2450 and 2304, respectively, according to GSE73003 and GSE37988 datasets). As the pathological changes in the tissue surrounding the tumor progress, the ratio of hyper-/hypomethylated DMSs in the tumor decreases. Thus, in tumor tissues compared with normal/fibrosis/cirrhosis of the liver, 75/62.5/47.7 % (GSE73003) and 16 % (GSE37988) of CpG sites are hypermethylated, respectively. Persistent hypermethylation of the ZNF154 and ZNF540 genes, as well as CCL20 hypomethylation, were registered in tumor tissue in relation to both liver fibrosis and liver cirrhosis. Protein products of the EDG4, CCL20, GPR109A, and GRM8 genes, whose CpG sites are characterized by changes in DNA methylation level in tumor tissue in the setting of cirrhosis and fibrosis, belong to "Signaling by G-protein-coupled receptors (GPCRs)" category. However, changes in the methylation level of the "driver" genes for oncopathology (АРС, CDKN2B, GSTP1, ELF4, TERT, WT1) are registered in tumor tissue in the setting of liver cirrhosis but not fibrosis. Among the genes hypermethylated in tumor tissue in the setting of liver cirrhosis, the most represented biological pathways are developmental processes, cell-cell signaling, transcription regulation, Wnt-protein binding. Genes hypomethylated in liver tumor tissue in the setting of liver cirrhosis are related to olfactory signal transduction, neuroactive ligand-receptor interaction, keratinization, immune response, inhibition of serine proteases, and zinc metabolism. The genes hypermethylated in the tumor are located at the 7p15.2 locus in the HOXA cluster region, and the hypomethylated CpG sites occupy extended regions of the genome in the gene clusters of olfactory receptors (11p15.4), keratin and keratin-associated proteins (12q13.13, 17q21.2, and 21q22.11), epidermal differentiation complex (1q21.3), and immune system function loci 9p21.3 (IFNA, IFNB1, IFNW1 cluster) and 19q13.41-19q13.42 (KLK, SIGLEC, LILR, KIR clusters). Among the genes of fibrogenesis or DNA repair, cg14143055 (ADAMDEC1) is located in the binding region of the HOX gene family transcription factors (TFs), while cg05921699 (CD79A), cg06196379 (TREM1) and cg10990993 (MLH1) are located in the binding region of the ZNF protein family transcription factor (TF). Thus, the DNA methylation profile in the liver in HCV-induced HCC is unique and differs depending on the degree of surrounding tissue lesion - liver fibrosis or liver cirrhosis.
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Affiliation(s)
- I A Goncharova
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - A A Zarubin
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - N P Babushkina
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - I A Koroleva
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
| | - M S Nazarenko
- Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia
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23
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Abdelhamed W, El-Kassas M. Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful. J Viral Hepat 2023; 30:148-159. [PMID: 36461645 DOI: 10.1111/jvh.13778] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/07/2022] [Accepted: 11/26/2022] [Indexed: 12/04/2022]
Abstract
The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
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24
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Dwivedi M, Dwivedi A, Mukherjee D. An Insight into Hepatitis C Virus: In Search of Promising Drug Targets. Curr Drug Targets 2023; 24:1127-1138. [PMID: 37907492 DOI: 10.2174/0113894501265769231020031857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/13/2023] [Accepted: 09/21/2023] [Indexed: 11/02/2023]
Abstract
Hepatitis C Virus (HCV) is a global health concern, chronically infecting over 70 million people worldwide. HCV is a bloodborne pathogen that primarily affects the liver, and chronic HCV infection can lead to cirrhosis, liver cancer, and liver failure over time. There is an urgent need for more effective approaches to prevent and treat HCV. This review summarizes current knowledge on the virology, transmission, diagnosis, and management of HCV infection. It also provides an in-depth analysis of HCV proteins as promising targets for antiviral drug and vaccine development. Specific HCV proteins discussed as potential drug targets include the NS5B polymerase, NS3/4A protease, entry receptors like CD81, and core proteins. The implications of HCV proteins as diagnostic and prognostic biomarkers are also explored. Current direct-acting antiviral therapies are effective but have cost, genotype specificity, and resistance limitations. This review aims to synthesize essential information on HCV biology and pathogenesis to inform future research on improved preventive, diagnostic, and therapeutic strategies against this global infectious disease threat.
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Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow- 226028, India
| | - Aditya Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Extension, Lucknow- 226028, India
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25
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Shaw R, Dutta B, Ghosh D, Bandopadhyay R. Hepatitis C—Route of Asymptomatic to Symptomatic Switch in Raising Hepatocarcinogenesis: Revisiting Nobel Prize 2020 in Physiology and Medicine. NATIONAL ACADEMY SCIENCE LETTERS 2022. [DOI: 10.1007/s40009-022-01192-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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26
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Spearman CW, Dusheiko G, Jonas E, Abdo A, Afihene M, Cunha L, Desalegn H, Kassianides C, Katsidzira L, Kramvis A, Lam P, Lesi OA, Micah EA, Musabeyezu E, Ndow G, Nnabuchi CV, Ocama P, Okeke E, Rwegasha J, Shewaye AB, Some FF, Tzeuton C, Sonderup MW. Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa. Lancet Gastroenterol Hepatol 2022; 7:1036-1048. [PMID: 35810766 DOI: 10.1016/s2468-1253(22)00041-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/26/2022] [Accepted: 02/02/2022] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma is a leading public health concern in sub-Saharan Africa, and it is most prevalent in young adults (median 45 years [IQR 35-57]). Overall, outcomes are poor, with a median survival of 2·5 months after presentation. Major risk factors for hepatocellular carcinoma are hepatitis B virus (HBV), hepatitis C virus, aflatoxin B1 exposure, and alcohol consumption, with metabolic dysfunction-associated fatty liver disease slowly emerging as a risk factor over the past few years. Crucially, these risk factors are preventable and manageable with effective implementation of the HBV birth-dose vaccination, treatment of chronic viral hepatitis, provision of harm reduction services, and by decreasing aflatoxin B1 exposure and harmful alcohol consumption. Primary prevention is central to the management of hepatocellular carcinoma, especially in poorly resourced environments. Effective screening and surveillance programmes with recall policies need to be implemented, because detection and curative management of hepatocellular carcinoma is possible if it is detected at an early stage, even in countries with minimal resources, with appropriate upskilling of medical personnel. The establishment of centres of excellence with advanced diagnostic and therapeutic capabilities within countries should improve hepatocellular carcinoma outcomes and assist in driving the implementation of much needed systematic data systems focused on hepatocellular carcinoma to establish the accurate burden in sub-Saharan Africa. Such data would support the public health importance of hepatocellular carcinoma and provide a strong basis for advocacy, programme development, resource allocation, and monitoring of progress in reducing mortality.
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Affiliation(s)
- C Wendy Spearman
- Division of Hepatology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
| | - Geoffrey Dusheiko
- University College London Medical School, London, UK; Kings College Hospital, London, UK
| | - Eduard Jonas
- Surgical Gastroenterology Unit, Division of General Surgery, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Abdelmounem Abdo
- National Centre for Gastrointestinal and Liver Disease, Ibn Sina Hospital, Alamarat, Khartoum, Sudan
| | - Mary Afihene
- Department of Medicine, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Lina Cunha
- Gastroenterology Unit, Maputo Private Hospital, Maputo, Mozambique
| | - Hailemichael Desalegn
- Department of Internal Medicine, St Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia
| | - Chris Kassianides
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Leolin Katsidzira
- Internal Medicine Unit, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Olufunmilayo A Lesi
- Gastroenterology and Hepatology Unit, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Eileen A Micah
- Department of Medicine, Komfo Anokye Teaching Hospital, Kumasi, Ghana
| | | | - Gibril Ndow
- Disease Control and Elimination Theme, MRC Unit The Gambia at the London School of Tropical Medicine, London, UK; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Chidi V Nnabuchi
- Asokoro District Hospital, Nile University Teaching Hospital, Abuja, Nigeria
| | - Ponsiano Ocama
- School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Edith Okeke
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, College of Health Sciences, University of Jos, Jos University Teaching Hospital, Jos, Nigeria
| | - John Rwegasha
- Gastroenterology Training Centre, Department of Internal Medicine, Muhimbili National Hospital, Dar Es Salaam, Tanzania
| | - Abate B Shewaye
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Fatuma F Some
- Department of Medicine, School of Medicine, College of Health Sciences, Moi University, Eldoret, Kenya
| | - Christian Tzeuton
- Faculty of Medicine and Pharmaceutical Sciences of Douala, University of Douala, Douala, Cameroon
| | - Mark W Sonderup
- Division of Hepatology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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27
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Badshah Y, Shabbir M, Khan K, Fatima M, Majoka I, Aslam L, Munawar H. Manipulation of Interleukin-6 (IL-6) and Transforming Growth Factor Beta-1(TGFβ-1) towards viral induced liver cancer pathogenesis. PLoS One 2022; 17:e0275834. [PMID: 36215278 PMCID: PMC9550071 DOI: 10.1371/journal.pone.0275834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver malignancy. Early diagnosis of HCC has always been challenging. This study aims to assess the pathogenicity and the prevalence of IL-6 -174G/C (rs1800795) and TGFβ-1 +29C/T (rs1800470) polymorphisms in HCV-infected HCC patients. Experimental strategies are integrated with computational approaches to analyse the pathogenicity of the TGFβ-1 +29C/T and IL-6-174 G/C polymorphisms in HCV-induced HCC. AliBaba2 was used to predict the effect of IL-6-174 G/C on transcription factor binding site in IL-6 gene. Structural changes in the mutant TGFβ-1 structure were determined through project HOPE. To assess the polymorphic prevalence of IL-6 -174G/C and TGFβ-1 +29C/T genotypes in HCC and control subjects, amplification refractory mutation system PCR (ARMS-PCR) was performed on 213 HCC and 216 control samples. GraphPad Prism version 8.0 was used for the statistical analysis of the results. In-silico analysis revealed the regulatory nature of both IL-6 -174G/C and TGFβ-1 +29C/T polymorphisms. ARMS-PCR results revealed that the individuals carrying TT genotype for TGFβ-1 gene have an increased risk of developing HCC (p<0.0001, OR = 5.403, RR = 2.062) as compared to individuals with CT and CC genotype. Similarly, GC genotype carriers for IL-6 gene exhibit an increased risk of HCC susceptibility (p<0.0001, OR = 2.276, RR = 1.512) as compared to the people carrying the GG genotype. Genotype TT of TGFβ-1 gene and genotype GC of IL-6 gene are found to be associated with HCV-induced HCC. IL-6 polymorphism may alter its transcription that leads to its pathogenicity. TGFβ-1 polymorphism may alter protein structure stability.
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Affiliation(s)
- Yasmin Badshah
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maria Shabbir
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Maha Fatima
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Iqra Majoka
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Laiba Aslam
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Huda Munawar
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
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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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The role of infections in the causation of cancer in Kenya. Cancer Causes Control 2022; 33:1391-1400. [PMID: 36087193 DOI: 10.1007/s10552-022-01625-3] [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: 03/01/2022] [Accepted: 08/31/2022] [Indexed: 12/09/2022]
Abstract
Cancer constitutes a major health care burden in the world today with the situation worsening in resource poor settings as seen in most Sub-Saharan African (SSA) countries. Infections constitute by far the most common risk factors for cancer in SSA and being a typical country in this region, Kenya has experienced an upsurge in the incidence of various types of cancers in the last few decades. Although there is limited population-based data in Kenya of infections-associated cancers, this review provides an up-to-date literature-based discussion on infections-associated cancers, their pathogenesis, and preventive approaches in the country. The primary infectious agents identified are largely viral (human immunodeficiency virus, human papillomavirus (HPV), Kaposi's sarcoma-associated herpes virus, Epstein-Barr virus, hepatitis B virus (HBV), hepatitis C virus), and also bacterial: Helicobacter pylori and parasitic: Schistosomiasis haematobium. Cancers associated with infections in Kenya are varied but the predominant ones are Non-Hodgkin lymphoma, Kaposi's sarcoma, Hodgkin lymphoma, Burkitt's lymphoma, cervical, liver, and gastric cancers. The mechanisms of infections-induced carcinogenesis are varied but they mainly seem to stem from disruption of signaling, chronic inflammation, and immunosuppression. Based on our findings, actionable cancer-preventive measures that are economically feasible and aligned with existing infrastructure in Kenya include screening and treatment of infections, implementation of cancer awareness and screening, and vaccination against infections primarily HBV and HPV. The development of vaccines against other infectious agents associated with causation of cancer remains also as an important goal in cancer prevention.
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Atif M, Mustaan MA, Falak S, Ghaffar A, Munir B. Targeting the effect of sofosbuvir on selective oncogenes expression level of hepatocellular carcinoma Ras/Raf/MEK/ERK pathway in Huh7 cell line. Saudi J Biol Sci 2022; 29:103332. [PMID: 35813116 PMCID: PMC9256646 DOI: 10.1016/j.sjbs.2022.103332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/21/2022] [Accepted: 05/29/2022] [Indexed: 11/29/2022] Open
Abstract
Direct acting antiviral agents are emerging line of treatment to eradicate Hepatitis C virus. Recent controversy over whether direct acting antiviral agents increase rate of hepatocellular carcinoma in HCV patients or prevent it, has increased the need to elaborate underlying mechanisms on molecular basis. This work was aimed to investigate the effect of sofosbuvir on the expression of selected oncogenes from the Ras/Raf/MEK/ERK pathway in Huh7 cell line. Results found concrete molecular evidence that sofosbuvir has significantly altered the expression of selected genes when huh7 cell line was treated with sofosbuvir. Nine genes related to HCC were found to be affected by sofosbuvir in a mixed effect manner. The relative expression of growth factors (VEGF, PDGFRB and HGF) was increased in sofosbuvir treated cell lines. The kinase family genes H-RAS, B-RAF, MET except MAPK1 were downregulated. Similarly, DUSP1 was upregulated and SPRY2 was slightly downregulated; both were negative feedback inhibitors of ERK signalling cascade. Sofosbuvir upregulated the growth factors and MAPK1 which suggests it to be a carcinogen. The downregulation of kinases and upregulation of DUSP1 make it an anticancer drug. Hence, the results from this study are important to prove that sofosbuvir neither reduce nor induce hepatocellular carcinoma.
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Affiliation(s)
- Muhammad Atif
- Department of Biochemistry, Government College University, Faisalabad 38000, Pakistan
| | | | - Sadia Falak
- Department of Biochemistry, University of Jhang, Jhang 35200, Pakistan
| | - Abdul Ghaffar
- Department of Biochemistry, Government College University, Faisalabad 38000, Pakistan
| | - Bushra Munir
- Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan
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Gallard C, Lebsir N, Khursheed H, Reungoat E, Plissonnier ML, Bré J, Michelet M, Chouik Y, Zoulim F, Pécheur EI, Bartosch B, Grigorov B. Heparanase-1 is upregulated by hepatitis C virus and favors its replication. J Hepatol 2022; 77:29-41. [PMID: 35085593 DOI: 10.1016/j.jhep.2022.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 01/03/2022] [Accepted: 01/13/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Over time, chronic HCV infection can lead to hepatocellular carcinoma (HCC), a process that involves changes to the liver extracellular matrix (ECM). However, the exact mechanisms by which HCV induces HCC remain unclear. Therefore, we sought to investigate the impact of HCV on the liver ECM, with a focus on heparanase-1 (HPSE). METHODS HPSE expression was assessed by quantitative reverse-transcription PCR, immunoblotting and immunofluorescence in liver biopsies infected or not with HCV, and in 10-day-infected hepatoma Huh7.5 cells. Cell lines deficient for or overexpressing HPSE were established to study its role during infection. RESULTS HCV propagation led to significant HPSE induction, in vivo and in vitro. HPSE enhanced infection when exogenously expressed or supplemented as a recombinant protein. Conversely, when HPSE expression was downregulated or its activity blocked, HCV infection dropped, suggesting a role of HPSE in the HCV life cycle. We further studied the underlying mechanisms of such observations and found that HPSE favored HCV release by enhancing CD63 synthesis and exosome secretion, but not by stimulating HCV entry or genome replication. We also showed that virus-induced oxidative stress was involved in HPSE induction, most likely through NF-κB activation. CONCLUSIONS We report for the first time that HCV infection is favored by HPSE, and upregulates HPSE expression and secretion, which may result in pathogenic alterations of the ECM. LAY SUMMARY Chronic hepatitis C virus (HCV) infection can lead to hepatocellular carcinoma development in a process that involves derangement of the extracellular matrix (ECM). Herein, we show that heparanase-1, a protein involved in ECM degradation and remodeling, favors HCV infection and is upregulated by HCV infection; this upregulation may result in pathogenic alterations of the ECM.
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Affiliation(s)
- Christophe Gallard
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Nadjet Lebsir
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Hira Khursheed
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Emma Reungoat
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Marie-Laure Plissonnier
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Jennifer Bré
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Maud Michelet
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Yasmina Chouik
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Fabien Zoulim
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France; Hospices Civils de Lyon, Lyon, France
| | - Eve-Isabelle Pécheur
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
| | - Birke Bartosch
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France
| | - Boyan Grigorov
- Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69434, France.
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Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals. Cancers (Basel) 2022; 14:cancers14112700. [PMID: 35681679 PMCID: PMC9179595 DOI: 10.3390/cancers14112700] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Chronic Hepatitis C virus (HCV) represents the main etiological factor for hepatocellular carcinoma (HCC) in developed countries. The introduction of direct-acting antivirals (DAAs) improved the eradication of the hepatitis C virus (HCV) but not the reduction in the incidence of HCV-associated HCC. Some patients still develop HCC, even after reaching a sustained virological response (SVR). This review is a summary of pre-clinical studies that investigated predictive biomarkers for HCC occurrence and recurrence in HCV-infected patients treated with DAAs. The presented biomarkers are found dysregulated in serum or tissue at specific time points (before, during, after DAA treatment or post SVR) and correlated with HCC-predisposing conditions. Thus, this review aims to improve the management of patients developing HCV-induced HCC. Abstract Hepatocellular carcinoma (HCC) is the sixth-most common type of cancer worldwide and chronic Hepatitis C virus (HCV) represents the main etiological factor in developed countries. HCV promotes hepatocarcinogenesis through persistent liver inflammation and dysregulation of cell signaling pathways. The introduction of direct-acting antivirals (DAAs) resulted in a significant improvement in the eradication of the virus, with an expected reduction of HCC incidence. However, the risk of HCC development can persist after DAA treatment. Recent studies have investigated the potential use of molecular biomarkers that predict HCC occurrence or recurrence helping the stratification of patients under surveillance. This review aimed to summarize all pre-clinical exploration of predictive biomarkers to identify DAA-treated patients at risk for HCC development. Dysregulated microRNAs, lncRNAs, histone modifications, cytokines, proteins, and sphingolipids represent various classes of HCC risk predictors identified in two different biological sources (tissue and serum). The non-invasive serum markers can provide a more accessible means to perform clinical monitoring and predict the risk of HCC. In addition, conditions like cirrhosis, predisposing to HCC, strongly correlate with most of the molecular predictors identified, supporting the value of these molecules as possible biomarkers of HCC in DAA-treated patients.
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Immune System Disorders, Cancer and Viral Infections: A New Treatment Opportunity for the Immune Checkpoint Inhibitors. Life (Basel) 2021; 11:life11121400. [PMID: 34947931 PMCID: PMC8709484 DOI: 10.3390/life11121400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/10/2021] [Accepted: 12/13/2021] [Indexed: 11/26/2022] Open
Abstract
The relationship between viral infections and cancer is well known and has been established for decades. Multiple tumours are generated from alterations secondary to viral infections 2 resulting from a dysregulation of the immune system in many cases. Certain causal relationships, such as that between the Epstein–Barr virus (EBV) in nasopharyngeal cancer or hepatitis C and B viruses in hepatocarcinoma, have been clearly established, and their implications for the prognosis and treatment of solid tumours are currently unknown. Multiple studies have evaluated the role that these infections may have in the treatment of solid tumours using immunotherapy. A possible relationship between viral infections and an increased response to immune checkpoint inhibitors (ICIs) has been established at a theoretical level in solid neoplasms, such as EBV-positive cavum cancer and human papillomavirus (HPV)-positive and oropharyngeal cancer. These could yield a greater response associated with the activation of the immune system secondary to viral infection, the consequence of which is an increase in survival in these patients. That is why the objective of this review is to assess the different studies or clinical trials carried out in patients with solid tumours secondary to viral infections and their relationship to the response to ICIs.
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Mir IH, Jyothi KC, Thirunavukkarasu C. The prominence of potential biomarkers in the diagnosis and management of hepatocellular carcinoma: Current scenario and future anticipation. J Cell Biochem 2021; 123:1607-1623. [PMID: 34897788 DOI: 10.1002/jcb.30190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/13/2021] [Accepted: 11/17/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive and truculent types of cancer. Early detection of HCC is a massive concern that can boost the overall survival rates of HCC patients. As a result, there is a continual quest for advancements in screening, diagnosis, and treatment strategies to enhance the prognosis at its early stages. However, the confluence of inflammation and cirrhosis hampers the early detection of HCC. The analysis of different types of biomarkers such as tissue biomarkers, serum biomarkers, protein biomarkers, autoantibody markers, and improved imaging techniques has played a vital role in ameliorating HCC monitoring responses. Therefore biomarkers that can identify HCC early with a high degree of sensitivity and specificity might be prodigiously serviceable in the diagnosis and treatment of this notorious disorder. This study offers an overview of the contemporary understanding of several types of biomarkers implicated in hepatocarcinogenesis and their applications in monitoring, diagnosis, and prognosis presage. In additament, we address the role of image techniques associated with HCC diagnosis.
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Affiliation(s)
- Ishfaq Hassan Mir
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
| | - K C Jyothi
- Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India
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Aboelwafa RA, Ellakany WI, Gamaleldin MA, Saad MA. The expression of microRNA-331-3p and microRNA-23b3 in Egyptian patients with early-stage hepatocellular carcinoma in hepatitis C-related liver cirrhosis. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00122-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatocellular carcinoma and hepatitis C are strongly associated. The current work aimed to study the expression levels of microRNA-331-3p and microRNA-23b-3p as propable biomarkers for detecting liver cancer (HCC) at its early stages in patients with HCV-related liver cirrhosis. The current prospective study included two hundred participants, divided into three groups: group I, 100 patients with HCV-related liver cirrhosis; group II, 50 HCC patients at early stages; and group III, 50 apparentlyhealthy controls. All patients had routine laboratory workup and ultrasound hepatic assessment. Values of microRNA-331-3p and microRNA-23b-3p were measured by real-time quantitative PCR.
Results
Levels of miR-331-3p were significantly higher in HCC patients than in cirrhotic patients and controls (p < 0.001), while levels of miR-23b-3p were significantly lower in HCC patients compared to cirrhotics and controls (p < 0.001). ROC curve revealed that miR-23b-3p had 80% sensitivity and 74% specificity, miR-331-3p had 66% sensitivity and 61% specificity, and AFP had 64% sensitivity and 61% specificity of 61% in discrimination between HCC patients from controls.
Conclusion
Serum miR-23b-3p is a more effective predictor than miR-331-3p and AFP for the development of hepatocellular carcinoma in hepatitis C (HCV)-related cirrhotic patients.
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Klöhn M, Schrader JA, Brüggemann Y, Todt D, Steinmann E. Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5867. [PMID: 34831021 PMCID: PMC8616277 DOI: 10.3390/cancers13225867] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus infections are the leading cause of viral hepatitis in humans, contributing to an estimated 3.3 million symptomatic cases and almost 44,000 deaths annually. Recently, HEV infections have been found to result in chronic liver infection and cirrhosis in severely immunocompromised patients, suggesting the possibility of HEV-induced hepatocarcinogenesis. While HEV-associated formation of HCC has rarely been reported, the expansion of HEV's clinical spectrum and the increasing evidence of chronic HEV infections raise questions about the connection between HEV and HCC. The present review summarizes current clinical evidence of the relationship between HEV and HCC and discusses mechanisms of virus-induced HCC development with regard to HEV pathogenesis. We further elucidate why the development of HEV-induced hepatocellular carcinoma has so rarely been observed and provide an outlook on possible experimental set-ups to study the relationship between HEV and HCC formation.
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Affiliation(s)
- Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Jil Alexandra Schrader
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- German Centre for Infection Research (DZIF), External Partner Site, 44801 Bochum, Germany
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Ko K, Akita T, Satake M, Tanaka J. Epidemiology of viral hepatitis C: Road to elimination in Japan. Glob Health Med 2021; 3:262-269. [PMID: 34782867 DOI: 10.35772/ghm.2021.01069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/26/2021] [Accepted: 07/26/2021] [Indexed: 12/30/2022]
Abstract
Although HCV infection was the main cause of HCC in Japan contributing 70% over two decades after its first cloning in 1989, it was markedly decreased to 49% in 2013 and expected to decrease continuously. Based on blood donor national database, the new incident cases were 0.4/100,000 person-years, the prevalence was 0.13% and the total number was 890,902-1,302,179 in 2015. Establishment of blood donor screening with anti-HCV measurement and nucleic acid test introduced by Japanese Red Cross as pioneer, high-level medical and surgical care, and the government's policy under the Basic Act on Hepatitis Control have changed its epidemiology and outbreak trend and also enforced the disruption of potential transmission cascades. HCV prevalence among the younger generation was extremely low in all regions, and the predominant age for HCC has shifted to over 60 years old population. Considering such changes, HCV induced HCC occurrence is supposed to be ultimately suppressed in the near future. However, taking into account society changes, regulating intravenous drugs users and monitoring high-risk groups such as tattoos, and men who have sex with men are indeed required in Japan. Understanding the epidemiological changes in HCV is important in assigning, modifying, and designating effective response systems. Selective or national action plans, strategic approaches, and cooperation between government sectors have a positive impact on HCV prevention and control. A dramatic decrease in total number of HCV carriers, increase in number of people treated with highly effective DAA, and subsequent high SVR indicates Japan might achieve WHO's target of HCV elimination by 2030.
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Affiliation(s)
- Ko Ko
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masahiro Satake
- Central Blood Institute, Japanese Red Cross Society, Tokyo, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Brozzetti S, Tancredi M, Bini S, De Lucia C, Antimi J, D’Alterio C, De Sanctis GM, Furlan C, Malpassuti VC, Lucatelli P, Di Martino M, Bezzi M, Ciardi A, Pascale RM. HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly. Cancers (Basel) 2021; 13:3025. [PMID: 34204186 PMCID: PMC8235445 DOI: 10.3390/cancers13123025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: "de novo occurrent HCC", "recurrent HCC", and "without HCC". Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: "de novo occurrent'' 18.13% and "recurrent'' 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% "de novo occurrent" HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.
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Affiliation(s)
- Stefania Brozzetti
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Marsia Tancredi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Simone Bini
- Department of Translational and Precision Medicine, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy
| | - Chiara De Lucia
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Jessica Antimi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Chiara D’Alterio
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Giuseppe Maria De Sanctis
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | - Caterina Furlan
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | | | - Pierleone Lucatelli
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Michele Di Martino
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Mario Bezzi
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | - Rosa Maria Pascale
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy;
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Lin CC, Liu TW, Yeh ML, Tsai YS, Tsai PC, Huang CF, Huang JF, Chuang WL, Dai CY, Yu ML. Significant down-regulation of growth hormone receptor expression revealed as a new unfavorable prognostic factor in hepatitis C virus-related hepatocellular carcinoma. Clin Mol Hepatol 2021; 27:313-328. [PMID: 33317258 PMCID: PMC8046631 DOI: 10.3350/cmh.2020.0247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/19/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND/AIMS Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC. METHODS The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed. RESULTS GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II-IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C. CONCLUSION Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.
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Affiliation(s)
- Ching-Chih Lin
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ta-Wei Liu
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Shan Tsai
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
| | - Ming-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine, Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan
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Hussein O, El-Ghitany EM, Omran M, Matariek G, Elbadaly EA, Hamdy R, Gamal A, Zayed MM, Nasr A, Hamdy O, Elbasiony M, Abdelwahab K. High Seroprevalence of Hepatitis C Virus Antibody in Breast Cancer Patients in Egypt. BREAST CANCER-BASIC AND CLINICAL RESEARCH 2021; 15:11782234211002499. [PMID: 33814915 PMCID: PMC7995286 DOI: 10.1177/11782234211002499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 02/12/2021] [Indexed: 11/16/2022]
Abstract
Background: Hepatitis C virus (HCV) is a known risk factor for hepatocellular carcinoma. Several epidemiological studies have pointed out to an association of HCV infection with other extrahepatic malignancies. The role of chronic HCV in breast cancer causation is less clear. Egypt is an endemic area of HCV infection with resulting significant morbidity. The association between HCV status and breast cancer risk in Egyptian women is hitherto unknown. Methods: A retrospective study was performed. The prevalence of anti-HCV seropositivity was estimated in a sample of women with a breast cancer diagnosis, retrieved from the hospital records, and was compared to the raw data of a population study in Egypt. Anti-HCV negative and positive patients were compared regarding the disease course and outcome. Results: Retrospective analysis revealed a markedly high prevalence of anti-HCV seropositivity in young breast cancer patients. In patients younger than 45 years, 13.4% were anti-HCV positive. Seropositivity was 6-fold higher in these patients than in adult females of the same age without cancer diagnosis (P = .003). The biological type, tumor size, nodal status, and disease-free survival were not affected by the patients’ HCV status. Conclusion: Young Egyptian breast cancer patients have a dramatically high prevalence of HCV seropositivity. Further population studies are strongly required to investigate the epidemiological association of these two significant health problems.
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Affiliation(s)
- Osama Hussein
- Oncology Center and Department of Surgery, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Engy Mohamed El-Ghitany
- Tropical Health Department, High Institute of Public Health, Alexandria University, Alexandria, Egypt
| | - Mawadda Omran
- Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | | | | | - Rana Hamdy
- Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Amira Gamal
- Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | | | - Ahmed Nasr
- Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Omar Hamdy
- Oncology Center and Department of Surgery, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed Elbasiony
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Mansoura University, Mansoura, Egypt
| | - Khaled Abdelwahab
- Oncology Center and Department of Surgery, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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41
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Zamaraev AV, Zhivotovsky B, Kopeina GS. Viral Infections: Negative Regulators of Apoptosis and Oncogenic Factors. BIOCHEMISTRY (MOSCOW) 2021. [PMID: 33202204 PMCID: PMC7590567 DOI: 10.1134/s0006297920100077] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The disruption of apoptotic cell death process is closely associated with the etiology of various diseases, including cancer. Permanent viral infections can cause different types of cancers. Oncogenic viruses manipulate both external and internal apoptosis pathways, and inhibit the activity of proapoptotic proteins and signaling pathways, which facilitates carcinogenesis. Ineffective immune surveillance or immune response suppression can induce uncontrolled virus propagation and host cell proliferation. In this review, we discuss current data that provide insights into mechanisms of apoptotic death suppression by viruses and their role in oncogenesis.
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Affiliation(s)
- A V Zamaraev
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia
| | - B Zhivotovsky
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia.,Institute of Environmental Medicine, Karolinska Institute, Stockholm, SE-171 77, Sweden
| | - G S Kopeina
- Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, 119192, Russia.
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42
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Abd-Elfattah ME, Naguib M, Elkheer M, Abdelsameea E, Nada A. The role of IL-4 gene polymorphism in HCV-related hepatocellular carcinoma in Egyptian patients. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00081-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Background
Interleukin-4 (IL-4), a pleiotropic anti-inflammatory cytokine, is produced mainly by activated T helper 2 (Th2). Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer. Alterations influencing IL-4 expression may disturb immune response and may be associated with HCC risk. We aimed to verify role of IL4 gene polymorphism (IL-4-589C/T (rs2243250)) in HCV-related hepatocellular carcinoma in Egyptian patients. IL-4-589C/T (rs2243250) polymorphism was examined in 50 patients with HCC on top of HCV, 40 patients with HCV-induced liver cirrhosis, and 30 healthy controls using the polymerase chain reaction- restriction fragment length polymorphism method.
Results
Overall IL-4 gene polymorphism (IL-4-589C/T (rs2243250)) showed significant difference between hepatocellular carcinoma group versus liver cirrhosis and healthy control groups. TT homozygous genotype was more prevalent in HCC group (24%) versus (5%) in liver cirrhosis and (3.3%) in control. TT homozygous genotype had 10 times more risk of hepatocellular carcinoma versus healthy control group and 6.33 times more risk versus cirrhotic patients group (p value = 0.018 and 0.016 respectively).
Conclusion
IL-4-589C/T (rs2243250) polymorphism, TT homozygous genetic model, may be a risk factor in HCV-related HCC in Egyptian patients.
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43
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The Pivotal Role of Viruses in the Pathogeny of Chronic Lymphocytic Leukemia: Monoclonal (Type 1) IgG K Cryoglobulinemia and Chronic Lymphocytic Leukemia Diagnosis in the Course of a Human Metapneumovirus Infection. Viruses 2021; 13:v13010115. [PMID: 33466993 PMCID: PMC7830454 DOI: 10.3390/v13010115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Type-1 cryoglobulinemia (CG) is a rare disease associated with B-cell lymphoproliferative disorder. Some viral infections, such as Epstein–Barr Virus infections, are known to cause malignant lymphoproliferation, like certain B-cell lymphomas. However, their role in the pathogenesis of chronic lymphocytic leukemia (CLL) is still debatable. Here, we report a unique case of Type-1 CG associated to a CLL transformation diagnosed in the course of a human metapneumovirus (hMPV) infection. Case presentation: A 91-year-old man was initially hospitalized for delirium. In a context of febrile rhinorrhea, the diagnosis of hMPV infection was made by molecular assay (RT-PCR) on nasopharyngeal swab. Owing to hyperlymphocytosis that developed during the course of the infection and unexplained peripheral neuropathy, a type-1 IgG Kappa CG secondary to a CLL was diagnosed. The patient was not treated for the CLL because of Binet A stage classification and his poor physical condition. Conclusions: We report the unique observation in the literature of CLL transformation and hMPV infection. We provide a mini review on the pivotal role of viruses in CLL pathophysiology.
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Helal M, Yan C, Gong Z. Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model. Sci Rep 2021; 11:1372. [PMID: 33446803 PMCID: PMC7809472 DOI: 10.1038/s41598-020-80621-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 12/11/2020] [Indexed: 01/29/2023] Open
Abstract
It has been well known that tumor progression is dependent on secreted factors not only from tumor cells but also from other surrounding non-tumor cells. In the current study, we investigated the role of cholangiocytes during hepatocarcinogenesis following induction of oncogenic krasV12 expression in hepatocytes using an inducible transgenic zebrafish model. Upon induction of carcinogenesis in hepatocytes, a progressive cell proliferation in cholangiocytes was observed. The proliferative response in cholangiocytes was induced by enhanced lipogenesis and bile acids secretion from hepatocytes through activation of Sphingosine 1 phosphate receptor 2 (S1pr2), a known cholangiocyte receptor involving in cholangiocyte proliferation. Enhancement and inhibition of S1pr2 could accelerate or inhibit cholangiocyte proliferation and hepatocarcinogenesis respectively. Gene expression analysis of hepatocytes and cholangiocytes showed that cholangiocytes stimulated carcinogenesis in hepatocytes via an inflammatory cytokine, Il17a/f1, which activated its receptor (Il17ra1a) on hepatocytes and enhanced hepatocarcinogenesis via an ERK dependent pathway. Thus, the enhancing effect of cholangiocytes on hepatocarcinogenesis is likely via an inflammatory loop.
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Affiliation(s)
- Mohamed Helal
- grid.4280.e0000 0001 2180 6431Department of Biological Sciences, National University of Singapore, Singapore, Singapore ,grid.419615.e0000 0004 0404 7762Marine Pollution Lab, Marine Environment Division, National Institute of Oceanography and Fisheries, Alexandria, Egypt
| | - Chuan Yan
- grid.4280.e0000 0001 2180 6431Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Zhiyuan Gong
- grid.4280.e0000 0001 2180 6431Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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45
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Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection. BIOLOGY 2021; 10:biology10010055. [PMID: 33451143 PMCID: PMC7828638 DOI: 10.3390/biology10010055] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/02/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Gut microbiota alteration is linked to many health disorders including hepatitis C virus (HCV) infection. This dysbiosis in turn impacts the coordination between the gut and the liver that is known as the gut–liver-axis. Here, we discuss the latest findings regarding the changes in gut microbiota structure and functionality post HCV infection and its treatment regimens. In addition, we underline the contribution of the microbiota alterations to HCV associated liver complications. Abstract The gut–liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review sheds light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection.
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46
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The Inflammasome Components NLRP3 and ASC Act in Concert with IRGM To Rearrange the Golgi Apparatus during Hepatitis C Virus Infection. J Virol 2021; 95:JVI.00826-20. [PMID: 33208442 PMCID: PMC7925091 DOI: 10.1128/jvi.00826-20] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022] Open
Abstract
Numerous pathogens can affect cellular homeostasis and organelle dynamics. Hepatitis C virus (HCV) triggers Golgi fragmentation through the immunity-related GTPase M (IRGM), a resident Golgi protein, to enhance its lipid supply for replication. Hepatitis C virus (HCV) infection triggers Golgi fragmentation through the Golgi-resident protein immunity-related GTPase M (IRGM). Here, we report the roles of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) and ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain [CARD]), two inflammasome components, in the initial events leading to this fragmentation. We show that ASC resides at the Golgi with IRGM at homeostasis. Upon infection, ASC dissociates from both IRGM and the Golgi and associates with HCV-induced NLRP3. NLRP3 silencing inhibits Golgi fragmentation. ASC silencing disrupts the Golgi structure in both control and infected cells and reduces the localization of IRGM at the Golgi. IRGM depletion in the ASC-silenced cells cannot totally restore the Golgi structure. These data highlight a role for ASC, upstream of the formation of the inflammasome, in regulating IRGM through its control on the Golgi. A similar mechanism occurs in response to nigericin treatment, but not in cells infected with another member of the Flaviviridae family, Zika virus (ZIKV). We propose a model for a newly ascribed function of the inflammasome components in Golgi structural remodeling during certain stimuli. IMPORTANCE Numerous pathogens can affect cellular homeostasis and organelle dynamics. Hepatitis C virus (HCV) triggers Golgi fragmentation through the immunity-related GTPase M (IRGM), a resident Golgi protein, to enhance its lipid supply for replication. Here, we reveal the role of the inflammasome components NLRP3 and ASC in this process, thus uncovering a new interplay between effectors of inflammation and viral infection or stress. We show that the inflammasome component ASC resides at the Golgi under homeostasis and associates with IRGM. Upon HCV infection, ASC is recruited to NLRP3 and dissociates from IRGM, causing Golgi fragmentation. Our results uncover that aside from their known function in the inflammation response, these host defense regulators also ensure the maintenance of intact intracellular structure in homeostasis, while their activation relieves factors leading to Golgi remodeling.
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47
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Gibriel AA, Al-Anany AM, Al-Arab MAE, Azzazy HME. Investigating circulatory microRNA expression profiles in Egyptian patients infected with hepatitis C virus mediated hepatic disorders. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Suresh D, Srinivas AN, Kumar DP. Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease. Front Oncol 2020; 10:601710. [PMID: 33330100 PMCID: PMC7734960 DOI: 10.3389/fonc.2020.601710] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is a highly aggressive cancer with mortality running parallel to its incidence and has limited therapeutic options. Chronic liver inflammation and injury contribute significantly to the development and progression of HCC. Several factors such as gender, age, ethnicity, and demographic regions increase the HCC incidence rates and the major risk factors are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), carcinogens (food contaminants, tobacco smoking, and environmental toxins), and inherited diseases. In recent years evidence highlights the association of metabolic syndrome (diabetes and obesity), excessive alcohol consumption (alcoholic fatty liver disease), and high-calorie intake (nonalcoholic fatty liver disease) to be the prime causes for HCC in countries with a westernized sedentary lifestyle. HCC predominantly occurs in the setting of chronic liver disease and cirrhosis (80%), however, 20% of the cases have been known in patients with non-cirrhotic liver. It is widely believed that there exist possible interactions between different etiological agents leading to the involvement of diverse mechanisms in the pathogenesis of HCC. Understanding the molecular mechanisms of HCC development and progression is imperative in developing effective targeted therapies to combat this deadly disease. Noteworthy, a detailed understanding of the risk factors is also critical to improve the screening, early detection, prevention, and management of HCC. Thus, this review recapitulates the etiology of HCC focusing especially on the nonalcoholic fatty liver disease (NAFLD)- and alcoholic fatty liver disease (AFLD)-associated HCC.
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Affiliation(s)
- Diwakar Suresh
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Jagadguru Sri Shivarathreeshwara (JSS) Medical College, JSS Academy of Higher Education and Research, Mysuru, India
| | - Akshatha N Srinivas
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Jagadguru Sri Shivarathreeshwara (JSS) Medical College, JSS Academy of Higher Education and Research, Mysuru, India
| | - Divya P Kumar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Jagadguru Sri Shivarathreeshwara (JSS) Medical College, JSS Academy of Higher Education and Research, Mysuru, India
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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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50
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Ng HHM, Lee RY, Goh S, Tay ISY, Lim X, Lee B, Chew V, Li H, Tan B, Lim S, Lim JCT, Au B, Loh JJH, Saraf S, Connolly JE, Loh T, Leow WQ, Lee JJX, Toh HC, Malavasi F, Lee SY, Chow P, Newell EW, Choo SP, Tai D, Yeong J, Lim TKH. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J Immunother Cancer 2020; 8:jitc-2020-000987. [PMID: 32847986 PMCID: PMC7451957 DOI: 10.1136/jitc-2020-000987] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality globally. Immune-checkpoint blockade (ICB) is one of the systemic therapy options for HCC. However, response rates remain low, necessitating robust predictive biomarkers. In the present study, we examined the expression of CD38, a molecule involved in the immunosuppressive adenosinergic pathway, on immune cells present in the tumor microenvironment. We then investigated the association between CD38 and ICB treatment outcomes in advanced HCC. Methods Clinically annotated samples from 49 patients with advanced HCC treated with ICB were analyzed for CD38 expression using immunohistochemistry (IHC), multiplex immunohistochemistry/immunofluorescence (mIHC/IF) and multiplex cytokine analysis. Results IHC and mIHC/IF analyses revealed that higher intratumoral CD38+ cell proportion was strongly associated with improved response to ICB. The overall response rates to ICB was significantly higher among patients with high proportion of total CD38+cells compared with patients with low proportion (43.5% vs 3.9%, p=0.019). Higher responses seen among patients with a high intratumoral CD38+cell proportion translated to a longer median progression-free survival (mPFS, 8.21 months vs 1.64 months, p=0.0065) and median overall survival (mOS, 19.06 months vs 9.59 months, p=0.0295). Patients with high CD38+CD68+macrophage density had a better mOS of 34.43 months compared with 9.66 months in patients with low CD38+CD68+ macrophage density. CD38hi macrophages produce more interferon γ (IFN-γ) and related cytokines, which may explain its predictive value when treated with ICB. Conclusions A high proportion of CD38+ cells, determined by IHC, predicts response to ICB and is associated with superior mPFS and OS in advanced HCC.
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Affiliation(s)
- Harry Ho Man Ng
- Duke-NUS Medical School, Singapore.,Division of Pathology, Singapore General Hospital, Singapore
| | - Ren Yuan Lee
- Division of Pathology, Singapore General Hospital, Singapore.,Nanyang Technological University, Singapore
| | - Siting Goh
- Division of Pathology, Singapore General Hospital, Singapore
| | | | - Xinru Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Bernett Lee
- Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Valerie Chew
- Duke-NUS Medical School, Singapore.,SingHealth Translational Immunology and Inflammation Centre (STIIC), Singapore Health Services Pte Ltd, Singapore
| | - Huihua Li
- Division of Medicine, Singapore General Hospital, Singapore.,Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore
| | - Benedict Tan
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Sherlly Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Jeffrey Chun Tatt Lim
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Bijin Au
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | | | - Sahil Saraf
- Division of Pathology, Singapore General Hospital, Singapore
| | - John Edward Connolly
- Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Tracy Loh
- Division of Pathology, Singapore General Hospital, Singapore
| | - Wei Qiang Leow
- Division of Pathology, Singapore General Hospital, Singapore
| | | | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Fabio Malavasi
- Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Torino, Torino, Italy
| | - Ser Yee Lee
- Duke-NUS Medical School, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Pierce Chow
- Duke-NUS Medical School, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Evan W Newell
- Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
| | - Su Pin Choo
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - David Tai
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore
| | - Joe Yeong
- Division of Pathology, Singapore General Hospital, Singapore .,Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (A*STAR), Singapore.,Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (A*STAR), Singapore
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