|
1
|
Hamdy NM, Sallam AAM, Elazazy O, Kabel AM, Salama RM, Gouhar SA, El-Daly SM, Darwish SF. LincRNA-miR interactions in hepatocellular carcinoma: comprehensive review and in silico analysis: a step toward ncRNA precision. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04285-7. [PMID: 40410550 DOI: 10.1007/s00210-025-04285-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 05/09/2025] [Indexed: 05/25/2025]
Abstract
The most prevalent form of primary liver cancer and one of the chief drivers of cancer-related mortality globally is hepatocellular carcinoma (HCC). Imminent evidence has indicated that non-coding RNAs (ncRNAs) play an integral part in the development and propagation of HCC. RNA stabilization, transcription regulation, chromatin and genomic architecture remodeling, enhancer-associated activity, and other varied properties set long intergenic ncRNA (lincRNA) genes apart from messenger RNA (mRNA)-encoding genes. Through a variety of processes, lincRNAs may generally be used to fine-tune the transcription of nearby genes with exceptional tissue specificity, underscoring our quickly developing knowledge of the non-coding genome. Through their binding with divergent cell targets, some HCC-related ncRNAs have been demonstrated to exhibit abnormal expression, contribute to malignant growth, evade apoptosis, and have invasive potential. Therefore, a better comprehension of lincRNA dysregulation might offer novel perspectives on the pathophysiology of HCC as well as innovative instruments for the early detection and management of HCC. In the present review, we provide an overview of the increasing relevance of lincRNAs as a major contributor to the pathophysiology of HCC, emphasizing their influence on signaling pathways implicated in the development, progression, and response to treatment of tumors. In addition, we go over the new approaches that target lincRNAs for HCC treatment as well as the possible therapeutic uses of lincRNAs as prognostic and diagnostic biomarkers for HCC.
Collapse
Affiliation(s)
- Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo, 11566, Egypt.
| | - Al-Aliaa M Sallam
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo, 11566, Egypt
- Biochemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ola Elazazy
- Biochemistry Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed M Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rania M Salama
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt
| | - Shaimaa A Gouhar
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, 12622, Egypt
| | - Sherien M El-Daly
- Medical Biochemistry Department, Medical Research and Clinical Studies Institute, National Research Centre, Giza, 12622, Egypt
- Cancer Biology and Genetics Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Giza, 12622, Egypt
| | - Samar F Darwish
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
| |
Collapse
|
|
2
|
Ali I, Muhammad S, Naqvi SSZH, Wei L, Yan W, Khan MF, Mahmood A, Liu H, Shah W. Hepatitis B Virus-Associated Liver Carcinoma: The Role of Iron Metabolism and Its Modulation. J Viral Hepat 2025; 32:e14016. [PMID: 39445513 DOI: 10.1111/jvh.14016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 08/17/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024]
Abstract
Hepatitis B virus (HBV) infection is a significant contributor to the development of hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide. Iron, a central co-factor in various metabolic pathways, plays an essential role in liver function, but its dysregulation can lead to severe health consequences. Accumulation of iron within hepatic cells over time is linked to increased liver injury and is strongly associated with sensitive exposure to a range of conditions, including cirrhosis, fibrosis and ultimately, HCC. This review explores the intricate interplay between iron metabolism and HCC within the context of HBV infection. Hepatic iron overload can arise from liver injury and disruptions in iron homeostasis, causing hepatic necrosis, inflammation, and fibrosis, ultimately culminating in carcinogenesis. Moreover, alterations in serum iron components in HBV-related scenarios have been observed to impact the persistence of HBV infection. Notably, the progression of HBV-associated liver damage exhibits distinct characteristics at various stages of liver disease. In addition to elucidating the complex relationship between iron metabolism and HCC in the context of HBV infection, this review also investigates the prognostic implications of systemic iron levels for HCC. Furthermore, it aims to provide a comprehensive understanding of the intricate interplay between iron metabolism and HCC, extending the discussion to the context of hepatitis C virus (HCV) infection. By shedding light on these multifaceted connections, this review aims to contribute to our understanding of the pathogenesis of HBV-associated HCC and potentially identify novel therapeutic avenues for intervention.
Collapse
Affiliation(s)
- Imran Ali
- Department of General Surgery, Subspecialty Hepatobiliary Surgery, Shanxi First Medical Hospital Affiliated With Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Shoaib Muhammad
- Department of Urology, First Hospital of Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Syed Shah Zaman Haider Naqvi
- Department of Endocrinology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences; Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Lingxi Wei
- Laboratory of Physiology, Shanxi Medical University, Jing Zhong, China
| | - Wenqi Yan
- Shandong University, Ji Nan, Shandong, China
| | - Muhammad Fiaz Khan
- Department of Zoology, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Ahmad Mahmood
- Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hong Liu
- Department of General Surgery, Subspecialty Hepatobiliary Surgery, Shanxi First Medical Hospital Affiliated With Shanxi Medical University, Yangzi Qu, Taiyuan, China
| | - Wahid Shah
- Translational Medicine Research Center, Shanxi Medical University, Taiyuan, China
- Shanxi Eye Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
3
|
Yan P, Yu X, Chen Z, Lan L, Kang J, Zhao B, Liu D. Assessing the consistency of FIB-4, APRI, and GPR in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with concurrent liver diseases. BMC Gastroenterol 2025; 25:191. [PMID: 40114058 PMCID: PMC11927168 DOI: 10.1186/s12876-025-03770-w] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
OBJECTIVE This study investigated the consistency of the FIB-4, APRI, and GPR indices in assessing significant liver fibrosis and cirrhosis in patients with Coronavirus Disease 2019(COVID-19) who also suffer from various liver diseases, providing references for the clinical selection and application for non-invasive assessment methods. METHODS The study evaluated 744 COVID-19 patients with coexisting liver diseases: 508 cases with non-alcoholic fatty liver disease (NAFLD), 158 cases with chronic hepatitis B (CHB), and 78 cases with a combination of both ailments. FIB-4, APRI, and GPR were employed to assess significant liver fibrosis and cirrhosis. Concordance among the methods was determined using Kappa analysis, and receiver operating characteristic (ROC) curves helped identify the optimal cutoff values for each index. RESULTS For COVID-19 patients with NAFLD, Kappa values for significant liver fibrosis were 0.81, 0.90, 0.80, and 0.79, and for cirrhosis, they were 0.88, 0.97,0.88, and 0.88, respectively (all p < 0.05). Among those with CHB, Kappa values were 0.81, 0.81, 0.83, and 0.75 for fibrosis, and0.87, 0.91, 0.88, and 0.92 for cirrhosis (all p < 0.05). In patients with coexisting liver diseases, the values were 0.87, 0.86, 0.86, and 0.78 for fibrosis, and 0.67, 0.69, 0.54, and 0.81for cirrhosis (all p < 0.05). Linear trend analysis revealed significant relationships between FIB-4 values, APRI values, GPR values, and the severity of COVID-19 (χ2 trend: 15.205,35.114, and 13.973, respectively, all p < 0.001), between FIB-4 values and APRI values and the coronavirus negative conversion time (all p < 0.05) in COVID-19 with NAFLD, and between FIB-4 values and GPR values and the coronavirus negative conversion time in patients with COVID-19 with CHB(all p < 0.05). CONCLUSION Using the current cutoff values, the non-invasive assessments demonstrated almost perfect consistency in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with liver diseases, though FIB-4 and GPR showed moderate consistency in cirrhosis evaluation in patients with coexisting liver conditions. Moreover, it also indicated that increased liver fibrosis correlates with more severe COVID-19 and prolonged coronavirus negative conversion time.
Collapse
Affiliation(s)
- Pan Yan
- School of Public Health, Chengdu Medical College, Chengdu, Sichuan Province, 610500, China
| | - Xiaoping Yu
- School of Preclinical Medicine, Chengdu University, Chengdu, Sichuan Province, 610106, China
| | - Zhu Chen
- Department of Drug Clinical Trial Center, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Lijuan Lan
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Jun Kang
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Bennan Zhao
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Dafeng Liu
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China.
- , No.377 Jingming Road, Jinjiang District, Chengdu City, Sichuan Province Chengdu, 610060, China.
| |
Collapse
|
|
4
|
Valente LC, Bacil GP, Riechelmann-Casarin L, Barbosa GC, Barbisan LF, Romualdo GR. Exploring in vitro modeling in hepatocarcinogenesis research: morphological and molecular features and similarities to the corresponding human disease. Life Sci 2024; 351:122781. [PMID: 38848937 DOI: 10.1016/j.lfs.2024.122781] [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: 01/06/2024] [Revised: 04/04/2024] [Accepted: 06/04/2024] [Indexed: 06/09/2024]
Abstract
The hepatocellular carcinoma (HCC) features a remarkable epidemiological burden, ranking as the third most lethal cancer worldwide. As the HCC-related molecular and cellular complexity unfolds as the disease progresses, the use of a myriad of in vitro models available is mandatory in translational preclinical research setups. In this review paper, we will compile cutting-edge information on the in vitro bioassays for HCC research, (A) emphasizing their morphological and molecular parallels with human HCC; (B) delineating the advantages and limitations of their application; and (C) offering perspectives on their prospective applications. While bidimensional (2D) (co) culture setups provide a rapid low-cost strategy for metabolism and drug screening investigations, tridimensional (3D) (co) culture bioassays - including patient-derived protocols as organoids and precision cut slices - surpass some of the 2D strategies limitations, mimicking the complex microarchitecture and cellular and non-cellular microenvironment observed in human HCC. 3D models have become invaluable tools to unveil HCC pathophysiology and targeted therapy. In both setups, the recapitulation of HCC in different etiologies/backgrounds (i.e., viral, fibrosis, and fatty liver) may be considered as a fundamental guide for obtaining translational findings. Therefore, a "multimodel" approach - encompassing the advantages of different in vitro bioassays - is encouraged to circumvent "model-biased" outcomes in preclinical HCC research.
Collapse
Affiliation(s)
- Leticia Cardoso Valente
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | - Gabriel Prata Bacil
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Luana Riechelmann-Casarin
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil
| | | | - Luís Fernando Barbisan
- São Paulo State University (UNESP), Institute of Biosciences, Botucatu, Department of Structural and Functional Biology, Brazil
| | - Guilherme Ribeiro Romualdo
- São Paulo State University (UNESP), Medical School, Botucatu, Experimental Research Unit (UNIPEX), Brazil.
| |
Collapse
|
|
5
|
Ozturk NB, Pham HN, Mouhaffel R, Ibrahim R, Alsaqa M, Gurakar A, Saberi B. A Longitudinal Analysis of Mortality Related to Chronic Viral Hepatitis and Hepatocellular Carcinoma in the United States. Viruses 2024; 16:694. [PMID: 38793576 PMCID: PMC11125803 DOI: 10.3390/v16050694] [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: 03/19/2024] [Revised: 04/25/2024] [Accepted: 04/27/2024] [Indexed: 05/26/2024] Open
Abstract
(1) Background: Hepatocellular carcinoma (HCC) contributes to the significant burden of cancer mortality in the United States (US). Despite highly efficacious antivirals, chronic viral hepatitis (CVH) remains an important cause of HCC. With advancements in therapeutic modalities, along with the aging of the population, we aimed to assess the contribution of CVH in HCC-related mortality in the US between 1999-2020. (2) Methods: We queried all deaths related to CVH and HCC in the multiple-causes-of-death files from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) database between 1999-2020. Using the direct method of standardization, we adjusted all mortality information for age and compared the age-adjusted mortality rates (AAMRs) across demographic populations and by percentile rankings of social vulnerability. Temporal shifts in mortality were quantified using log-linear regression models. (3) Results: A total of 35,030 deaths were identified between 1999-2020. The overall crude mortality increased from 0.27 in 1999 to 8.32 in 2016, followed by a slight reduction to 7.04 in 2020. The cumulative AAMR during the study period was 4.43 (95% CI, 4.39-4.48). Males (AAMR 7.70) had higher mortality rates compared to females (AAMR 1.44). Mortality was higher among Hispanic populations (AAMR 6.72) compared to non-Hispanic populations (AAMR 4.18). Higher mortality was observed in US counties categorized as the most socially vulnerable (AAMR 5.20) compared to counties that are the least socially vulnerable (AAMR 2.53), with social vulnerability accounting for 2.67 excess deaths per 1,000,000 person-years. (4) Conclusions: Our epidemiological analysis revealed an overall increase in CVH-related HCC mortality between 1999-2008, followed by a stagnation period until 2020. CVH-related HCC mortality disproportionately affected males, Hispanic populations, and Black/African American populations, Western US regions, and socially vulnerable counties. These insights can help aid in the development of strategies to target vulnerable patients, focus on preventive efforts, and allocate resources to decrease HCC-related mortality.
Collapse
Affiliation(s)
- N. Begum Ozturk
- Department of Medicine, Beaumont Hospital, Royal Oak, MI 48073, USA
| | - Hoang Nhat Pham
- Department of Medicine, University of Arizona Tucson, Tucson, AZ 85721, USA
| | - Rama Mouhaffel
- Department of Medicine, University of Arizona Tucson, Tucson, AZ 85721, USA
| | - Ramzi Ibrahim
- Department of Medicine, University of Arizona Tucson, Tucson, AZ 85721, USA
| | - Marwan Alsaqa
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA
| | - Ahmet Gurakar
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Suite 918, Baltimore, MD 21205, USA
| | - Behnam Saberi
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02130, USA
| |
Collapse
|
|
6
|
Cirovic A, Satarug S. Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium. Int J Mol Sci 2024; 25:1851. [PMID: 38339129 PMCID: PMC10855822 DOI: 10.3390/ijms25031851] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 01/31/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Cadmium (Cd) is an environmental toxicant of worldwide public health significance. Diet is the main non-workplace Cd exposure source other than passive and active smoking. The intestinal absorption of Cd involves transporters for essential metals, notably iron and zinc. These transporters determine the Cd body burden because only a minuscule amount of Cd can be excreted each day. The International Agency for Research on Cancer listed Cd as a human lung carcinogen, but the current evidence suggests that the effects of Cd on cancer risk extend beyond the lung. A two-year bioassay demonstrated that Cd caused neoplasms in multiple tissues of mice. Also, several non-tumorigenic human cells transformed to malignant cells when they were exposed to a sublethal dose of Cd for a prolonged time. Cd does not directly damage DNA, but it influences gene expression through interactions with essential metals and various proteins. The present review highlights the epidemiological studies that connect an enhanced risk of various neoplastic diseases to chronic exposure to environmental Cd. Special emphasis is given to the impact of body iron stores on the absorption of Cd, and its implications for breast cancer prevention in highly susceptible groups of women. Resistance to cell death and other cancer phenotypes acquired during Cd-induced cancer cell transformation, under in vitro conditions, are briefly discussed. The potential role for the ZnT1 efflux transporter in the cellular acquisition of tolerance to Cd cytotoxicity is highlighted.
Collapse
Affiliation(s)
- Aleksandar Cirovic
- Institute of Anatomy, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Soisungwan Satarug
- Kidney Disease Research Collaborative, Translational Research Institute, Woolloongabba, Brisbane, QLD 4102, Australia
| |
Collapse
|
|
7
|
Bunz M, Eisele M, Hu D, Ritter M, Kammerloher J, Lampl S, Schindler M. CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells. Front Cell Infect Microbiol 2024; 14:1338606. [PMID: 38357447 PMCID: PMC10864554 DOI: 10.3389/fcimb.2024.1338606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024] Open
Abstract
The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout in hepatoma cells. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as a regulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might be relevant for viral persistence and chronic infection.
Collapse
Affiliation(s)
- Maximilian Bunz
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Mona Eisele
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Dan Hu
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Michael Ritter
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| | - Julia Kammerloher
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Sandra Lampl
- Institute of Virology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany
| | - Michael Schindler
- Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany
| |
Collapse
|
|
8
|
Maliko M, Su FH, Kamiza AB, Su MJ, Yeh CC. The association between hepatic viral infections and cancers: a cross-sectional study in the Taiwan adult population. Clin Exp Med 2024; 24:20. [PMID: 38279980 PMCID: PMC10821961 DOI: 10.1007/s10238-023-01292-x] [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: 10/04/2023] [Accepted: 12/28/2023] [Indexed: 01/29/2024]
Abstract
BACKGROUND Hepatitis B (HBV) and hepatitis C (HCV) viruses are diseases of global public health concern and are associated with liver cancer. Recent studies have revealed associations between hepatic viral infections and extrahepatic cancers. This study aimed to explore the associations between hepatitis B and C viruses and cancer at baseline in the Taiwan Biobank database while controlling for a wide range of confounding variables. METHODS In a cross-sectional study of adults aged > 20 years, we compared the distribution of demographic factors, lifestyle, and comorbidities between viral and nonviral hepatic groups using the chi-square test. Univariate and multivariate logistic regressions were performed to observe the associations between hepatitis B and C viral infections and cancers by estimating the odds ratio (OR) and 95% confidence interval (CI). Multivariate regression analysis was adjusted for sociodemographic factors, lifestyle, and comorbidities. RESULTS From the database, 2955 participants were identified as having HCV infection, 15,305 as having HBV infection, and 140,108 as the nonviral group. HBV infection was associated with an increased likelihood of liver cancer (adjusted OR (aOR) = 6.60, 95% CI = 3.21-13.57, P < 0.001) and ovarian cancer (aOR = 4.63, 95% CI = 1.98-10.83, P = 0.001). HCV infection was observed to increase the likelihood of liver cancer (aOR = 4.90, 95% CI = 1.37-17.53, P = 0.015), ovarian cancer (aOR = 8.50, 95% CI = 1.78-40.69, P = 0.007), and kidney cancer (aOR = 12.89, 95% CI = 2.41-69.01, P = 0.003). CONCLUSION Our findings suggest that hepatic viral infections are associated with intra- and extrahepatic cancers. However, being cross-sectional, causal inferences cannot be made. A recall-by-genotype study is recommended to further investigate the causality of these associations.
Collapse
Affiliation(s)
- Moreen Maliko
- School of Public Health, College of Public Health, Taipei Medical University, 10F Biomedical Technology Building, No.301, Yuantong Rd., Zhonghe Dist., New Taipei City, 235603, Taiwan
| | - Fu-Hsiung Su
- Department of Family Medicine, Cardinal Tien Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Abram Bunya Kamiza
- Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa
- The African Computational Genomic (TACG) Research Group, MRC/UVRI and LSHTM, Entebbe, Uganda
| | - Ming-Jang Su
- School of Public Health, College of Public Health, Taipei Medical University, 10F Biomedical Technology Building, No.301, Yuantong Rd., Zhonghe Dist., New Taipei City, 235603, Taiwan
- Department of Clinical Pathology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 235041, Taiwan
| | - Chih-Ching Yeh
- School of Public Health, College of Public Health, Taipei Medical University, 10F Biomedical Technology Building, No.301, Yuantong Rd., Zhonghe Dist., New Taipei City, 235603, Taiwan.
- Department of Public Health, College of Public Health, China Medical University, Taichung, 406, Taiwan.
- Cancer Center, Wan Fang Hospital, Taipei Medical University, New Taipei City, 116, Taiwan.
- Master Program in Applied Epidemiology, College of Public Health, Taipei Medical University, New Taipei City, 235603, Taiwan.
| |
Collapse
|
|
9
|
Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
10
|
Rayginia TP, Keerthana CK, Shifana SC, Pellissery MJ, Abhishek A, Anto RJ. Phytochemicals as Potential Lead Molecules against Hepatocellular Carcinoma. Curr Med Chem 2024; 31:5199-5221. [PMID: 38213177 DOI: 10.2174/0109298673275501231213063902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/31/2023] [Accepted: 11/16/2023] [Indexed: 01/13/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, accounting for 85-90% of liver cancer cases and is a leading cause of cancer-related mortality worldwide. The major risk factors for HCC include hepatitis C and B viral infections, along with chronic liver diseases, such as cirrhosis, fibrosis, and non-alcoholic steatohepatitis associated with metabolic syndrome. Despite the advancements in modern medicine, there is a continuous rise in the annual global incidence rate of HCC, and it is estimated to reach >1 million cases by 2025. Emerging research in phytomedicine and chemotherapy has established the anti-cancer potential of phytochemicals, owing to their diverse biological activities. In this review, we report the major phytochemicals that have been explored in combating hepatocellular carcinoma and possess great potential to be used as an alternative or in conjunction with the existing HCC treatment modalities. An overview of the pre-clinical observations, mechanism of action and molecular targets of some of these phytochemicals is also incorporated.
Collapse
Affiliation(s)
- Tennyson Prakash Rayginia
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | - Chenicheri Kizhakkeveettil Keerthana
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Department of Biotechnology, University of Kerala, Thiruvananthapuram, Kerala, 695011, India
| | | | - Maria Joy Pellissery
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
| | - Ajmani Abhishek
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, 695014, India
- Molecular Bioassay Laboratory, Institute of Advanced Virology, Thiruvananthapuram, Kerala, 695317, India
| |
Collapse
|
|
11
|
Diakite M, Shaw-Saliba K, Lau CY. Malignancy and viral infections in Sub-Saharan Africa: A review. FRONTIERS IN VIROLOGY (LAUSANNE, SWITZERLAND) 2023; 3:1103737. [PMID: 37476029 PMCID: PMC10358275 DOI: 10.3389/fviro.2023.1103737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/22/2023]
Abstract
The burden of malignancy related to viral infection is increasing in Sub-Saharan Africa (SSA). In 2018, approximately 2 million new cancer cases worldwide were attributable to infection. Prevention or treatment of these infections could reduce cancer cases by 23% in less developed regions and about 7% in developed regions. Contemporaneous increases in longevity and changes in lifestyle have contributed to the cancer burden in SSA. African hospitals are reporting more cases of cancer related to infection (e.g., cervical cancer in women and stomach and liver cancer in men). SSA populations also have elevated underlying prevalence of viral infections compared to other regions. Of 10 infectious agents identified as carcinogenic by the International Agency for Research on Cancer, six are viruses: hepatitis B and C viruses (HBV and HCV, respectively), Epstein-Barr virus (EBV), high-risk types of human papillomavirus (HPV), Human T-cell lymphotropic virus type 1 (HTLV-1), and Kaposi's sarcoma herpesvirus (KSHV, also known as human herpesvirus type 8, HHV-8). Human immunodeficiency virus type 1 (HIV) also facilitates oncogenesis. EBV is associated with lymphomas and nasopharyngeal carcinoma; HBV and HCV are associated with hepatocellular carcinoma; KSHV causes Kaposi's sarcoma; HTLV-1 causes T-cell leukemia and lymphoma; HPV causes carcinoma of the oropharynx and anogenital squamous cell cancer. HIV-1, for which SSA has the greatest global burden, has been linked to increasing risk of malignancy through immunologic dysregulation and clonal hematopoiesis. Public health approaches to prevent infection, such as vaccination, safer injection techniques, screening of blood products, antimicrobial treatments and safer sexual practices could reduce the burden of cancer in Africa. In SSA, inequalities in access to cancer screening and treatment are exacerbated by the perception of cancer as taboo. National level cancer registries, new screening strategies for detection of viral infection and public health messaging should be prioritized in SSA's battle against malignancy. In this review, we discuss the impact of carcinogenic viruses in SSA with a focus on regional epidemiology.
Collapse
Affiliation(s)
- Mahamadou Diakite
- University Clinical Research Center, University of Sciences, Techniques, and Technologies, Bamako, Mali
| | - Kathryn Shaw-Saliba
- Collaborative Clinical Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Chuen-Yen Lau
- HIV Dynamics and Replication Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States
| |
Collapse
|
|
12
|
Wu Y, Ou S, Liao X, Han C, Yang C, Qin W, Tan Y, Lao Q, Peng T, Ye X. Massive Hepatocellular Carcinoma with Situs Inversus Totalis Achieved a Complete Response Following Camrelizumab Plus Apatinib and Combined with Two-Stage Hepatectomy: A Case Report. Pharmgenomics Pers Med 2023; 16:111-120. [PMID: 36785780 PMCID: PMC9921441 DOI: 10.2147/pgpm.s376596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 11/18/2022] [Indexed: 02/10/2023] Open
Abstract
Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Two-stage hepatectomy (TSH) combined with translational therapy for hepatocellular carcinoma (HCC) with SIT has been rarely reported. We report a 41-year-old man with giant hepatocellular carcinoma (71 mm × 55 mm × 51 mm) whose future residual liver (FLR) and standard liver volume (SLV) ratio at first diagnosis was 37.4%. Preoperative volume assessment of portal vein ligation (PVL) revealed inadequate hypertrophy of FLR. After a multidisciplinary group discussion (MDT), the patient decided to follow conversion therapy. Three months later, ratio of the FLR/SLV increased from 37.4% to 71% after operation, which met the surgical requirements. Second hepatectomy, right lobectomy was successful. There was no recurrence after six months of follow-up. In our case, conversion therapy appears to be effective in maintaining residual liver hyperplasia, reducing tumor load, and preventing tumor progression in patients with large HCC during TSH.
Collapse
Affiliation(s)
- Yining Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Shenjian Ou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Yufeng Tan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Quan Lao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China
| |
Collapse
|
|
13
|
Oncolytic viruses as emerging therapy against cancers including Oncovirus-induced cancers. Eur J Pharmacol 2023; 939:175393. [PMID: 36435236 DOI: 10.1016/j.ejphar.2022.175393] [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: 08/30/2022] [Revised: 11/03/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022]
Abstract
There are several human viruses with known potential for causing cancers including, Hepatitis B virus, Hepatitis C virus, Epstein-Barr virus, Kaposi's sarcoma herpesvirus, Human T-cell lymphotropic virus, Human papillomavirus, and Merkel cell polyomavirus. Cancer is the second leading cause of death that affects humans worldwide, especially in developing countries. Surgery, chemotherapy, and radiotherapy can cure about 60% of humans with cancer but recurrent and metastatic diseases remain a major reason for death. In recent years, understanding the molecular characteristics of cancer cells has led to the improvement of therapeutic strategies using novel emerging therapies. Oncolytic viruses with the potential of lysing cancer cells defined the field of oncolytic virology, hence becoming a biotechnology tool rather than just a cause of disease. This study mainly focused on targeting cell proliferation and death pathways in human tumor-inducing viruses by developing innovative therapies for cancer patients based on the natural oncolytic properties of reovirus. To kill tumor cells efficiently and reduce the chance of recurrence both the direct ability of reovirus infection to lyse the tumor cells and the stimulation of a potent host immune response are applied. Hence, bioengineered stem cells can be used as smart carriers to improve the efficacy of oncolytic reovirus and safety profiles.
Collapse
|
|
14
|
Moustafa S, Kassela K, Bampali M, Dovrolis N, Kakkanas A, Beloukas A, Mavromara P, Karakasiliotis I. Hepatitis C Core Protein Induces a Genotype-Specific Susceptibility of Hepatocytes to TNF-Induced Death In Vitro and In Vivo. Viruses 2022; 14:v14112521. [PMID: 36423130 PMCID: PMC9692671 DOI: 10.3390/v14112521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/01/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in the proliferation, inflammation, and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of the HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh 7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only the HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of the core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal), we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing the HCV 4a core protein were more susceptible to the LPS/Dgal model, while mice expressing the HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis while linking HCV core protein genetic variability to differential pathology in vivo.
Collapse
Affiliation(s)
- Savvina Moustafa
- Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Katerina Kassela
- Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Maria Bampali
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Nikolas Dovrolis
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Athanassios Kakkanas
- Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Apostolos Beloukas
- National AIDS Reference Center of Southern Greece, Department of Public Health Policy, University of West Attica, 12243 Athens, Greece
- Molecular Microbiology & Immunology Lab, Department of Biomedical Sciences, University of West Attica, 11521 Athens, Greece
| | - Penelope Mavromara
- Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Ioannis Karakasiliotis
- Molecular Virology Laboratory, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
- Laboratory of Biology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Correspondence:
| |
Collapse
|
|
15
|
Lu K, Pan Y, Huang Z, Liang H, Ding ZY, Zhang B. TRIM proteins in hepatocellular carcinoma. J Biomed Sci 2022; 29:69. [PMID: 36100865 PMCID: PMC9469581 DOI: 10.1186/s12929-022-00854-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/02/2022] [Indexed: 11/19/2022] Open
Abstract
The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC.
Collapse
Affiliation(s)
- Kan Lu
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China
| | - Yonglong Pan
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China
| | - Zhao Huang
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China
| | - Ze-Yang Ding
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, and Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, Hubei, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| |
Collapse
|
|
16
|
Mofed D, Sabet S, Baiomy AA, Salem TZ. The Transgene Expression of the Immature Form of the HCV Core Protein (C191) and the LncRNA MEG3 Increases Apoptosis in HepG2 Cells. Curr Issues Mol Biol 2022; 44:3632-3647. [PMID: 36005145 PMCID: PMC9406719 DOI: 10.3390/cimb44080249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) are regulated in cancer cells, including lncRNA MEG3, which is downregulated in Hepatocellular Carcinoma (HCC). In addition, hepatitis C virus (HCV) core proteins are known to dysregulate important cellular pathways that are linked to HCC development. In this study, we were interested in evaluating the overexpression of lncRNA MEG3, either alone or in combination with two forms of HCV core protein (C173 and C191) in HepG2 cells. Cell viability was assessed by MTT assay. Transcripts' levels of key genes known to be regulated in HCC, such as p53, DNMT1, miRNA152, TGF-b, and BCL-2, were measured by qRT-PCR. Protein expression levels of caspase-3 and MKI67 were determined by immunocytochemistry and apoptosis assays. The co-expression of lncRNA MEG3 and C191 resulted in a marked increase and accumulation of dead cells and a reduction in cell viability. In addition, a marked increase in the expression of tumor suppressor genes (p53 and miRNA152), as well as a marked decrease in the expression of oncogenes (DNMT1, BCL2, and TGF-b), were detected. Moreover, apoptosis assay results revealed a significant increase in total apoptosis (early and late). Finally, immunocytochemistry results detected a significant increase in apoptotic marker caspase-3 and a decrease in tumor marker MKI67. In this study, transgene expression of C191 and lncRNA MEG3 showed induction in apoptosis in HepG2 cells greater than the expression of each one alone. These results suggest potential anticancer characteristics.
Collapse
Affiliation(s)
- Dina Mofed
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Zoology Graduate Program, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Salwa Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Ahmed A. Baiomy
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Tamer Z. Salem
- Molecular Biology and Virology Lab, Biomedical Sciences Program, Zewail City of Science and Technology, October Gardens, 6th of October City, Giza 12578, Egypt
- Department of Microbial Genetics, Agricultural Genetic Engineering Research Institute (AGERl), Agricultural Research Center (ARC), Giza 12619, Egypt
- National Biotechnology Network of Expertise (NBNE), Academy of Science Research and Technology (ASRT), Cairo 11334, Egypt
- Correspondence: ; Tel.: +20-1014114122
| |
Collapse
|
|
17
|
Desrochers GF, Filip R, Bastianelli M, Stern T, Pezacki JP. microRNA-27b regulates hepatic lipase enzyme LIPC and reduces triglyceride degradation during hepatitis C virus infection. J Biol Chem 2022; 298:101983. [PMID: 35483451 PMCID: PMC9163519 DOI: 10.1016/j.jbc.2022.101983] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 03/24/2022] [Accepted: 03/26/2022] [Indexed: 11/26/2022] Open
Abstract
miRNAs are short, noncoding RNAs that negatively and specifically regulate protein expression, the cumulative effects of which can result in broad changes to cell systems and architecture. The miRNA miR-27b is known to regulate lipid regulatory pathways in the human liver and is also induced by the hepatitis C virus (HCV). However, the functional targets of miR-27b are not well established. Herein, an activity-based protein profiling method using a serine hydrolase probe, coupled with stable isotope labeling and mass spectrometry identified direct and indirect targets of miR-27b. The hepatic lipase C (LIPC) stood out as both highly dependent on miR-27b and as a major modulator of lipid pathway misregulation. Modulation of miR-27b using both exogenous miRNA mimics and inhibitors demonstrated that transcription factors Jun, PPARα, and HNF4α, all of which also influence LIPC levels and activity, are regulated by miR-27b. LIPC was furthermore shown to affect the progress of the life cycle of HCV and to decrease levels of intracellular triglycerides, upon which HCV is known to depend. In summary, this work has demonstrated that miR-27b mediates HCV infection by downregulating LIPC, thereby reducing triglyceride degradation, which in turn increases cellular lipid levels.
Collapse
Affiliation(s)
| | - Roxana Filip
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada
| | - Micheal Bastianelli
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
| | - Tiffany Stern
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada
| | - John Paul Pezacki
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada.
| |
Collapse
|
|
18
|
Kadiri DD, Peela S, Ganguli D. Effect of cirrhosis and hepatitis on the prognosis of liver cancer. THERANOSTICS AND PRECISION MEDICINE FOR THE MANAGEMENT OF HEPATOCELLULAR CARCINOMA 2022:51-72. [DOI: 10.1016/b978-0-323-98806-3.00002-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
19
|
Saurav S, Tanwar J, Ahuja K, Motiani RK. Dysregulation of host cell calcium signaling during viral infections: Emerging paradigm with high clinical relevance. Mol Aspects Med 2021; 81:101004. [PMID: 34304899 PMCID: PMC8299155 DOI: 10.1016/j.mam.2021.101004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/18/2021] [Accepted: 07/16/2021] [Indexed: 12/22/2022]
Abstract
Viral infections are one of the leading causes of human illness. Viruses take over host cell signaling cascades for their replication and infection. Calcium (Ca2+) is a versatile and ubiquitous second messenger that modulates plethora of cellular functions. In last two decades, a critical role of host cell Ca2+ signaling in modulating viral infections has emerged. Furthermore, recent literature clearly implicates a vital role for the organellar Ca2+ dynamics (influx and efflux across organelles) in regulating virus entry, replication and severity of the infection. Therefore, it is not surprising that a number of viral infections including current SARS-CoV-2 driven COVID-19 pandemic are associated with dysregulated Ca2+ homeostasis. The focus of this review is to first discuss the role of host cell Ca2+ signaling in viral entry, replication and egress. We further deliberate on emerging literature demonstrating hijacking of the host cell Ca2+ dynamics by viruses. In particular, a variety of viruses including SARS-CoV-2 modulate lysosomal and cytosolic Ca2+ signaling for host cell entry and replication. Moreover, we delve into the recent studies, which have demonstrated the potential of several FDA-approved drugs targeting Ca2+ handling machinery in inhibiting viral infections. Importantly, we discuss the prospective of targeting intracellular Ca2+ signaling for better management and treatment of viral pathogenesis including COVID-19. Finally, we highlight the key outstanding questions in the field that demand critical and timely attention.
Collapse
Affiliation(s)
- Suman Saurav
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Jyoti Tanwar
- CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi-110025, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Kriti Ahuja
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India
| | - Rajender K Motiani
- Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad-121001, Delhi-NCR, India.
| |
Collapse
|
|
20
|
Wei J, Wang B, Gao X, Sun D. Prognostic Value of a Novel Signature With Nine Hepatitis C Virus-Induced Genes in Hepatic Cancer by Mining GEO and TCGA Databases. Front Cell Dev Biol 2021; 9:648279. [PMID: 34336819 PMCID: PMC8322788 DOI: 10.3389/fcell.2021.648279] [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: 01/13/2021] [Accepted: 05/25/2021] [Indexed: 01/29/2023] Open
Abstract
Background Hepatitis C virus-induced genes (HCVIGs) play a critical role in regulating tumor development in hepatic cancer. The role of HCVIGs in hepatic cancer remains unknown. This study aimed to construct a prognostic signature and assess the value of the risk model for predicting the prognosis of hepatic cancer. Methods Differentially expressed HCVIGs were identified in hepatic cancer data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases using the library (“limma”) package of R software. The protein–protein interaction (PPI) network was constructed using the Cytoscape software. Functional enrichment analysis was performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Univariate and multivariate Cox proportional hazard regression analyses were applied to screen for prognostic HCVIGs. The signature of HCVIGs was constructed. Gene Set Enrichment Analysis (GSEA) compared the low-risk and high-risk groups. Finally, the International Cancer Genome Consortium (ICGC) database was used to validate this prognostic signature. Polymerase chain reaction (PCR) was performed to validate the expression of nine HCVIGs in the hepatic cancer cell lines. Results A total of 143 differentially expressed HCVIGs were identified in TCGA hepatic cancer dataset. Functional enrichment analysis showed that DNA replication was associated with the development of hepatic cancer. The risk score signature was constructed based on the expression of ZIC2, SLC7A11, PSRC1, TMEM106C, TRAIP, DTYMK, FAM72D, TRIP13, and CENPM. In this study, the risk score was an independent prognostic factor in the multivariate Cox regression analysis [hazard ratio (HR) = 1.433, 95% CI = 1.280–1.605, P < 0.001]. The overall survival curve revealed that the high-risk group had a poor prognosis. The Kaplan–Meier Plotter online database showed that the survival time of hepatic cancer patients with overexpression of HCVIGs in this signature was significantly shorter. The prognostic signature-associated GO and KEGG pathways were significantly enriched in the risk group. This prognostic signature was validated using external data from the ICGC databases. The expression of nine prognostic genes was validated in HepG2 and LO-2. Conclusion This study evaluates a potential prognostic signature and provides a way to explore the mechanism of HCVIGs in hepatic cancer.
Collapse
Affiliation(s)
- Jianming Wei
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Bo Wang
- Department of Paediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Xibo Gao
- Department of Dermatology, Tianjin Children's Hospital, Tianjin, China
| | - Daqing Sun
- Department of Paediatric Surgery, Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
21
|
Hatta MNA, Mohamad Hanif EA, Chin SF, Neoh HM. Pathogens and Carcinogenesis: A Review. BIOLOGY 2021; 10:533. [PMID: 34203649 PMCID: PMC8232153 DOI: 10.3390/biology10060533] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 12/24/2022]
Abstract
Cancer is a global health problem associated with genetics and unhealthy lifestyles. Increasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent infection that cause inflammation and DNA damage, initiation of oncogene expression, and immunosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of ten pathogens, their implications, and some future considerations for better management of the disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus (cervical cancer), and Kaposi's Sarcoma Herpes Virus (Kaposi's sarcoma).
Collapse
Affiliation(s)
| | | | | | - Hui-min Neoh
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Ya’acob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (M.N.A.H.); (E.A.M.H.); (S.-F.C.)
| |
Collapse
|
|
22
|
Lim Y, Ku NO. Revealing the Roles of Keratin 8/18-Associated Signaling Proteins Involved in the Development of Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:6401. [PMID: 34203895 PMCID: PMC8232640 DOI: 10.3390/ijms22126401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/08/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023] Open
Abstract
Although hepatocellular carcinoma (HCC) is developed with various etiologies, protection of hepatocytes seems basically essential to prevent the incidence of HCC. Keratin 8 and keratin 18 (K8/K18) are cytoskeletal intermediate filament proteins that are expressed in hepatocytes. They maintain the cell shape and protect cells under stress conditions. Their protective roles in liver damage have been described in studies of mouse models, and K8/K18 mutation frequency in liver patients. Interestingly, K8/K18 bind to signaling proteins such as transcription factors and protein kinases involved in HCC development. Since K8/K18 are abundant cytoskeletal proteins, K8/K18 binding with the signaling factors can alter the availability of the factors. Herein, we discuss the potential roles of K8/K18 in HCC development.
Collapse
Affiliation(s)
- Younglan Lim
- Interdisciplinary Program of Integrated OMICS for Biomedical Sciences, Yonsei University, Seoul 03722, Korea;
| | - Nam-On Ku
- Interdisciplinary Program of Integrated OMICS for Biomedical Sciences, Yonsei University, Seoul 03722, Korea;
- Department of Bio-Convergence ISED, Underwood International College, Yonsei University, Seoul 03722, Korea
| |
Collapse
|
|
23
|
Péneau C, Zucman-Rossi J, Nault JC. Genomics of Viral Hepatitis-Associated Liver Tumors. J Clin Med 2021; 10:1827. [PMID: 33922394 PMCID: PMC8122827 DOI: 10.3390/jcm10091827] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/15/2021] [Accepted: 04/18/2021] [Indexed: 12/25/2022] Open
Abstract
Virus-related liver carcinogenesis is one of the main contributors of cancer-related death worldwide mainly due to the impact of chronic hepatitis B and C infections. Three mechanisms have been proposed to explain the oncogenic properties of hepatitis B virus (HBV) infection: induction of chronic inflammation and cirrhosis, expression of HBV oncogenic proteins, and insertional mutagenesis into the genome of infected hepatocytes. Hepatitis B insertional mutagenesis modifies the function of cancer driver genes and could promote chromosomal instability. In contrast, hepatitis C virus promotes hepatocellular carcinoma (HCC) occurrence mainly through cirrhosis development whereas the direct oncogenic role of the virus in human remains debated. Finally, adeno associated virus type 2 (AAV2), a defective DNA virus, has been associated with occurrence of HCC harboring insertional mutagenesis of the virus. Since these tumors developed in a non-cirrhotic context and in the absence of a known etiological factor, AAV2 appears to be the direct cause of tumor development in these patients via a mechanism of insertional mutagenesis altering similar oncogenes and tumor suppressor genes targeted by HBV. A better understanding of virus-related oncogenesis will be helpful to develop new preventive strategies and therapies directed against specific alterations observed in virus-related HCC.
Collapse
Affiliation(s)
- Camille Péneau
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, F-75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France; (C.P.); (J.Z.-R.)
- Functional Genomics of Solid Tumors Laboratory, Équipe Labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, F-75006 Paris, France
- Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, F-93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, F-93000 Bobigny, France
| |
Collapse
|
|
24
|
Muzica CM, Stanciu C, Huiban L, Singeap AM, Sfarti C, Zenovia S, Cojocariu C, Trifan A. Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: A debate near the end. World J Gastroenterol 2020; 26:6770-6781. [PMID: 33268960 PMCID: PMC7684455 DOI: 10.3748/wjg.v26.i43.6770] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/27/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Direct acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, achieving high rates (≥ 95%) of sustained virological response, with a good safety profile and high compliance rates. Consequently, it had been expected that viral clearance will reduce morbidity and mortality rates, as well as the risk of hepatocellular carcinoma (HCC). However, since 2016, concerns have been raised over an unexpected high rate of HCC occurrence and recurrence after DAA therapy, which led to an avalanche of studies with contradictory results. We aimed to review the most recent and relevant articles regarding the risk of HCC after DAA treatment and identify the associated risk factors.
Collapse
Affiliation(s)
- Cristina Maria Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Laura Huiban
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Catalin Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Sebastian Zenovia
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Camelia Cojocariu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| |
Collapse
|
|
25
|
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.
Collapse
|
|
26
|
Li S, Liu R, Pan Q, Wang G, Cheng D, Yang J, Chen H, Xu G. De novo lipogenesis is elicited dramatically in human hepatocellular carcinoma especially in hepatitis C virus-induced hepatocellular carcinoma. MedComm (Beijing) 2020; 1:178-187. [PMID: 34766116 PMCID: PMC8491216 DOI: 10.1002/mco2.15] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 05/30/2020] [Accepted: 06/02/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. Abnormal de novo lipogenesis is reported to be involved in hepatocarcinogenesis. In current study, de novo lipogenesis and its association with patient survival rate were investigated in human HCC samples induced by hepatitis B virus (HBV), hepatitis C virus (HCV), or nonviral factors. Hepatic mRNA and protein levels of lipogenic transcription factors and lipid synthesis enzymes were examined by realtime‐PCR (RT‐PCR) and western blot. Association of gene expression and patient survival was analyzed using The Cancer Genome Atlas (TCGA) data. Lipogenic pathway regulators such as AKT2, SREBP1c, PPARγ, and lipogenic enzymes such as ACC and FAS were increased in human HCC when compared with control livers. Notably, a more robust increase in de novo lipogenesis was observed in HCV‐HCC when compared to HBV‐HCC and nonviral HCC. High FAS and ACC expression correlated with poor overall survival (OS) in HCV‐HCC. High expression of lipogenesis gene panel significantly correlated with poor OS in HCV‐HCC, but not in HBV‐HCC or nonviral HCC. In sum, de novo lipogenesis is stimulated dramatically in human HCC especially in HCV‐HCC.
Collapse
Affiliation(s)
- Shaojian Li
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Ruonan Liu
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Qinling Pan
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Genshu Wang
- Department of Hepatic Surgery and Liver Transplantation Center The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China
| | - Daorou Cheng
- Hepatobiliary Pancreaticosplenic Surgery Shunde Hospital of Southern Medical University Foshan China
| | - Jie Yang
- Department of Physiology School of Medicine Jinan University Guangzhou China
| | - Hui Chen
- Guangdong Key Laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-sen University Guangzhou China
| | - Geyang Xu
- Department of Physiology School of Medicine Jinan University Guangzhou China
| |
Collapse
|
|
27
|
Abstract
HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.
Collapse
|
|
28
|
Roshdy F, Farag MMS, El-Ahwany E, Mahmode O, Mousa AA, El Talkawy M, Essawy F. Long non-coding RNA HOTAIR and HOTTIP as potential biomarkers for hepatitis C virus genotype 4-induced hepatocellular carcinoma. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2020. [DOI: 10.1186/s43042-020-0048-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract
Background
Long non-coding RNAs (lncRNAs) homeobox (Hox) transcript antisense intergenic RNA (HOTAIR) and HOXA transcript at the distal tip (HOTTIP) have been suggested to be implicated in liver cancer tumorigenesis and progression; however, little is known about the role of the plasma HOTAIR and HOTTIP in liver cancer diagnosis and prognosis. The current study aimed at measuring the plasma levels of long non-coding RNAs (HOTAIR and HOTTIP) expression in chronic liver disease (CLD) due to HCV genotype 4 infection with/without cirrhosis and HCC patients in an attempt to evaluate the potential benefits of these new circulating as non-invasive diagnostic biomarkers and a novel therapeutic strategy for liver cirrhosis and carcinogenesis of Egyptian patients. Hundred subjects were included in this study, divided into two groups; group I (50 patients) were classified into subgroup Ia (CLD without cirrhosis, n = 25) and subgroup Ib (CLD with cirrhosis, n = 25), group II (CLD patients with HCC, n = 25), and control (healthy volunteer, n = 25). The expression of lncRNAs (HOTAIR and HOTTIP) genes was analyzed by real-time PCR.
Results
LncRNAs (HOTAIR and HOTTIP) showed upregulation in all diseased groups, which was in consistent with the progression of the disease toward the HCC stage. In addition, HOTAIR and HOTTIP showed a diagnostic ability to discriminate between cases of cirrhosis and HCC compared with healthy control (p < 0.001), while HOTAIR and HOTTIP did not show a discrimination significant differences between cirrhotic cases and non-cirrhotic cases. By using receiver operating characteristic curve (ROC) analysis, it was found that LncRNAs (HOTAIR and HOTTIP) could diagnose liver cancer with 64.0% sensitivity and 86.0% specificity and 48.0% sensitivity and 88.0% specificity. Furthermore, both genes can be considered as the predictor and prognostic parameters for cirrhosis (OR = 1.111, p = 0.05) and (OR = 1.07, p = 0.05) respectively, and HCC (OR = 1.047, p = 0.01) and (OR = 1.05, p = 0.003). The increased HOTAIR and HOTTIP expression were associated with advanced tumor stages and higher grades.
Conclusion
These results strongly prompt us that HOTAIR and HOTTIP genes can be used as non-invasive prognostic biomarkers and new therapeutic targets for HCV genotype 4-induced HCC.
Collapse
|
|
29
|
Resham S, Saalim M, Manzoor S, Ahmad H, Bangash TA, Latif A, Jaleel S. Mechanistic study of interaction between IL-22 and HCV core protein in the development of hepatocellular carcinoma among liver transplant recipients. Microb Pathog 2020; 142:104071. [PMID: 32074496 DOI: 10.1016/j.micpath.2020.104071] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 02/04/2020] [Accepted: 02/13/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) infects more than 170 million people worldwide that represents a major threat to global public health. Several viruses including HCV have developed mechanisms against the cellular responses essentially "hijacking" the antiviral responses generated against it. Interleukin 22 activated JAK-STAT pathways are responsible for several functions including liver regeneration, antiviral responses and cell cycle regulation. OBJECTIVES Present study aims to un-reveal the speculated role of HCV core protein in perturbing IL-22 mediated JAK-STAT pathway. Principally investigating through interaction with IL-22 and SOCS-3 proteins. PATIENTS AND METHODOLOGY Total 36 liver transplant patients were enrolled in the study. Out of which 24 were found HCV + ve. Immunohistochemistry (IHC) based qualitative expression analysis of IL-22, SOCS-3 and HCV core protein was carried out. Microscopy was performed for detection and visualization of immunostained liver tissues and biopsies. RESULTS Hepatic expression of IL-22, HCV core protein and SOCS-3 showed that SOCS-3 expression levels were considerably high compared to HCV core and IL-22 protein. IL-22's moderate to high expression was found in 70% of the liver transplant patient sample. Total 87% patients showed moderate to high SOCS-3 expression. However, the overall expression of HCV core was stronger in 87% of cirrhotic patients and 14% in HCC patients. Suggesting the presence of HCV core protein clearly impacted the IL-22 mediated cellular signaling (JAK-STAT pathway leading towards hepatocarcinogenesis. CONCLUSION HCV core and IL-22 and SOCS-3 molecules are found to be correlated statistically under this study. Concluded from this study that HCV core protein plays a potential role in diverging the hepatocytes from normal to carcinogenic. One cell signaling path cannot decide, the direct role of a single viral protein in developing viral induced hepatocarcinogenesis. Interpreting the complex network of cell signaling involved in HCC development is impractical to study under single study. That is why step by step unmasking the interactive role of few molecules under single study is the ideal way to resolve the impact of viral proteins on cell signaling. SOCS-3 is mediator for dysregulating IL-22 mediated liver regenerative pathway. Moreover, SOCS-3 and STAT-3 molecules are proposed to be a potential therapeutic target for managing HCC progression.
Collapse
Affiliation(s)
- Saleha Resham
- Atta-ur-Rahman School of Applied Bio-Sciences, Department of Healthcare Biotechnology, National University of Sciences and Technology, Islamabad, 44000, Pakistan
| | - Muhammad Saalim
- Atta-ur-Rahman School of Applied Bio-Sciences, Department of Healthcare Biotechnology, National University of Sciences and Technology, Islamabad, 44000, Pakistan
| | - Sobia Manzoor
- Atta-ur-Rahman School of Applied Bio-Sciences, Department of Healthcare Biotechnology, National University of Sciences and Technology, Islamabad, 44000, Pakistan.
| | - Hassam Ahmad
- HepatopancreatoBiliary Liver Transplant Unit, Shaikh Zayd Hospital Lahore, 54000, Punjab, Pakistan
| | - Tariq Ali Bangash
- HepatopancreatoBiliary Liver Transplant Unit, Shaikh Zayd Hospital Lahore, 54000, Punjab, Pakistan
| | - Amer Latif
- HepatopancreatoBiliary Liver Transplant Unit, Shaikh Zayd Hospital Lahore, 54000, Punjab, Pakistan
| | - Shahla Jaleel
- Department of Histopathology, Shaikh Zayd Hospital Lahore, 54000, Punjab, Pakistan
| |
Collapse
|
|
30
|
Miuma S, Miyamoto J, Taura N, Fukushima M, Sasaki R, Haraguchi M, Shibata H, Sato S, Miyaaki H, Nakao K. Influence of Interferon-free Direct-acting Antiviral Therapy on Primary Hepatocellular Carcinoma Recurrence: A Landmark Time Analysis and Time-dependent Extended Cox Proportional Hazards Model Analysis. Intern Med 2020; 59:901-907. [PMID: 32238660 PMCID: PMC7184089 DOI: 10.2169/internalmedicine.3382-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective The influence of interferon (IFN)-free direct-acting antiviral (DAA) on hepatocellular carcinoma (HCC) recurrence remains unclear. Previous retrospective analyses revealed that the time interval between HCC curative treatment and IFN-free DAA induction is the critical factor affecting HCC recurrence. Thus, this study aimed to examine the influence of DAA therapy on HCC recurrence considering this interval. Methods Factors contributing to HCC recurrence were retrospectively analyzed using a landmark time analysis and time-dependent extended Cox proportional hazards model. Patients After screening 620 patients who were diagnosed with primary HCC from January 2001 to December 2016, 76 patients with early-stage (primary and solitary) disease who received curative treatment and were positive for serum hepatitis C virus RNA were included. Results HCC recurrence was observed in 8 of 17 (47.1%) patients who had received IFN-free DAA therapy and 45 of 59 (76.3%) who had not. No significant difference was seen between the IFN-free DAA (-) and IFN-free DAA (+) groups in the landmark time and time-dependent Cox proportional hazards model analyses. However, IFN-free DAA therapy tended to decrease the HCC recurrence rate after curative treatment for primary HCC in patients with chronic hepatitis. In addition, IFN-free DAA therapy tended to decrease the second HCC recurrence rate after treatment for the first HCC recurrence. Conclusion Our results, with a consideration of the time interval between HCC curative treatment and IFN-free DAA induction, showed that IFN-free DAA therapy was not associated with early-stage HCC recurrence after curative treatment.
Collapse
Affiliation(s)
- Satoshi Miuma
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Junya Miyamoto
- Nagasaki University Hospital Clinical Research Center, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Masanori Fukushima
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Ryu Sasaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Masafumi Haraguchi
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Hidetaka Shibata
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Shuntaro Sato
- Nagasaki University Hospital Clinical Research Center, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Japan
| |
Collapse
|
|
31
|
Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells. Cells 2019; 8:cells8111410. [PMID: 31717433 PMCID: PMC6912740 DOI: 10.3390/cells8111410] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.
Collapse
|
|
32
|
Aydin Y, Kurt R, Song K, Lin D, Osman H, Youngquist B, Scott JW, Shores NJ, Thevenot P, Cohen A, Dash S. Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A- miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression. Cancers (Basel) 2019; 11:1407. [PMID: 31547152 PMCID: PMC6827087 DOI: 10.3390/cancers11101407] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/14/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.
Collapse
Affiliation(s)
- Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Ramazan Kurt
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Hanadi Osman
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Brady Youngquist
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - John W Scott
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Nathan J Shores
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| | - Paul Thevenot
- Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA.
| | - Ari Cohen
- Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA.
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
- Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
| |
Collapse
|
|
33
|
Minarovits J, Niller HH. Truncated oncoproteins of retroviruses and hepatitis B virus: A lesson in contrasts. INFECTION GENETICS AND EVOLUTION 2019; 73:342-357. [DOI: 10.1016/j.meegid.2019.05.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/14/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
|
|
34
|
Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, Ma GX, Nguyen MT. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293. [PMID: 31148900 PMCID: PMC6529884 DOI: 10.3748/wjg.v25.i19.2279] [Citation(s) in RCA: 159] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/27/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
Collapse
Affiliation(s)
- Olorunseun O Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Trisheena Harricharran
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Jeannette Huaman
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Anna Galuza
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Oluwatoyin Odumuwagun
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
- Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
| | - Yin Tan
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Grace X Ma
- Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Minhhuyen T Nguyen
- Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
| |
Collapse
|
|
35
|
Mahmoudvand S, Shokri S, Taherkhani R, Farshadpour F. Hepatitis C virus core protein modulates several signaling pathways involved in hepatocellular carcinoma. World J Gastroenterol 2019; 25:42-58. [PMID: 30643357 PMCID: PMC6328967 DOI: 10.3748/wjg.v25.i1.42] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/07/2018] [Accepted: 12/13/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and hepatitis C virus (HCV) infection plays a major role in HCC development. The molecular mechanisms by which HCV infection leads to HCC are varied. HCV core protein is an important risk factor in HCV-associated liver pathogenesis and can modulate several signaling pathways involved in cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress and lipid metabolism. The dysregulation of signaling pathways such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), Wnt/β-catenin (WNT), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor α (PPARα) by HCV core protein is implicated in the development of HCC. Therefore, it has been suggested that this protein be considered a favorable target for further studies in the development of HCC. In addition, considering the axial role of these signaling pathways in HCC, they are considered druggable targets for cancer therapy. Therefore, using strategies to limit the dysregulation effects of core protein on these signaling pathways seems necessary to prevent HCV-related HCC.
Collapse
Affiliation(s)
- Shahab Mahmoudvand
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Somayeh Shokri
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715794, Iran
- Department of Medical Virology, School of Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
| | - Reza Taherkhani
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| |
Collapse
|
|
36
|
Dhanasekaran R, Nault JC, Roberts LR, Zucman-Rossi J. Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Gastroenterology 2019; 156:492-509. [PMID: 30404026 PMCID: PMC6340723 DOI: 10.1053/j.gastro.2018.11.001] [Citation(s) in RCA: 148] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/31/2018] [Accepted: 11/01/2018] [Indexed: 02/07/2023]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer.
Collapse
Affiliation(s)
| | - Jean-Charles Nault
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France; Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jessica Zucman-Rossi
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte De Recherche 1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France; Hôpital Europeen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
| |
Collapse
|
|
37
|
Jindal A, Thadi A, Shailubhai K. Hepatocellular Carcinoma: Etiology and Current and Future Drugs. J Clin Exp Hepatol 2019; 9:221-232. [PMID: 31024205 PMCID: PMC6477125 DOI: 10.1016/j.jceh.2019.01.004] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/14/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.
Collapse
Key Words
- AMP, adenosine monophosphate
- AMPK, AMP-activated protein kinase
- ATP, adenosine 5′-triphosphate
- BMF, Bcl2 modifying factor
- BMI, body mass index
- CDK, cyclin-dependent kinase
- CTGF, connective tissue growth factor
- CTL, cytotoxic T lymphocyte
- CTLA, cytotoxic T-lymphocyte-associated protein
- ECM, extracellular matrix
- EFGR, endothelial growth factor receptor
- EGFR, epidermal growth factor receptor
- EMT, Epithelial–mesenchymal transition
- ERK, extracellular signal-regulated kinase
- FDA, Food and Drug Administration
- GFG, fibroblast growth factor
- HBV, hepatitis B virus
- HBcAg, hepatitis B core antibody
- HBsAg, HBV surface antigen
- HCC, Hepatocellular carcinoma
- HCV, hepatitis B virus
- HDV, hepatitis D virus
- HIF, hypoxia-inducible factor
- HIV, human immunodeficiency virus
- IGFR, insulin-like growth factor
- JAK, janus kinase
- MAPK, mitogen-activated protein kinase
- MDSC, myeloid-derived suppressor cell
- NASH, nonalcoholic steatohepatitis
- NK, natural killer
- NKT, natural killer T cell
- ORR, objective response rate
- OS, overall survival
- PAPSS1, 3′-phosphoadenosine 5′-phosphosulfate synthase 1
- PD-L1, programmed death ligand1
- PD1, programmed cell death protein 1
- PDGFR, platelet-derived growth factor receptor
- PEDF, pigment epithelium-derived factor
- PFS, progression-free survival
- PI3K, phosphoinositide 3-kinases
- PTEN, phosphatase and tensin homolog
- PUMA, p53 upregulated modulator of apoptosis
- RFA, radiofrequency ablation
- Rb, retinoblastoma protein
- SCF, stem cell factor
- SHP1, src homology 2 domain–containing phosphatase 1
- STAT3, signal transducer and activator of transcription 3
- TACE, transarterial chemoembolization
- TGF 1, transforming growth factor-1
- TK, tyrosine kinase
- TKI, Tyrosine kinase inhibitor
- TRKA, tropomyosin receptor kinase A
- Treg, regulatory T cells
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- bFGF, basic fibroblast growth factor
- combination therapy
- cyclin-dependent kinase inhibitors
- hepatocellular carcinoma
- hepatology
- tyrosine kinase inhibitors
Collapse
Affiliation(s)
- Aastha Jindal
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Address for correspondence: Aastha Jindal, Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA.
| | - Anusha Thadi
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Kunwar Shailubhai
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Research & Development, Tiziana Lifesciences, Doylestown, PA 18902, USA
| |
Collapse
|
|
38
|
Kogiso T, Sagawa T, Kodama K, Taniai M, Katagiri S, Egawa H, Yamamoto M, Tokushige K. Hepatocellular carcinoma after direct-acting antiviral drug treatment in patients with hepatitis C virus. JGH OPEN 2018; 3:52-60. [PMID: 30834341 PMCID: PMC6386743 DOI: 10.1002/jgh3.12105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 08/26/2018] [Accepted: 10/09/2018] [Indexed: 01/05/2023]
Abstract
Background and Aim Given the use of direct‐acting antivirals (DAAs) to treat hepatitis C virus (HCV), their effects on hepatocarcinogenesis should be determined. Methods This study enrolled 349 patients with HCV who underwent DAA treatment at our hospital between 2014 and 2018. Their median age was 65 years, and 184 were male; 301 cases were of HCV serotype 1, and 48 were of serotype 2. The DAA treatment was daclatasvir/asunaprevir in 107 cases, sofosbuvir (SOF)/ledipasvir in 147 cases, ritonavir‐boosted ombitasvir/paritaprevir in 28 cases, elbasvir/grazoprevir in 19 cases, and SOF/ribavirin in 48 cases. The patients’ histories included hepatocellular carcinoma (HCC) in 45 cases, liver transplant (LT) in 10 cases, and kidney transplant (KT) in 17 cases. Results Sustained virological responses occurred in 335 cases (96%). DAA treatment was initiated a median of 16.3 months after HCC treatment. After DAA treatment, 15 cases (33%) had recurrence of HCC after a median of 11.6 months, and 3 cases (1%) developed de novo HCC. Six LT patients and one KT patient had HCC; however, no HCC was observed after DAA. The incidence of HCC was significantly higher in patients with multiple HCC treatments in the Cox hazard model (hazard ratio 1.664, 95% confidence interval 1.134–2.441, P < 0.01). Surgical resection or LT reduced the risk of HCC. Conclusions DAA did not increase the rate of HCC, even in immunosuppressed patients. However, careful follow‐up for HCC recurrence is required in previously treated cases.
Collapse
Affiliation(s)
- Tomomi Kogiso
- Department of Internal Medicine, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Takaomi Sagawa
- Department of Internal Medicine, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Kazuhisa Kodama
- Department of Internal Medicine, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Makiko Taniai
- Department of Internal Medicine, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Satoshi Katagiri
- Department of Surgery Tokyo Women's Medical University, Yachiyo Medical Center Yachiyo Japan.,Department of Surgery, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Hiroto Egawa
- Department of Surgery, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| | - Katsutoshi Tokushige
- Department of Internal Medicine, Institute of Gastroenterology Tokyo Women's Medical University Tokyo Japan
| |
Collapse
|
|
39
|
Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
Collapse
|
|
40
|
Wang H, Swann R, Thomas E, Innes HA, Valerio H, Hayes PC, Allen S, Barclay ST, Wilks D, Fox R, Bhattacharyya D, Kennedy N, Morris J, Fraser A, Stanley AJ, Gunson R, Mclntyre PG, Hunt A, Hutchinson SJ, Mills PR, Dillon JF. Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis. J Viral Hepat 2018; 25:930-938. [PMID: 29577515 DOI: 10.1111/jvh.12897] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 02/11/2018] [Indexed: 12/13/2022]
Abstract
Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause-specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01-1.65) and HCC (HR: 1.64, 95% CI: 1.09-2.49), but not liver-related death (HR: 1.02, 95% CI: 0.80-1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.
Collapse
Affiliation(s)
- H Wang
- Dundee Epidemiology and Biostatistics Unit, Population Health Sciences, University of Dundee, Dundee, UK
| | - R Swann
- Department of Gastroenterology, Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - E Thomas
- Department of Medicine for the Elderly, North Middlesex Hospital, London, UK
| | - H A Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - H Valerio
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - P C Hayes
- Liver Transplant Unit, Royal Infirmary Edinburgh, Edinburgh, UK
| | - S Allen
- Department of Infectious Diseases, University Hospital Crosshouse, Kilmarnock, UK
| | - S T Barclay
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - D Wilks
- Department of Infectious Diseases, Western General Hospital, Edinburgh, UK
| | - R Fox
- The Brownlee Centre, Glasgow, UK
| | | | | | - J Morris
- Department of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, UK
| | - A Fraser
- Aberdeen Royal Infirmary, Aberdeen, UK
| | - A J Stanley
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - R Gunson
- West of Scotland Virology Centre, Glasgow Royal Infirmary, Glasgow, UK
| | - P G Mclntyre
- Department of Microbiology, Ninewells Hospital and Medical School, Dundee, UK
| | - A Hunt
- Department of Virology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - S J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK
- Health Protection Scotland, Glasgow, UK
| | - P R Mills
- Department of Gastroenterology, Gartnavel General Hospital, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - J F Dillon
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, UK
| |
Collapse
|
|
41
|
Frakes JM, Abuodeh YA, Naghavi AO, Echevarria MI, Shridhar R, Friedman M, Kim R, El-Haddad G, Kis B, Biebel B, Sweeney J, Choi J, Anaya D, Giuliano AR, Hoffe SE. Viral hepatitis associated hepatocellular carcinoma outcomes with yttrium-90 radioembolization. J Gastrointest Oncol 2018; 9:546-552. [PMID: 29998020 DOI: 10.21037/jgo.2018.03.04] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Viral associated (VA) malignancies have recently been correlated with improved outcomes. We sought to evaluate outcomes of patients with hepatocellular carcinoma (HCC) with and without viral hepatitis (hepatitis B and C) treated with lobar yttrium-90 radioembolization (Y-90 RE). Methods After IRB approval, an institutional database of patients with HCC who received RE between 2009-2014 was queried and 99 patients were identified that received a total of 122 lobar RE. Charts were reviewed to capture previous treatments, viral hepatitis status, α-fetoprotein values (AFP), Child-Pugh class (CP), albumin-bilirubin score (ALBI), portal vein thrombosis (PVT), volumes treated and doses delivered. Comparison was made with Chi-square and Mann-Whitney U test. Intrahepatic control (IHC), extrahepatic control (EHC), progression free survival (PFS), and overall survival (OS) were calculated according to the Kaplan-Meier method stratified by cause of underlying liver disease (viral vs. non-viral) and survival differences were assessed via the log-rank test. Hazard ratios were calculated using Cox regression. Results Median follow up for VA HCC and non-VA (NVA) HCC patients was 10.9 months (range, 0.8-46.7 months) and 11.8 months (range, 1.1-62.8 months), respectively. Patients with VA HCC (n=44) were younger (P<0.001) and had smaller pretreatment liver volumes (P<0.001); however, there was no difference with respect to gender, pre-treatment AFP, CP, ALBI, PVT, extrahepatic disease, previous treatment, or dose delivered. Median doses for VA and NVA HCC patients were 129.5 Gy (range, 90-215.8 Gy) and 131 Gy (range, 100.9-265 Gy), respectively (P=0.75). One year IHC showed a strong trend to better control for VA HCC at 67% versus 34% for NVA HCC (P=0.067) but 1 year EHC was significantly worse at 63% for VA HCC versus 86% for NVA HCC (P=0.027). There were no significant differences in survival, with a 1-year PFS of 45% for VA HCC versus 31% for NVA HCC (P=0.56) and 1 year OS of 46% versus 55% (P=0.55). Patients that received salvage treatments, CP A, no PVT, and those without extrahepatic disease had improved OS. Conclusions Patients with VA HCC had a trend to improved IHC and significantly worse EHC. Prospective investigation of novel systemic therapies following Y-90 RE in patients with VA HCC is warranted to potentially further extend survival in VA HCC patients by addressing extra-hepatic disease.
Collapse
Affiliation(s)
- Jessica M Frakes
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Yazan A Abuodeh
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Arash O Naghavi
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Michelle I Echevarria
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Ravi Shridhar
- Department of Radiation Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Ghassan El-Haddad
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Bela Kis
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Benjamin Biebel
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Jennifer Sweeney
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Junsung Choi
- Department of Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Daniel Anaya
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Anna R Giuliano
- Center of Infection Research Center, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Sarah E Hoffe
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| |
Collapse
|
|
42
|
Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
43
|
Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017; 9:1305-1314. [PMID: 29359013 PMCID: PMC5756719 DOI: 10.4254/wjh.v9.i36.1305] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/08/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.
Collapse
Affiliation(s)
- Mohammad Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Priyanka Gupta
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Khushboo Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| |
Collapse
|
|
44
|
Zheng H, Li P, Kwok JG, Korrapati A, Li WT, Qu Y, Wang XQ, Kisseleva T, Wang-Rodriguez J, Ongkeko WM. Alcohol and hepatitis virus-dysregulated lncRNAs as potential biomarkers for hepatocellular carcinoma. Oncotarget 2017; 9:224-235. [PMID: 29416609 PMCID: PMC5787460 DOI: 10.18632/oncotarget.22921] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 11/09/2017] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths because of frequent late detection and poor therapeutic outcomes, necessitating the need to identify effective biomarkers for early diagnosis and new therapeutic targets for effective treatment. Long noncoding RNAs (lncRNAs) have emerged as promising molecular markers for diagnosis and treatment. Through analysis of patient samples from The Cancer Genome Atlas database, we identified putative lncRNAs dysregulated in HCC and by its risk factors, hepatitis infection and alcohol consumption. We identified 184 lncRNAs dysregulated in HCC tumors versus paired normal samples, 53 lncRNAs dysregulated in alcohol-drinking patients with hepatitis B, and 5, 456 lncRNAs dysregulated in patients with hepatitis infection. A panel of these candidate lncRNAs’ expressions correlated significantly with patient survival, clinical variables, and known genomic alteration in HCC. Two most significantly dysregulated lncRNAs in our computational analysis, lnc-CFP-1:1 and lnc-CD164L2-1:1, were validated in vitro to be dysregulated by alcohol. Our findings suggest that lncRNAs dysregulated by different etiologies of HCC serve as potential disease markers and can be further investigated to develop personalized prevention, diagnosis, and treatment strategies.
Collapse
Affiliation(s)
- Hao Zheng
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Pinxue Li
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - James G Kwok
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Avinaash Korrapati
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Wei Tse Li
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Yuanhao Qu
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Xiao Qi Wang
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| | - Jessica Wang-Rodriguez
- Veterans Administration Medical Center and Department of Pathology, University of California, San Diego, La Jolla, California, USA
| | - Weg M Ongkeko
- Department of Surgery, University of California, San Diego, La Jolla, California, USA
| |
Collapse
|
|
45
|
Marot A, Henrion J, Knebel JF, Moreno C, Deltenre P. Alcoholic liver disease confers a worse prognosis than HCV infection and non-alcoholic fatty liver disease among patients with cirrhosis: An observational study. PLoS One 2017; 12:e0186715. [PMID: 29077714 PMCID: PMC5659599 DOI: 10.1371/journal.pone.0186715] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/08/2017] [Indexed: 02/07/2023] Open
Abstract
Background Cirrhosis is a heterogeneous clinical condition that includes patients at wide-ranging stages of severity. The role of the underlying liver disease on patient prognosis remains unclear. Aim To assess the impact of the underlying liver disease on the occurrence of hepatocellular carcinoma (HCC) and death. Methods Data related to the occurrence of HCC and death were collected during a 21-year period among patients with cirrhosis related to alcoholic liver disease (ALD) (n = 529), chronic hepatitis C virus (HCV) infection (n = 145) or non-alcoholic fatty liver disease (NAFLD) (n = 78). Results At inclusion, ALD patients were younger than HCV and NAFLD patients (56 vs. 67 vs. 63 years; p<0.001) and had worse liver function (percent of patients with Child-Pugh stages B or C: 48% vs. 8% vs. 17%; p<0.001). During follow-up, 85 patients developed HCC and 379 died. The 10-year cumulative incidence rate of HCC was lower in ALD patients than in HCV and NAFLD patients (8.4% vs. 22.0% vs. 23.7%; p<0.001). The 10-year cumulative incidence rates of mortality were not statistically different between ALD, HCV and NAFLD patients (58.1% vs. 47.7% vs. 49.9%; p = 0.078). Alcohol abstinence and viral eradication were associated with reduced mortality among ALD and HCV patients, respectively. In multivariate analyses, ALD was associated with a reduced risk of HCC (0.39; 95% CI, 0.20–0.76; p = 0.005) but with a higher risk of mortality (1.53; 95% CI, 1.20–1.95; p<0.001). ALD patients died more frequently from decompensation of cirrhosis. Conclusion Despite a lower incidence of HCC, patients with ALD-related cirrhosis have a worse outcome than those with chronic HCV infection or NAFLD-related cirrhosis.
Collapse
Affiliation(s)
- Astrid Marot
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Université de Lausanne, Lausanne, Switzerland
| | - Jean Henrion
- Division of Gastroenterology and Hepatology, Centres hospitaliers de Jolimont, Haine-Saint-Paul, Belgium
| | - Jean-François Knebel
- Laboratory for Investigative Neurophysiology (The LINE), Department of Radiology and Department of Clinical Neurosciences, University Hospital Center and University of Lausanne, Lausanne, Switzerland
- EEG Brain Mapping Core, Centre for Biomedical Imaging (CIBM), Lausanne, Switzerland
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Pierre Deltenre
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, Université de Lausanne, Lausanne, Switzerland
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- * E-mail:
| |
Collapse
|
|
46
|
Medvedev R, Ploen D, Spengler C, Elgner F, Ren H, Bunten S, Hildt E. HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles. Free Radic Biol Med 2017; 110:300-315. [PMID: 28673615 DOI: 10.1016/j.freeradbiomed.2017.06.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 06/26/2017] [Accepted: 06/29/2017] [Indexed: 02/07/2023]
Abstract
Viruses are known to exploit the autophagic machinery for their own benefit. In case of the hepatitis C virus autophagy is induced. As autophagy serves as a degradation pathway to maintain cellular homeostasis, it is activated in response to cellular stress such as elevated levels of reactive oxygen species (ROS). Elevated levels of ROS trigger phosphorylation of the autophagic adaptor protein p62 on Ser349 (pS[349] p62) that is involved in the induction of autophagy. Consequently, pS[349] p62 binds with a higher affinity to Keap1 thereby releasing Nrf2 from the complex with Keap1. Although the released Nrf2 should induce as a heterodimer with the sMaf proteins the expression of Nrf2/ARE-dependent genes, in HCV-positive cells no activation of cytoprotective genes occurs even though elevated amounts of pS[349] p62 are present. In HCV-positive cells, free Nrf2 is trapped via delocalized sMaf proteins at the replicon complexes on the cytoplasmic face of the ER and is therefore prevented from its entry into the nucleus. Scavenging of ROS leads to decreased levels of pS[349] p62 and impaired induction of autophagy. Both, inhibition of autophagy and scavenging of ROS result in decreased amounts of released viral particles. Taken together, these data identify an intricate mechanism of HCV-dependent inhibition of Nrf2/ARE-mediated gene expression which counteracts pS[349] p62-induced activation of Nrf2. Thereby elevated ROS-levels are preserved that in turn activate autophagy to favor HCV particle release.
Collapse
Affiliation(s)
- Regina Medvedev
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Daniela Ploen
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Catrina Spengler
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Fabian Elgner
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Huimei Ren
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Sarah Bunten
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51-59, D-63225 Langen, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Gießen-Marburg-Langen, Germany.
| |
Collapse
|
|
47
|
Xie C, Ma B, Wang N, Wan L. Comparison of serological assessments in the diagnosis of liver fibrosis in bile duct ligation mice. Exp Biol Med (Maywood) 2017; 242:1398-1404. [PMID: 28669222 DOI: 10.1177/1535370217718179] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Liver fibrosis assessment is essential to make a prognosis and to determine the appropriate anti-fibrosis treatment. Non-invasive serum markers are widely studied in patients to assess liver fibrosis due to the limitations of liver biopsy. When using animal models to study the mechanism and intervention of hepatic fibrosis, serum markers might be useful for the continuous assessment of liver fibrosis in individual animals, which could avoid the influence of biological differences between individuals. However, it is unclear whether serum markers can assess hepatic fibrosis in the animal model. In the present study, we evaluated and compared the ability of four serum markers to assess liver fibrosis in bile duct ligation mice. According to the stages of liver fibrosis assessed by pathological changes, mice in this study were divided into five groups (F0, F1, F2, F3, and F4). Subsequently, four serum markers, aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis index based on the 4 factors (FIB-4), and Forns Index, were calculated for each group. Furthermore, the correlations between serum markers and pathological stages and the ability of serological markers to evaluate liver fibrosis were analyzed. AAR, APRI, FIB-4, and Forns Index could significantly distinguish F0-2 from F3-4 mice. APRI, FIB-4, and Forns Index could detect F0-3 from F4 mice. Among these four markers, FIB-4 was the best able to distinguish ≥F2 and ≥F3, with area under the curve values of 0.882 and 0.92, respectively. Forns Index was best for diagnosing F4 with area under the curve value of 0.879. These results demonstrated that serum markers could be used for assessing liver fibrosis in bile duct ligation mice, and therefore, these markers might lead to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals. Impact statement The assessment of liver fibrosis is essential for making a prognosis and determining the appropriate anti-fibrosis treatment. In studies focusing on the mechanism and treatment of liver fibrosis using animal models, it would be more accurate to continuously evaluate liver fibrosis in a single animal to avoid individual biological differences. Unfortunately, it is difficult to perform continuous assessment through liver biopsy in the most commonly used rodent models. It is unclear whether serum markers, which have been used in hepatic fibrosis patients, could be used in animal models. Our results demonstrate that serum markers could be used for assessing liver fibrosis in bile duct ligation mice. This study might contribute to more accurate diagnostic and therapeutic studies through continuous monitoring in individual animals.
Collapse
Affiliation(s)
- Chengxia Xie
- 1 Regenerative Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China
| | - Bo Ma
- 1 Regenerative Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China
| | - Ning Wang
- 1 Regenerative Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China
| | - Lin Wan
- 1 Regenerative Medicine Research Center, West China Hospital, Sichuan University, Sichuan 610041, China.,2 Key Lab of Transplant Engineering and Immunology, MOH, West China Hospital, Sichuan University, Sichuan 610041, China
| |
Collapse
|
|
48
|
Elemeery MN, Badr AN, Mohamed MA, Ghareeb DA. Validation of a serum microRNA panel as biomarkers for early diagnosis of hepatocellular carcinoma post-hepatitis C infection in Egyptian patients. World J Gastroenterol 2017; 23:3864-3875. [PMID: 28638226 PMCID: PMC5467072 DOI: 10.3748/wjg.v23.i21.3864] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 01/18/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prospective importance of serum micro (mi)RNAs (miR-125b, miR-138b, miR-1269, miR-214-5p, miR-494, miR375 and miR-145) as early biomarkers for the diagnosis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).
METHODS Two-hundred and fifty HCV4a patients, 224 HCV4a-HCC patients, and 84 healthy controls were enrolled in the study. Expression levels of miR214-5p, miR-125b, miR-1269 and miR-375 were quantified using quantitative real-time PCR.
RESULTS Expression of the selected miRNAs in serum was significantly lower in HCC patients than in the healthy controls, except for miR-1269 and miR-494. There was a significant difference between HCC and HCV patients, in particular for HCC and late stage fibrosis, rather than HCV patients and early fibrosis. It is obvious that miR-1269 was significantly upregulated in HCC cases compared to hepatic fibrosis cases. Each miRNA can show HCC progression. Multivariate logistic regression analysis indicated that the tested panel of miRNAs (miR214-5p, miR-125b, miR-1269 and miR-375) represent accurate and specific indictors of HCC development.
CONCLUSION This study presents a panel of miRNAs with strong power as putative diagnostic and prognostic biomarkers for HCV-induced HCC. Moreover, miR-214-5p and miR-1269 could be considered as early biomarkers for tracking the progress of liver fibrosis to HCC.
Collapse
|
|
49
|
Abstract
Liver cancer remains one of the most common human cancers with a high mortality rate. Therapies for hepatocellular carcinoma (HCC) remain ineffective, due to the heterogeneity of HCC with regard to both the etiology and mutation spectrum, as well as its chemotherapy resistant nature; thus surgical resection and liver transplantation remain the gold standard of patient care. The most common etiologies of HCC are extrinsic factors. Humans have multiple defense mechanisms against extrinsic factor-induced carcinogenesis, of which tumor suppressors play crucial roles in preventing normal cells from becoming cancerous. The tumor suppressor p53 is one of the most frequently mutated genes in liver cancer. p53 regulates expression of genes involved in cell cycle progression, cell death, and cellular metabolism to avert tumor development due to carcinogens. This review article mainly summarizes extrinsic factors that induce liver cancer and potentially have etiological association with p53, including aflatoxin B1, vinyl chloride, non-alcoholic fatty liver disease, iron overload, and infection of hepatitis viruses.
Collapse
Affiliation(s)
- Tim Link
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Tomoo Iwakuma
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| |
Collapse
|
|
50
|
Zhou JJ, Meng Z, He XY, Cheng D, Ye HL, Deng XG, Chen RF. Hepatitis C virus core protein increases Snail expression and induces epithelial-mesenchymal transition through the signal transducer and activator of transcription 3 pathway in hepatoma cells. Hepatol Res 2017; 47:574-583. [PMID: 27381678 DOI: 10.1111/hepr.12771] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 06/19/2016] [Accepted: 06/29/2016] [Indexed: 12/07/2022]
Abstract
AIM Aberrant expression of Snail, a mediator of epithelial-mesenchymal transition (EMT), is crucial for cancer invasiveness and metastasis. Although hepatitis C virus (HCV) core protein has been implicated in hepatocarcinogenesis, the relationship between HCV core and Snail expression has not been clarified. METHODS HepG2 and Huh7 stable cell lines were established by transfection with pcDNA-HCVc. HepG2-HCVc and Huh7-HCVc cells were co-administered with AG490. Cell migration and invasiveness were tested. STAT3 and Snail expression was analyzed by Real-time PCR and Western blot. RESULTS We found that HCV core is capable of increasing Snail expression and inducing EMT in hepatoma cells. HCV core-induced Snail expression was accompanied by activation of signal transducer and activator of transcription 3 (STAT3), inhibition of STAT3 abrogated HCV core-induced Snail expression and EMT. Furthermore, chromatin immunoprecipitation showed that phosphorylated STAT3 directly binds to the Snail promoter. CONCLUSION Collectively, these results suggest that HCV core would play a role in hepatocellular carcinoma invasiveness and metastasis by activating the STAT3 pathway, increasing Snail expression and subsequently triggering EMT. These findings would advance the understanding of HCV-mediated invasiveness and metastasis, and might provide a new potential therapeutic target for HCV-related hepatocellular carcinoma.
Collapse
Affiliation(s)
- Jia-Jia Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Zhe Meng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Xiao-Yu He
- Laboratory of Biomechanics and Physiology, Guangdong Provincial Institute of Sports Science, Guangzhou, Guangdong Province, China
| | - Di Cheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Hui-Lin Ye
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Xiao-Geng Deng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Ru-Fu Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| |
Collapse
|