|
1
|
Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
Collapse
Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| |
Collapse
|
|
2
|
Pol S. [Hepatocellular carcinoma (HCC)]. MEDECINE TROPICALE ET SANTE INTERNATIONALE 2024; 4:mtsi.v4i4.2024.614. [PMID: 40070978 PMCID: PMC11892391 DOI: 10.48327/mtsi.v4i4.2024.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/15/2024] [Indexed: 03/14/2025]
Abstract
Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.
Collapse
Affiliation(s)
- Stanislas Pol
- AP-HP. Centre Université Paris Centre, Groupe hospitalier Cochin Port Royal, Département médical universitaire de Cancérologie et spécialités médico-chirurgicales, Service des maladies du foie, Paris, France; Université Paris Cité, F-75006, Paris, France
| |
Collapse
|
|
3
|
Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
Collapse
Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy; (L.G.); (L.C.); (V.M.); (F.T.); (I.M.); (G.E.); (R.B.); (M.E.A.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| |
Collapse
|
|
4
|
Capasso M, Cossiga V, Guarino M, Ranieri L, Morisco F. The Role of Hepatitis Viruses as Drivers of Hepatocancerogenesis. Cancers (Basel) 2024; 16:1505. [PMID: 38672587 PMCID: PMC11048534 DOI: 10.3390/cancers16081505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28-30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer.
Collapse
Affiliation(s)
| | - Valentina Cossiga
- Diseases of the Liver and Biliary System Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.G.); (L.R.); (F.M.)
| | | | | | | |
Collapse
|
|
5
|
Elbahrawy A, Atalla H, Mahmoud AA, Eliwa A, Alsawak A, Alboraie M, Madian A, Alashker A, Mostafa S, Alwassief A, Aly HH. Prediction and surveillance of de novo HCC in patients with compensated advanced chronic liver disease after hepatitis C virus eradication with direct antiviral agents. FRONTIERS IN VIROLOGY 2023; 3. [DOI: 10.3389/fviro.2023.1227317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The risk of hepatocellular carcinoma (HCC) diminishes in patients with hepatitis C virus (HCV)-related advanced chronic liver disease after virological cure. However, despite viral clearance, HCV-induced epigenetic alterations, immune dysregulations, and hepatic parenchymal injuries remain, contributing to de novo HCC occurrence. While HCC incidence is low (0.45 – 0.5%) in patients with advanced fibrosis (F3), the presence of liver cirrhosis and clinically significant portal hypertension increases the HCC risk. The cost-effectiveness of lifelong HCC surveillance in patients with compensated advanced chronic liver disease (cACLD) has sparked debate, raising questions about the most reliable noninvasive tests and stratification models for predicting HCC in patients with sustained virological response (SVR). Furthermore, identifying cACLD patients who may not require long-term HCC surveillance after SVR remains crucial. Several HCC risk stratification scores have been suggested for patients with cACLD, and emerging evidence supports individualized care based on personalized risk assessments. This review focuses on revising the pretreatment and posttreatment predictors of HCC, as well as the indications for HCC surveillance in cACLD patients treated with direct-acting antivirals.
Collapse
|
|
6
|
Liu W, Gao L, Hou X, Feng S, Yan H, Pan H, Zhang S, Yang X, Jiang J, Ye F, Zhao Q, Wei L, Han Z. TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300350. [PMID: 37085918 PMCID: PMC10288241 DOI: 10.1002/advs.202300350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/14/2023] [Indexed: 05/03/2023]
Abstract
The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.
Collapse
Affiliation(s)
- Wenting Liu
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lu Gao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Shiyao Feng
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Haixin Yan
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Hongyu Pan
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Shichao Zhang
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Xue Yang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Fei Ye
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| |
Collapse
|
|
7
|
Mahmood F, Xu R, Awan MUN, Jia T, Zhang T, Shi W, Liu M, Han Q, Zhu Q, Zhang Q, Song Y, Xia X, Zhang J. Transcriptomics based identification of S100A3 as the key anti-hepatitis B virus factor of 16F16. Biomed Pharmacother 2023; 163:114904. [PMID: 37207431 DOI: 10.1016/j.biopha.2023.114904] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 05/12/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023] Open
Abstract
More than 250 million people worldwide have chronic hepatitis B virus (HBV) infections, resulting in over 1 million annual fatalities because HBV cannot be adequately treated with current antivirals. Hepatocellular carcinoma (HCC) risk is elevated in the presence of the HBV. Novel and powerful medications that specifically target the persistent viral components are needed to remove infection. This study aimed to use HepG2.2.15 cells and the rAAV-HBV1.3 C57BL/6 mouse model established in our laboratory to examine the effects of 16F16 on HBV. The transcriptome analysis of the samples was performed to examine the impact of 16F16 therapy on host factors. We found that the HBsAg and HBeAg levels significantly decreased in a dose-dependent manner following the 16F16 treatment. 16F16 also showed significant anti-hepatitis B effects in vivo. The transcriptome analysis showed that 16F16 regulated the expression of several proteins in HBV-producing HepG2.2.15 cells. As one of the differentially expressed genes, the role of S100A3 in the anti-hepatitis B process of 16F16 was further investigated. The expression of the S100A3 protein significantly decreased following the 16F16 therapy. And upregulation of S100A3 caused an upregulation of HBV DNA, HBsAg, and HBeAg in HepG2.2.15 cells. Similarly, knockdown of S100A3 significantly reduced the levels of HBsAg, HBeAg, and HBV DNA. Our findings proved that S100A3 might be a new target for combating HBV pathogenesis. 16F16 can target several proteins involved in HBV pathogenesis, and may be a promising drug precursor molecule for the treatment of HBV.
Collapse
Affiliation(s)
- Faisal Mahmood
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Ruixian Xu
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Maher Un Nisa Awan
- Laboratory of Molecular Neurobiology, Medical Faculty, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Ting Jia
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Taoping Zhang
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Wengang Shi
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Min Liu
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Qinqin Han
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Qianhua Zhu
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Qilin Zhang
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China
| | - Yuzhu Song
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China.
| | - Xueshan Xia
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China.
| | - Jinyang Zhang
- Molecular Medicine Research Centre of Yunnan Province, Faculty of Life Science and Technology, Kunming University of Science and Technology, 727 Jingming South Road, Kunming 650500, China.
| |
Collapse
|
|
8
|
Sant’Anna TB, Araujo NM. Adeno-associated virus infection and its impact in human health: an overview. Virol J 2022; 19:173. [PMID: 36316711 PMCID: PMC9623951 DOI: 10.1186/s12985-022-01900-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/04/2022] [Accepted: 10/10/2022] [Indexed: 01/24/2023] Open
Abstract
Discovered as a contaminant of adenovirus stocks in the 1960s, adeno-associated virus (AAV) is a mono-stranded DNA virus that depends on helper factors to replicate. Even though AAV is endemic in the human population (35-80%), it is remarkable that many issues concerning the natural infection by this virus remain unanswered. In this study, we reflect on the main basic aspects of AAV biology and provide an overview of the studies exploring the impact of AAV infection on human health, focusing on three major research areas including, (i) cervical and (ii) liver cancer, and (iii) reproductive system disorders. Conflicting results have been obtained into the association of AAV infection with the occurrence of adverse reproductive outcomes, such as placental complications, spontaneous abortion, and fertility disorders, or with a protective role in HPV-related cervical carcinogenesis. Noteworthy, recent reports have identified AAV insertional mutagenesis as a novel risk factor for the development of hepatocellular carcinoma. This latest finding raises concern regarding the widespread usage of AAV vectors in liver-targeted gene therapy.
Collapse
Affiliation(s)
- Thaís B Sant’Anna
- grid.418068.30000 0001 0723 0931Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | - Natalia M Araujo
- grid.418068.30000 0001 0723 0931Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| |
Collapse
|
|
9
|
Schemmer P, Burra P, Hu R, Hüber CM, Loinaz C, Machida K, Vogel A, Samuel D. State of the art treatment of hepatitis B virus hepatocellular carcinoma and the role of hepatitis B surface antigen post-liver transplantation and resection. Liver Int 2022; 42:288-298. [PMID: 34846790 PMCID: PMC9300017 DOI: 10.1111/liv.15124] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 11/17/2021] [Accepted: 11/28/2021] [Indexed: 01/27/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is the major aetiology of hepatocellular carcinoma (HCC). The optimal goal of therapy, hepatitis B surface antigen (HBsAg) loss and anti-HBs production, is achieved rarely and HBsAg-associated HCC risk is well recognized. Here we review the role of HBsAg in HCC, the link between HBsAg and HCC recurrence post-liver transplantation or resection, and the implications for therapy. HBV-associated carcinogenesis is a multifactorial process. The observation that HBV-related HCC can occur in the absence of cirrhosis is compatible with a direct oncogenic effect of the virus, which may occur via multiple mechanisms, including those mediated by both mutated and unmutated HBsAg. HCC recurrence in HBsAg-positive patients post-liver transplantation has been reported in 10%-15% of patients and is likely to be because of expansion of residual HCC tumour cell populations containing integrated HBV DNA, which expand and independently replicate HBV, leading to the recurrence of both HCC and HBV. The direct role of HBsAg in HCC recurrence post-liver resection is less clear. Cirrhosis is the most important risk factor for HCC development, and precancerous cirrhotic liver remains after resection, with the potential to undergo malignant transformation regardless of the existence of HBV-derived oncogenic drivers. The role of HBsAg in the development of HCC and its recurrence post-surgical intervention has multiple implications for therapy and suggests a potential role for immunotherapy in the future management of HCC, in particular post-liver transplantation. Use of hepatitis B immunoglobulins that target HBsAg directly, alongside immune-oncology therapies, may be relevant in this setting.
Collapse
Affiliation(s)
- Peter Schemmer
- General, Visceral and Transplant SurgeryDepartment of SurgeryMedical University of GrazGrazAustria
| | - Patrizia Burra
- Department of Surgery, Oncology, and GastroenterologyPadua University HospitalPaduaItaly
| | - Rey‐Heng Hu
- Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
| | | | - Carmelo Loinaz
- Department of General and Digestive SurgeryUniversity Hospital 12 de OctubreMadridSpain
| | - Keigo Machida
- Keck Hospital of University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and EndocrinologyMedizinische Hochschule HannoverHannoverGermany
| | - Didier Samuel
- Centre HepatobiliaireUniversity Hospital Paul BrousseUniversity Paris‐Saclay and Inserm‐Paris Saclay Research Unit 1193VillejuifFrance
| |
Collapse
|
|
10
|
Anderson MA, Niyonsenga M, Rosman D, Gee MS. Comparison of Abdominopelvic CT Diagnoses at Academic Teaching Hospitals in Rwanda and the United States. JOURNAL OF GLOBAL RADIOLOGY 2022. [DOI: 10.7191/jgr.2022.1160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Purpose: The purpose of this study was to compare the disease processes encountered on abdominal and pelvic CT examinations at academic teaching hospitals in Rwanda and the United States and to highlight how these differences may impact a global radiology collaboration.
Materials and Methods: In this retrospective study, we included 130 patients (mean 59 +/-17 years, range 20-91, F:M 74:56) who underwent abdominal/pelvic CT examinations between April 1st-12th, 2019. CT examinations were prospectively encountered in clinical work at the Centre Hospitalier Universitaire de Kigali or University Teaching Hospital of Kigali (CHUK) in Kigali, Rwanda, where the radiology report impression, patient age, gender, study indication, CT protocol, and clinical diagnosis were recorded when available. Abdominal/pelvic CT examinations at the Massachusetts General Hospital (MGH) in Boston, Massachusetts, United States were then retrospectively reviewed for the same information. Patient age and gender were compared using Student’s t-test and Chi-square statistic. Frequency of formal recommendations in radiology reports, available comparison of CT examinations, presence of known diagnoses, and intravenous and oral contrast media use were compared using Fisher’s exact test. Diagnostic categories were qualitatively compared.
Results: A wide variety of pathology was encountered by abdominal/pelvic CT at both sites of imaging, with qualitative differences observed in cancer types, infectious agents, and how imaging guides care. Patients in Rwanda were older (p=0.0017), more likely to receive intravenous (p < 0.05) and positive oral contrast (p < 0.05) media and less likely to receive a formal recommendation in their radiology report (p < 0.05). Patients in the United States were more likely to have an available prior abdominal/pelvic CT (p < 0.05), to present for follow-up of a known diagnosis (p < 0.05), and to receive a formal recommendation in their radiology report (p < 0.05).
Conclusion: Participation in global radiology collaborations is beneficial for radiologists by broadening exposure to pathologies and practice different from their own institution and region.
Collapse
Affiliation(s)
| | - Michel Niyonsenga
- University of Rwanda College of Medicine and Health Sciences, Centre Hospitalier Universitaire de Kigali
| | - David Rosman
- Massachusetts General Hospital, Harvard Medical School
| | | |
Collapse
|
|
11
|
Multiomics interrogation into HBV (Hepatitis B virus)-host interaction reveals novel coding potential in human genome, and identifies canonical and non-canonical proteins as host restriction factors against HBV. Cell Discov 2021; 7:105. [PMID: 34725333 PMCID: PMC8560872 DOI: 10.1038/s41421-021-00337-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/22/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B Virus (HBV) constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing were conducted on a recently established HBV replication system, through which we identified multiomic differentially expressed genes (DEGs) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical open reading frames (ncORFs) including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown of SIRT6 had opposite effect. Furthermore, the expression of SIRT6 was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infection in vitro and in vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.
Collapse
|
|
12
|
Montella L, Sarno F, Ambrosino A, Facchini S, D’Antò M, Laterza MM, Fasano M, Quarata E, Ranucci RAN, Altucci L, Berretta M, Facchini G. The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma. Cells 2021; 10:1909. [PMID: 34440678 PMCID: PMC8393830 DOI: 10.3390/cells10081909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.
Collapse
Affiliation(s)
- Liliana Montella
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Federica Sarno
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Annamaria Ambrosino
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Sergio Facchini
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Maria D’Antò
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Maria Maddalena Laterza
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Morena Fasano
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Ermelinda Quarata
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Raffaele Angelo Nicola Ranucci
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Lucia Altucci
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Gaetano Facchini
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| |
Collapse
|
|
13
|
Yuan S, Liao G, Zhang M, Zhu Y, Wang K, Xiao W, Jia C, Dong M, Sun N, Walch A, Xu P, Zhang J, Deng Q, Hu R. Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection. J Hepatol 2021; 75:74-85. [PMID: 33621634 DOI: 10.1016/j.jhep.2021.02.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS HBV remains a global threat to human health. It remains incompletely understood how HBV self-restricts in the host during most adult infections. Thus, we performed multi-omics analyses to systematically interrogate HBV-host interactions and the life cycle of HBV. METHODS RNA-sequencing and ribosome profiling were conducted with cell-based models for HBV replication and gene expression. The novel translational events or products hereby detected were then characterized, and functionally assessed in both cell and mouse models. Moreover, quasi-species analyses of HBV subpopulations were conducted with patients at immune tolerance or activation phases, using next- or third-generation sequencing. RESULTS We identified EnhI-SL (Enhancer I-stem loop) as a new cis element in the HBV genome; mutations disrupting EnhI-SL were found to elevate viral polymerase expression. Furthermore, while re-discovering HpZ/P', a previously under-explored isoform of HBV polymerase, we also identified HBxZ, a novel short isoform of HBX. Having confirmed their existence, we functionally characterized them as potent suppressors of HBV gene expression and genome replication. Mechanistically, HpZ/P' was found to repress HBV gene expression partially by interacting with, and sequestering SUPV3L1. Activation of the host immune system seemed to reduce the abundance of HBV mutants deficient in HpZ/P' or with disruptions in EnhI-SL. Finally, SRSF2, a host RNA spliceosome protein that is downregulated by HBV, was found to promote the splicing of viral pre-genomic RNA and HpZ/P' biogenesis. CONCLUSION This study has identified multiple self-restricting HBV-host interactions. In particular, SRSF2-HpZ/P' appeared to constitute another negative feedback mechanism in the HBV life cycle. Targeting host splicing machinery might thus represent a strategy to intervene in HBV-host interactions. LAY SUMMARY There remain many unknowns about the natural history of HBV infection in adults. Herein, we identified new HBV-host mechanisms which could be responsible for self-restricting infections. Targeting these mechanisms could be a promising strategy for the treatment of HBV infections.
Collapse
Affiliation(s)
- Shilin Yuan
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guanghong Liao
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Menghuan Zhang
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yuanfei Zhu
- Key Laboratory of Medical Molecular Virology (MOE & MOH), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Kun Wang
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Weidi Xiao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, Beijing 102206, China
| | - Caiwei Jia
- Medical College, Guizhou University, Guiyang, Guizhou 550025, China
| | - Minhui Dong
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Na Sun
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Axel Walch
- Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Ping Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Beijing Institute of Lifeomics, Beijing 102206, China.
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital and Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China.
| | - Qiang Deng
- Key Laboratory of Medical Molecular Virology (MOE & MOH), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Ronggui Hu
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advance Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
| |
Collapse
|
|
14
|
Brozzetti S, Tancredi M, Bini S, De Lucia C, Antimi J, D’Alterio C, De Sanctis GM, Furlan C, Malpassuti VC, Lucatelli P, Di Martino M, Bezzi M, Ciardi A, Pascale RM. HCC in the Era of Direct-Acting Antiviral Agents (DAAs): Surgical and Other Curative or Palliative Strategies in the Elderly. Cancers (Basel) 2021; 13:3025. [PMID: 34204186 PMCID: PMC8235445 DOI: 10.3390/cancers13123025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/14/2021] [Accepted: 06/15/2021] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver malignancies, and elderlies have the highest incidence rates. Direct-acting antiviral agents (DAAs) have shown satisfying results in terms of HCV sustained viral response (SVR). However, data regarding HCC risk post-DAA-SVR is still conflicting. This study aims to consider HCC onset in moderate underlying liver disease. We conducted a retrospective study on 227 chronically infected patients (cHCV), treated with DAAs. Patients were divided into three groups: "de novo occurrent HCC", "recurrent HCC", and "without HCC". Fifty-six patients aged <65 years (yDAA) were studied separately. HCC patients aged ≥65 years (DAA-HCC) were compared to a historical group of 100 elderly HCC patients, treated with peginterferon (Peg-IFN) ± ribavirin antiviral agents, non-SVR (hHCC). The HCC prevalence in DAA patients was 32.75%: "de novo occurrent'' 18.13% and "recurrent'' 14.62%, despite 42.85% of them having no fibrosis to mild or moderate fibrosis (F0-F1-F2). yDAA showed 5.36% "de novo occurrent" HCC. Curative procedure rates were compared between DAA-HCC and hHCC at the first and at recurrent presentation (22 (39.29%) vs. 72 (72%); 17 (30.36%) vs. 70 (70%), respectively (p < 0.001)). No significant difference was found in 3-year OS (p = 0.6). However, in cause-specific mortality analysis, HCC-related death was higher in the DAA-treated group, whereas cirrhosis-related death was more common in the historical group (p = 0.0288), considering together the two causes of death. A more accurate patient stratification according to multifactorial and new diagnostic investigations identifying HCC risk might allow an improvement in management and access to curative therapies.
Collapse
Affiliation(s)
- Stefania Brozzetti
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Marsia Tancredi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Simone Bini
- Department of Translational and Precision Medicine, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy
| | - Chiara De Lucia
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Jessica Antimi
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Chiara D’Alterio
- Department of Surgery “Pietro Valdoni”, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (S.B.); (M.T.); (C.D.L.); (J.A.); (C.D.)
| | - Giuseppe Maria De Sanctis
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | - Caterina Furlan
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (G.M.D.S.); (C.F.)
| | | | - Pierleone Lucatelli
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Michele Di Martino
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Mario Bezzi
- Department of Radiological Sciences Policlinico Umberto I, University of Rome La Sapienza, 00161 Rome, Italy; (P.L.); (M.D.M.); (M.B.)
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy;
| | - Rosa Maria Pascale
- Department of Medical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy;
| |
Collapse
|
|
15
|
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
|
|
16
|
Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, Peppelenbosch MP, Liu J, Pan Q. Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection. J Infect Dis 2020; 221:1677-1687. [PMID: 31778167 PMCID: PMC7184909 DOI: 10.1093/infdis/jiz633] [Citation(s) in RCA: 220] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis delta virus (HDV) coinfects with hepatitis B virus (HBV) causing the most severe form of viral hepatitis. However, its exact global disease burden remains largely obscure. We aim to establish the global epidemiology, infection mode-stratified disease progression, and clinical outcome of HDV infection. METHODS We conducted a meta-analysis with a random-effects model and performed data synthesis. RESULTS The pooled prevalence of HDV is 0.80% (95% confidence interval [CI], 0.63-1.00) among the general population and 13.02% (95% CI, 11.96-14.11) among HBV carriers, corresponding to 48-60 million infections globally. Among HBV patients with fulminant hepatitis, cirrhosis, or hepatocellular carcinoma, HDV prevalence is 26.75% (95% CI, 19.84-34.29), 25.77% (95% CI, 20.62-31.27), and 19.80% (95% CI, 10.97-30.45), respectively. The odds ratio (OR) of HDV infection among HBV patients with chronic liver disease compared with asymptomatic controls is 4.55 (95% CI, 3.65-5.67). Hepatitis delta virus-coinfected patients are more likely to develop cirrhosis than HBV-monoinfected patients with OR of 3.84 (95% CI, 1.79-8.24). Overall, HDV infection progresses to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years, on average. CONCLUSIONS Findings suggest that HDV poses a heavy global burden with rapid progression to severe liver diseases, urging effective strategies for screening, prevention, and treatment.
Collapse
Affiliation(s)
- Zhijiang Miao
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Shaoshi Zhang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Xumin Ou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Shan Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, People’s Republic of China
| | - Wenshi Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Jiaye Liu
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
17
|
Itami-Matsumoto S, Hayakawa M, Uchida-Kobayashi S, Enomoto M, Tamori A, Mizuno K, Toyoda H, Tamura T, Akutsu T, Ochiya T, Kawada N, Murakami Y. Circulating Exosomal miRNA Profiles Predict the Occurrence and Recurrence of Hepatocellular Carcinoma in Patients with Direct-Acting Antiviral-Induced Sustained Viral Response. Biomedicines 2019; 7:87. [PMID: 31684167 PMCID: PMC6966514 DOI: 10.3390/biomedicines7040087] [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: 09/18/2019] [Revised: 10/30/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection patients (CH) results in a sustained viral response (SVR) in over 95% of patients. However, hepatocellular carcinoma (HCC) occurs in 1-5% of patients who achieved an SVR after treatment with interferon. We attempted to develop a minimally invasive and highly reliable method of predicting the occurrence and recurrence of HCC in patients who achieved an SVR with DAA therapy. The exosomal miRNA expression patterns of 69 CH patients who underwent HCC curative treatment and 70 CH patients were assessed using microarray analysis. We identified a miRNA expression pattern characteristic of SVR-HCC by using machine learning. Twenty-five of 69 patients had HCC recurrence. The expression of four exosomal miRNAs predicted HCC recurrence with 85.3% accuracy. Fifteen of 70 patients had HCC occurrence. The expression of four exosomal miRNAs predicted the onset of HCC with 85.5% accuracy. The expression patterns of miR-4718, 642a-5p, 6826-3p, and 762 in exosomes were positively correlated with those in the liver, and downregulation of these miRNAs induced cell proliferation and prevented apoptosis in vitro. Aberrant expression of four miRNAs, which was used for prediction, was associated with HCC onset after HCV eradication. Expression patterns of exosomal miRNAs are a promising tool to predict SVR-HCC.
Collapse
Affiliation(s)
- Saori Itami-Matsumoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Michiyo Hayakawa
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Sawako Uchida-Kobayashi
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Kazuyuki Mizuno
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan.
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki, Gifu 503-8502, Japan.
| | - Takeyuki Tamura
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Tatsuya Akutsu
- Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan.
| | - Takahiro Ochiya
- Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| | - Yoshiki Murakami
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
| |
Collapse
|
|
18
|
Lee SW, Lee TY, Peng YC, Yang SS, Yeh HZ, Chang CS. Sorafenib treatment on Chinese patients with advanced hepatocellular carcinoma: A study on prognostic factors of the viral and tumor status. Medicine (Baltimore) 2019; 98:e17692. [PMID: 31689794 PMCID: PMC6946266 DOI: 10.1097/md.0000000000017692] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Sorafenib is of proven efficacy in treating patients of hepatocellular carcinoma (HCC). Our study was aimed to determine the factors influence the sorafenib efficacy.We evaluated data of HCC patients receiving sorafenib from June 2012 to October 2016. All HCC cases were of the Barcelona Clinic Liver Cancer (BCLC) classification stage C. The exclusion criteria: those of BCLC classification stage A or B, with the absence or co-infection of hepatitis B (HBV) and hepatitis C (HCV). The presence of HBV, HCV, macoscopic vascular invasion (MVI) or extrahepatic spread (EHS) was recorded for each patient. Time-to-progression (TTP) and overall survival (OS) were analyzed.Among a total of 90 HCC patients, 48 (53.3%) had HBV infection, 42 (46.7%) had HCV infection, 51 (56.7%) had MVI, and 39 (43.3%) had EHS. Patients with HCV infection showed better TTP and OS than those with HBV infection. Patients with EHS had a longer TTP and OS than those with MVI. For patients with HBV infection, those with EHS had a longer TTP (mean 4.60 vs 2.64 months, P = .002) and OS (mean 6.65 vs 4.53 months, P = .045) compared to those with MVI. Among those with MVI, patients with HBV infection had a poorer TTP (mean 2.64 vs 4.74 months, P = .019) and shorter OS (mean 4.53 vs 7.00 months, P = .059) compared to those with HCV infection.HCC patients with HCV infection or with the presence of EHS showed better sorafenib efficacy.
Collapse
Affiliation(s)
- Shou-Wu Lee
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Chung Shan Medical University, Taichung
| | - Teng-Yu Lee
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Chung Shan Medical University, Taichung
| | - Yen-Chun Peng
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Yang Ming University, Taipei, Taiwan
| | - Sheng-Shun Yang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Yang Ming University, Taipei, Taiwan
| | - Hong-Zen Yeh
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Yang Ming University, Taipei, Taiwan
| | - Chi-Sen Chang
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital
- Department of Internal Medicine, Chung Shan Medical University, Taichung
| |
Collapse
|
|
19
|
Bender D, Hildt E. Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis. Int J Mol Sci 2019; 20:ijms20184659. [PMID: 31546975 PMCID: PMC6769940 DOI: 10.3390/ijms20184659] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/15/2022] Open
Abstract
With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.
Collapse
Affiliation(s)
- Daniela Bender
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institut, Paul-Ehrlich-Straβe 51-59, D-63225 Langen, Germany.
| |
Collapse
|
|
20
|
Gundogdu R, Hergovich A. MOB (Mps one Binder) Proteins in the Hippo Pathway and Cancer. Cells 2019; 8:cells8060569. [PMID: 31185650 PMCID: PMC6627106 DOI: 10.3390/cells8060569] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/03/2019] [Accepted: 06/04/2019] [Indexed: 12/22/2022] Open
Abstract
The family of MOBs (monopolar spindle-one-binder proteins) is highly conserved in the eukaryotic kingdom. MOBs represent globular scaffold proteins without any known enzymatic activities. They can act as signal transducers in essential intracellular pathways. MOBs have diverse cancer-associated cellular functions through regulatory interactions with members of the NDR/LATS kinase family. By forming additional complexes with serine/threonine protein kinases of the germinal centre kinase families, other enzymes and scaffolding factors, MOBs appear to be linked to an even broader disease spectrum. Here, we review our current understanding of this emerging protein family, with emphases on post-translational modifications, protein-protein interactions, and cellular processes that are possibly linked to cancer and other diseases. In particular, we summarise the roles of MOBs as core components of the Hippo tissue growth and regeneration pathway.
Collapse
Affiliation(s)
- Ramazan Gundogdu
- Vocational School of Health Services, Bingol University, 12000 Bingol, Turkey.
| | - Alexander Hergovich
- UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
| |
Collapse
|
|
21
|
Lau YFC, Li Y, Kido T. Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis. Asian J Androl 2019; 21:260-269. [PMID: 29974883 PMCID: PMC6498724 DOI: 10.4103/aja.aja_43_18] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 04/17/2018] [Indexed: 12/13/2022] Open
Abstract
The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum.
Collapse
Affiliation(s)
- Yun-Fai Chris Lau
- Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center and Institute for Human Genetics, University of California, San Francisco, CA 94121, USA
| | - Yunmin Li
- Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center and Institute for Human Genetics, University of California, San Francisco, CA 94121, USA
| | - Tatsuo Kido
- Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center and Institute for Human Genetics, University of California, San Francisco, CA 94121, USA
| |
Collapse
|
|
22
|
Prostaglandin E2 facilitates Hepatitis B virus replication by impairing CTL function. Mol Immunol 2018; 103:243-250. [DOI: 10.1016/j.molimm.2018.08.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 07/18/2018] [Accepted: 08/07/2018] [Indexed: 12/23/2022]
|
|
23
|
Liu H, Li B. The functional role of exosome in hepatocellular carcinoma. J Cancer Res Clin Oncol 2018; 144:2085-2095. [PMID: 30062486 DOI: 10.1007/s00432-018-2712-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with limited therapeutic options. Exosome is a member of extracellular vesicles that can be released by different cells in liver to communicate with other cells. HCC development has been characterized by a dysfunction of exosome regulation through many molecular mechanisms. The aim of the present review is to summarize the literature on exosomes in HCC, their roles in hepatocarcinogenesis from liver disease, molecules exchange between tumor cells and neighboring cells, metastasis, chemoresistant, immunosuppression, early diagnose and therapy application. METHODS Literatures about HCC and exosomes from PubMed databases were reviewed in this article. RESULTS As our review described, exosomes can induce malignant transformation of liver disease via promoting viral diffusion and inflammation, exchange oncogenic factors between tumor cells, sustain tumor growth by neighboring stromal cells, play a important role in metastasis, trigger chemoresistance through transmitting long noncoding RNAs, stimulate immune activation as well as immune evasion, be utilized in biomarkers discovery and therapeutic options. CONCLUSIONS Available data suggested that exosomes may play an important role in HCC development. More studies on the way that exosomes mediated the HCC progression are needed to promote the clinical utilization of exosomes.
Collapse
Affiliation(s)
- Hongyu Liu
- R&D Department of Guanglian Biomedical Technology (Tianjin) Co., Ltd., Tianjin, 300000, China
| | - Baoguo Li
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| |
Collapse
|
|
24
|
More than just oncogenes: mechanisms of tumorigenesis by human viruses. Curr Opin Virol 2018; 32:48-59. [PMID: 30268926 DOI: 10.1016/j.coviro.2018.09.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 09/05/2018] [Accepted: 09/14/2018] [Indexed: 12/18/2022]
Abstract
Most humans are infected with at least one of the known human cancer viruses during their lifetimes. While the initial infection with these viruses does not cause major disease, infected cells can acquire cancer hallmarks, particularly upon immunosuppression or exposure to co-carcinogenic stimuli. Even though cancer formation represents a rare outcome of a viral infection, approximately one out of eight human cancers has a viral etiology. Viral cancers present unique opportunities for prophylaxis, diagnosis, and therapy, as demonstrated by the success of HBV and HPV vaccines and HCV antivirals in decreasing the incidence of tumors that are caused by these viruses. Here we review common characteristics and mechanisms of action of the human oncogenic viruses.
Collapse
|
|
25
|
Zhao D, Jiang X, Xu Y, Yang H, Gao D, Li X, Gao L, Ma C, Liang X. Decreased Siglec-9 Expression on Natural Killer Cell Subset Associated With Persistent HBV Replication. Front Immunol 2018; 9:1124. [PMID: 29899741 PMCID: PMC5988867 DOI: 10.3389/fimmu.2018.01124] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 05/03/2018] [Indexed: 12/23/2022] Open
Abstract
Siglec-9 is an MHC-independent inhibitory receptor selectively expressed on CD56dim NK cells. Its role in infection diseases has not been investigated yet. Here, we studied the potential regulatory roles of NK Siglec-9 in the pathogenesis of chronic hepatitis B (CHB) infection. Flow cytometry evaluated the expression of Siglec-9 and other receptors on peripheral NK cells. Immunofluorescence staining was used to detect Siglec-9 ligands on liver biopsy tissues and cultured hepatocyte cell lines. Siglec-9 blocking assay was carried out and cytokine synthesis and CD107a degranulation was detected by flow cytometry. Compared to healthy donors, CHB patients had decreased Siglec-9+ NK cells, which reversely correlated with serum hepatitis B e antigen and HBV DNA titer. Siglec-9 expression on NK cells from patients achieving sustained virological response recovered to the level of normal donors. Neutralization of Siglec-9 restored cytokine synthesis and degranulation of NK cells from CHB patients. Immunofluorescence staining showed increased expression of Siglec-9 ligands in liver biopsy tissues from CHB patients and in hepatocyte cell lines infected with HBV or stimulated with inflammatory cytokines (IL-6 or TGF-β). These findings identify Siglec-9 as a negative regulator for NK cells contributing to HBV persistence and the intervention of Siglec-9 signaling might be of potentially translational significance.
Collapse
Affiliation(s)
- Di Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China.,Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Xuemei Jiang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China.,Department of Hepatic Diseases, Jinan Infectious Disease Hospital, Jinan, China
| | - Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Huimin Yang
- Department of Nephrology, Qilu Hospital, Shandong University, Jinan, China
| | - Dongni Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Xueen Li
- Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, Shandong University School of Medicine, Jinan, China
| |
Collapse
|
|
26
|
Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study. BMC Cancer 2018; 18:401. [PMID: 29631561 PMCID: PMC5891974 DOI: 10.1186/s12885-018-4292-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 03/22/2018] [Indexed: 02/08/2023] Open
Abstract
Background Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. Methods From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. Results Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81–1.16) and 0.96 (0.80–1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46–14.1). Conclusion Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe. Electronic supplementary material The online version of this article (10.1186/s12885-018-4292-y) contains supplementary material, which is available to authorized users.
Collapse
|
|
27
|
Zhang T, Liu W, Meng W, Zhao H, Yang Q, Gu SJ, Xiao CC, Jia CC, Fu BS. Downregulation of miR-542-3p promotes cancer metastasis through activating TGF-β/Smad signaling in hepatocellular carcinoma. Onco Targets Ther 2018; 11:1929-1939. [PMID: 29670368 PMCID: PMC5896681 DOI: 10.2147/ott.s154416] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) accounts for more than 90% of primary liver cancer. Although great progress has been made on HCC molecular mechanism and therapy techniques, the prognosis of HCC patient is poor due to high metastasis and recurrence. Materials and methods Expression of miR-542-3p was quantified by quantitative real-time PCR (qRT-PCR). The role of miR-542-3p in HCC metastasis was examined using transwell and 3D-culture assay. qRT-PCR, Western blotting and luciferase reporter assay were used to elucidate the mechanisms of miR-542-3p-mediated cancer metastasis. Results and Conclusion In the research, we found that miR-542-3p is decreased in HCC cell lines and tissues, and downregulation of miR-542-3p enhances, while upregulation suppresses HCC cell invasion ability. Further assay demonstrated that miR-542-3p can directly target TGF-β1 3′ untranslated region (3′UTR) to influence TGF-β/Smad signaling pathway, and suppression of miR-542-3p can hyperactivate TGF-β/Smad pathway and further to promote Epithelial-Mesenchyme Transition (EMT) and induce poor prognosis. Lastly, the clinical correlation analysis illustrated that miR-542-3p is negatively related with the activity of TGF-β1. In summary, our results find that miR-542-3p takes an important role on HCC progression and provide more evidence of microRNAs (miRNAs) for cancer therapy.
Collapse
Affiliation(s)
- Tong Zhang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Wei Liu
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Wei Meng
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Hui Zhao
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Qing Yang
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Shi-Jie Gu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| | - Cui-Cui Xiao
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chang-Chang Jia
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Bin-Sheng Fu
- Department of Hepatic Surgery, Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Institute of Sun Yat-sen University, Guangzhou, People's Republic of China.,Organ Transplantation Research Center of Guangdong Province, Guangzhou, People's Republic of China
| |
Collapse
|
|
28
|
Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol 2018; 326:52-59. [PMID: 28860007 DOI: 10.1016/j.cellimm.2017.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/02/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
|
|
29
|
Beasley's 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention. Cancer Epidemiol 2018; 53:195-199. [PMID: 29396075 DOI: 10.1016/j.canep.2018.01.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/05/2018] [Accepted: 01/11/2018] [Indexed: 12/25/2022]
Abstract
The 1981 Lancet paper by Beasley et al., "Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan" is a seminal publication that clearly demonstrated that chronic infection with hepatitis B virus (HBV), as measured by seropositivity for the hepatitis B surface antigen (HBsAg), preceded the development of hepatocellular carcinoma (HCC). In doing so, this study paved the way for liver cancer prevention efforts through the implementation of hepatitis B vaccination programs. In this commentary, we will describe the discovery of HBV, which led to the study by Beasley et al.; summarize the major findings of the Beasley paper and its implications; discuss the importance of well-designed cohort studies for prevention activities; and consider the ramifications of the Beasley study and the work that has followed since.
Collapse
|
|
30
|
Yasunaga J, Matsuoka M. Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development. Cancer Sci 2018; 109:24-32. [PMID: 29143406 PMCID: PMC5765297 DOI: 10.1111/cas.13443] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/02/2017] [Accepted: 11/08/2017] [Indexed: 12/30/2022] Open
Abstract
Chronic infection is one of the major causes of cancer, and there are several mechanisms for infection-mediated oncogenesis. Some pathogens encode gene products that behave like oncogenic factors, hijacking cellular pathways to promote the survival and proliferation of infected cells in vivo. Some of these viral oncoproteins trigger a cellular damage defense response leading to senescence; however, other viral factors hinder this suppressive effect, suggesting that cooperation of those viral factors is important for malignant transformation. Coinfection with multiple agents is known to accelerate cancer development in certain cases. For example, parasitic or bacterial infection is a risk factor for adult T-cell leukemia-lymphoma induced by human T-cell leukemia virus type 1, and Epstein-Barr virus and malaria are closely associated with endemic Burkitt lymphoma. Human immunodeficiency virus type 1 infection is accompanied by various types of infection-related cancer. These findings indicate that these oncogenic pathogens can cooperate to overcome host barriers against cancer development. In this review, the authors focus on the collaborative strategies of pathogens for oncogenesis from two different points of view: (i) the cooperation of two or more different factors encoded by a single pathogen; and (ii) the acceleration of oncogenesis by coinfection with multiple agents.
Collapse
Affiliation(s)
- Jun‐Ichirou Yasunaga
- Laboratory of Virus ControlInstitute for Frontier Life and Medical SciencesKyoto UniversityKyotoJapan
| | - Masao Matsuoka
- Laboratory of Virus ControlInstitute for Frontier Life and Medical SciencesKyoto UniversityKyotoJapan
- Department of Hematology, Rheumatology, and Infectious DiseasesKumamoto University School of MedicineKumamotoJapan
| |
Collapse
|
|
31
|
Protective Effects of Moringa oleifera on HBV Genotypes C and H Transiently Transfected Huh7 Cells. J Immunol Res 2017; 2017:6063850. [PMID: 29214184 PMCID: PMC5682080 DOI: 10.1155/2017/6063850] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 08/25/2017] [Accepted: 09/16/2017] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis B infection treatment implicates a long-lasting treatment. M. oleifera extracts contain compounds with antiviral, antioxidant, and antifibrotic properties. In this study, the effect of M. oleifera was evaluated in Huh7 cells expressing either HBV genotypes C or H for the antiviral, antifibrotic, anti-inflammatory, and antioxidative responses. Huh7 cells were treated with an aqueous extract of M. oleifera (leaves) at doses of 0, 30, 45, or 60 μg/mL. The replicative virus and TGF-β1, CTGF, CAT, IFN-β1, and pgRNA expressions were measured by real time. HBsAg and IL-6 titers were determined by ELISA. CTGF, TGF-β1, IFN-β1, and pgRNA expressions decreased with M. oleifera treatment irrespective of the HBV genotype. HBsAg secretion in the supernatant of transfected Huh7 cells with both HBV genotypes was decreased regardless of the dose of M. oleifera. Similar effect was observed in proinflammatory cytokine IL-6, which had a tendency to decrease at 24 hours of treatment. Transfection with both HBV genotypes strongly decreased CAT expression, which is retrieved with M. oleifera treatment. M. oleifera treatment reduced fibrosis markers, IL-6, and HBsAg secretion in HBV genotypes C and H. However, at the level of replication, only HBV-DNA genotype C was slightly reduced with this treatment.
Collapse
|
|
32
|
Mozzi A, Pontremoli C, Sironi M. Genetic susceptibility to infectious diseases: Current status and future perspectives from genome-wide approaches. INFECTION GENETICS AND EVOLUTION 2017; 66:286-307. [PMID: 28951201 PMCID: PMC7106304 DOI: 10.1016/j.meegid.2017.09.028] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 09/20/2017] [Accepted: 09/21/2017] [Indexed: 02/06/2023]
Abstract
Genome-wide association studies (GWASs) have been widely applied to identify genetic factors that affect complex diseases or traits. Presently, the GWAS Catalog includes > 2800 human studies. Of these, only a minority have investigated the susceptibility to infectious diseases or the response to therapies for the treatment or prevention of infections. Despite their limited application in the field, GWASs have provided valuable insights by pinpointing associations to both innate and adaptive immune response loci, as well as novel unexpected risk factors for infection susceptibility. Herein, we discuss some issues and caveats of GWASs for infectious diseases, we review the most recent findings ensuing from these studies, and we provide a brief summary of selected GWASs for infections in non-human mammals. We conclude that, although the general trend in the field of complex traits is to shift from GWAS to next-generation sequencing, important knowledge on infectious disease-related traits can be still gained by GWASs, especially for those conditions that have never been investigated using this approach. We suggest that future studies will benefit from the leveraging of information from the host's and pathogen's genomes, as well as from the exploration of models that incorporate heterogeneity across populations and phenotypes. Interactions within HLA genes or among HLA variants and polymorphisms located outside the major histocompatibility complex may also play an important role in shaping the susceptibility and response to invading pathogens.
Relatively few GWASs for infectious diseases were performed. Phenotype heterogeneity and case/control misclassification can affect GWAS power. Adaptive and innate immunity loci were identified in several infectious disease GWASs. Unexpected loci (e.g., lncRNAs) were also associated with infection susceptibility. GWASs should integrate host and pathogen diversity and use complex association models.
Collapse
Affiliation(s)
- Alessandra Mozzi
- Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842 Bosisio Parini, Italy
| | - Chiara Pontremoli
- Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842 Bosisio Parini, Italy
| | - Manuela Sironi
- Bioinformatics, Scientific Institute IRCCS E.MEDEA, 23842 Bosisio Parini, Italy.
| |
Collapse
|
|
33
|
Zhen C, Zhu C, Chen H, Xiong Y, Tan J, Chen D, Li J. Systematic analysis of molecular mechanisms for HCC metastasis via text mining approach. Oncotarget 2017; 8:13909-13916. [PMID: 28108733 PMCID: PMC5355149 DOI: 10.18632/oncotarget.14692] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 01/03/2017] [Indexed: 11/29/2022] Open
Abstract
Objective To systematically explore the molecular mechanism for hepatocellular carcinoma (HCC) metastasis and identify regulatory genes with text mining methods. Results Genes with highest frequencies and significant pathways related to HCC metastasis were listed. A handful of proteins such as EGFR, MDM2, TP53 and APP, were identified as hub nodes in PPI (protein-protein interaction) network. Compared with unique genes for HBV-HCCs, genes particular to HCV-HCCs were less, but may participate in more extensive signaling processes. VEGFA, PI3KCA, MAPK1, MMP9 and other genes may play important roles in multiple phenotypes of metastasis. Materials and methods Genes in abstracts of HCC-metastasis literatures were identified. Word frequency analysis, KEGG pathway and PPI network analysis were performed. Then co-occurrence analysis between genes and metastasis-related phenotypes were carried out. Conclusions Text mining is effective for revealing potential regulators or pathways, but the purpose of it should be specific, and the combination of various methods will be more useful.
Collapse
Affiliation(s)
- Cheng Zhen
- Beijing 302 Hospital, Beijing, 100039, China
| | | | | | - Yiru Xiong
- Beijing 302 Hospital, Beijing, 100039, China
| | - Junyuan Tan
- Beijing 302 Hospital, Beijing, 100039, China
| | - Dong Chen
- Beijing 302 Hospital, Beijing, 100039, China
| | - Jin Li
- Beijing 302 Hospital, Beijing, 100039, China
| |
Collapse
|
|
34
|
Shirvani-Dastgerdi E, Winer BY, Celià-Terrassa T, Kang Y, Tabernero D, Yagmur E, Rodríguez-Frías F, Gregori J, Luedde T, Trautwein C, Ploss A, Tacke F. Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy. J Hepatol 2017; 67:246-254. [PMID: 28392234 PMCID: PMC6016549 DOI: 10.1016/j.jhep.2017.03.027] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 03/01/2017] [Accepted: 03/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients chronically infected with the hepatitis B virus (HBV) and receiving long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression, despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF). One patient died from aggressive hepatocellular carcinoma (HCC). METHODS Serum samples from the two patients at different time points were analyzed using ultra-deep pyrosequencing analysis. HBV mutations were identified and transiently transfected into hepatoma cells in vitro using replication-competent HBV vectors, and functionally analyzed. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). RESULTS Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69∗ mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69∗ mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. CONCLUSIONS The rtS78T/sC69∗ HBV mutation, associated with enhanced replication and insufficient response to antiviral treatment, may favor long-term persistence of these isolates. In addition to the increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose patients to carcinogenic effects. LAY SUMMARY Long-term treatment with antiviral drugs carries the risk of selecting mutations in the hepatitis B virus (HBV). We herein report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a distinct mutation, rtS78T/sC69∗, that abolishes HBsAg detection, enhances replication, sustains exosome-mediated virion secretion and decreases susceptibility to antivirals, thereby representing a potentially high-risk mutation for HBV-infected individuals.
Collapse
Affiliation(s)
- Elham Shirvani-Dastgerdi
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany; Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Benjamin Y Winer
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | | | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - David Tabernero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | - Eray Yagmur
- Medical Care Centre, Dr Stein and Colleagues, Mönchengladbach, Germany
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | | | - Tom Luedde
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Frank Tacke
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
| |
Collapse
|
|
35
|
Casadei Gardini A, Frassineti GL, Foschi FG, Ercolani G, Ulivi P. Sorafenib and Regorafenib in HBV- or HCV-positive hepatocellular carcinoma patients: Analysis of RESORCE and SHARP trials. Dig Liver Dis 2017; 49:943-944. [PMID: 28546063 DOI: 10.1016/j.dld.2017.04.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 04/27/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Andrea Casadei Gardini
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
| | - Giovanni Luca Frassineti
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | | | - Giorgio Ercolani
- Department of General Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| |
Collapse
|
|
36
|
Metabolomics and eicosanoid analysis identified serum biomarkers for distinguishing hepatocellular carcinoma from hepatitis B virus-related cirrhosis. Oncotarget 2017; 8:63890-63900. [PMID: 28969038 PMCID: PMC5609970 DOI: 10.18632/oncotarget.19173] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 06/04/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. It is a type of inflammation-related cancer that usually follows liver hepatitis that mostly caused by hepatitis B virus (HBV) in China. However, the metabolism disturbance of HCC and HBV-cirrhosis is not yet fully understood. In addition, there is little research on the relationships between inflammation mediators and HCC. In this study, we investigated serum metabolic abnormalities in HBV-cirrhosis and HCC patients through non-targeted metabolomics and targeted eicosanoid analysis. Metabolomic analysis identified 14 metabolites, i.e. malate, citrate, succinate, lysine, carnitine, proline, ornithine, serine, phenylalanine, tyrosine, arachidonic acid arabinose, galactose and uric acid are consistently altered in HBV-cirrhosis and HCC patients. Meanwhile, eicosanoid analysis uncovered several prostaglandins and leukotrienes are implicated in pathological processes in HBV-cirrhosis and HCC. Finally, these identified biomarkers possessed strong potential to distinguish and diagnose HCC from healthy controls and HBV-cirrhosis patients. This study provided a new perspective to understand the mechanism and discover probable biomarkers of HCC.
Collapse
|
|
37
|
Ju LL, Chen L, Li JH, Wang YF, Lu RJ, Bian ZL, Shao JG. Effect of NDC80 in human hepatocellular carcinoma. World J Gastroenterol 2017; 23:3675-3683. [PMID: 28611520 PMCID: PMC5449424 DOI: 10.3748/wjg.v23.i20.3675] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 02/23/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of nuclear division cycle (NDC)80 in human hepatocellular carcinogenesis.
METHODS NDC80 gene expression was analyzed by real-time reverse transcription polymerase chain reaction in 47 paired hepatocellular carcinoma (HCC) and adjacent tissues. The HCC cell line SMMC-7721 was transfected with lentivirus to silence endogenous NDC80 gene expression, which was confirmed by real-time polymerase chain reaction and western blotting. The effects of NDC80 silencing on SMMC-7721 cell proliferation were evaluated by Cellomics ArrayScan VTI imaging. Cell cycle analysis and apoptosis were detected with flow cytometry. Colony formation was assessed by fluorescence microscopy.
RESULTS NDC80 expression levels in HCC tissues were significantly higher than those in the adjacent tissues. Functional studies demonstrated that NDC80 silencing significantly reduced SMMC-7721 cell proliferation and colony formation. Knockdown of NDC80 resulted in increased apoptosis and cell cycle arrest at S-phase. NDC80 contributed to HCC progression by reducing apoptosis and overcoming cell cycle arrest.
CONCLUSION Elevated expression of NDC80 may play a role in promoting the development of HCC.
Collapse
|
|
38
|
Hepatitis D, B and C virus (HDV/HBV/HCV) coinfection as a diagnostic problem and therapeutic challenge. Clin Exp Hepatol 2017; 3:23-27. [PMID: 28856286 PMCID: PMC5497452 DOI: 10.5114/ceh.2017.65500] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 11/05/2016] [Indexed: 01/05/2023] Open
Abstract
Coinfection with hepatitis D virus (HDV) in chronic hepatitis B is associated with more rapid progression to liver cirrhosis. We present two cases of infection with hepatitis D, B and C viruses. Both male patients were primarily diagnosed as infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBsAg-positive and anti-HCV-positive. The first patient was treated with interferon, lamivudine and pegylated interferon. A full virological and biochemical response was achieved. The second patient was treated with interferon and ribavirin, lamivudine and twice with pegylated interferon. In the ultrasound elastography progression of liver fibrosis to F4 was described. HDV infection should be considered in patients with HBV minireplication, high activity of aminotransferases and progression of liver disease despite a good virological response to anti-HBV treatment. Efficacy of interferon in HDV infection is severely limited.
Collapse
|