|
1
|
Hui RWH, Mak LY, Fung J, Seto WK, Yuen MF. Expanding treatment indications in chronic hepatitis B: Should we treat all patients? Hepatol Int 2025; 19:304-314. [PMID: 39961977 PMCID: PMC12003542 DOI: 10.1007/s12072-025-10785-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/26/2025] [Indexed: 04/17/2025]
Abstract
Nucleos(t)ide analogues (NUCs) are first-line agents for chronic hepatitis B (CHB). Current guidelines provide recommendations for NUC initiation, yet the guidelines are complex and restrictive. Accumulating data on hepatitis B virus (HBV) replication and HBV integration suggests that there are no real quiescent disease phases in CHB, and treatment-ineligible patients in current guidelines still have substantial risks of cirrhosis and hepatocellular carcinoma. Expanding CHB treatment indications can effectively reduce the risks of liver-related complications. Furthermore, treatment indication expansion can be cost-effective, and can simplify care pathways to remove treatment barriers. Potential caveats for treatment expansion include risks of non-compliance, long-term side effects from NUCs, and poor patient acceptability. Nonetheless, these caveats are not insurmountable, and the benefits of treatment expansion outweigh the disadvantages. There is consensus among hepatologists in supporting treatment indication expansion, although expert panels have varying recommendations on treatment strategies. A treat-all approach, which involves treating all CHB patients, has also been proposed. A treat-all strategy is straightforward, and should yield the greatest benefits from a population health perspective. However, the feasibility of new treatment strategies, especially the treat-all approach, is influenced by multiple factors including local epidemiology, healthcare resource availability, and socioeconomic factors. A one-size-fits-all approach is not optimal, and treatment expansion strategies that are tailored based on local data should yield the greatest impact toward hepatitis elimination.
Collapse
Affiliation(s)
- Rex Wan-Hin Hui
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - James Fung
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
| |
Collapse
|
|
2
|
Li X, Kong D, Hu W, Zheng K, You H, Tang R, Kong F. Insight into the mechanisms regulating liver cancer stem cells by hepatitis B virus X protein. Infect Agent Cancer 2024; 19:56. [PMID: 39529119 PMCID: PMC11555838 DOI: 10.1186/s13027-024-00618-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous disease with high recurrence and mortality. It is well known that a large proportion of HCCs are caused by hepatitis B virus (HBV) infection. In particular, the HBV X protein (HBX), a multifunctional molecule produced by the virus, plays a leading role in hepatocarcinogenesis. However, the molecular mechanisms underlying HBX-mediated HCC remain not fully elucidated. Recently, liver cancer stem cells (LCSCs), a unique heterogeneous subpopulation of the malignancy, have received particular attention owing to their close association with tumorigenesis. Especially, the modulation of LCSCs by HBX by upregulating CD133, CD44, EpCAM, and CD90 plays a significant role in HBV-related HCC development. More importantly, not only multiple signaling pathways, including Wnt/β-catenin signaling, transforming growth factor-β (TGF-β) signaling, phosphatidylinositol-3-kinase (PI-3 K)/AKT signaling, and STAT3 signaling pathways, but also epigenetic regulation, such as DNA and histone methylation, and noncoding RNAs, including lncRNA and microRNA, are discovered to participate in regulating LCSCs mediated by HBX. Here, we summarized the mechanisms underlying different signaling pathways and epigenetic alterations that contribute to the modulation of HBX-induced LCSCs to facilitate hepatocarcinogenesis. Because LCSCs are important in hepatic carcinogenesis, understanding the regulatory factors controlled by HBX might open new avenues for HBV-associated liver cancer treatment.
Collapse
Affiliation(s)
- Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Delong Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- Experimental Animal Center, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wei Hu
- NanJing Drum Tower Hospital Group Suqian Hospital, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| |
Collapse
|
|
3
|
Li D, Hamadalnil Y, Tu T. Hepatitis B Viral Protein HBx: Roles in Viral Replication and Hepatocarcinogenesis. Viruses 2024; 16:1361. [PMID: 39339838 PMCID: PMC11437454 DOI: 10.3390/v16091361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/20/2024] [Accepted: 08/21/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis B virus (HBV) infection remains a major public health concern worldwide, with approximately 296 million individuals chronically infected. The HBV-encoded X protein (HBx) is a regulatory protein of 17 kDa, reportedly responsible for a broad range of functions, including viral replication and oncogenic processes. In this review, we summarize the state of knowledge on the mechanisms underlying HBx functions in viral replication, the antiviral effect of therapeutics directed against HBx, and the role of HBx in liver cancer development (including a hypothetical model of hepatocarcinogenesis). We conclude by highlighting major unanswered questions in the field and the implications of their answers.
Collapse
Affiliation(s)
- Dong Li
- The Westmead Institute for Medical Research, Faculty of Medicine, The University of Sydney, Westmead, NSW 2145, Australia;
| | | | - Thomas Tu
- The Westmead Institute for Medical Research, Faculty of Medicine, The University of Sydney, Westmead, NSW 2145, Australia;
- Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia
| |
Collapse
|
|
4
|
Zhao H, Ling Y, He J, Dong J, Mo Q, Wang Y, Zhang Y, Yu H, Tang C. Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma. Drug Resist Updat 2024; 74:101084. [PMID: 38640592 DOI: 10.1016/j.drup.2024.101084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/22/2024] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.
Collapse
Affiliation(s)
- Hongxing Zhao
- Department of Radiology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yuhang Ling
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jie He
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Jinling Dong
- Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Qinliang Mo
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Yao Wang
- Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Ying Zhang
- Central Laboratory, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatology, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Hongbin Yu
- Department of General Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China
| | - Chengwu Tang
- Huzhou Key Laboratory of Translational Medicine, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China; Department of Hepatopancreatobiliary Surgery, First affiliated Hospital of Huzhou University, Huzhou, Zhejiang Province, China.
| |
Collapse
|
|
5
|
Sukowati CH, El-Khobar K, Jasirwan COM, Kurniawan J, Gani RA. Stemness markers in hepatocellular carcinoma of Eastern vs. Western population: Etiology matters? Ann Hepatol 2024; 29:101153. [PMID: 37734662 DOI: 10.1016/j.aohep.2023.101153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.
Collapse
Affiliation(s)
- Caecilia Hc Sukowati
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park campus Basovizza, SS14 km 163.5, Trieste 34149, Italy; Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia.
| | - Korri El-Khobar
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency of Indonesia (BRIN), B.J. Habibie Building, Jl. M.H. Thamrin No. 8, Jakarta Pusat 10340, Indonesia
| | - Chyntia Olivia Maurine Jasirwan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Juferdy Kurniawan
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| | - Rino Alvani Gani
- Hepatobiliary Division, Medical Staff Group of Internal Medicine, Faculty of Medicine, Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital, Jl. Pangeran Diponegoro No.71, Jakarta 10430, Indonesia
| |
Collapse
|
|
6
|
Li J, Chen Y, Guo X, Bai X, Xu X, Han T, Tan A, Liu N, Xia Y, Sun Q, Guo X, Chen J, Kang J. lncNBAT1/APOBEC3A is a mediator of HBX-induced chemoresistance in diffuse large B cell lymphoma cells. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:1064-1077. [PMID: 35228900 PMCID: PMC8850662 DOI: 10.1016/j.omtn.2022.01.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 01/21/2022] [Indexed: 12/28/2022]
Abstract
Individuals with diffuse large B cell lymphoma (DLBCL) infected with hepatitis B virus (HBV) have worse chemotherapy efficacy and poorer outcomes. It is still unclear whether long noncoding RNAs (lncRNAs) serve as prognostic and therapeutic targets in the chemotherapy resistance of individuals with DLBCL and HBV infection. Here we found that the core component of HBV (HBX) directly upregulated the expression of lncNBAT1, which was closely associated with the chemotherapy outcomes of HBV-infected individuals with DLBCL. Upregulation of lncNBAT1 reduced the sensitivity of DLBCL cells to chemotherapeutic agents (methotrexate [MTX] or cytarabine [Ara-C]) that induced S phase arrest, whereas knockdown of lncNBAT1 significantly relieved the chemoresistance of HBX-expressing DLBCLs. Mechanistically, lncNBAT1 could interact with the signal transducer and activator of transcription 1 (STAT1) to prevent its enrichment at the promoter region of the functional target gene apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A), inhibiting expression of APOBEC3A and inducing resistance to MTX in DLBCL cells. Furthermore, clinical data analysis showed that lncNBAT1 and APOBEC3A expression was closely related to the poor prognosis and short survival of individuals with DLBCL. Our findings suggest a potential prognostic marker and a candidate lncRNA target for treating HBV-infected individuals with DLBCL.
Collapse
Affiliation(s)
- Jianguo Li
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yaqi Chen
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xuecong Guo
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xiaofei Bai
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xu Xu
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Tong Han
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Ailing Tan
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Nana Liu
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Yuchen Xia
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Qiaoyi Sun
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Xudong Guo
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.,Institute for Advanced Study, Tongji University, Shanghai 200092, China
| | - Jie Chen
- Department of Hematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
| | - Jiuhong Kang
- Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| |
Collapse
|
|
7
|
You H, Qin S, Zhang F, Hu W, Li X, Liu D, Kong F, Pan X, Zheng K, Tang R. Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection. Front Immunol 2022; 13:829923. [PMID: 35251017 PMCID: PMC8891514 DOI: 10.3389/fimmu.2022.829923] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open
Abstract
As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.
Collapse
Affiliation(s)
- Hongjuan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Suping Qin
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Fulong Zhang
- Imaging Department, The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Wei Hu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Xiaocui Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Dongsheng Liu
- Nanjing Drum Tower Hospital Group Suqian Hospital, The Affiliate Suqian Hospital of Xuzhou Medical University, Suqian, China
| | - Fanyun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
| | - Xiucheng Pan
- Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kuiyang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
8
|
Li W, Duan X, Zhu C, Liu X, Jeyarajan AJ, Xu M, Tu Z, Sheng Q, Chen D, Zhu C, Shao T, Cheng Z, Salloum S, Schaefer EA, Kruger AJ, Holmes JA, Chung RT, Lin W. Hepatitis B and Hepatitis C Virus Infection Promote Liver Fibrogenesis through a TGF-β1-Induced OCT4/Nanog Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:672-684. [PMID: 35022275 PMCID: PMC8770612 DOI: 10.4049/jimmunol.2001453] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 11/13/2021] [Indexed: 02/03/2023]
Abstract
Hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection accelerates liver fibrosis progression compared with HBV or HCV monoinfection. Octamer binding transcription factor 4 (OCT4) and Nanog are direct targets of the profibrogenic TGF-β1 signaling cascade. We leveraged a coculture model to monitor the effects of HBV and HCV coinfection on fibrogenesis in both sodium taurocholate cotransporting polypeptide-transfected Huh7.5.1 hepatoma cells and LX2 hepatic stellate cells (HSCs). We used CRISPR-Cas9 to knock out OCT4 and Nanog to evaluate their effects on HBV-, HCV-, or TGF-β1-induced liver fibrogenesis. HBV/HCV coinfection and HBx, HBV preS2, HCV Core, and HCV NS2/3 overexpression increased TGF-β1 mRNA levels in sodium taurocholate cotransporting polypeptide-Huh7.5.1 cells compared with controls. HBV/HCV coinfection further enhanced profibrogenic gene expression relative to HBV or HCV monoinfection. Coculture of HBV and HCV monoinfected or HBV/HCV coinfected hepatocytes with LX2 cells significantly increased profibrotic gene expression and LX2 cell invasion and migration. OCT4 and Nanog guide RNA independently suppressed HBV-, HCV-, HBV/HCV-, and TGF-β1-induced α-SMA, TIMP-1, and Col1A1 expression and reduced Huh7.5.1, LX2, primary hepatocyte, and primary human HSC migratory capacity. OCT4/Nanog protein expression also correlated positively with fibrosis stage in liver biopsies from patients with chronic HBV or HCV infection. In conclusion, HBV and HCV independently and cooperatively promote liver fibrogenesis through a TGF-β1-induced OCT4/Nanog-dependent pathway.
Collapse
Affiliation(s)
- Wenting Li
- Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
- Department of Infectious Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Xiaoqiong Duan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan Province, China
| | - Chuanlong Zhu
- Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China
- Department of Infectious Disease, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiao Liu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Southwest University, College of Animal Science and Technology, Chongqing, China
| | - Andre J Jeyarajan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Min Xu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Zeng Tu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Microbiology, College of Basic Medical Science, Chongqing Medical University, Chongqing, China
| | - Qiuju Sheng
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Dong Chen
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Chuanwu Zhu
- Department of Hepatology, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Tuo Shao
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Zhimeng Cheng
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Shadi Salloum
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Esperance A Schaefer
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Annie J Kruger
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC; and
| | - Jacinta A Holmes
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
- Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA;
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA;
| |
Collapse
|
|
9
|
Leonardi L, Sibéril S, Alifano M, Cremer I, Joubert PE. Autophagy Modulation by Viral Infections Influences Tumor Development. Front Oncol 2021; 11:743780. [PMID: 34745965 PMCID: PMC8569469 DOI: 10.3389/fonc.2021.743780] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/27/2021] [Indexed: 12/21/2022] Open
Abstract
Autophagy is a self-degradative process important for balancing cellular homeostasis at critical times in development and/or in response to nutrient stress. This is particularly relevant in tumor model in which autophagy has been demonstrated to have an important impact on tumor behavior. In one hand, autophagy limits tumor transformation of precancerous cells in early stage, and in the other hand, it favors the survival, proliferation, metastasis, and resistance to antitumor therapies in more advanced tumors. This catabolic machinery can be induced by an important variety of extra- and intracellular stimuli. For instance, viral infection has often been associated to autophagic modulation, and the role of autophagy in virus replication differs according to the virus studied. In the context of tumor development, virus-modulated autophagy can have an important impact on tumor cells' fate. Extensive analyses have shed light on the molecular and/or functional complex mechanisms by which virus-modulated autophagy influences precancerous or tumor cell development. This review includes an overview of discoveries describing the repercussions of an autophagy perturbation during viral infections on tumor behavior.
Collapse
Affiliation(s)
- Lucas Leonardi
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.,Sorbonne Université, Univ Paris, Paris, France
| | - Sophie Sibéril
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.,Sorbonne Université, Univ Paris, Paris, France
| | - Marco Alifano
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.,Department of Thoracic Surgery, Hospital Cochin Assistance Publique Hopitaux de Paris, Paris, France
| | - Isabelle Cremer
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.,Sorbonne Université, Univ Paris, Paris, France
| | - Pierre-Emmanuel Joubert
- Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS1138, Centre de Recherche des Cordeliers, Paris, France.,Sorbonne Université, Univ Paris, Paris, France
| |
Collapse
|
|
10
|
Liu K, Ou JHJ. Regulators of liver cancer stem cells. World J Stem Cells 2021; 13:1127-1133. [PMID: 34567430 PMCID: PMC8422929 DOI: 10.4252/wjsc.v13.i8.1127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/06/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. It is often detected at a stage when there are few therapeutic options. Liver cancer stem cells (LCSCs) are highly tumorigenic and resistant to chemotherapy and radiation therapy. Their presence in HCC is a major reason why HCC is difficult to treat. The development of LCSCs is regulated by a variety of factors. This review summarizes recent advances on the factors that regulate the development of LCSCs. Due to the importance of LCSCs in the development of HCC, a better understanding of how LCSCs are regulated will help to improve the treatments for HCC patients.
Collapse
Affiliation(s)
- Kai Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, United States
| |
Collapse
|
|
11
|
Zhang C, Xiao C, Ren G, Cai D, Long L, Li J, Li K, Tang Y, Huang T, Deng W. C-terminal-truncated hepatitis B virus X protein promotes hepatocarcinogenesis by activating the MAPK pathway. Microb Pathog 2021; 159:105136. [PMID: 34390769 DOI: 10.1016/j.micpath.2021.105136] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE C-terminally truncated hepatitis B virus X (ctHBx) is frequently detected in hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV) integrated into their genomes, but the molecular mechanisms of ctHBx-related oncogenic signaling remain unclear. In this study, the effects of ctHBx on HepG2 cells were investigated by measuring ctHBx-induced changes in the cell cycle-related target proteins cell division cycle 25C (cdc25C) and p53 downstream of the mitogen-activated protein kinase (MAPK) pathway. MATERIALS AND METHODS ctHBx lentiviruses were constructed and transfected into HepG2 cells. Then, we investigated HepG2 cell line function by conducting the Cell Counting Kit-8 (CCK8) assay, clone formation assay, scratch wound testing, Transwell assays and flow cytometry to examine cell cycle and apoptosis. Western blotting (WB) was performed to detect proteins related to and downstream of the extracellular signal-regulated kinase(ERK)/c-Jun N-terminal kinase(JNK)/p38 MAPK pathway, including cdc25C and p53. RESULTS ctHBx significantly enhanced the proliferation, migration, invasion and colony-forming capability of HepG2 cells. In addition, ctHBx activated the ERK/JNK/p38 MAPK signaling pathway to regulate cell viability by affecting the expression of cyclin-related proteins, including cdc25C and p53. CONCLUSION The present study demonstrates that ctHBx promote the formation and development of HCC via regulating MAPK/cdc25C and p53 axis. ctHBx should be the driving factor of HBV-induced hepatocarcinogenesis.
Collapse
Affiliation(s)
- Chaojun Zhang
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Chanchan Xiao
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Guanhua Ren
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Dongmei Cai
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Long Long
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Jilin Li
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Kezhi Li
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Yanping Tang
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Tianren Huang
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Wei Deng
- Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
| |
Collapse
|
|
12
|
de Mattos ÂZ, Debes JD, Boonstra A, Yang JD, Balderramo DC, Sartori GDP, de Mattos AA. Current impact of viral hepatitis on liver cancer development: The challenge remains. World J Gastroenterol 2021; 27:3556-3567. [PMID: 34239269 PMCID: PMC8240060 DOI: 10.3748/wjg.v27.i24.3556] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/11/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.
Collapse
MESH Headings
- Adult
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/prevention & control
- Hepatitis B/complications
- Hepatitis B/epidemiology
- Hepatitis B/prevention & control
- Hepatitis B virus
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/epidemiology
- Hepatitis, Viral, Human/complications
- Hepatitis, Viral, Human/epidemiology
- Humans
- Infant, Newborn
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
- Risk Factors
Collapse
Affiliation(s)
- Ângelo Zambam de Mattos
- Department of Gastroenterology and Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90020-090, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology and Infectious Diseases, University of Minnesota, Minneapolis, MN 55455, United States
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam NL-3015, Netherlands
| | - Ju-Dong Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Domingo C Balderramo
- Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Córdoba 5016, Argentina
- Department of Medicine, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba 5016, Argentina
| | - Giovana D P Sartori
- Department of Internal Medicine, Hospital Nossa Senhora da Conceição, Porto Alegre 91350-200, Brazil
| | - Angelo Alves de Mattos
- Department of Gastroenterology and Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90020-090, Brazil
- Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre, Porto Alegre 90050-170, Brazil
| |
Collapse
|
|
13
|
Sadri Nahand J, Rabiei N, Fathazam R, Taghizadieh M, Ebrahimi MS, Mahjoubin-Tehran M, Bannazadeh Baghi H, Khatami A, Abbasi-Kolli M, Mirzaei HR, Rahimian N, Darvish M, Mirzaei H. Oncogenic viruses and chemoresistance: What do we know? Pharmacol Res 2021; 170:105730. [PMID: 34119621 DOI: 10.1016/j.phrs.2021.105730] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Chemoresistance is often referred to as a major leading reason for cancer therapy failure, causing cancer relapse and further metastasis. As a result, an urgent need has been raised to reach a full comprehension of chemoresistance-associated molecular pathways, thereby designing new therapy methods. Many of metastatic tumor masses are found to be related with a viral cause. Although combined therapy is perceived as the model role therapy in such cases, chemoresistant features, which is more common in viral carcinogenesis, often get into way of this kind of therapy, minimizing the chance of survival. Some investigations indicate that the infecting virus dominates other leading factors, i.e., genetic alternations and tumor microenvironment, in development of cancer cell chemoresistance. Herein, we have gathered the available evidence on the mechanisms under which oncogenic viruses cause drug-resistance in chemotherapy.
Collapse
Affiliation(s)
- Javid Sadri Nahand
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Saeid Ebrahimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology and Nanotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - AliReza Khatami
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Maryam Darvish
- Department of Medical Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
14
|
Siddiqui ZI, Azam SA, Khan WH, Afroz M, Farooqui SR, Amir F, Azmi MI, Anwer A, Khan S, Mehmankhah M, Parveen S, Kazim SN. An in vitro Study on the Role of Hepatitis B Virus X Protein C-Terminal Truncation in Liver Disease Development. Front Genet 2021; 12:633341. [PMID: 33777103 PMCID: PMC7994528 DOI: 10.3389/fgene.2021.633341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/02/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis B virus X protein C-terminal 127 amino acid truncation is often found expressed in hepatocellular carcinoma (HCC) tissue samples. The present in vitro study tried to determine the role of this truncation mutant in the hepatitis B-related liver diseases such as fibrosis, cirrhosis, HCC, and metastasis. HBx gene and its 127 amino acid truncation mutant were cloned in mammalian expression vectors and transfected in human hepatoma cell line. Changes in cell growth/proliferation, cell cycle phase distribution, expression of cell cycle regulatory genes, mitochondrial depolarization, and intracellular reactive oxygen species (ROS) level were analyzed. Green fluorescent protein (GFP)-tagged version of HBx and the truncation mutant were also created and the effects of truncation on HBx intracellular expression pattern and localization were studied. Effect of time lapse on protein expression pattern was also analyzed. The truncation mutant of HBx is more efficient in inducing cell proliferation, and causes more ROS production and less mitochondrial depolarization as compared with wild type (wt) HBx. In addition, gene expression is altered in favor of carcinogenesis in the presence of the truncation mutant. Furthermore, mitochondrial perinuclear aggregation is achieved earlier in the presence of the truncation mutant. Therefore, HBx C-terminal 127 amino acid truncation might be playing important roles in the development of hepatitis B-related liver diseases by inducing cell proliferation, altering gene expression, altering mitochondrial potential, inducing mitochondrial clustering and oxidative stress, and changing HBx expression pattern.
Collapse
Affiliation(s)
- Zaheenul Islam Siddiqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.,Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Syed Ali Azam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Wajihul Hasan Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Masarrat Afroz
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Sabihur Rahman Farooqui
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Fatima Amir
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Md Iqbal Azmi
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ayesha Anwer
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Saniya Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Mahboubeh Mehmankhah
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Shama Parveen
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| |
Collapse
|
|
15
|
Ngo MHT, Jeng HY, Kuo YC, Nanda JD, Brahmadhi A, Ling TY, Chang TS, Huang YH. The Role of IGF/IGF-1R Signaling in Hepatocellular Carcinomas: Stemness-Related Properties and Drug Resistance. Int J Mol Sci 2021; 22:ijms22041931. [PMID: 33669204 PMCID: PMC7919800 DOI: 10.3390/ijms22041931] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/10/2021] [Accepted: 02/10/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.
Collapse
Affiliation(s)
- Mai-Huong Thi Ngo
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Han-Yin Jeng
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Yung-Che Kuo
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
| | - Josephine Diony Nanda
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Ageng Brahmadhi
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
| | - Thai-Yen Ling
- Department and Graduate Institute of Pharmacology, National Taiwan University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| | - Yen-Hua Huang
- International PhD Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-H.T.N.); (J.D.N.); (A.B.)
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan; (H.-Y.J.); (Y.-C.K.)
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (T.-Y.L.); (T.-S.C.); (Y.-H.H.); Tel.: +886-2-2312-3456 (ext. 8-8322) (T.-Y.L.); +886-5-3621-000 (ext. 2242) (T.-S.C.); +886-2-2736-1661 (ext. 3150) (Y.-H.H.)
| |
Collapse
|
|
16
|
Lin CL, Chien RN, Chu YD, Liang KH, Huang YH, Ke PY, Lin KH, Lin YH, Yeh CT. Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression. Hepatol Int 2020; 14:973-984. [PMID: 32770306 DOI: 10.1007/s12072-020-10079-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/22/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment. METHODS Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized. RESULTS We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels. CONCLUSIONS Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.
Collapse
Affiliation(s)
- Chih-Lang Lin
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Kung-Hao Liang
- Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ya-Hui Huang
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.,College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Po-Yuan Ke
- Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan
| | - Kwang-Huei Lin
- Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan. .,Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan. .,Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan.
| |
Collapse
|
|
17
|
The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 2020; 5:87. [PMID: 32532960 PMCID: PMC7292831 DOI: 10.1038/s41392-020-0187-x] [Citation(s) in RCA: 655] [Impact Index Per Article: 131.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/14/2020] [Accepted: 04/26/2020] [Indexed: 02/07/2023] Open
Abstract
Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
Collapse
|
|
18
|
Tsui YM, Chan LK, Ng IOL. Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential. Br J Cancer 2020; 122:1428-1440. [PMID: 32231294 PMCID: PMC7217836 DOI: 10.1038/s41416-020-0823-9] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/30/2020] [Accepted: 03/09/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stemness, referring to the stem-cell-like phenotype of cancer cells, has been recognised to play important roles in different aspects of hepatocarcinogenesis. A number of well-established cell-surface markers already exist for liver cancer stem cells, with potential new markers of liver cancer stem cells being identified. Both genetic and epigenetic factors that affect various signalling pathways are known to contribute to cancer stemness. In addition, the tumour microenvironment—both physical and cellular—is known to play an important role in regulating cancer stemness, and the potential interaction between cancer stem cells and their microenvironment has provided insight into the regulation of the tumour-initiating ability as well as the cellular plasticity of liver CSCs. Potential specific therapeutic targeting of liver cancer stemness is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcome by reducing chemoresistance.
Collapse
Affiliation(s)
- Yu-Man Tsui
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lo-Kong Chan
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Irene Oi-Lin Ng
- Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong. .,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong.
| |
Collapse
|
|
19
|
BNIP3L-Dependent Mitophagy Promotes HBx-Induced Cancer Stemness of Hepatocellular Carcinoma Cells via Glycolysis Metabolism Reprogramming. Cancers (Basel) 2020; 12:cancers12030655. [PMID: 32168902 PMCID: PMC7139741 DOI: 10.3390/cancers12030655] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/02/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is one of predisposing factors for hepatocellular carcinoma (HCC). The role of HBV x protein (HBx) in mediating the induction and maintenance of cancer stemness during HBV-related HCC attracts considerable attention, but the exact mechanism has not been clearly elucidated. Here, ABCG2-dependent stem-like side population (SP) cells, which are thought to be liver cancer stem cells (LCSCs), were present in HCC cells, and the fraction of this subset was increased in HBx-expressing HCC cells. In addition, glycolysis was upregulated in LCSCs and HBx-expressing HCC cells, and intervention of glycolysis attenuated cancer stem-like phenotypes. Mitochondria play an important role in the maintenance of energy homeostasis, BNIP3L-dependent mitophagy was also activated in LCSCs and HBx-expressing HCC cells, which triggered a metabolic shift toward glycolysis. In summary, we proposed a positive feedback loop, in which HBx induced BNIP3L-dependent mitophagy which upregulated glycolytic metabolism, increasing cancer stemness of HCC cells in vivo and in vitro. BNIP3L might be a potential therapeutic target for intervention of LCSCs-associated HCC. Anti-HBx, a monoclonal antibody targeting intracellular HBx, had the potential to delay the progression of HBV infection related-HCC.
Collapse
|
|
20
|
Wang Q, Cheng ST, Chen J. HBx mediated Increase of SIRT1 Contributes to HBV-related Hepatocellular Carcinoma Tumorigenesis. Int J Med Sci 2020; 17:1783-1794. [PMID: 32714081 PMCID: PMC7378664 DOI: 10.7150/ijms.43491] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 05/26/2020] [Indexed: 12/16/2022] Open
Abstract
Objective: Hepatocellular carcinoma (HCC) is one of the main causes of cancer-related deaths worldwide, and chronic hepatitis B virus (HBV) infection is strongly associated with HCC development, but the pathogenesis of HBV-related HCC remains obscure. Sirtuin 1 (SIRT1) has been implicated to enhance the replication of HBV and to promote the tumorigenesis of HCC. In this study, we aim to investigate the functional role of SIRT1 on HBV viral protein and HBV-induced HCC. Methods: Tumorous liver tissues from patient diagnosed with HBV-related HCC were collected and further divided into two groups (with or without metastasis). Then, the mRNA and protein level of SIRT1 in those tissues were detected by real time PCR and Western blot, respectively. Meanwhile, the protein level of epithelial-mesenchymal transition (EMT) relative markers in those tissues was determined by Western blot. Furthermore, the expression of SIRT1 in HBV-expressing HCC cells was examined. Next, the relationship between viral proteins and SIRT1 expression were determined by real time PCR and Western blot. In addition, the potential role of HBx-upregulated SIRT1 in HCC proliferation, migration and invasion were analyzed by cell viability assays, cell proliferation assay, wound healing assay, transwell assay and Western blot. Results: In this study, we found that the expression of SIRT1 was obviously increased in patients with metastasis compared to the patients without metastasis. Consistently, the expression of SIRT1 was also upregulated in HBV-expressing HCC cells compared to the controls. Further investigation showed that viral protein HBx was responsible for the elevated SIRT1 in HBV-expressing HCC cells. Meanwhile, the expression of HBx could be upregulated by SIRT1. Additionally, functional studies showed that HBx-elevated SIRT1 could promote HCC cell proliferation, migration and invasion. Importantly, HBx induced HCC proliferation and migration could be suppressed by Nicotinamide in a dose dependent manner. Conclusions: Our findings uncovered the positive role of SIRT1 in HBx-mediated tumorigenesis which implicated the potential role of SIRT1 in HBV-related HCC treatment.
Collapse
Affiliation(s)
- Qing Wang
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Sheng-Tao Cheng
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Juan Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| |
Collapse
|
|
21
|
Hasanin AH, Matboli M, Seleem HS. Hesperidin suppressed hepatic precancerous lesions via modulation of exophagy in rats. J Cell Biochem 2019; 121:1295-1306. [PMID: 31489981 DOI: 10.1002/jcb.29363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 08/23/2019] [Indexed: 12/21/2022]
Abstract
The enormous cost of modern medicines warrants alternative strategies for the better management of hepatocellular carcinoma. Recently, exosomes have been shown to relay the oncogenic information through the horizontal transfer of RNAs between the cells. In this study, we modulated exosomal production and autophagy (exophagy) by the administration of hesperidin and evaluated its effect on the development of hepatic precancerous lesion (HPC) in rats. Diethylnitrosamine and 2-acetylaminofluorene were used in vivo to induce HPC in rats. Rats were allocated into five groups: naïve, HPC, and three hesperidin treated (50, 100, and 200 mg/kg/d; orally) for 4 consecutive days per week for 16 weeks. Liver tissues and blood samples were collected for histopathological, immunohistochemical, and transmission electron microscope examinations, liver function, alfa-fetoprotein level, and isolation of exosomal and autophagy RNAs. Hesperidin administration showed hepato-protective effects and improved the microscopic hepatic features with a decrease in glutathione S-transferase placental precancerous foci and the abundance of exosomes in liver tissues. Hesperidin improved liver function with a significant decrease in alfa-fetoprotein levels. Hesperidin dose-dependently decreased exosomal RAB11A messsenger RNA and long noncoding RNA-RP11-583F2.2 along with the increase in exosomal miR-1298, involved in the exophagy process. In conclusion, hesperidin likely suppresses liver carcinogenesis in rat model via the modulation of exosomal secretion and autophagy.
Collapse
Affiliation(s)
- Amany H Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Marwa Matboli
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan S Seleem
- Department of Histology, Faculty of Medicine, Menoufia University, Cairo, Egypt.,Histology Department, Faculty of Medicine, Unaizah College of Medicine, Al Qassim University, Buraydah, KSA
| |
Collapse
|
|
22
|
Meng C, Liu T, Liu YW, Zhang LZ, Wang YL. Hepatitis B Virus cccDNA in Hepatocellular Carcinoma Tissue Increases the Risk of Recurrence After Liver Transplantation. Transplant Proc 2019; 51:3364-3368. [PMID: 31358449 DOI: 10.1016/j.transproceed.2019.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/23/2019] [Accepted: 04/25/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND High hepatitis B virus (HBV) DNA level is strongly associated with hepatocellular carcinoma (HCC) development in chronic HBV infection. The aim of this study was to investigate the association between intrahepatic HBV DNA titer and post-liver transplantation (LT) prognosis for HBV-related HCC (HBV-HCC) patients. METHODS A total of 60 patients with HBV-HCC who underwent LT were retrospectively studied. Using quantitative TaqMan fluorescent real-time polymerase chain reaction assay, HBV total DNA (tDNA) and covalently closed circular DNA (cccDNA) were both quantified in tumor tissue (TT) and adjacent non-tumor tissue (ANTT) from the explanted liver. RESULTS The loads of tDNA and cccDNA in ANTT were associated with serum HBV DNA levels. Multivariate analysis showed that the presence of vascular invasion and cccDNA in TT were independent risk factors for tumor recurrence. The group of patients with cccDNA titers ≥31ogl0 copies/μg in TT had significantly higher cumulative recurrence rates than those with <31ogl0 copies/μg group. The cccDNA titers predicted the tumor recurrence with an area under the receiver operating characteristic curve of 0.664. CONCLUSIONS Our findings would assist the clinical implementation of a more personalized therapy for tumor recurrence control and improve the prognosis of HBV-HCC patients.
Collapse
Affiliation(s)
- C Meng
- Department of Clinical Laboratory, Tianjin Second People's Hospital, Tianjin Institute of Hepatology, Tianjin, China
| | - T Liu
- Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | - Y W Liu
- Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland
| | - L Z Zhang
- Department of Hepatobiliary Surgery, People's Hospital of Zhucheng City, Shandong, China
| | - Y L Wang
- Department of Clinical Laboratory, 2nd Hospital of Tianjin Medical University, Tianjin, China.
| |
Collapse
|
|
23
|
Wu DM, Zheng ZH, Zhang YB, Fan SH, Zhang ZF, Wang YJ, Zheng YL, Lu J. Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:237. [PMID: 31171015 PMCID: PMC6554918 DOI: 10.1186/s13046-019-1239-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 05/21/2019] [Indexed: 02/06/2023]
Abstract
Background Liver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC. Methods A microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced. Results LncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway. Conclusion This study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway. Electronic supplementary material The online version of this article (10.1186/s13046-019-1239-3) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China
| | - Zi-Hui Zheng
- State Key Laboratory Cultivation Base For TCM Quality and Efficacy, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Ying-Bo Zhang
- Department of Pathology, Qiqihar Medical University, Qiqihar, 161006, People's Republic of China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China. .,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China. .,College of Health Sciences, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, People's Republic of China.
| |
Collapse
|
|
24
|
Homeobox Genes and Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11050621. [PMID: 31058850 PMCID: PMC6562709 DOI: 10.3390/cancers11050621] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/27/2019] [Accepted: 04/27/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Homeobox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Homeobox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.
Collapse
|
|
25
|
Matboli M, ElGwad AA, Hasanin AH, El-Tawdi A, Habib EK, Elmansy RA, Ibrahim D, Shehata H, Tash F. Pantoprazole attenuates tumorigenesis via inhibition of exosomal secretion in a rat model of hepatic precancerous lesion induced by diethylnitrosamine and 2-acetamidofluorene. J Cell Biochem 2019; 120:14946-14959. [PMID: 31009125 DOI: 10.1002/jcb.28757] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 12/21/2018] [Accepted: 01/07/2019] [Indexed: 02/06/2023]
Abstract
The present study aimed to evaluate the potential therapeutic effect of pantoprazole, a proton-pump inhibitor, on precancerous lesion (PCL) in rats. diethylnitrosamine and 2-acetylaminofluorene were used to induce PCL in rats, in vivo. The rats were treated with three doses of pantoprazole (100, 50, and 25 mg/kg; three times weekly) during the last 4 weeks of the total 10 weeks of the experiment. Blood and liver tissue samples were collected for measurement of the exosomal abundance and exosomal competing endogenous RNA markers. Results revealed that pantoprazole administration had an ameliorating effect on liver function tests and microscopic features of the liver; and decreased exosome abundance in the liver tissue samples and sera of the rats. Meanwhile, the treatment also resulted in a dose-dependent decrease in exosomal RAB11A mRNA and long noncoding RNA RP11-513I15.6, which is an important participant in th exosomal secretion process with an increase in exosomal miRNA-1262. Based on these results, we postulated that pantoprazole has the potential to attenuate liver tumorigenesis in this rat model.
Collapse
Affiliation(s)
- Marwa Matboli
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Asmaa Abd ElGwad
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Amany H Hasanin
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed El-Tawdi
- Department of General surgery, Military Medical Academy, Cairo, Egypt
| | - Eman K Habib
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Rasha Ahmed Elmansy
- Department of Anatomy and Embryology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.,Department of Anatomy and Embryology, Faculty of Medicine, Unaizah College of Medicine, AlQassim University, AlQassim, KSA
| | - Doaa Ibrahim
- Department of Clinical Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hanan Shehata
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| | - Fathy Tash
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Ain Shams University, Abbassia, Cairo, Egypt
| |
Collapse
|
|
26
|
Mao X, Tey SK, Ko FCF, Kwong EML, Gao Y, Ng IOL, Cheung ST, Guan XY, Yam JWP. C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis. Cancer Lett 2019; 444:60-69. [DOI: 10.1016/j.canlet.2018.12.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/26/2018] [Accepted: 12/18/2018] [Indexed: 02/08/2023]
|
|
27
|
Song X, Tan S, Wu Z, Xu L, Wang Z, Xu Y, Wang T, Gao C, Gong Y, Liang X, Gao L, Spear BT, Ma C. HBV suppresses ZHX2 expression to promote proliferation of HCC through miR-155 activation. Int J Cancer 2018; 143:3120-3130. [PMID: 29752719 DOI: 10.1002/ijc.31595] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 03/29/2018] [Accepted: 05/03/2018] [Indexed: 12/18/2022]
Abstract
Initiation of hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection is a complex process that includes both oncogene activation and tumor suppressor inhibition. The HBV X (HBx) protein has an important and complex role in processes leading to HCC. We previously identified the mammalian Zinc fingers and homeoboxes 2 (ZHX2) gene as an HCC-associated tumor suppressor gene. In the present study, we investigated whether the oncogenic properties of HBV and, more specifically, HBx, involved ZHX2 silencing. Our data indicates that ZHX2 expression is significantly decreased in tumor tissues from HBV-positive HCC patients and livers from HBV transgenic mice. In vitro and in vivo studies confirmed that HBV-encoded proteins, particularly HBx, inhibits both the expression and tumor suppression properties of ZHX2. Further analyses identified miR-155, a well-known oncomiR in various cancers, as an important link between HBx and ZHX2 inhibition. Increased miR-155 levels were found in HBV-positive tumors, livers of HBV transgenic mice and HBx-overexpressing hepatoma cell lines. MiR-155 overexpression reduced ZHX2 levels via miR-155 seed sites in the ZHX2 3'UTR, whereas blocking miR-155 levels led to increased ZHX2 levels. Taken together, our data indicate that HCC-promoting properties of HBV may include ZHX2 silencing via a miR-155 dependent pathway and suggests a novel therapy for HBV-related HCC.
Collapse
Affiliation(s)
- Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Siyu Tan
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Leiqi Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Yong Xu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Tixiao Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Chengjiang Gao
- Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, People's Republic of China
| | - Yaoqin Gong
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Genetics, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China
| | - Brett T Spear
- Department of Microbiology, Immunology and Molecular Genetics, Lexington, KY.,Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, Shandong University School of Basic Medical Science, Jinan, Shandong, 250012, People's Republic of China.,Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, People's Republic of China
| |
Collapse
|
|
28
|
Chang Z, Wang Y, Zhou X, Long JE. STAT3 roles in viral infection: antiviral or proviral? Future Virol 2018; 13:557-574. [PMID: 32201498 PMCID: PMC7079998 DOI: 10.2217/fvl-2018-0033] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which can be activated by cytokines, growth factor receptors, and nonreceptor-like tyrosine kinase. An activated STAT3 translocates into the nucleus and combines with DNA to regulate the expression of target genes involved in cell proliferation, differentiation, apoptosis and metastasis. Recent studies have shown that STAT3 plays important roles in viral infection and pathogenesis. STAT3 exhibits a proviral function in several viral infections, including those of HBV, HCV, HSV-1, varicella zoster virus, human CMV and measles virus. However, in some circumstances, STAT3 has an antiviral function in other viral infections, such as enterovirus 71, severe acute respiratory syndrome coronavirus and human metapneumovirus. This review summarizes the roles of STAT3 in viral infection and pathogenesis, and briefly discusses the molecular mechanisms involved in these processes.
Collapse
Affiliation(s)
- Zhangmei Chang
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Kunshan Center For Disease Control & Prevention, 458 Tongfengxi Road, Kunshan, Jiangsu, 215301, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Kunshan Center For Disease Control & Prevention, 458 Tongfengxi Road, Kunshan, Jiangsu, 215301, PR China
| | - Yan Wang
- Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China
| | - Xin Zhou
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China
| | - Jian-Er Long
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China
| |
Collapse
|
|
29
|
Smirnova OA, Bartosch B, Zakirova NF, Kochetkov SN, Ivanov AV. Polyamine Metabolism and Oxidative Protein Folding in the ER as ROS-Producing Systems Neglected in Virology. Int J Mol Sci 2018; 19:1219. [PMID: 29673197 PMCID: PMC5979612 DOI: 10.3390/ijms19041219] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 04/03/2018] [Accepted: 04/11/2018] [Indexed: 12/23/2022] Open
Abstract
Reactive oxygen species (ROS) are produced in various cell compartments by an array of enzymes and processes. An excess of ROS production can be hazardous for normal cell functioning, whereas at normal levels, ROS act as vital regulators of many signal transduction pathways and transcription factors. ROS production is affected by a wide range of viruses. However, to date, the impact of viral infections has been studied only in respect to selected ROS-generating enzymes. The role of several ROS-generating and -scavenging enzymes or cellular systems in viral infections has never been addressed. In this review, we focus on the roles of biogenic polyamines and oxidative protein folding in the endoplasmic reticulum (ER) and their interplay with viruses. Polyamines act as ROS scavengers, however, their catabolism is accompanied by H₂O₂ production. Hydrogen peroxide is also produced during oxidative protein folding, with ER oxidoreductin 1 (Ero1) being a major source of oxidative equivalents. In addition, Ero1 controls Ca2+ efflux from the ER in response to e.g., ER stress. Here, we briefly summarize the current knowledge on the physiological roles of biogenic polyamines and the role of Ero1 at the ER, and present available data on their interplay with viral infections.
Collapse
Affiliation(s)
- Olga A Smirnova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia.
| | - Birke Bartosch
- Cancer Research Center Lyon, INSERM U1052 and CNRS 5286, Lyon University, 69003 Lyon, France.
- DevWeCan Laboratories of Excellence Network (Labex), Lyon 69003, France.
| | - Natalia F Zakirova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia.
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia.
| | - Alexander V Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow 119991, Russia.
| |
Collapse
|
|
30
|
Fang X, Wu HH, Ren JJ, Liu HZ, Li KZ, Li JL, Tang YP, Xiao CC, Huang TR, Deng W. Associations between serum HBX quasispecies and their integration in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:11857-11866. [PMID: 31966550 PMCID: PMC6966043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 11/10/2017] [Indexed: 06/10/2023]
Abstract
HBV quasispecies are closely related to the course and outcome of liver disease. However, whether the complexity and diversity of HBX quasispecies affects its integration in the liver cell and thereby enhances the resultant carcinogenesis is still not clear. 15 HCC patients were recruited; genomic DNA and HBV DNA were extracted from liver cancer tissue and serum respectively. The integrated HBX fragment in liver cancer tissue was amplified by Alu repeat sequence-polymerase chain reaction (Alu-PCR) and sequenced. The serum HBX gene was amplified by nested PCR and sequenced. Quasispecies complexity and diversity, phylogenetic characteristics, lymphocyte count and survival time between HBX-integrated and HBX-unintegrated patients were evaluated. Results showed that the integrated HBX fragment was detected in the tumor tissue of nine patients, and the integration rate was 60.00% (9/15). Compared with the HBX-unintegrated patients, the HBX-integrated patients had a higher quasispecies complexity (P=0.028 and 0.004, at the nucleotide and amino acid levels, respectively). The HBX-integrated patients had a tendency of higher quasispecies diversity, lower lymphocyte count and the survival time. A total of 12 mutation sites were revealed in the HBX-integrated fragment after alignment with the reference sequence. In these, the HBX-integrated groups had significantly higher mutation frequencies at C1497T, A1630G, G1721A, A1762T/G1764A and A1774G. This study revealed influence factors of HBX integration both in virus and the host. The increased complexity and diversity of HBX quasispecies might destroy the host immune balance, and lead to HBX integration ultimately.
Collapse
Affiliation(s)
- Xiang Fang
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hang-Hang Wu
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Jing-Jing Ren
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hai-Zhou Liu
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ke-Zhi Li
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ji-Lin Li
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yan-Ping Tang
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Chan-Chan Xiao
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tian-Ren Huang
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Wei Deng
- Department of Experimental Research, Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
31
|
Lu G, Ma Y, Jia C, Yang H, Xie R, Luo P, Chai L, Cai H, Cai M, Lv Z, Cong X, Fu D. Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer. Oncol Lett 2017; 14:5952-5958. [PMID: 29113231 PMCID: PMC5661598 DOI: 10.3892/ol.2017.6902] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 06/15/2017] [Indexed: 12/15/2022] Open
Abstract
MicroRNAs (miRNAs) serve an important role in tumorigenesis and development. Although a low expression of miR-125a in hepatocellular carcinoma (HCC) has been reported, the clinical significance remains unknown. In the current study, the data of Gene Expression Omnibus datasets was analyzed and significantly low expression of miR-125a in HCC was verified. Furthermore, the expression and clinical significance of miR-125a was investigated in 27 normal liver and 98 HCC tissue samples using reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that the level of miR-125a expression was lower in HCC biopsies compared with that in normal liver tissues. Survival analysis established that miR-125a expression was negatively associated with the prognosis of HCC. Multivariate survival analysis demonstrated that patients with HCC with lowmiR-125a and Ki67-positive expression have shorter overall, and disease-free survival times. Altogether, the results of the current study provide the first evidence that reducedmiR-125a expression is associated with HCC progression and poor prognosis in patients, suggesting that miR-125a may have potential prognostic value as a tumor biomarker for patients with HCC.
Collapse
Affiliation(s)
- Gaixia Lu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yushui Ma
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chengyou Jia
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Huiqiong Yang
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ruting Xie
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Pei Luo
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Li Chai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Haidong Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Mingxiang Cai
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Xianling Cong
- Tissue Bank, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
| | - Da Fu
- Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China.,Research Center of Clinical Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| |
Collapse
|