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Pol S. [Hepatocellular carcinoma (HCC)]. MEDECINE TROPICALE ET SANTE INTERNATIONALE 2024; 4:mtsi.v4i4.2024.614. [PMID: 40070978 PMCID: PMC11892391 DOI: 10.48327/mtsi.v4i4.2024.614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 10/15/2024] [Indexed: 03/14/2025]
Abstract
Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.
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Affiliation(s)
- Stanislas Pol
- AP-HP. Centre Université Paris Centre, Groupe hospitalier Cochin Port Royal, Département médical universitaire de Cancérologie et spécialités médico-chirurgicales, Service des maladies du foie, Paris, France; Université Paris Cité, F-75006, Paris, France
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Wang Y, Guan X, Lv F, Rong Y, Meng X, Tong Y, Ma X, Zheng H, Chen C, Xie S, Zhang H, Dong F, Guo L, Lu R. HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis. Tumour Virus Res 2024; 18:200290. [PMID: 39032828 PMCID: PMC11331954 DOI: 10.1016/j.tvr.2024.200290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 07/04/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and hepatitis B X (HBx) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of HBx integration in DLBCL. The data showed that clinical DLBCL cells demonstrated HBx integration, and the sequencing analysis of integrated sites validated HBx integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the HBx-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the HBx-negative samples. Therefore, HBx integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.
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Affiliation(s)
- Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaolin Guan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangfang Lv
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yi Rong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xin Meng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ying Tong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaolu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Cuncun Chen
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Heng Zhang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Feng Dong
- Department of Outpatient Office, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Wang Z, Li N, Cai P, Zhang C, Cao G, Yin J. Mechanism of HBx carcinogenesis interaction with non-coding RNA in hepatocellular carcinoma. Front Oncol 2023; 13:1249198. [PMID: 37746253 PMCID: PMC10517716 DOI: 10.3389/fonc.2023.1249198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/24/2023] [Indexed: 09/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is an extremely malignant tumor that affects individuals throughout the world. One of the main causes of HCC is hepatitis B virus (HBV). Therefore, it is crucial to understand the mechanisms underlying HBV carcinogenesis. Increasing evidence suggests that the HBV X protein (HBx), which is encoded by HBV, plays a significant role in cell apoptosis, DNA damage repair, and cell cycle regulation. This ultimately leads to the development of HCC. Additionally, recent studies have shown that non-coding RNA (ncRNA) also contributes to the carcinogenesis and pathogenesis of different of tumors. ncRNA plays a significant role in the formation of HCC by regulating the inflammatory signaling pathway, activating immune cells, and modifying epigenetics. However, it remains unclear whether ncRNA is involved in the regulation of the carcinogenic mechanisms of HBx. This article reviews the carcinogenic mechanism of HBx and its interaction with ncRNA, providing a novel strategy for the clinical diagnosis and treatment of HCC.
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Affiliation(s)
- Zhuoran Wang
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Nan Li
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Peng Cai
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai, China
| | - Cunzhen Zhang
- Department of Hepatic Surgery I (Ward I), Shanghai Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai, China
| | - Jianhua Yin
- Department of Epidemiology, Faculty of Navy Medicine, Navy Medical University, Shanghai, China
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Fazlalipour M, Ghoreshi ZAS, Molaei HR, Arefinia N. The Role of DNA Viruses in Human Cancer. Cancer Inform 2023; 22:11769351231154186. [PMID: 37363356 PMCID: PMC10286548 DOI: 10.1177/11769351231154186] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 01/03/2023] [Indexed: 06/28/2023] Open
Abstract
This review discusses the possible involvement of infections-associated cancers in humans, with virus infections contributing 15% to 20% of total cancer cases in humans. DNA virus encoded proteins interact with host cellular signaling pathways and control proliferation, cell death and genomic integrity viral oncoproteins are known to bind cellular Deubiquitinates (DUBs) such as cyclindromatosis tumor suppressor, ubiquitin-specific proteases 7, 11, 15 and 20, and A-20 to improve their intracellular stability and cellular signaling pathways and finally transformation. Human papillomaviruses (cervical carcinoma, oral cancer and laryngeal cancer); human polyomaviruses (mesotheliomas, brain tumors); Epstein-Barr virus (B-cell lymphoproliferative diseases and nasopharyngeal carcinoma); Kaposi's Sarcoma Herpesvirus (Kaposi's Sarcoma and primary effusion lymphomas); hepatitis B (hepatocellular carcinoma (HCC)) cause up to 20% of malignancies around the world.
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Affiliation(s)
- Mehdi Fazlalipour
- WHO Collaborating Center for Reference and Research on Rabies, Pasteur Institute of Iran (IPI), Tehran, Iran
- Research Center for Emerging and Reemerging Infectious diseases, Pasteur Institute of Iran (IPI), Tehran, Iran
| | | | - Hamid Reza Molaei
- Department of Medical Bacteriology and Virology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Nasir Arefinia
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
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Zongo SV, Djigma FW, Yonli AT, Sorgho PA, Nagalo BM, Traore L, Somda D, Amegnona LJ, Languie E, Some CCB, Sia LMJ, Sourabie IB, Sombie RA, Serme AK, Obiri-Yeboah D, Simpore J. Association of DRB1*11 and DRB1*12 alleles of the HLA system with the evolution of the Hepatitis B virus infection in Burkina Faso. Mol Biol Rep 2023; 50:5039-5047. [PMID: 37101005 DOI: 10.1007/s11033-023-08353-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/22/2023] [Indexed: 04/28/2023]
Abstract
BACKGROUND Hepatitis B Virus (HBV) infection affect all social strata of humanity and in the absence of any management, this infection has a different outcome from one infected person to another. This suggests that there are specific individual factors that influence the outcome of the pathology. Sex, immunogenetics and age of contraction of the virus have been cited as factors that influence the evolution of the pathology. In this study, we looked at two alleles of the Human Leucocyte Antigen (HLA) system to measure their possible involvement in the evolution of HBV infection. METHOD AND RESULTS We conducted a cohort study involving 144 individuals spread over 04 distinct stages of infection and then compared allelic frequencies in these populations. A multiplex PCR was conducted and the data obtained was analyzed using R and SPSS software. Our study revealed a predominance of HLA-DRB1*12 in our study population without, however, showing a significant difference between HLA-DRB1*11 and HLA-DRB1*12. The HLA-DRB1*12 proportion was significantly higher in chronic hepatitis B (CHB) and resolved hepatitis B (RHB) compared to cirrhosis and hepatocellular carcinoma (HCC) (p-value = 0,002). Carrying HLA-DRB1*12 has been associated with a low risk of complication of infection (CHB → cirrhosis; OR 0,33 p-value 0,017; RHB → HCC OR 0,13; p-value = 0,00,045) whereas the presence of HLA-DRB1*11 in the absence of HLA-DRB1*12 increased the risk of developing severe liver disease. However, a strong interaction of these alleles with the environment could modulate the infection. CONCLUSION Our study shown that HLA-DRB1*12 is the most frequent and it's carriage may be protective in the development of infection.
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Affiliation(s)
- Sidnooma Véronique Zongo
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Florencia Wendkuuni Djigma
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso.
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso.
| | - Albert Théophane Yonli
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Pegdwendé Abel Sorgho
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Bolni Marius Nagalo
- Division of Hematology and Oncology, Mayo Clinic, Arizona, 13400 E. Shea Blvd. , Scottsdale, AZ, 85259, USA
| | - Lassina Traore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dogfounianalo Somda
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Lanyo Jospin Amegnona
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Eugène Languie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Couna Christiane Bere Some
- Centre Hospitalier Universitaire Yalgado Ouedraogo (CHU-YO), P.O. Box: 03 BP 7022, Ouagadougou 03, Burkina Faso
| | | | - Issa Boaffi Sourabie
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
| | - Roger Arsène Sombie
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Abdel Karim Serme
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
| | - Dorcas Obiri-Yeboah
- Department of Microbiology and Immunology, School of Medical Sciences, University of Cape Coast, PMB, Cape Coast, Cape Coast, Ghana
| | - Jacques Simpore
- Laboratoire de Biologie Moléculaire Et de Génétique, Université Joseph KI-ZERBO, P.O. Box 7021, Ouagadougou 03, Burkina Faso
- Centre de Recherche Biomoléculaire Pietro Annigoni (CERBA), P.O. Box 364, Ouagadougou 01, Burkina Faso
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Tran NH. Shifting Epidemiology of Hepatocellular Carcinoma in Far Eastern and Southeast Asian Patients: Explanations and Implications. Curr Oncol Rep 2022; 24:187-193. [DOI: 10.1007/s11912-021-01160-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2021] [Indexed: 01/02/2023]
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Kremsdorf D, Lekbaby B, Bablon P, Sotty J, Augustin J, Schnuriger A, Pol J, Soussan P. Alternative splicing of viral transcripts: the dark side of HBV. Gut 2021; 70:2373-2382. [PMID: 34535538 DOI: 10.1136/gutjnl-2021-324554] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 09/06/2021] [Indexed: 02/06/2023]
Abstract
Regulation of alternative splicing is one of the most efficient mechanisms to enlarge the proteomic diversity in eukaryotic organisms. Many viruses hijack the splicing machinery following infection to accomplish their replication cycle. Regarding the HBV, numerous reports have described alternative splicing events of the long viral transcript (pregenomic RNA), which also acts as a template for viral genome replication. Alternative splicing of HBV pregenomic RNAs allows the synthesis of at least 20 spliced variants. In addition, almost all these spliced forms give rise to defective particles, detected in the blood of infected patients. HBV-spliced RNAs have long been unconsidered, probably due to their uneasy detection in comparison to unspliced forms as well as for their dispensable role during viral replication. However, recent data highlighted the relevance of these HBV-spliced variants through (1) the trans-regulation of the alternative splicing of viral transcripts along the course of liver disease; (2) the ability to generate defective particle formation, putative biomarker of the liver disease progression; (3) modulation of viral replication; and (4) their intrinsic propensity to encode for novel viral proteins involved in liver pathogenesis and immune response. Altogether, tricky regulation of HBV alternative splicing may contribute to modulate multiple viral and cellular processes all along the course of HBV-related liver disease.
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Affiliation(s)
- Dina Kremsdorf
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France
| | - Bouchra Lekbaby
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France
| | - Pierre Bablon
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France
| | - Jules Sotty
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France
| | - Jérémy Augustin
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France
| | - Aurélie Schnuriger
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France.,Assistance Publique - Hôpitaux de Paris, Département de Virologie, GHU Paris-Est, Paris, France
| | - Jonathan Pol
- Institut National de la Santé et de la Recherche Médicale U1138, Centre de Recherche des Cordeliers, Université de Paris, Sorbonne Université, Paris, France.,Metabolomics ann Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
| | - Patrick Soussan
- Institut National de la Santé et de la Recherche Médicale U938, Centre de Recherche de Saint Antoine, Sorbonne Université-Faculté Saint Antoine, Paris, France .,Assistance Publique - Hôpitaux de Paris, Département de Virologie, GHU Paris-Est, Paris, France
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Zhao Z, Zhu Y, Ni X, Lin J, Li H, Zheng L, Zhang C, Qi X, Huo H, Lou X, Fan Q, Bao Y, Luo M. Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC. Cancer Cell Int 2021; 21:517. [PMID: 34583704 PMCID: PMC8479900 DOI: 10.1186/s12935-021-02214-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 09/15/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS The risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan-Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias. RESULTS A high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33). CONCLUSION The GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.
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Affiliation(s)
- Zhifeng Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Yiming Zhu
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Xiaochun Ni
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Lei Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Xiaoliang Qi
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Xiaolou Lou
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Qiang Fan
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China
| | - Yongyang Bao
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China.
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Huangpu District, Shanghai, People's Republic of China.
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Hu G, Zhai S, Yu S, Huang Z, Gao R. Circular RNA circRHOBTB3 is downregulated in hepatocellular carcinoma and suppresses cell proliferation by inhibiting miR-18a maturation. Infect Agent Cancer 2021; 16:48. [PMID: 34187598 PMCID: PMC8243428 DOI: 10.1186/s13027-021-00384-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Circular RNA circRHOBTB3 has been characterized as a tumor suppressor in gastric cancer, while its role in hepatocellular carcinoma (HCC) is unknown. This study was carried out to analyze the role of circRHOBTB3 in HCC. METHODS In this study, circRHOBTB3, mature miR-18a, and miR-18a precursor in HCC and paired non-cancer tissues were detected by RT-qPCR. The role of circRHOBTB3 in the production of mature miR-18a was explored by transfecting circRHOBTB3 expression vector into HCC cells, followed by RT-qPCR to determine the expression of mature miR-18a and miR-18a precursor. The role of circRHOBTB3 and miR-18a in HCC cell proliferation was studied using CCK-8 assay. RESULTS CircRHOBTB3 was under-expressed in HCC compared to normal tissues. In HCC cells, circRHOBTB3 overexpression decreased mature miR-18a level but not miR-18a precursor. Cell proliferation analysis showed that circRHOBTB3 overexpression decreased cell proliferation while miR-18a overexpression increased cell proliferation. Moreover, circRHOBTB3 suppressed the role of miR-18a in cell proliferation. CONCLUSIONS CircRHOBTB3 is downregulated in HCC and may suppress cell proliferation by reducing miR-18a production.
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Affiliation(s)
- Gang Hu
- Department of General Surgery, Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Shusen Zhai
- Department of Oncology, Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Sheng Yu
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou City, Guangdong Province, 510515, People's Republic of China.
| | - Zhen Huang
- Department of General Surgery, Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Ran Gao
- Department of General Surgery, Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
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Klufah F, Mobaraki G, Liu D, Alharbi RA, Kurz AK, Speel EJM, Winnepenninckx V, Zur Hausen A. Emerging role of human polyomaviruses 6 and 7 in human cancers. Infect Agent Cancer 2021; 16:35. [PMID: 34001216 PMCID: PMC8130262 DOI: 10.1186/s13027-021-00374-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Currently 12 human polyomaviruses (HPyVs) have been identified, 6 of which have been associated with human diseases, including cancer. The discovery of the Merkel cell polyomavirus and its role in the etiopathogenesis in the majority of Merkel cell carcinomas has drawn significant attention, also to other novel HPyVs. In 2010, HPyV6 and HPyV7 were identified in healthy skin swabs. Ever since it has been speculated that they might contribute to the etiopathogenesis of skin and non-cutaneous human cancers. MAIN BODY Here we comprehensively reviewed and summarized the current evidence potentially indicating an involvement of HPyV6 and HPyV7 in the etiopathogenesis of neoplastic human diseases. The seroprevalence of both HPyV6 and 7 is high in a normal population and increases with age. In skin cancer tissues, HPyV6- DNA was far more often prevalent than HPyV7 in contrast to cancers of other anatomic sites, in which HPyV7 DNA was more frequently detected. CONCLUSION It is remarkable to find that the detection rate of HPyV6-DNA in tissues of skin malignancies is higher than HPyV7-DNA and may indicate a role of HPyV6 in the etiopathogenesis of the respected skin cancers. However, the sheer presence of viral DNA is not enough to prove a role in the etiopathogenesis of these cancers.
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Affiliation(s)
- Faisal Klufah
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Ghalib Mobaraki
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Dan Liu
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Raed A Alharbi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Anna Kordelia Kurz
- Department of Internal Medicine IV, RWTH Aachen University Hospital, Aachen, Germany
| | - Ernst Jan M Speel
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Véronique Winnepenninckx
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Axel Zur Hausen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
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11
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Tian J, Hu D. LncRNA SLC16A1-AS1 is upregulated in hepatocellular carcinoma and predicts poor survival. Clin Res Hepatol Gastroenterol 2021; 45:101490. [PMID: 33744723 DOI: 10.1016/j.clinre.2020.07.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/26/2020] [Accepted: 07/01/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Long non-coding RNAs (LncRNAs) are broadly transcribed in the genome of human and animals, they play critical roles in cellular process, and participate in the progression of multiple diseases, including cancer. SLC16A1-AS1 is a tumor suppressive lncRNA in lung cancer. This study aimed to investigate the involvement of lncRNA SLC16A1-AS1 in hepatocellular carcinoma (HCC). METHOD A total of 64 HCC patients were subjected to biopsy to obtain paired HCC and non-tumor tissues. Expression of SLC16A1-AS1 and miR-141 in paired tissues was determined by RT-qPCR. Correlations were analyzed by linear regression. Overexpression of SLC16A1-AS1 and miR-141 were achieved in HCC cells to explore the interactions between them. The methylation of the gene encoding miR-141 in HCC cells was detected by methylation-specific PCR (MSP). CCK-8 assay was performed for cell proliferation assay. RESULTS SLC16A1-AS1 was upregulated in HCC and its high expression levels predicted poor survival of HCC patients. Expression levels of miR-141 were lower in HCC patients and were inversely correlated with the expression levels of SLC16A1-AS1. In HCC cells, overexpression of SLC16A1-AS1 led to downregulation of miR-141, while overexpression of miR-141 did not regulate the expression of SLC16A1-AS1. In addition, overexpression of SLC16A1-AS1 led to increased methylation of miR-141. And overexpression of SLC16A1-AS1 attenuated the inhibitory effects of miR-141 on HCC cell proliferation. CONCLUSION SLC16A1-AS1 is upregulated in HCC and predicts poor survival. In addition, SLC16A1-AS1 may downregulate miR-141 through methylation to promote cancer cell proliferation.
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Affiliation(s)
- Jianfeng Tian
- Department of General Surgery, Affiliated Cixi Hospital, Wenzhou Medical University, 315300 Zhejiang Province, PR China
| | - Dengdi Hu
- Department of General Surgery, Affiliated Cixi Hospital, Wenzhou Medical University, 315300 Zhejiang Province, PR China.
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12
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Elalfy H, Besheer T, Elhammady D, Mesery AE, Shaltout SW, El-Maksoud MA, Amin AI, Bekhit AN, Aziz MAE, El-Bendary M. Pathological characterization of occult hepatitis B virus infection in hepatitis C virus-associated or non-alcoholic steatohepatitis-related hepatocellular carcinoma. World J Meta-Anal 2020; 8:67-77. [DOI: 10.13105/wjma.v8.i2.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/08/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
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13
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The correlations between hepatitis B virus infection and hepatocellular carcinoma with portal vein tumor thrombus or extrahepatic metastasis. Eur J Gastroenterol Hepatol 2020; 32:373-377. [PMID: 31441795 DOI: 10.1097/meg.0000000000001514] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Portal vein tumor thrombus (PVTT) and extrahepatic metastasis are associated with the prognosis of hepatocellular carcinoma (HCC). We aimed to investigate the effect of hepatitis B virus (HBV) infection on HCC patients with PVTT or extrahepatic metastasis. PATIENTS AND METHODS The clinical data of 639 patients with HCC from our hospital were retrospectively analyzed to analyze the correlation between HBV and HCC with PVTT or extrahepatic metastasis. RESULTS Univariate analysis revealed that positive hepatitis B virus surface antigen (HBsAg), a detectable serum hepatitis B virus DNA load (>500 IU/ml), cirrhosis and ascites were associated with the presence of PVTT. Positive hepatitis B virus e antigen (HBeAg), cirrhosis and ascites were associated with the presence of extrahepatic metastasis. In a multivariate regression analysis carried out a detectable serum hepatitis B virus DNA load, cirrhosis and ascites were independent risk factors of PVTT. Ascites was an independent risk factor of extrahepatic metastasis. The patients in the PVTT of type III/IV group and the PVTT of type I/II group had a significantly higher rate of positive serum HBsAg, a detectable serum hepatitis B virus DNA load (>500 IU/ml) and HBsAg + HBeAb + HBcAb test positive compared with those in the PVTT-negative group. HBsAg + HBeAb + HBcAb test positive was significantly associated with the presence of extrahepatic metastasis (P=0.028). CONCLUSIONS HBV infection and replication status are associated with the formation of PVTT or extrahepatic metastasis in patients with HCC.
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14
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Park S, Ha YN, Dezhbord M, Lee AR, Park ES, Park YK, Won J, Kim NY, Choo SY, Shin JJ, Ahn CH, Kim KH. Suppression of Hepatocyte Nuclear Factor 4 α by Long-term Infection of Hepatitis B Virus Contributes to Tumor Cell Proliferation. Int J Mol Sci 2020; 21:ijms21030948. [PMID: 32023898 PMCID: PMC7037729 DOI: 10.3390/ijms21030948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major factor in the development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play a key role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppression of HNF4α in cells which stably express HBV whole genome or HBx protein alone, while transient transfection of HBV replicon or HBx plasmid had no effect on the HNF4α level. Importantly, in the stable HBV- or HBx-expressing hepatocytes, the downregulated level of HNF4α was restored by inhibiting the ERK signaling pathway. Our data show that HNF4α was suppressed during long-term HBV infection in cultured HepG2-NTCP cells as well as in a mouse model following hydrodynamic injection of pAAV-HBV or in mice intravenously infected with rAAV-HBV. Importantly, HNF4α downregulation increased cell proliferation, which contributed to the formation and development of tumor in xenograft nude mice. The data presented here provide proof of the effect of HBV infection in manipulating the HNF4α regulatory pathway in HCC development.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Kyun-Hwan Kim
- Correspondence: ; Tel.: +82-2-2030-7833; Fax: +82-2-2049-6192
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15
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Zhang X, Wu X, Hu Q, Wu J, Wang G, Hong Z, Ren J. Mitochondrial DNA in liver inflammation and oxidative stress. Life Sci 2019; 236:116464. [PMID: 31078546 DOI: 10.1016/j.lfs.2019.05.020] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
Abstract
The function of liver is highly dependent on mitochondria producing ATP for biosynthetic and detoxifying properties. Accumulating evidence indicates that most hepatic disorders are characterized by profound mitochondrial dysfunction. Mitochondrial dysfunction not only exhibits mitochondrial DNA (mtDNA) damage and depletion, but also releases mtDNA. mtDNA is a closed circular molecule encoding 13 of the polypeptides of the oxidative phosphorylation system. Extensive mtDNA lesions could exacerbate mitochondrial oxidative stress and subsequently cause damage to hepatocytes. When mtDNA leaves the confines of mitochondria to the cytosolic and extracellular environment, it can act as damage-associated molecular patterns (DAMPs) to trigger the inflammatory response through the Toll-like receptor 9, inflammasomes, and stimulator of interferon genes (STING) pathways and further exacerbate hepatocellular damage and even remote organs injury. In addition, mtDNA also plays a vital role in hepatitis B virus (HBV)-related liver injury and hepatocellular carcinoma (HCC). In this review, we describe mtDNA alterations during liver injury, focusing on the mechanisms of mtDNA-mediated liver inflammation and oxidative stress injury.
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Affiliation(s)
- Xufei Zhang
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China.
| | - Qiongyuan Hu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Jie Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Gefei Wang
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Zhiwu Hong
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing 210002, PR China; Lab for Trauma and Surgical Infections, Jinling Hospital, Nanjing 210002, PR China.
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16
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Zhang L, Chen Y, Zhang LJ, Wang M, Chang DL, Wan WW, Zhang BX, Zhang WG, Chen XP. HBV induces different responses of the hepatocytes and oval cells during HBV-related hepatic cirrhosis. Cancer Lett 2019; 443:47-55. [PMID: 30503551 DOI: 10.1016/j.canlet.2018.11.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 11/20/2018] [Accepted: 11/24/2018] [Indexed: 12/26/2022]
Abstract
Although hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma (HCC) cause a sever health problem worldwide, the underlying mechanisms are still elusive. This study aimed to investigate the responses of different cell types isolated from HBV transgenic mice. A cross-sectional set of hepatocytes and oval cells were obtained from HBV transgenic and control mice. Flow cytometry, immunohistochemistry and microarray were applied to investigate the cell biology of the hepatocytes and oval cells. Our results showed that HBV induced the proliferation of both cell oval cells and hepatocytes, and induced cell death of HBV hepatocytes while had minimal effects on oval cells. Further molecular and pathways analysis identified some genes and signaling pathways may be responsible for the different responses between oval cells and hepatocytes. In addition, analyses of selectively ten genes by IHC staining in human samples were consistent with microarray data. In summary, HBV transgenic mice is a useful model for studying the biological behaviors of oval cells affected by HBV and HBV-cirrhosis. Also, our results help better understand the mechanisms of HBV induced cirrhosis, and provide novel progenitor markers or prognostic/therapeutic markers.
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Affiliation(s)
- Lei Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yan Chen
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China
| | - Li-Jun Zhang
- Institute for Personalized Medicine, Pennsylvania State University-College of Medicine, Hershey, PA, 17033, USA
| | - Ming Wang
- Public Health Sciences, Pennsylvania State University-College of Medicine, Hershey, PA, 17033, USA
| | - Dong-Lei Chang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Wei-Wei Wan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Wan-Guang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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17
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Wong MCS, Huang JLW, George J, Huang J, Leung C, Eslam M, Chan HLY, Ng SC. The changing epidemiology of liver diseases in the Asia-Pacific region. Nat Rev Gastroenterol Hepatol 2019; 16:57-73. [PMID: 30158570 DOI: 10.1038/s41575-018-0055-0] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.
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Affiliation(s)
- Martin C S Wong
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Jason L W Huang
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Junjie Huang
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Colette Leung
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Henry L Y Chan
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Siew C Ng
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
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18
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Effect of PAK1 gene silencing on proliferation and apoptosis in hepatocellular carcinoma cell lines MHCC97-H and HepG2 and cells in xenograft tumor. Gene Ther 2018; 25:284-296. [PMID: 29802374 DOI: 10.1038/s41434-018-0016-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/08/2017] [Accepted: 12/20/2017] [Indexed: 12/13/2022]
Abstract
This study intends to explore the effect of the PAK1 gene silencing on apoptosis and proliferation of hepatocellular carcinoma (HCC) MHCC97-H and HepG2 cells and cells in xenograft tumor. MHCC97-H and HepG2 cells and mice with xenograft tumor in vivo were randomly divided into control, empty vector and PAK1 shRNA groups. Morphology and the expression of green fluorescent protein of MHCC97-H and HepG2 cells and cells in xenograft tumor were observed. MTT assay and flow cytometry were used to detect proliferation, cell cycle and apoptosis of MHCC97-H and HepG2 cells and cells in xenograft tumor. The expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2, p21, p53, Bax and Bcl-2 were measured using the quantitative reverse transcription polymerase chain reaction and western blotting. Compared with the control and empty vector groups, number of adherent cells of MHCC97-H and HepG2 cells and cells in xenograft tumor was reduced, and green fluorescent cells became round and reduced in the PAK1 shRNA group. Cell proliferation, the cells at S phase, the mRNA and protein expressions of PAK1, PCNA, Ki67, Cyclin E, CDK2 and Bcl-2 of MHCC97-H and HepG2 cells and cells in xenograft tumor were decreased, while the cells at G1 phase, apoptosis rate, the mRNA and protein expressions of p21, p53 and Bax of MHCC97-H and HepG2 cells and cells in xenograft tumor were increased in the PAK1 shRNA group. PAK1 gene silencing decreases proliferation of MHCC97-H cells, HepG2 cells and cells in xenograft tumor through the p53/p21 pathway.
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19
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Significance of Glypican-3 in Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients. J Gastrointest Cancer 2018; 50:434-441. [DOI: 10.1007/s12029-018-0095-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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20
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Mao R, Liu J, Liu G, Jin S, Xue Q, Ma L, Fu Y, Zhao N, Xing J, Li L, Qiu Y, Lin B. Whole genome sequencing of matched tumor, adjacent non-tumor tissues and corresponding normal blood samples of hepatocellular carcinoma patients revealed dynamic changes of the mutations profiles during hepatocarcinogenesis. Oncotarget 2018; 8:26185-26199. [PMID: 28412734 DOI: 10.18632/oncotarget.15428] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 02/01/2017] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has become the third most deadly disease worldwide and HBV is the major factor in Asia and Africa. We conducted 9 WGS (whole genome sequencing) analyses for matched samples of tumor, adjacent non-tumor tissues and normal blood samples of HCC patients from three HBV positive patients. We then validated the mutations identified in a larger cohort of 177 HCC patients. We found that the number of the unique somatic mutations (average of 59,136) in tumor samples is significantly less than that in adjacent non-tumor tissues (average 83, 633). We discovered that the TP53 R249S mutation occurred in 7.7% of the HCC patients, and it was significantly associated with poor diagnosis. In addition, we found that the L104P mutation in the VCX gene (Variable charge, X-linked) was absent in white blood cell samples, but present at 11.1% frequency in the adjacent tissues and increased to 14.6% in HCC tissues, suggesting that this mutation might be a tumor driver gene driving HCC carcinogenesis. Finally, we identified a TK1-RNU7 fusion, which would result in a deletion of 103 amino acids from its C-terminal. The frequencies of this fusion event decreased from the adjacent tissues (29.2%) to the tumors (16.7%), suggesting that a truncated thymidine Kinase1 (TK1) caused by the fusion event might be deleterious and be selected against during tumor progression. The three-way comparisons allow the identification of potential driver mutations of carcinogenesis. Furthermore, our dataset provides the research community a valuable dataset for identifying dynamic changes of mutation profiles and driver mutations for HCC.
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Affiliation(s)
- Ruifang Mao
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Jie Liu
- Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Guanfeng Liu
- Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Shanshan Jin
- Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Qingzhong Xue
- Departmant of Agronomy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, P. R. China
| | - Liang Ma
- Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Yan Fu
- College of Animal Sciences, Zhejiang University, Hangzhou, P. R. China
| | - Na Zhao
- Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China
| | - Jinliang Xing
- State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Lanjuan Li
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yunqing Qiu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Biaoyang Lin
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Systems Biology Division, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Province, P.R. China.,Departmant of Urology, University of Washington, Seattle, WA, USA
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21
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Tu T, Bühler S, Bartenschlager R. Chronic viral hepatitis and its association with liver cancer. Biol Chem 2017; 398:817-837. [PMID: 28455951 DOI: 10.1515/hsz-2017-0118] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 04/13/2017] [Indexed: 02/06/2023]
Abstract
Chronic infection with hepatitis viruses represents the major causative factor for end-stage liver diseases, including liver cirrhosis and primary liver cancer (hepatocellular carcinoma, HCC). In this review, we highlight the current understanding of the molecular mechanisms that drive the hepatocarcinogenesis associated with chronic hepatitis virus infections. While chronic inflammation (associated with a persistent, but impaired anti-viral immune response) plays a major role in HCC initiation and progression, hepatitis viruses can also directly drive liver cancer. The mechanisms by which hepatitis viruses induce HCC include: hepatitis B virus DNA integration into the host cell genome; metabolic reprogramming by virus infection; induction of the cellular stress response pathway by viral gene products; and interference with tumour suppressors. Finally, we summarise the limitations of hepatitis virus-associated HCC model systems and the development of new techniques to circumvent these shortcomings.
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22
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Gao Q, Wang K, Chen K, Liang L, Zheng Y, Zhang Y, Xiang J, Tang N. HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma. Cancer Sci 2017; 108:1328-1337. [PMID: 28498550 PMCID: PMC5497798 DOI: 10.1111/cas.13277] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 04/10/2017] [Accepted: 05/01/2017] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus X protein plays a crucial role in the pathogenesis of hepatocellular carcinoma. We previously showed that the tumor suppressor ARID2 inhibits hepatoma cell cycle progression and tumor growth. Here, we evaluated whether hepatitis B virus X protein was involved in the modulation of ARID2 expression and hepatocarcinogenesis associated with hepatitis B virus infection. ARID2 expression was downregulated in HBV‐replicative hepatoma cells, HBV transgenic mice, and HBV‐related clinical HCC tissues. The expression levels of HBx were negatively associated with those of ARID2 in hepatocellular carcinoma tissues. Furthermore, HBx suppressed ARID2 at transcriptional level. Mechanistically, the promoter region of ARID2 gene inhibited by HBx was located at nt‐1040/nt‐601 and contained potential ATOH1 binding elements. In addition, ectopic expression of ATOH1 or mutation of ATOH1 binding sites within ARID2 promoter partially abolished HBx‐triggered ARID2 transcriptional repression. Functionally, ARID2 abrogated HBx‐enhanced migration and proliferation of hepatoma cells, whereas depletion of ATOH1 enhanced tumorigenecity of HCC cells. Therefore, our findings suggested that deregulation of ARID2 by HBx through ATOH1 may be involved in HBV‐related hepatocellular carcinoma development.
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Affiliation(s)
- Qingzhu Gao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ke Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Liang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yaqiu Zheng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yunzhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jin Xiang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.,The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (CCID), Zhejiang University, Hangzhou, China
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23
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Liang R, Lin Y, Ye JZ, Yan XX, Liu ZH, Li YQ, Luo XL, Ye HH. High expression of RBM8A predicts poor patient prognosis and promotes tumor progression in hepatocellular carcinoma. Oncol Rep 2017; 37:2167-2176. [PMID: 28259942 DOI: 10.3892/or.2017.5457] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 01/30/2017] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a huge threat for human health worldwide. As a complicated tumor, the molecular basis for HCC development especially metastasis requires exploration. Although RNA binding motif (RBM) proteins are closely related to various cancers, the clinical importance and underlying mechanisms of RBM8A in HCC remain elusive. In this study, we found that RBM8A was highly expressed in HCC tumor tissues compared to normal liver tissues. Overexpression of RBM8A was associated with HbsAg and Edmondson pathological grading. Moreover, Kaplan-Meier survival analysis showed that high expression of RBM8A was related to the poor overall survival and progression-free survival of patients with HCC. Gain- and loss-of-function experiments further demonstrated that RBM8A promoted tumor cell migration and invasion in HCC via activation of epithelial-mesenchymal transition signaling pathway. It is also noteworthy that RBM8A is required for tumor cell proliferation and anti-apoptosis in HCC. Altogether, our results revealed a close relationship between RBM8A and HCC prognosis as well as a critical tumor-promoting function of RBM8A in HCC progression, suggesting that RBM8A might be a potential bio-marker and drug target in HCC therapy.
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Affiliation(s)
- Rong Liang
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Yan Lin
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Jia-Zhou Ye
- Department of Hepatobilliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530022, P.R. China
| | - Xue-Xin Yan
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Zhi-Hui Liu
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Yong-Qiang Li
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Xiao-Ling Luo
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 5300221, P.R. China
| | - Hai-Hong Ye
- Department of Hepatobilliary Surgery, Affiliated Minzu Hospital of Guangxi Medical University, Nanning, Guangxi 530001, P.R. China
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24
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Chen YY, Lee LW, Hong WN, Lo SJ. Expression of hepatitis B virus surface antigens induces defective gonad phenotypes in Caenorhabditis elegans. World J Virol 2017; 6:17-25. [PMID: 28239568 PMCID: PMC5303856 DOI: 10.5501/wjv.v6.i1.17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 09/15/2016] [Accepted: 11/29/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To test whether a simple animal, Caenorhabditis elegans (C. elegans), can be used as an alternative model to study the interaction between hepatitis B virus antigens (HBsAg) and host factors.
METHODS Three plasmids that were able to express the large, middle and small forms of HBsAgs (LHBsAg, MHBsAg, and SHBsAg, respectively) driven by a ubiquitous promoter (fib-1) and three that were able to express SHBsAg driven by different tissue-specific promoters were constructed and microinjected into worms. The brood size, egg-laying rate, and gonad development of transgenic worms were analyzed using microscopy. Levels of mRNA related to endoplasmic reticulum stress, enpl-1, hsp-4, pdi-3 and xbp-1, were determined using reverse transcription polymerase reaction (RT-PCRs) in three lines of transgenic worms and dithiothreitol (DTT)-treated wild-type worms.
RESULTS Severe defects in egg-laying, decreases in brood size, and gonad retardation were observed in transgenic worms expressing SHBsAg whereas moderate defects were observed in transgenic worms expressing LHBsAg and MHBsAg. RT-PCR analysis revealed that enpl-1, hsp-4 and pdi-3 transcripts were significantly elevated in worms expressing LHBsAg and MHBsAg and in wild-type worms pretreated with DTT. By contrast, only pdi-3 was increased in worms expressing SHBsAg. To further determine which tissue expressing SHBsAg could induce gonad retardation, we substituted the fib-1 promoter with three tissue-specific promoters (myo-2 for the pharynx, est-1 for the intestines and mec-7 for the neurons) and generated corresponding transgenic animals. Moderate defective phenotypes were observed in worms expressing SHBsAg in the pharynx and intestines but not in worms expressing SHBsAg in the neurons, suggesting that the secreted SHBsAg may trigger a cross-talk signal between the digestive track and the gonad resulting in defective phenotypes.
CONCLUSION Ectopic expression of three forms of HBsAg that causes recognizable phenotypes in transgenic worms suggests that C. elegans can be used as an alternative model for studying virus-host interactions because the resulting phenotype is easily detected through microscopy.
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25
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Xu Z, Zhai L, Yi T, Gao H, Fan F, Li Y, Wang Y, Li N, Xing X, Su N, Wu F, Chang L, Chen X, Dai E, Zhao C, Yang X, Cui C, Xu P. Hepatitis B virus X induces inflammation and cancer in mice liver through dysregulation of cytoskeletal remodeling and lipid metabolism. Oncotarget 2016; 7:70559-70574. [PMID: 27708241 PMCID: PMC5342574 DOI: 10.18632/oncotarget.12372] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 09/13/2016] [Indexed: 12/31/2022] Open
Abstract
Hepatitis B virus X protein (HBx) participates in the occurrence and development processes of hepatocellular carcinoma (HCC) as a multifunctional regulation factor. However, the underlying molecular mechanism remains obscure. Here, we describe the use of p21HBx/+ mouse and SILAM (Stable Isotope Labeling in Mammals) strategy to define the pathological mechanisms for the occurrence and development of HBx induced liver cancer. We systematically compared a series of proteome samples from regular mice, 12- and 24-month old p21HBx/+ mice representing the inflammation and HCC stages of liver disease respectively and their nontransgenic wild-type (WT) littermates. Totally we identified 22 and 97 differentially expressed proteins out of a total of 2473 quantified proteins. Bioinformatics analysis suggested that the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. Interestingly, the protein-protein interaction MS study revealed that HBx directly interacted with multiple proteins in these two pathways. The same effect of up-regulation of cytoskeleton and lipid metabolism related proteins, including CDC42, CFL1, PPARγ and ADFP, was also observed in the Huh-7 cells transfected with HBx. More importantly, CFL1 and ADFP were specifically accumulated in HBV-associated HCC (HBV-HCC) patient samples, and their expression levels were positively correlated with the severity of HBV-related liver disease. These results provide evidence that HBx induces the dysregulation of cytoskeleton remodeling and lipid metabolism and leads to the occurrence and development of liver cancer. The CFL1 and ADFP might be served as potential biomarkers for prognosis and diagnosis of HBV-HCC.
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Affiliation(s)
- Zhongwei Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin, 300309, China
| | - Linghui Zhai
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Tailong Yi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
- Anhui Medical University, Hefei, 230032, China
| | - Huiying Gao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Fengxu Fan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
- Anhui Medical University, Hefei, 230032, China
| | - Yanchang Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Youliang Wang
- Beijing Institute of Bioengineering, Beijing, 100071, P. R. China
| | - Ning Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Xiaohua Xing
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Na Su
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Feilin Wu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Lei Chang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Xiuli Chen
- The Fifth Hospital of Shijiazhuang City, Shijiazhuang, 050021, China
| | - Erhei Dai
- The Fifth Hospital of Shijiazhuang City, Shijiazhuang, 050021, China
| | - Chao Zhao
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, and Research Center on Aging and Medicine, Fudan University, Shanghai, 200032, China
| | - Xiao Yang
- Beijing Institute of Bioengineering, Beijing, 100071, P. R. China
| | - Chunping Cui
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
| | - Ping Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Engineering Research Center for Protein Drugs, National Center for Protein Sciences Beijing, Institute of Radiation Medicine, Beijing, 102206, P.R. China
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and Wuhan University School of Pharmaceutical Sciences, Wuhan, 430072, P. R. China
- Anhui Medical University, Hefei, 230032, China
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Brito AF, Abrantes AM, Tralhão JG, Botelho MF. Targeting Hepatocellular Carcinoma: What did we Discover so Far? Oncol Rev 2016; 10:302. [PMID: 27994769 PMCID: PMC5136756 DOI: 10.4081/oncol.2016.302] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 08/19/2016] [Accepted: 08/24/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is increasingly considered an issue of global importance. Its rates of incidence and mortality have been markedly increasing over the last decades. Among risk factors, some should be highlighted, namely the infections by hepatitis B and C virus, as well as clinical cases of cirrhosis. HCC is characterized as asymptomatic disease in the initial stages which most often leads to a late diagnosis. At molecular and genetic level HCC represents a highly complex tumor entity, including a wide variety of mutations, thus accounting for different mechanisms of resistance towards therapeutic approaches. In particular, mutations of the TP53 gene, as well as a deregulation between the expression of pro- and anti-apoptotic proteins of the BCL-2 family are observed. Regarding treatment modalities, surgical procedures offer the best chance of cure, however, due to a late diagnosis, most of concerned patients cannot be subjected to them. Chemotherapy and radiotherapy are also ineffective, and currently, the treatment with sorafenib is the most commonly used systemic therapy although it can only increase the patient survival for some months. In this sense, a quick and accurate investigation is of utmost importance in order to develop ways of early diagnosis as well as new therapies for HCC.
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Affiliation(s)
- Ana Filipa Brito
- Faculty of Medicine of University of Coimbra, Pólo III - Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Celas. 3000-548 Coimbra, Portugal. +351.239480200 - +351.239480217.
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27
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Chiu AP, Tschida BR, Lo LH, Moriarity BS, Rowlands DK, Largaespada DA, Keng VW. Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma. World J Gastroenterol 2015; 21:12157-12170. [PMID: 26576100 PMCID: PMC4641133 DOI: 10.3748/wjg.v21.i42.12157] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 09/18/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV-associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia.
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28
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Abstract
BACKGROUND Infection is one of the main risk factors for cancer. OBJECTIVES Epidemiology, pathogenesis, and disease burden of infection-related cancers were reviewed by infectious agents. FINDINGS Chronic infection with Epstein-Barr virus, hepatitis B and C viruses, Kaposi sarcoma herpes virus, human immunodeficiency virus (HIV) type 1, human papillomavirus (HPV), human T-cell lymphotropic virus type 1, Helicobacter pylori, Clonorchis sinensis, Opisthorchis viverrini, and Schistosoma haematobium are associated with nasopharyngeal carcinoma; lymphoma and leukemia, including non-Hodgkin lymphoma, Hodgkin lymphoma, and Burkitt lymphoma; hepatocellular carcinoma; Kaposi sarcoma; oropharyngeal carcinoma; cervical carcinoma and carcinoma of other anogential sites; adult T-cell leukemia/lymphoma; gastric carcinoma; cholangiocarcinoma; and urinary bladder cancer. In 2008, approximately 2 million new cancer cases (16%) worldwide were attributable to infection. If these infections could be prevented and/or treated, it is estimated that there would be about 23% fewer cancers in less developed regions of the world, and about 7% fewer cancers in more developed regions. CONCLUSION Widespread application of existing public health methods for the prevention of infection, such as vaccination, safer injection practices, quality-assured screening of all donated blood and blood components, antimicrobial treatments, and safer sex practices, including minimizing one's lifetime number of sexual partners and condom use, could have a substantial effect on the future burden of cancer worldwide.
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29
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Iannacone M, Guidotti LG. Mouse Models of Hepatitis B Virus Pathogenesis. Cold Spring Harb Perspect Med 2015; 5:cshperspect.a021477. [PMID: 26292984 DOI: 10.1101/cshperspect.a021477] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The host range of hepatitis B virus (HBV) is limited to humans and chimpanzees. As discussed in the literature, numerous studies in humans and chimpanzees have generated a great deal of information on the mechanisms that cause viral clearance, viral persistence, and disease pathogenesis during acute or chronic HBV infection. Relevant pathogenetic studies have also been performed in those few species representing natural hosts of hepadnaviruses that are related to HBV, such as the woodchuck hepatitis virus and the duck hepatitis virus. Further insight has been gained from multidisciplinary studies in transgenic or humanized chimeric mouse models expressing and/or replicating HBV to varying degrees. We provide here a concise summary of the available HBV mouse models as well as of the contributions of these models to our understanding of HBV pathogenesis.
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Affiliation(s)
- Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Luca G Guidotti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy Department of Immunology & Microbial Sciences, The Scripps Research Institute, La Jolla, California 92037
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30
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Tu T, Budzinska MA, Shackel NA, Jilbert AR. Conceptual models for the initiation of hepatitis B virus-associated hepatocellular carcinoma. Liver Int 2015; 35:1786-800. [PMID: 25640596 DOI: 10.1111/liv.12773] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 12/18/2014] [Indexed: 12/18/2022]
Abstract
Although chronic hepatitis B virus (HBV) infection is a known risk factor for the development of hepatocellular carcinoma (HCC), the steps involved in the progression from normal liver to HCC are poorly understood. In this review, we apply five conceptual models, previously proposed by Vineis et al. to explain carcinogenesis in general, to explore the possible steps involved in the initiation and evolution of HBV-associated HCC. Available data suggest that the most suitable and inclusive model is based on evolution of hepatocyte subpopulations. In this evolutionary model, HCC-associated changes are driven by selection and subsequent clonal expansion of phenotypically altered hepatocyte subpopulations in the microenvironment of the HBV-infected liver. This model can incorporate the wide range of mechanisms proposed to play a role in the initiation of HCC including oncogenic HBV proteins, integration of HBV DNA and chronic inflammation of the liver. The model may assist in the early prevention, detection and treatment of HCC and may guide future studies of the initiation of HBV-associated HCC.
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Affiliation(s)
- Thomas Tu
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.,Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Magdalena A Budzinska
- Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Nicholas A Shackel
- Liver Cell Biology, Centenary Institute, Sydney, NSW, Australia.,Sydney Medical School, University of Sydney, Sydney, NSW, Australia.,A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Allison R Jilbert
- Department of Molecular and Cellular Biology, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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31
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Zhang X, Ding HG. Key role of hepatitis B virus mutation in chronic hepatitis B development to hepatocellular carcinoma. World J Hepatol 2015; 7:1282-1286. [PMID: 26019744 PMCID: PMC4438503 DOI: 10.4254/wjh.v7.i9.1282] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/19/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). The HBV mutations, which include point mutation, deletion, insertion and truncation mutation of HBV gene in 4 open reading frames (S, C, P, X), are closely associated with HCC pathogenesis. Some mutations accumulated during chronic HBV infection could be regarded as a biomarker to predict the occurrence of HCC. The detection of the mutations in clinical practice could be helpful for defining better preventive and therapeutic strategies and, moreover, predicting the progression of liver disease.
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Affiliation(s)
- Xin Zhang
- Xin Zhang, Hui-Guo Ding, Department of Gastroenterology and Hepatology, Beijing You'an Hospital affiliated with Capital Medical University, Beijing 100069, China
| | - Hui-Guo Ding
- Xin Zhang, Hui-Guo Ding, Department of Gastroenterology and Hepatology, Beijing You'an Hospital affiliated with Capital Medical University, Beijing 100069, China
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32
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Quetier I, Brezillon N, Revaud J, Ahodantin J, DaSilva L, Soussan P, Kremsdorf D. C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis. J Gen Virol 2014; 96:614-625. [PMID: 25519169 DOI: 10.1099/vir.0.070680-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus X protein (HBx) is involved in the development of hepatocellular carcinoma (HCC). The HBx sequence is a preferential site of integration into the human genome, leading to the formation of C-terminal-truncated HBx proteins (Ct-HBx). We previously reported that Ct-HBx proteins were able to potentiate cell transformation in vitro. Our present goal was to compare the ability of Ct-HBx and full-length HBx (FL-HBx) proteins to develop or enhance HCC in transgenic mice. In the absence of treatment, neither Ct-HBx- nor FL-HBx-transgenic mice developed HCC. In young mice treated with diethylnitrosamine (DEN) at 8 months of age, a significantly higher incidence and number of liver lesions were observed in Ct-HBx mice than in FL-HBx and control mice. The earlier development of tumours in Ct-HBx-transgenic mice was associated with increased liver inflammation. At 10 months, macroscopic and microscopic analyses showed that, statistically, FL-HBx mice developed more liver lesions with a larger surface area than control mice. Furthermore, during DEN-induced initiation of HCC, Ct-HBx- and FL-HBx-transgenic mice showed higher expression of IL-6, TNF-α and IL-1β transcripts, activation of STAT3, ERK and JNK proteins and an increase in cell apoptosis. In conclusion, in DEN-treated transgenic mice, the expression of Ct-HBx protein causes a more rapid onset of HCC than does FL-HBx protein. HBV genome integration leading to the expression of a truncated form of HBx protein may therefore facilitate HCC development in chronically infected patients.
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Affiliation(s)
- Ivan Quetier
- Institut Pasteur, Département de Virologie, Paris, France
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
| | - Nicolas Brezillon
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
- Institut Pasteur, Département de Virologie, Paris, France
| | - Julien Revaud
- Institut Pasteur, Département de Virologie, Paris, France
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
| | - James Ahodantin
- Institut Pasteur, Département de Virologie, Paris, France
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
| | - Lucie DaSilva
- Institut Pasteur, Département de Virologie, Paris, France
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
| | - Patrick Soussan
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Institut Pasteur, Département de Virologie, Paris, France
- Service de Virologie, Hôpital Tenon, Paris, France
- Université Pierre et Marie Curie, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
| | - Dina Kremsdorf
- Institut Pasteur, Département de Virologie, Paris, France
- Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France
- Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France
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33
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Coffin CS, Rezaeeaval M, Pang JX, Alcantara L, Klein P, Burak KW, Myers RP. The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther 2014; 40:1262-9. [PMID: 25312649 DOI: 10.1111/apt.12990] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 08/22/2014] [Accepted: 09/25/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND North American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). AIM To determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model. METHODS In this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression. RESULTS Five hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00). CONCLUSIONS In this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC.
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Affiliation(s)
- C S Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Zuo C, Xia M, Wu Q, Zhu H, Liu J, Liu C. Role of antiviral therapy in reducing recurrence and improving survival in hepatitis B virus-associated hepatocellular carcinoma following curative resection (Review). Oncol Lett 2014; 9:527-534. [PMID: 25624883 PMCID: PMC4301553 DOI: 10.3892/ol.2014.2727] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 11/07/2014] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related mortality worldwide, with the majority of cases associated with persistent hepatitis B virus (HBV) or hepatitis C virus infection. In particular, chronic HBV infection is a predominant risk factor for the development of HCC in Asian and African populations. Hepatic resection, liver transplantion and radiofrequency ablation are increasingly used for the curative treatment of HCC, however, the survival rate of HCC patients who have undergone curative resection remains unsatisfactory due to the high recurrence rate. HCC is a complex disease that is typically resistant to the most commonly used types of chemotherapy and radiotherapy; therefore, the development of novel treatment strategies is required to improve the survival rate of this disease. A high viral load of HBV DNA is the most important correctable risk factor for HCC recurrence, for example nucleos(t)ide analogs improve the outcome following curative resection of HBV-associated HCC, and interferon-α exhibits antitumor activity against various types of cancer via direct inhibitory effects on tumor cells, anti-angiogenesis, enhanced immunogenicity of tumors, immunomodulatory effects and liver dysfunction. In the present review, antiviral treatment for HBV-associated HCC is described as a strategy to reduce recurrence and improve survival.
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Affiliation(s)
- Chaohui Zuo
- Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China ; Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL 32610-0275, USA
| | - Man Xia
- Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL 32610-0275, USA ; Department of Gynaecological Oncology, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Qunfeng Wu
- Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL 32610-0275, USA
| | - Haizhen Zhu
- Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingshi Liu
- Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Chen Liu
- Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL 32610-0275, USA
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Akamatsu S, Hayes CN, Tsuge M, Miki D, Akiyama R, Abe H, Ochi H, Hiraga N, Imamura M, Takahashi S, Aikata H, Kawaoka T, Kawakami Y, Ohishi W, Chayama K. Differences in serum microRNA profiles in hepatitis B and C virus infection. J Infect 2014; 70:273-87. [PMID: 25452043 DOI: 10.1016/j.jinf.2014.10.017] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 09/18/2014] [Accepted: 10/17/2014] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Patients infected with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) are at greater risk of cirrhosis and hepatocellular carcinoma. The objective of this study was to identify virus-specific serum microRNA profiles associated with liver function and disease progression. Microarray analysis of serum microRNAs was performed using the Toray 3D array system in 22 healthy subjects, 42 HBV patients, and 30 HCV patients. Selected microRNAs were then validated by qRT-PCR in 186 HBV patients, 107 HCV patients, and 22 healthy subjects. RESULTS Microarray analysis showed up-regulation of a number of microRNAs in serum of both HBV and HCV patients. In qRT-PCR analysis, miR-122, miR-99a, miR-125b, miR-720, miR-22, and miR-1275 were up-regulated both in HBV patients relative to healthy subjects, and all except miR-1275 were up-regulated in HBeAg-positive patients relative to HBeAg-negative patients. Specific microRNAs were independently associated with different aspects of HBV infection. MiR-122 was independently associated with HBV DNA level, whereas miR-125b was independently associated with levels of HBV DNA, HBsAg, and HBeAg. MiR-22 and miR-1275 were independently associated with serum γ-glutamyl transpeptidase levels. CONCLUSIONS Serum microRNA levels reflect differences in the etiology and stage of viral hepatitis.
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Affiliation(s)
- Sakura Akamatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Rie Akiyama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | | | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Waka Ohishi
- Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
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Sustained inhibition of hepatitis B virus replication in vivo using RNAi-activating lentiviruses. Gene Ther 2014; 22:163-71. [PMID: 25338920 DOI: 10.1038/gt.2014.94] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 08/26/2014] [Accepted: 09/17/2014] [Indexed: 12/15/2022]
Abstract
Chronic infection with hepatitis B virus (HBV) puts individuals at high risk for complicating cirrhosis and liver cancer, but available treatment to counter the virus rarely eliminates infection. Although harnessing RNA interference (RNAi) to silence HBV genes has shown the potential, achieving efficient and durable silencing of viral genes remains an important goal. Here we report on the propagation of lentiviral vectors (LVs) that successfully deliver HBV-targeting RNAi activators to liver cells. Mono- and tricistronic artificial primary microRNAs (pri-miRs) derived from pri-miR-31, placed under transcriptional control of the liver-specific modified murine transthyretin (mTTR) promoter, caused efficient inhibition of HBV replication markers. The tricistronic cassette was capable of silencing a mutant viral target and the effects were observed without disrupting the function of an endogenous miR (miR-16). The mTTR promoter stably expressed a reporter transgene in mouse livers over a study period of 1 year. Good silencing of HBV genes, without evidence of toxicity, was demonstrated following intravenous injection of LVs into neonatal HBV transgenic mice. Collectively, these data indicate that LVs may achieve sustained inhibition of HBV replication that is appealing for their therapeutic use.
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Chen Y, Williams V, Filippova M, Filippov V, Duerksen-Hughes P. Viral carcinogenesis: factors inducing DNA damage and virus integration. Cancers (Basel) 2014; 6:2155-86. [PMID: 25340830 PMCID: PMC4276961 DOI: 10.3390/cancers6042155] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 10/03/2014] [Accepted: 10/09/2014] [Indexed: 12/13/2022] Open
Abstract
Viruses are the causative agents of 10%-15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer.
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Affiliation(s)
- Yan Chen
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Vonetta Williams
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Maria Filippova
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
| | - Valery Filippov
- Department of Basic Science, Loma Linda University, Loma Linda, CA 92354, USA.
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Suhail M, Abdel-Hafiz H, Ali A, Fatima K, Damanhouri GA, Azhar E, Chaudhary AGA, Qadri I. Potential mechanisms of hepatitis B virus induced liver injury. World J Gastroenterol 2014; 20:12462-12472. [PMID: 25253946 PMCID: PMC4168079 DOI: 10.3748/wjg.v20.i35.12462] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 03/25/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.
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Liu H, Lou G, Li C, Wang X, Cederbaum AI, Gan L, Xie B. HBx inhibits CYP2E1 gene expression via downregulating HNF4α in human hepatoma cells. PLoS One 2014; 9:e107913. [PMID: 25238230 PMCID: PMC4169590 DOI: 10.1371/journal.pone.0107913] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 08/21/2014] [Indexed: 12/23/2022] Open
Abstract
CYP2E1, one of the cytochrome P450 mixed-function oxidases located predominantly in liver, plays a key role in metabolism of xenobiotics including ethanol and procarcinogens. Recently, down-expression of CYP2E1 was found in hepatocellular carcinoma (HCC) with the majority to be chronic hepatitis B virus (HBV) carriers. In this study, we tested a hypothesis that HBx may inhibit CYP2E1 gene expression via hepatocyte nuclear factor 4α (HNF4α). By enforced HBx gene expression in cultured HepG2 cells, we determined the effect of HBx on CYP2E1 mRNA and protein expression. With a bioinformatics analysis, we found a consensus HNF-4α binding sequence located on −318 to −294 bp upstream of human CYP2E1 promoter. Using reporter gene assay and site-directed mutagenesis, we have shown that mutation of this site dramatically decreased CYP2E1 promoter activity. By silencing endogenous HNF-4α, we have further validated knockdown of HNF-4α significantly decreased CYP2E1expression. Ectopic overexpression of HBx in HepG2 cells inhibits HNF-4α expression, and HNF-4α levels were inversely correlated with viral proteins both in HBV-infected HepG2215 cells and as well as HBV positive HCC liver tissues. Moreover, the HBx-induced CYP2E1 reduction could be rescued by ectopic supplement of HNF4α protein expression. Furthermore, human hepatoma cells C34, which do not express CYP2E1, shows enhanced cell growth rate compared to E47, which constitutively expresses CYP2E1. In addition, the significantly altered liver proteins in CYP2E1 knockout mice were detected with proteomics analysis. Together, HBx inhibits human CYP2E1 gene expression via downregulating HNF4α which contributes to promotion of human hepatoma cell growth. The elucidation of a HBx-HNF4α-CYP2E1 pathway provides novel insight into the molecular mechanism underlining chronic HBV infection associated hepatocarcinogenesis.
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Affiliation(s)
- Hongming Liu
- Department of Hepatobiliary Surgery, Daping Hospital & Institute of Surgery Research, The Third Military Medical University, Chongqing, China
| | - Guiyu Lou
- Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, China
| | - Chongyi Li
- Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, China
| | - Xiaodong Wang
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Chongqing Biomean Technology Co., Ltd, Chongqing, China
| | - Arthur I. Cederbaum
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Lixia Gan
- Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing, China
- * E-mail: (LG); (BX)
| | - Bin Xie
- Department of Hepatobiliary Surgery, Daping Hospital & Institute of Surgery Research, The Third Military Medical University, Chongqing, China
- * E-mail: (LG); (BX)
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Tanase AM, Dumitrascu T, Dima S, Grigorie R, Marchio A, Pineau P, Popescu I. Influence of hepatitis viruses on clinicopathological profiles and long-term outcome in patients undergoing surgery for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2014; 13:162-172. [PMID: 24686543 DOI: 10.1016/s1499-3872(14)60026-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The global risk of hepatocellular carcinoma (HCC) is largely due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. In recent years, however, an increased prevalence of non-viral HCC has been noted. The clinical impact of the presence/absence of viral infections in HCC remains controversial. The present study aimed to assess the effect of hepatitis viruses on demographics, clinical and pathological features and long-term outcome in a large cohort of Romanian patients who underwent surgery for HCC. METHODS The study included 404 patients with HCC who had undergone resection, transplantation or radiofrequency ablation at a single institution between 2001 and 2010. The patients were divided into four groups: 85 patients with hepatitis B virus infection (HBV group), 164 patients with hepatitis C virus infection (HCV group), 39 patients with hepatitis B and C virus co-infection (HBCV group), and 116 patients without viral infection (non-BC group). RESULTS The patients of both HBV (56.0+/-11.3 years) and HBCV groups (56.0+/-9.9 years) were significantly younger than those of the HCV (61.0+/-8.5 years, P=0.001) and non-BC groups (61.0+/-13.0 years, P=0.002). Interestingly, the prevalence of liver cirrhosis was significantly lower in the non-BC group (47%) than in any other subsets (72%-90%, P<0.002). Furthermore, the non-BC patients were more advanced according to the Barcelona Clinic Liver Cancer stages than the patients of the HCV or HBCV groups (P<0.020); accordingly, they were more frequently assessed beyond the Milan criteria than any other groups (P=0.001). No significant differences in the disease-free or overall survival rates were observed among these groups. CONCLUSIONS Patients with non-viral HCC are diagnosed at advanced ages and stages, a situation plausibly due to the poor effectiveness of cancer surveillance in community practice. The presence of viral infections does not appear to impair the long-term prognosis after surgical treatment in patients with HCC; however, there is a trend for worse disease-free survival rates in HBCV patients, though statistical significance was not reached.
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Affiliation(s)
- Anna-Maria Tanase
- Center of General Surgery and Liver Transplant, Fundeni Clinical Institute, Fundeni Street No. 258, 022328, Bucharest, Romania.
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Matos MADD, Ferreira RC, Rodrigues FP, Marinho TA, Lopes CLR, Novais ACM, Motta-Castro ARC, Teles SA, Souto FJD, Martins RMB. Occult hepatitis B virus infection among injecting drug users in the Central-West Region of Brazil. Mem Inst Oswaldo Cruz 2014; 108:S0074-02762013000300386. [PMID: 23778654 DOI: 10.1590/s0074-02762013000300019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Accepted: 08/08/2012] [Indexed: 02/08/2023] Open
Abstract
The prevalence of occult hepatitis B virus (HBV) infection was investigated in 149 hepatitis B surface antigen (HBsAg) negative injecting drug users (IDUs) in the Central-West Region of Brazil. Of these individuals, 19 were positive for HBV DNA, resulting in an occult HBV infection prevalence of 12.7% (19/149); six of these 19 individuals had anti-HBV core and/or anti-HBV surface antibodies and 13 were negative for HBV markers. All IDUs with occult hepatitis B reported sexual and/or parenteral risk behaviours. All HBV DNA-positive samples were successfully genotyped. Genotype D was the most common (17/19), followed by genotype A (2/19). These findings reveal a high prevalence of occult HBV infection and the predominance of genotype D among IDUs in Brazil's Central-West Region.
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Munaf A, Memon MS, Kumar P, Ahmed S, Kumar MB. Comparison of viral hepatitis-associated hepatocellular carcinoma due to HBV and HCV - cohort from liver clinics in Pakistan. Asian Pac J Cancer Prev 2014; 15:7563-7. [PMID: 25292029 DOI: 10.7314/apjcp.2014.15.18.7563] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the first cause of death in cirrhotic patients, mostly due to viral hepatitis with HCV or HBV infection. This study was performed to estimate the true prevalence of viral hepatitis-related HCC and the demographic and clinical-pathological associations with the two virus types. MATERIALS AND METHODS This cross sectional observational study enrolled clinical data base of 188 HCC patients and variables included from baseline were age, sex, area of residence, clinical-pathological features such as underlying co-morbidity, presence or absence of liver cirrhosis, macrovascular involvement, tumor extension and metastasis, liver lobes involved, serum alpha-fetoprotein level, and hepatitis serologies. RESULTS Overall prevalence of HCV- and HBV-related HCC was 66.0% and 34.0%, respectively. Patients with HCV were more likely to develop HCC at advanced age (52.4±11.9 vs. 40.7±12.09 years), with highly raised serum AFP levels (≥400ng/ml) 78.2% (HBV 67.1%), large tumor size (HCV-66% >5 cm, HBV-59.3%), and presence of portal vein thrombosis (8.06%, HBV 1.56%). A binominal multivariate analysis showed that HCV-HCC group were more likely to be cirrhotic (OR=0.245, 95%CI: 0.117, 0.516) and had more than two times higher rate of solitary macrovascular involvement (OR=2.533, 95%CI: 1.162, 5.521) as compared with HBV associated HCC. CONCLUSIONS Statistically significant variations were observed from baseline to clinical-pathological characteristics in HCV vs HBV associated HCC. Our study suggests prompt and early screening for high risk patients so that the rate of progression of these chronic viral diseases to cirrhosis and cancer can be decreased.
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Affiliation(s)
- Alvina Munaf
- Asian Institute of Medical Sciences, Hyderabad, Pakistan E-mail :
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Zhang W, Guo Z, Zhang L, Liu Z, Li J, Ji Z, Xu R, Zhao N, Li F, Chen X, Yan Y, Zhang J, An Q, Yang H, Den Z, Shao Z. Maternal immunization promotes the immune response of neonates towards hepatitis B vaccine. J Viral Hepat 2013; 20:875-81. [PMID: 24304457 DOI: 10.1111/jvh.12103] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 02/27/2013] [Indexed: 12/12/2022]
Abstract
Infants infected with hepatitis B virus (HBV) face the risk of developing severe complications. Unfortunately, in spite of universal vaccination programmes, 5% or more of vaccinated newborns still do not achieve protective levels of anti-hepatitis B virus surface antigen titres (anti-HBs). The aim of this study was to use animal experiments and population-based research to determine whether maternal vaccination against HBV affects the outcome of neonatal vaccination. Six sows and 53 newborn piglets were used for this study and randomly assigned to the vaccination group (three 20 μg doses of recombinant HBV vaccine). All the piglets were followed up to 10 weeks of age, and peripheral blood was withdrawn for measurement of anti-HBs. A cross-sectional study was also conducted on 449 mothers with infants. A structured questionnaire was used to collect demographic, medical and maternal data, and their peripheral blood was collected for measurement of anti-HBs. The results of animal experiments demonstrated that nonvaccinated piglets born to vaccinated sows and nonvaccinated piglets born to nonvaccinated sows were negative for anti-HBs. Repeated measures analysis of variance showed that the titres of anti-HBs in vaccinated piglets born to vaccinated sows were significantly higher than in vaccinated piglets born to nonvaccinated sows (P < 0.05). In a population-based study, a cumulative logistic regression analysis showed that the strongest influences on neonatal anti-HBs titres were delay of the first vaccination dose [OR = 3.02(95% CI: 1.72-5.30)] and maternal anti-HBs titres [OR = 2.48(95% CI: 2.03-3.04)]. In conclusion, high maternal anti-HBs titres can enhance the response to HBV vaccination in infants.
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Affiliation(s)
- W Zhang
- Department of Epidemiology, School of Public Health, The Fourth Military Medical University, Xi'an, China
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Arora A, Sharma P, Tyagi P, Singla V, Arora V, Bansal N, Toshniwal J, Kumar A. Hepatitis B Virus Infection can Cause Hepatocellular Carcinoma in Less Advanced Liver Cirrhosis: A Comparative Study of 142 Patients from North India. J Clin Exp Hepatol 2013; 3:288-95. [PMID: 25755516 PMCID: PMC3940433 DOI: 10.1016/j.jceh.2013.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 08/15/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS The clinical profile of patients with hepatocellular carcinoma (HCC) may differ depending on the etiology of HCC. There is no study from India comparing the clinical profile of patients of HCC due to hepatitis B virus (HBV) infection with other etiologies. METHODS We retrospectively reviewed the records of patients clinically diagnosed as HCC between Nov 2000 and Dec 2012 admitted under a single unit of Department of Gastroenterology at our hospital. We compared the clinical presentation of patients of Hepatitis B virus etiology (HBV group) with other etiologies (Non-HBV group). RESULTS One hundred and forty-two patients were included (median age 60 years [range 30-83], 92% males). The etiology was HBV in 56 (39%) and among the non-HBV group (n = 86, 61%) the etiological spectrum was following: alcohol 31 (22%), cryptogenic 26 (18%), HCV 27 (19%), and miscellaneous 2 (1%). The median age of presentation was significantly less for HBV group than in non-HBV (56 [30-77] vs. 62 [42-83] years, P < 0.01). Clinical evidence of cirrhosis was significantly less common in the HBV group than non-HBV group (74% vs 98%, P < 0.01). HBV group had lower CTP score than non-HBV (median CTP score 7 vs 8,P < 0.05). Ascites was more common in non-HBV group than HBV group (65% vs 43%, P = 0.018). The BCLC staging was: A 13%, B 23%, C 35%, and D 29%, and there was no difference in tumor characteristics or BCLC staging between HBV or the non-HBV group. CONCLUSIONS HBV is a common cause of HCC in India, accounting for 39% of cases. The tumor characteristics of HCC due to HBV is similar to other etiologies, however, HBV causes HCC at an earlier age, and in less advanced or even absence of cirrhosis, thus further consolidating the directly carcinogenic potential of HBV.
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Affiliation(s)
- Anil Arora
- Address for correspondence: Chairman, Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India.
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Li HP, Zeng XC, Zhang B, Long JT, Zhou B, Tan GS, Zeng WX, Chen W, Yang JY. miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β. Carcinogenesis 2013; 34:2443-2451. [PMID: 23740840 DOI: 10.1093/carcin/bgt206] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
It has been demonstrated that nuclear factor-kappa B (NF-κB), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-κB pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-κB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c-Myc through inhibition of NF-κB pathway initiated by direct targeting of the IKBKB 3'-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies.
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MESH Headings
- Animals
- Apoptosis
- Blotting, Western
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Adhesion
- Cell Cycle
- Cell Movement
- Cell Proliferation
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Flow Cytometry
- Fluorescent Antibody Technique
- Gene Expression Regulation, Neoplastic
- Humans
- I-kappa B Kinase/antagonists & inhibitors
- I-kappa B Kinase/genetics
- I-kappa B Kinase/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- RNA, Messenger/genetics
- RNA, Small Interfering/genetics
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
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Affiliation(s)
- He-Ping Li
- Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
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Bayliss J, Lim L, Thompson AJV, Desmond P, Angus P, Locarnini S, Revill PA. Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma. J Hepatol 2013; 59:1022-8. [PMID: 23811301 DOI: 10.1016/j.jhep.2013.06.018] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/04/2013] [Accepted: 06/18/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC. METHODS Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads. RESULTS spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (τ=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R(2)=0.189). CONCLUSIONS HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC.
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Affiliation(s)
- Julianne Bayliss
- Division of Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria 3051, Australia.
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Hepatitis B virus HBx protein impairs liver regeneration through enhanced expression of IL-6 in transgenic mice. J Hepatol 2013; 59:285-91. [PMID: 23542345 DOI: 10.1016/j.jhep.2013.03.021] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Revised: 02/19/2013] [Accepted: 03/19/2013] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Conflicting results have been reported regarding the impact of hepatitis B virus X protein (HBx) expression on liver regeneration triggered by partial hepatectomy (PH). In the present report we investigated the mechanisms by which HBx protein alters hepatocyte proliferation after PH. METHODS PH was performed on a transgenic mouse model in which HBx expression is under the control of viral regulatory elements and liver regeneration was monitored. LPS, IL-6 neutralizing antibody, and SB203580 were injected after PH to evaluate IL-6 participation during liver regeneration. RESULTS Cell cycle progression of hepatocytes was delayed in HBx transgenic mice compared to WT animals. Moreover, HBx induced higher secretion of IL-6 soon after PH. Upregulation of IL-6 was associated with an elevation of STAT3 phosphorylation, SOCS3 transcript accumulation and a decrease in ERK1/2 phosphorylation in the livers of HBx transgenic mice. The involvement of IL-6 overexpression in cell cycle deregulation was confirmed by the inhibition of liver regeneration in control mice after the upregulation of IL-6 expression using LPS. In addition, IL-6 neutralization with antibodies was able to restore liver regeneration in HBx mice. Finally, the direct role of p38 in IL-6 secretion after PH was demonstrated using SB203580, a pharmacological inhibitor. CONCLUSIONS HBx is able to induce delayed hepatocyte proliferation after PH, and HBx-induced IL-6 overexpression is involved in delayed liver regeneration. By modulating IL-6 expression during liver proliferation induced by stimulation of the cellular microenvironment, HBx may participate in cell cycle deregulation and progression of liver disease.
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Johnson PJ. How do mechanisms of hepatocarcinogenesis (HBV, HCV, and NASH) affect our understanding and approach to HCC? Am Soc Clin Oncol Educ Book 2013:0011300132. [PMID: 23714479 DOI: 10.14694/edbook_am.2013.33.e132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
The major etiologic factors for hepatocellular carcinoma (HCC), including chronic hepatitis B and C virus infections and nonalcoholic fatty liver disease, are now well established by epidemiologic investigations. The mechanisms by which these factors result in HCC have been extensively investigated but have not, to date, resulted in the development of specific therapeutic interventions. Other frequently occurring dysregulated pathways, including the Wnt/β-catenin signaling pathway, are proving difficult to target, but there are early suggestions that patients with "MET-high" HCC may benefit from the c-MET inhibitor tivantinib. Chronic inflammation and consequent cell damage and regenerative proliferation are common to all etiologic factors, and emerging evidence suggests that anti-inflammatory agents such as aspirin deserve further investigation as preventive agents.
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Affiliation(s)
- Philip J Johnson
- From the Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
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Jung SY, Kim YJ. C-terminal region of HBx is crucial for mitochondrial DNA damage. Cancer Lett 2012; 331:76-83. [PMID: 23246371 DOI: 10.1016/j.canlet.2012.12.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/04/2012] [Accepted: 12/04/2012] [Indexed: 02/07/2023]
Abstract
HBx is strongly associated with hepatocellular carcinoma development through transcription factor activation and reactive oxygen species (ROSs) production. However, the exact role of HBx during hepatocellular carcinogenesis is not fully understood. Recently, it was reported that C-terminal truncated HBx is associated with tumor metastasis. In the present study, we confirmed that the C-terminal region of HBx is required for ROS production and 8-oxoguanine (8-oxoG) formation, which is considered as a reliable biomarker of oxidative stress. These results suggest ROS production induced by the C-terminal region of HBx leads to mitochondrial DNA damage, which may play a role in HCC development.
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Affiliation(s)
- Seung-Youn Jung
- Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea
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Luo L, Chen S, Gong Q, Luo N, Lei Y, Guo J, He S. Hepatitis B virus X protein modulates remodelling of minichromosomes related to hepatitis B virus replication in HepG2 cells. Int J Mol Med 2012; 31:197-204. [PMID: 23128981 DOI: 10.3892/ijmm.2012.1165] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 08/14/2012] [Indexed: 11/05/2022] Open
Abstract
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is organised into minichromosomes by histone and non-histone proteins. Remodelling of minichromosomes is crucial for the regulation of HBV replication, which is dependent on the presence of the hepatitis B virus X protein (HBx). However, the mechanisms of HBx-dependent HBV replication remain obscure. The objective of this study was to investigate the mechanism of HBx-dependent HBV replication through the pathway of chromatin remodelling. The role of HBx was investigated by transfecting human HepG2 cells with the linear full-length HBV genome (wild-type) or HBx-deficient mutant HBV DNA (HBx mutant). Our results showed that although the formation of cccDNA was not affected by HBx, HBV replication, transcription and antigen secretion were all significantly reduced, resulting from the absence of HBx. The acetylation, mono-methylation and phosphorylation of cccDNA-bound histone H3 were associated with HBV replication. In addition, the levels of cccDNA-bound methylated, phosphorylated and acetylated histone H3 decreased sharply in HBx mutant HBV DNA. HBx modulated not only the status of acetylation but also the methylation and phosphorylation of histone H3 bound to the cccDNA during HBV replication in HepG2 cells. These findings suggest that HBx plays an important role in modulating the remodelling of minichromosomes related to HBV replication and it may regulate viral replication through the pathway of chromatin remodelling.
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Affiliation(s)
- Li Luo
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
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