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Epremyan KK, Goleva TN, Rogov AG, Lavrushkina SV, Zinovkin RA, Zvyagilskaya RA. The First Yarrowia lipolytica Yeast Models Expressing Hepatitis B Virus X Protein: Changes in Mitochondrial Morphology and Functions. Microorganisms 2022; 10:microorganisms10091817. [PMID: 36144419 PMCID: PMC9501646 DOI: 10.3390/microorganisms10091817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Chronic hepatitis B virus infection is the dominant cause of hepatocellular carcinoma, the main cause of cancer death. HBx protein, a multifunctional protein, is essential for pathogenesis development; however, the underlying mechanisms are not fully understood. The complexity of the system itself, and the intricate interplay of many factors make it difficult to advance in understanding the mechanisms underlying these processes. The most obvious solution is to use simpler systems by reducing the number of interacting factors. Yeast cells are particularly suitable for studying the relationships between oxidative stress, mitochondrial dynamics (mitochondrial fusion and fragmentation), and mitochondrial dysfunction involved in HBx-mediated pathogenesis. For the first time, genetically modified yeast, Y. lipolytica, was created, expressing the hepatitis B virus core protein HBx, as well as a variant fused with eGFP at the C-end. It was found that cells expressing HBx experienced stronger oxidative stress than the control cells. Oxidative stress was alleviated by preincubation with the mitochondria-targeted antioxidant SkQThy. Consistent with these data, in contrast to the control cells (pZ-0) containing numerous mitochondrial forming a mitochondrial reticulum, in cells expressing HBx protein, mitochondria were fragmented, and preincubation with SkQThy partially restored the mitochondrial reticulum. Expression of HBx had a significant influence on the bioenergetic function of mitochondria, making them loosely coupled with decreased respiratory rate and reduced ATP formation. In sum, the first highly promising yeast model for studying the impact of HBx on bioenergy, redox-state, and dynamics of mitochondria in the cell and cross-talk between these parameters was offered. This fairly simple model can be used as a platform for rapid screening of potential therapeutic agents, mitigating the harmful effects of HBx.
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Affiliation(s)
- Khoren K. Epremyan
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
- Correspondence: (K.K.E.); (R.A.Z.); Tel.: +7-(917)-575-3560 (K.K.E.)
| | - Tatyana N. Goleva
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
| | - Anton G. Rogov
- National Research Center “Kurchatov Institute”, Akademika Kurchatova pl. 1, 123182 Moscow, Russia
| | - Svetlana V. Lavrushkina
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, Russia
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Leninskye Gory 1/73, 119234 Moscow, Russia
| | - Roman A. Zinovkin
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskye Gory 1/40, 119992 Moscow, Russia
| | - Renata A. Zvyagilskaya
- A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Ave. 33/2, 119071 Moscow, Russia
- Correspondence: (K.K.E.); (R.A.Z.); Tel.: +7-(917)-575-3560 (K.K.E.)
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Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review. Cells 2022; 11:cells11040741. [PMID: 35203390 PMCID: PMC8870387 DOI: 10.3390/cells11040741] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
With 296 million cases estimated worldwide, chronic hepatitis B virus (HBV) infection is the most common risk factor for hepatocellular carcinoma (HCC). HBV-encoded oncogene X protein (HBx), a key multifunctional regulatory protein, drives viral replication and interferes with several cellular signalling pathways that drive virus-associated hepatocarcinogenesis. This review article provides a comprehensive overview of the role of HBx in modulating the various hallmarks of HCC by supporting tumour initiation, progression, invasion and metastasis. Understanding HBx-mediated dimensions of complexity in driving liver malignancies could provide the key to unlocking novel and repurposed combinatorial therapies to combat HCC.
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Xu D, Cai J, Wan ZK, Gao H, Sun Y. Pathophysiological role of prostaglandin E synthases in liver diseases. Prostaglandins Other Lipid Mediat 2021; 154:106552. [PMID: 33930567 DOI: 10.1016/j.prostaglandins.2021.106552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 04/11/2021] [Accepted: 04/23/2021] [Indexed: 12/20/2022]
Abstract
Prostaglandin E synthases (PGESs) convert cyclooxygenase (COX)-derived prostaglandin H2 (PGH2) into prostaglandin E2 (PGE2) and comprise at least three types of structurally and biologically distinct enzymes. Two of these, namely microsomal prostaglandin E synthase-1 (mPGES-1) and mPGES-2, are membrane-bound enzymes. mPGES-1 is an inflammation-inducible enzyme that converts PGH2 into PGE2. mPGES-2 is a bifunctional enzyme that generally forms a complex with haem in the presence of glutathione. This enzyme can metabolise PGH2 into malondialdehyde and can produce PGE2 after its separation from haem. In this review, we discuss the role of PGESs, particularly mPGES-1 and mPGES-2, in the pathogenesis of liver diseases. A better understanding of the roles of PGESs in liver disease may aid in the development of treatments for patients with liver diseases.
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Affiliation(s)
- Delong Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Jie Cai
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Zhi-Kang Wan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Hang Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China
| | - Ying Sun
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People's Republic of China.
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Xie J, Wang M, Cheng A, Jia R, Zhu D, Liu M, Chen S, Zhao X, Yang Q, Wu Y, Zhang S, Luo Q, Wang Y, Xu Z, Chen Z, Zhu L, Liu Y, Yu Y, Zhang L, Chen X. The role of SOCS proteins in the development of virus- induced hepatocellular carcinoma. Virol J 2021; 18:74. [PMID: 33849568 PMCID: PMC8045357 DOI: 10.1186/s12985-021-01544-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 04/03/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host's antiviral responses to achieve persistent infection. CONCLUSIONS This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.
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Affiliation(s)
- Jinyan Xie
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mingshu Wang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Anchun Cheng
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China.
| | - Renyong Jia
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Dekang Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Mafeng Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shun Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - XinXin Zhao
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qiao Yang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ying Wu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Shaqiu Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Qihui Luo
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yin Wang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhiwen Xu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Zhengli Chen
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhu
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yunya Liu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Yanling Yu
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Ling Zhang
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
| | - Xiaoyue Chen
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
- Avian Disease Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu City, 611130, Sichuan, People's Republic of China
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Torresi J, Tran BM, Christiansen D, Earnest-Silveira L, Schwab RHM, Vincan E. HBV-related hepatocarcinogenesis: the role of signalling pathways and innovative ex vivo research models. BMC Cancer 2019; 19:707. [PMID: 31319796 PMCID: PMC6637598 DOI: 10.1186/s12885-019-5916-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Accepted: 07/09/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is the leading cause of liver cancer, but the mechanisms by which HBV causes liver cancer are poorly understood and chemotherapeutic strategies to cure liver cancer are not available. A better understanding of how HBV requisitions cellular components in the liver will identify novel therapeutic targets for HBV associated hepatocellular carcinoma (HCC). MAIN BODY The development of HCC involves deregulation in several cellular signalling pathways including Wnt/FZD/β-catenin, PI3K/Akt/mTOR, IRS1/IGF, and Ras/Raf/MAPK. HBV is known to dysregulate several hepatocyte pathways and cell cycle regulation resulting in HCC development. A number of these HBV induced changes are also mediated through the Wnt/FZD/β-catenin pathway. The lack of a suitable human liver model for the study of HBV has hampered research into understanding pathogenesis of HBV. Primary human hepatocytes provide one option; however, these cells are prone to losing their hepatic functionality and their ability to support HBV replication. Another approach involves induced-pluripotent stem (iPS) cell-derived hepatocytes. However, iPS technology relies on retroviruses or lentiviruses for effective gene delivery and pose the risk of activating a range of oncogenes. Liver organoids developed from patient-derived liver tissues provide a significant advance in HCC research. Liver organoids retain the characteristics of their original tissue, undergo unlimited expansion, can be differentiated into mature hepatocytes and are susceptible to natural infection with HBV. CONCLUSION By utilizing new ex vivo techniques like liver organoids it will become possible to develop improved and personalized therapeutic approaches that will improve HCC outcomes and potentially lead to a cure for HBV.
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Affiliation(s)
- Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Bang Manh Tran
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Dale Christiansen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Linda Earnest-Silveira
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Renate Hilda Marianne Schwab
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
| | - Elizabeth Vincan
- The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
- Victorian Infectious Diseases Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010 Australia
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA 6845 Australia
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Chen S, Wang Z, Wan S, Huang H, Liang H. Effect of modified Xiaochaihu decoction‑containing serum on HepG2.2.15 cells via the JAK2/STAT3 signaling pathway. Mol Med Rep 2017; 16:7416-7422. [PMID: 28944901 PMCID: PMC5865873 DOI: 10.3892/mmr.2017.7561] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 06/19/2017] [Indexed: 01/30/2023] Open
Abstract
The present study aimed to investigate the possible mechanisms underlying the effect of modified Xiaochaihu decoction (mXCHD) in the treatment of chronic hepatitis B (CHB). Patients with CHB, in addition to liver stagnation and spleen deficiency syndrome were randomly assigned to receive either Chinese (mXCHD) or western (entecavir) treatment, with 30 cases in each group. Serum was collected following treatment with mXCHD or entecavir for 7 days. A healthy group of 30 individuals was also included. HepG2.2.15 cells were cultured in vitro and randomly divided into four groups: Healthy; entecavir-treated; 10% mXCHD-treated; and 20% mXCHD-treated. The HepG2.2.15 cells in the four groups were treated with either serum from the healthy volunteers, entecavir-containing serum, or mXCHD-containing serum at different concentrations (10 or 20%, respectively). Following treatment with the corresponding serum, cell proliferation was examined using an MTT assay, and the expression of hepatitis B surface antigen (HBsAg) in the cell supernatant was detected using an enzyme-linked immunosorbent assay. The mRNA and protein expression levels of Janus kinase (JAK)2 and signal transducer and activator of transcription (STAT)3 were measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The results indicated that the most effective treatment for the promotion of HepG2.2.15 cell proliferation was a 20% concentration of mXCHD serum. The expression of HBsAg was significantly decreased in the groups treated with 10 and 20% mXCHD 48 h following intervention (P<0.01). The mRNA and protein expression levels of STAT3 in the 20% mXCHD serum group were significantly increased, compared with those in the healthy group (P<0.01 and P<0.05, respectively), whereas no significant difference was observed in the expression of JAK2 among the four groups. These results indicated that mXCHD suppressed the hepatitis B virus, and treatment of the cells with mXCHD-containing serum promoted HepG2.2.15 cell proliferation via modulating the expression of STAT3, which may contribute to the clinical efficacy of mXCHD against CHB.
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Affiliation(s)
- Shaofang Chen
- College of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zhanglin Wang
- College of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Shichuan Wan
- College of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Hai Huang
- College of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Huiqing Liang
- College of Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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Huang F, Cai P, Wang Y, Zhou X, Chen H, Liao W, Mao Y, Zha X, Zhang H, Hu Z. Up-regulation of brain-expressed X-linked 2 is critical for hepatitis B virus X protein-induced hepatocellular carcinoma development. Oncotarget 2017; 8:65789-65799. [PMID: 29029472 PMCID: PMC5630372 DOI: 10.18632/oncotarget.19477] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/28/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Chronic hepatitis B virus (HBV) infection is a major cause for HCC. Hepatitis B virus X (HBx), one of four proteins encoded by HBV genome, plays a vital role in the pathogenesis of HBV-induced HCC. However, the molecular mechanisms of HBx-triggered HCC remain largely undetermined. Here we revealed that the expression of Brain-expressed X-linked 2 (BEX2) and Osteopontin (OPN) were elevated in liver tissues of HBV transgenic mice and human HCC specimens. Moreover, a positive correlation between BEX2 and OPN was exhibited in samples from HCC patients with HBV infection. The protein levels of BEX2 and OPN were both higher in HBV-positive HCC specimens compared to that of HBV-negative HCC specimens. HBx potentiated OPN expression through up-regulation of BEX2. Importantly, the depletion of BEX2 suppressed tumorigenic potential of HCC cells with highly expressed HBx. We demonstrated the important role of BEX2 in HCC pathogenesis, and BEX2 may be a novel therapeutic target for HCC patients with HBV infection. The newly identified HBx/BEX2/OPN signaling cassette is implicated in the pathogenesis of HBV-induced HCC.
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Affiliation(s)
- Fuqiang Huang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pei Cai
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanan Wang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xian Zhou
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongyu Chen
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenjun Liao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yilei Mao
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaojun Zha
- Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China
| | - Hongbing Zhang
- State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhongdong Hu
- Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.,State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Li W, Li M, Liao D, Lu X, Gu X, Zhang Q, Zhang Z, Li H. Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma. Oncotarget 2016; 7:55110-55127. [PMID: 27391153 PMCID: PMC5342405 DOI: 10.18632/oncotarget.10399] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 06/17/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBxΔ31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBxΔ31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBxΔ31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBxΔ31 exerts this function via down-regulating Maspin, RhoGDIα and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBxΔ31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBxΔ31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.
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Affiliation(s)
- Weihua Li
- Department of Gastroenterology, Zhujiang Hospital of Nanfang Medical University, Guangzhou 510280, China
| | - Man Li
- Department of Infectious Disease and Hepatology, Hepatitis Research Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Dongjiang Liao
- Pathology Research Room, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510120, China
| | - Xinpeng Lu
- Pathology Research Room, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, Guangzhou 510120, China
| | - Xia Gu
- Department of Pathology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Qianqian Zhang
- Department of Infectious Disease and Hepatology, Hepatitis Research Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Zhixiang Zhang
- Department of Infectious Disease and Hepatology, Hepatitis Research Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Hui Li
- Department of Infectious Disease and Hepatology, Hepatitis Research Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
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9
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Niller HH, Ay E, Banati F, Demcsák A, Takacs M, Minarovits J. Wild type HBx and truncated HBx: Pleiotropic regulators driving sequential genetic and epigenetic steps of hepatocarcinogenesis and progression of HBV-associated neoplasms. Rev Med Virol 2015; 26:57-73. [PMID: 26593760 DOI: 10.1002/rmv.1864] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 09/30/2015] [Accepted: 10/15/2015] [Indexed: 12/23/2022]
Abstract
Hepatitis B virus (HBV) is one of the causative agents of hepatocellular carcinoma. The molecular mechanisms of tumorigenesis are complex. One of the host factors involved is apparently the long-lasting inflammatory reaction which accompanies chronic HBV infection. Although HBV lacks a typical viral oncogene, the HBx gene encoding a pleiotropic regulatory protein emerged as a major player in liver carcinogenesis. Here we review the tumorigenic functions of HBx with an emphasis on wild type and truncated HBx variants, and their role in the transcriptional dysregulation and epigenetic reprogramming of the host cell genome. We suggest that HBx acquired by the HBV genome during evolution acts like a cellular proto-onc gene that is activated by deletion during hepatocarcinogenesis. The resulting viral oncogene (v-onc gene) codes for a truncated HBx protein that facilitates tumor progression. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Hans Helmut Niller
- Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany
| | - Eva Ay
- Department of Retrovirology, National Center for Epidemiology, Budapest, Hungary
| | - Ferenc Banati
- RT-Europe Nonprofit Research Center, Mosonmagyarovar, Hungary
| | - Anett Demcsák
- University of Szeged, Faculty of Dentistry, Department of Oral Biology and Experimental Dental Research, Szeged, Hungary
| | - Maria Takacs
- Division of Virology, National Center for Epidemiology, Budapest, Hungary
| | - Janos Minarovits
- University of Szeged, Faculty of Dentistry, Department of Oral Biology and Experimental Dental Research, Szeged, Hungary
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10
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Zhang JJ, Fan YC, Zhang ZH, Han J, Wang LY, Li T, Zhang F, Yin YP, Hu LH, Yang Y, Sun FK, Wang K. Methylation of suppressor of cytokine signalling 1 gene promoter is associated with acute-on-chronic hepatitis B liver failure. J Viral Hepat 2015; 22:307-317. [PMID: 25045829 DOI: 10.1111/jvh.12286] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 05/14/2014] [Indexed: 12/13/2022]
Abstract
Suppressor of cytokine signalling 1 (SOCS1) was demonstrated to play an important negative role in fulminant hepatitis and might be involved in acute-on-chronic hepatitis B liver failure (ACHBLF). This study was therefore to identify the potential role of SOCS1 and its promoter methylation pattern in ACHBLF patients. Sixty ACHBLF patients, 60 chronic hepatitis B (CHB) patients and 30 healthy controls were investigated in this study. We found that expression of SOCS1 mRNA in CHB and ACHBLF patients was significantly higher than that in healthy controls. The serum level of IL-6, IFN-γ and TNF-α was significantly higher in ACHBLF than CHB. Increased serum level of IL-6, IFN-γ and TNF-α was correlated with total bilirubin, ALT, PTA and MELD scores in ACHBLF. The degree of methylation of the SOCS1 in ACHBLF patients (35.0%, 21/60) was significantly higher than that in CHB patients (16.7%, 10/60). Furthermore, methylated group showed lower level of SOCS1, and higher MELD scores and mortality rate when compared with unmethylated group of ACHBLF. These results suggested that SOCS1 might contribute to immune-related liver damage in ACHBLF, and its aberrant methylation may be a key event for the prognosis of ACHBLF.
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Affiliation(s)
- J-J Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
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11
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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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12
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Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B. Cytotechnology 2014; 67:1-12. [PMID: 25002206 DOI: 10.1007/s10616-014-9761-9] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 06/23/2014] [Indexed: 01/11/2023] Open
Abstract
As cellular models for in vitro liver cancer and toxicity studies, HepG2 and Hep3B are the two most frequently used liver cancer cell lines. Because of their similarities they are often treated as the same in experimental studies. However, there are many differences that have been largely over-sighted or ignored between them. In this review, we summarize the differences between HepG2 and Hep3B cell lines that can be found in the literature based on PubMed search. We particularly focus on the differential gene expression, differential drug responses (chemosensitivity, cell cycle and growth inhibition, and gene induction), signaling pathways associated with these differences, as well as the factors in governing these differences between HepG2 and Hep3B cell lines. Based on our analyses of the available data, we suggest that neither HBx nor p53 may be the crucial factor to determine the differences between HepG2 and Hep3B cell lines although HBx regulates the expression of the majority of genes that are differentially expressed between HepG2 and Hep3B. Instead, the different maturation stages in cancer development of the original specimen between HepG2 and Hep3B may be responsible for the differences between them. This review provides insight into the molecular mechanisms underlying the differences between HepG2 and Hep3B and help investigators especially the beginners in the areas of liver cancer research and drug metabolism to fully understand, and thus better use and interpret the data from these two cell lines in their studies.
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13
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Du LY, Cui YL, Chen EQ, Cheng X, Liu L, Tang H. Correlation between the suppressor of cytokine signaling-1 and 3 and hepatitis B virus: possible roles in the resistance to interferon treatment. Virol J 2014; 11:51. [PMID: 24636575 PMCID: PMC3995528 DOI: 10.1186/1743-422x-11-51] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 03/06/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The suppressor of cytokine signaling family (SOCS) is an important negative regulator in the JAK-STAT signaling pathway. This study was designed to explore the correlation between SOCS-1, 2 and 3, Hepatitis B Virus (HBV) and interferon (IFN), and the relationship between SOCS and IFN therapeutic efficacy. METHODS Four types of mouse models were established. Mice were administered with HBV replicative plasmid pHBV4.1 and IFN inducer Poly IC (Group A), pHBV4.1 (Group B), Poly IC (Group C) and saline (Group D), respectively. Liver tissues were harvested from the mice and SOCS expression was determined. Meanwhile, patients with chronic hepatitis B (CHB) were treated with pegylated interferon α-2b for 24-48 weeks. Liver biopsy was collected and the baseline SOCS expression was determined. Serum assay was performed for efficacy evaluation and correlation analysis. RESULTS In animal studies, the expression level of SOCS-1 and 3 was found in the descending order of B, A, C and D. The difference between Group B and D suggested that HBV could induce SOCS. The difference between Group A and C suggested that HBV could still induce SOCS with up-regulated endogenous IFN. The difference between Group C and D suggested that ploy IC could induce SOCS, while the difference between Group B and A suggested that Poly IC might have a stronger inhibition effect for SOCS. There was no difference in SOCS-2 expression. In clinical studies, eight of twenty-four enrolled patients achieved either complete or partial therapeutic response. The expression of both SOCS-1 and 3 was higher in CHB patients than in normal controls. The baseline HBV-DNA level was positively correlated with SOCS-1 and 3. The age, viral genotype, HBVDNA, SOCS-1 and SOCS-3 were found to be related to IFN efficacy. CONCLUSION HBV could induce both SOCS-1 and 3 expression regardless of endogenous IFN level. Elevated IFN could directly up-regulate SOCS-1 and 3 expression, but it could also indirectly down-regulate SOCS-1 and 3 expression by inhibiting HBV replication. HBV might play a more important role in the SOCS up-regulation than IFN, a possible reason why patients with high HBV viral load encounter poor efficacy of IFN treatment.
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Affiliation(s)
- Ling-yao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Yao-li Cui
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - En-qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Xing Cheng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Li Liu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041 China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
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14
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Chen S, Liu C, Wang X, Li X, Chen Y, Tang N. 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) promotes apoptosis of HBx-positive liver cells. Chem Biol Interact 2014; 214:26-32. [PMID: 24582817 DOI: 10.1016/j.cbi.2014.02.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 12/26/2013] [Accepted: 02/19/2014] [Indexed: 12/22/2022]
Abstract
This study aims to investigate the inflammatory response characteristics of liver cells caused by HBV x protein (HBx) and the unique function of the PGE2 inhibitor on HBx-positive liver cells. Tetrazolium blue colorimetric method, flow cytometry, and Western blot were performed to detect the proliferation, cycle, and apoptosis protein expression of HBx-positive HL7702 liver and control cells. The effect of the PGE2 inhibitor 15-Deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) on the growth of HL7702-HBx was also observed. HBx induces the PGE2 accumulation in HL7702 liver cells and promotes their growth and inhibits their apoptosis. HL7702-HBx and HL7702 cells showed increased apoptosis rate, increased apoptosis-promoting protein expression, and reduced apoptosis-inhibiting protein expression under the effect of 15d-PGJ2, and the changes in HL7702-HBx cells were more significant than in HL7702 cells. HBx expression causes liver cells to be more sensitive to the apoptosis-promoting function of 15d-PGJ2. Therefore, the use of 15d-PGJ2 may be a new method for the prevention or treatment of inflammatory changes to cancer caused by HBV infection in liver cells.
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Affiliation(s)
- Siyan Chen
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Chong Liu
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Xiaoqian Wang
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Xiujin Li
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Yanling Chen
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Nanhong Tang
- Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China.
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15
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Ye H, Zhang C, Wang BJ, Tan XH, Zhang WP, Teng Y, Yang X. Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice. Oncogene 2013; 33:5133-8. [PMID: 24213574 DOI: 10.1038/onc.2013.468] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 08/03/2013] [Accepted: 10/04/2013] [Indexed: 02/07/2023]
Abstract
Although the activation of Ras pathway is frequently observed in human hepatocellular carcinoma (HCC), the in vivo role of Ras activation in HCC initiation and progression is underdetermined. To test the consequence of Kras activation in hepatocyte, we generated a hepatocyte-specific Kras(G12D) transgenic mouse strain and observed spontaneous development of HCC in these mice. Remarkably, HBV X protein (HBx) expression significantly promotes the formation and malignant progression of Kras(G12D)-driven HCC as shown with the accelerated tumor onset, the increased tumor burden and the more poorly differentiated lesions. At the cellular level, concomitant expression of Kras(G12D) and HBx results in a robust increase in hepatocellular proliferation. We reveal that the Akt, MAPK, p53 and TGF-β pathways are deregulated in the Kras(G12D)-driven HCCs. Also, the dysregulation is more pronounced in the HCCs developed in Kras(G12D) and HBx double transgenic mice. In addition, the altered expressions of β-catenin, CD44 and E-cadherin are only observed in the Kras(G12D) and HBx double transgenic mice. These results demonstrate a crucial role of Ras activation in hepatocellular carcinogenesis and the functional synergy between Kras(G12D) and HBx in HCC initiation and progression. The novel genetic mouse models that closely recapitulate the histopathologic progression and molecular alterations of human HCC may potentially facilitate the future therapeutic studies.
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Affiliation(s)
- H Ye
- 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
| | - C Zhang
- 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
| | - B-J Wang
- State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
| | - X-H Tan
- State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
| | - W-P Zhang
- Department of Pathophysiology, Second Military Medical University, Shanghai, China
| | - Y Teng
- State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
| | - X Yang
- 1] Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University School of Medicine, Shanghai, China [2] State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing, China
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16
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Duan CH, Tai S. Role of hepatitis B virus X protein in hepatocarcinogenesis. Shijie Huaren Xiaohua Zazhi 2013; 21:2397-2402. [DOI: 10.11569/wcjd.v21.i24.2397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer-related death. Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor for HCC. Evidence suggests that the HBV X protein (HBx) plays a crucial role in the carcinogenesis of HCC. HBx is a multifunctional regulator that plays a key role in the occurrence, development, invasion and metastasis of cancers. Due to its important roles in the development of HCC, the research on the HBx protein has become a hot topic in recent years. This review describes the latest advances in understanding the role of the HBx protein in hepatocarcinogenesis.
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17
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Ayub A, Ashfaq UA, Haque A. HBV induced HCC: major risk factors from genetic to molecular level. BIOMED RESEARCH INTERNATIONAL 2013; 2013:810461. [PMID: 23991421 PMCID: PMC3749539 DOI: 10.1155/2013/810461] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 07/09/2013] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is a deadly and emerging disease leading to death in Asian countries. High hepatitis B virus (HBV) load and chronic hepatitis B (CHB) infection increase the risk of developing HCC. HBV is a DNA virus that can integrate DNA into host genome thereby increase the yield of transactivator protein HBxAg that may deregulate many pathways involving in metabolism of cells. Several monogenic and polygenic risk factors are also involved in HCC development. This review summarizes the mechanism involved in HCC development and discusses some promising therapies to make HCC curative.
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Affiliation(s)
- Ambreen Ayub
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
| | - Asma Haque
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
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18
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Xie J, Zhang Y, Zhang Q, Han Y, Yin J, Pu R, Shen Q, Lu W, Du Y, Zhao J, Han X, Zhang H, Cao G. Interaction of signal transducer and activator of transcription 3 polymorphisms with hepatitis B virus mutations in hepatocellular carcinoma. Hepatology 2013; 57:2369-77. [PMID: 23386590 DOI: 10.1002/hep.26303] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 01/10/2013] [Indexed: 12/14/2022]
Abstract
UNLABELLED Hepatitis B virus (HBV) mutations and signal transducer and activator of transcription 3 (STAT3) activation are closely associated with hepatocellular carcinoma (HCC). However, single nucleotide polymorphisms (SNPs) of STAT3 have not been implicated in HCC susceptibility. This study was designed to evaluate the effect of STAT3 SNPs and their interactions with HBV mutations on HCC risk. A total of 2,011 HBV-infected subjects (including 1,021 HCC patients) and 1,012 healthy controls were involved in this study. SNPs rs4796793 (-1697, C>G), rs2293152 (intron 11, C>G), and rs1053004 (3' untranslated region, T>C) were genotyped using quantitative polymerase chain reaction. HBV mutations were determined via direct sequencing. It was found that rs2293152 (GG versus CC) was significantly associated with HCC risk compared with the subjects without HCC, adjusting for age and sex (adjusted odds ratio [AOR], 1.30; 95% confidence interval [CI], 1.04-1.62). The impact of rs2293152 was greater in women compared with men. Compared with HCC-free HBV-infected subjects, rs2293152 GG was solely associated with HCC in women (AOR, 2.04; 95% CI, 1.15-3.61). rs2293152 GG was significantly associated with high viral load (≥1 × 10(4) copies/mL) (AOR, 1.37; 95%, CI 1.01-1.88) and increased frequencies of T1674C/G (AOR, 1.61; 95% CI, 1.06-2.46) and A1762T/G1764A (AOR, 1.64; 95% CI, 1.14-2.35). In multivariate regression analyses, multiplicative interaction of rs1053004 with T1674C/G significantly increased HCC risk, whereas rs2293152 and A1726C interaction reduced it, adjusting for covariates including HBV mutations in the enhancer II/basal core promoter/precore region; the interaction of rs4796793 with preS2 start codon mutation significantly increased HCC risk, adjusting for covariates including HBV mutations in the preS region. CONCLUSION STAT3 SNPs appear to predispose the host with HBV mutations to hepatocarcinogenesis, and this effect may differ in men versus women. STAT3 SNPs may have applicability in future HCC surveillance algorithms. (Hepatology 2013;57:2369-2377).
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Affiliation(s)
- Jiaxin Xie
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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Blanchard AA, Ma X, Dueck KJ, Penner C, Cooper SC, Mulhall D, Murphy LC, Leygue E, Myal Y. Claudin 1 expression in basal-like breast cancer is related to patient age. BMC Cancer 2013; 13:268. [PMID: 23721519 PMCID: PMC3674926 DOI: 10.1186/1471-2407-13-268] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 05/21/2013] [Indexed: 01/03/2023] Open
Abstract
Background Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype. In these tumors, the claudin 1 protein, usually localized in the cell membrane, is often mislocalized to the cytoplasm. Methods To examine the clinical relevance of this observation, we have generated and analyzed an invasive HBC tissue microarray consisting of 151 breast tumor samples; 79 of which presented a basal-like phenotype (i.e. ER-ve, PR-ve HER2-ve, CK5/6 or EGFR+ve). We also interrogated the outcome of claudin 1 knockdown in a human BLBC cell line, BT-20. Results Immunohistochemical analysis of this patient cohort revealed a significant association between high claudin 1 expression and BLBCs in women 55 years of age and older. Interestingly, no significant association was found between claudin 1 and nodal involvement, tumor grade or tumor size. Regression analysis however, showed a significant positive association between claudin 1 and claudin 4, even though claudin 4 did not significantly correlate with patient age. Claudin 1 knockdown in BT-20 cells resulted in decreased cell migration. It also significantly altered the expression of several genes involved in epithelial-mesenchymal-transition (EMT); in particular, SERPINE 1 (PAI1) and SSP1 (osteopontin), known to inhibit EMT and cancer cell migration. Conversely, genes known to maintain EMT through their interaction, SNAIL2, TCF4 and FOXC2 were significantly down regulated. Conclusions The association of high claudin 1 protein levels observed in tumors derived from older women with BLBC, suggests that claudin 1 has the potential to serve as a marker which can identify a specific subgroup of patients within the BLBC subtype and thus, further contribute to the characterization of these ill-defined breast cancers. More importantly, our studies strongly suggest that claudin 1 directly participates in promoting breast cancer progression, possibly through the alteration of expression of EMT genes.
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Affiliation(s)
- Anne A Blanchard
- Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada
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Delgado-Ortega M, Marc D, Dupont J, Trapp S, Berri M, Meurens F. SOCS proteins in infectious diseases of mammals. Vet Immunol Immunopathol 2012; 151:1-19. [PMID: 23219158 PMCID: PMC7112700 DOI: 10.1016/j.vetimm.2012.11.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Revised: 10/31/2012] [Accepted: 11/13/2012] [Indexed: 12/17/2022]
Abstract
As for most biological processes, the immune response to microbial infections has to be tightly controlled to remain beneficial for the host. Inflammation is one of the major consequences of the host's immune response. For its orchestration, this process requires a fine-tuned interplay between interleukins, endothelial cells and various types of recruited immune cells. Suppressors of cytokine signalling (SOCS) proteins are crucially involved in the complex control of the inflammatory response through their actions on various signalling pathways including the JAK/STAT and NF-κB pathways. Due to their cytokine regulatory functions, they are frequent targets for exploitation by infectious agents trying to escape the host's immune response. This review article aims to summarize our current knowledge regarding SOCS family members in the different mammalian species studied so far, and to display their complex molecular interactions with microbial pathogens.
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Affiliation(s)
- Mario Delgado-Ortega
- Institut National de la Recherche Agronomique (INRA), UMR1282 Infectiologie et Santé Publique, F-37380 Nouzilly, France
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Högfeldt T, Bahnassy AA, Kwiecinska A, Osterborg A, Tamm KP, Porwit A, Zekri ARN, Lundahl J, Khaled HM, Mellstedt H, Moshfegh A. Patients with activated B-cell like diffuse large B-cell lymphoma in high and low infectious disease areas have different inflammatory gene signatures. Leuk Lymphoma 2012; 54:996-1003. [PMID: 23046110 DOI: 10.3109/10428194.2012.738365] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with an association with inflammation and viral infections. We hypothesize that environmental factors may be involved in the pathogenesis of DLBCL. In this study, we compared gene expression profiles of lymph node tissues from patients with DLBCL from two different geographical areas with diverse environmental exposures. Specimens from Egyptian and Swedish patients with DLBCL as well as controls were studied. Gene expression analysis using microarray and quantitative polymerase chain reaction demonstrated significantly higher expression of signal transducer and activator of transcription 3 (STAT3) in Swedish as compared to Egyptian patients and control materials from both countries. This was confirmed at protein level using confocal microscopy. The receptor tyrosine kinase ROR1, a "survival factor" for malignant cells, was overexpressed and significantly related to the STAT3 expression pattern. The difference in the expression of genes involved in inflammatory responses and in the tumorigenic process of DLBCL might relate to infectious agents and/or other environmental exposures.
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Affiliation(s)
- Therese Högfeldt
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
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GUO PENGTAO, YANG DONG, SUN ZHE, XU HUIMIAN. Hepatitis B virus X protein plays an important role in gastric ulcers. Oncol Rep 2012; 28:1653-8. [DOI: 10.3892/or.2012.2011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 07/09/2012] [Indexed: 11/06/2022] Open
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Chuang LY, Guh JY, Chao LK, Lu YC, Hwang JY, Yang YL, Cheng TH, Yang WY, Chien YJ, Huang JS. Anti-proliferative effects of cinnamaldehyde on human hepatoma cell lines. Food Chem 2012. [DOI: 10.1016/j.foodchem.2012.02.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Mason WS. Hepadnaviruses and Hepatocellular Carcinoma. CANCER ASSOCIATED VIRUSES 2012:531-569. [DOI: 10.1007/978-1-4614-0016-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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25
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Han YF, Zhao J, Ma LY, Yin JH, Chang WJ, Zhang HW, Cao GW. Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma. World J Gastroenterol 2011; 17:4258-70. [PMID: 22090781 PMCID: PMC3214700 DOI: 10.3748/wjg.v17.i38.4258] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 07/12/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus (HBV) infection contributes to > 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged > 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8+ T cells and regulatory T cells or Th1 and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.
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Yip WK, Cheng ASL, Zhu R, Lung RWM, Tsang DPF, Lau SSK, Chen Y, Sung JG, Lai PBS, Ng EKO, Yu J, Wong N, To KF, Wong VWS, Sung JJY, Chan HLY. Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in hepatocellular carcinoma development. PLoS One 2011; 6:e22888. [PMID: 21829663 PMCID: PMC3150371 DOI: 10.1371/journal.pone.0022888] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2010] [Accepted: 07/07/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. METHODS Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. RESULTS Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. CONCLUSION Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis.
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Affiliation(s)
- Wing-Kit Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alfred Sze-Lok Cheng
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ranxu Zhu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Raymond Wai-Ming Lung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Daisy Pui-Fong Tsang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Suki Shuk-Kei Lau
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yangchao Chen
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jonathan Gabriel Sung
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Paul Bo-San Lai
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Enders Kai-On Ng
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Nathalie Wong
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ka-Fai To
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Joseph Jao-Yiu Sung
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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Ma J, Sun T, Park S, Shen G, Liu J. The role of hepatitis B virus X protein is related to its differential intracellular localization. Acta Biochim Biophys Sin (Shanghai) 2011; 43:583-8. [PMID: 21693548 DOI: 10.1093/abbs/gmr048] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection has been strongly associated with hepatocellular carcinoma. HBV encodes an oncogenic hepatitis B virus X protein (HBx), which is a multifunctional regulator that modulates signal transduction, transcription, cell cycle progress, protein degradation, apoptosis, and genetic stability through direct and indirect interaction with host factors. The subcellular localization of HBx is primarily cytoplasmic, with a small fraction in the nucleus. In addition, high levels of HBx expression lead to an abnormal mitochondrial distribution. The dynamic distribution of HBx could be important to the multiple functions of HBx at different stages of the HBV life cycle. This short review presents an overview of the differential roles of HBx as a function of its intracellular localization.
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Affiliation(s)
- Jingwei Ma
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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28
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Zemel R, Issachar A, Tur-Kaspa R. The role of oncogenic viruses in the pathogenesis of hepatocellular carcinoma. Clin Liver Dis 2011; 15:261-79, vii-x. [PMID: 21689612 DOI: 10.1016/j.cld.2011.03.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
HBV and HCV have major roles in hepatocarcinogenesis. More than 500 million people are infected with hepatitis viruses and, therefore, HCC is highly prevalent, especially in those countries endemic for HBV and HCV. Viral and host factors contribute to the development of HCC. The main viral factors include the circulating load of HBV DNA or HCV RNA and specific genotypes. Various mechanisms are involved in the host-viral interactions that lead to HCC development, among which are genetic instability, self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasiveness. Prevention of HBV by vaccination, as well as antiviral therapy against HBV and for HCV seem able to inhibit the development of HCC.
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Affiliation(s)
- Romy Zemel
- Department of Medicine D and the Liver Institute, Rabin Medical Center, Beilinson Hospital, Molecular Hepatology Research Laboratory, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 39 Jabotinsky Street, Petah-Tikva 49100, Israel
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29
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Cho EY, Choi CS, Cho JH, Kim HC. Association between Hepatitis B Virus X Gene Mutations and Clinical Status in Patients with Chronic Hepatitis B Infection. Gut Liver 2011; 5:70-6. [PMID: 21461076 DOI: 10.5009/gnl.2011.5.1.70] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 10/22/2010] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND/AIMS Few reports have described the association between mutations in the entire X gene of the hepatitis B virus (HBV) and the clinical status of HBV-infected patients. We studied the association between HBV X gene mutations and the disease status of patients infected with HBV genotype C. METHODS Mutations in the HBV X genes of 194 patients were determined by direct sequencing. The subject population consisted of patients with chronic hepatitis (n=60), liver cirrhosis (n=65), and hepatocellular carcinoma (HCC) (n=69). The sequencing results of these 3 groups were compared. RESULTS Each of the mutations G1386M, C1485T, C1653T, T1753V, A1762T, and G1764A was significantly associated with the patient's clinical status. The T1753V (p<0.001) and A1762T/G1764A (p<0.001) mutations were found more frequently in Hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients. Specific X gene mutations (G1386M, C1653T, and A1762T/G1764A) were more prevalent in patients with liver cirrhosis and HCC than in chronic hepatitis patients (p<0.005 for all). In addition, the T1753V (p<0.001) and C1485T (p<0.001) mutations were significantly more prevalent in HCC patients than in chronic hepatitis patients. Only the prevalence of the T1753V mutation increased as the HBV infection progressed from liver cirrhosis to HCC (p=0.023). CONCLUSIONS Our findings show a difference in the pattern of X gene mutations that were associated with the clinical status of patients with chronic HBV infection.
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Affiliation(s)
- Eun Young Cho
- Department of Internal Medicine, Wonkwang University Hospital, Wonkwang University College of Medicine, Iksan, Korea
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Keng VW, Tschida BR, Bell JB, Largaespada DA. Modeling hepatitis B virus X-induced hepatocellular carcinoma in mice with the Sleeping Beauty transposon system. Hepatology 2011; 53:781-90. [PMID: 21374658 PMCID: PMC3079950 DOI: 10.1002/hep.24091] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2010] [Accepted: 11/11/2010] [Indexed: 12/12/2022]
Abstract
UNLABELLED The mechanisms associated with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remain elusive, and there are currently no well-established animal models for studying this disease. Using the Sleeping Beauty transposon as a delivery system, we introduced an oncogenic component of HBV, the hepatitis B virus X (HBx) gene, into the livers of fumarylacetoacetate hydrolase (Fah) mutant mice via hydrodynamic tail vein injections. Coexpression of Fah complementary DNA from the transposon vector allowed for the selective repopulation of genetically corrected hepatocytes in Fah mutant mice. The process of hydrodynamic delivery induced liver inflammation, and the subsequent selective repopulation of hepatocytes carrying the transgene(s) could provide useful genetic information about the mechanisms of HBV-induced hyperplasia. Short hairpin RNA directed against transformation-related protein 53 (shp53) or other tumor suppressor genes and oncogenes [e.g., constitutively active neuroblastoma RAS viral (v-ras) oncogene homolog with Gly12Val substitution (NRAS(G12V) )] could also be codelivered with HBx by this system so that we could determine whether oncogenic cooperation existed. We found that the expression of HBx induced the activation of β-catenin expression in hydrodynamically injected livers, and this indicated its association with the Wnt signaling pathway in HBV-induced hyperplasia. HBx coinjected with shp53 accelerated the formation of liver hyperplasia in these mice. As expected, constitutively active NRAS(G12V) alone was sufficient to induce liver hyperplasia, and its tumorigenicity was augmented when it was coinjected with shp53. Interestingly, HBx did not seem to cooperate with constitutively active NRAS(G12V) in driving liver tumorigenesis. CONCLUSION This system can be used as a model for studying the various genetic contributions of HBV to liver hyperplasia and finally HCC in an in vivo system.
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Affiliation(s)
- Vincent W. Keng
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA
| | - Barbara R. Tschida
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jason B. Bell
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - David A. Largaespada
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA, Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA, Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA
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Su RK, Yuan SG. Advances in understanding the role of STAT3 in the pathogenesis of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2010; 18:2240-2246. [DOI: 10.11569/wcjd.v18.i21.2240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is an important nuclear transcription factor that, once activated, can regulate the transcription of target genes. STAT3 is overexpressed in hepatocellular carcinoma (HCC). It has been demonstrated that STAT3 can be activated by HBV, HCV and diverse oncoproteins. The dysregulation of STAT/SOCS signaling also results in constitutive activation of STAT3. Aberrantly activated STAT3 can contribute to the malignant transformation of liver cells and result in the occurrence of HCC by inducing dysregulation of c-Myc, EGFR, TGF, survivin and VEGF. This paper summarizes the critical role of STAT3 in the pathogenesis of HCC and explores the possibility of using STAT3 as a target for HCC therapy.
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Koeberlein B, zur Hausen A, Bektas N, Zentgraf H, Chin R, Nguyen LT, Kandolf R, Torresi J, Bock CT. Hepatitis B virus overexpresses suppressor of cytokine signaling-3 (SOCS3) thereby contributing to severity of inflammation in the liver. Virus Res 2010; 148:51-59. [PMID: 20005910 DOI: 10.1016/j.virusres.2009.12.003] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Revised: 12/03/2009] [Accepted: 12/03/2009] [Indexed: 12/25/2022]
Abstract
The mechanism by which hepatitis B virus (HBV) infection causes severe inflammatory liver diseases is multifactorial and related to interactions with cell signaling pathways and the ensuing inflammatory response. Activation of JAK/STAT/SOCS signaling is essential for the induction of cellular antiviral responses, contributes to apoptosis and is negatively regulated by SOCS proteins. Recent reports have shown that SOCS3 activation interferes with viral protein expression and treatment response and thereby plays a major role in hepatitis virus infections. We analyzed the expression of SOCS3 in liver specimens from HBV-infected patients using immunohistochemistry (IHC) and determined the effect of HBV on STAT/SOCS signaling in functional cell culture experiments (HuH-7) using HBV-expressing adenoviral constructs (AdHBV). Increased expression of SOCS3 protein was identified in liver specimens from patients with chronic HBV-infection and this correlated with the severity of liver inflammation. In accordance with the IHC-findings, in vitro analyses demonstrated that HBV infection of HuH7 cells was associated with increased expression of SOCS3 protein. In spite of the over expression of its negative regulator SOCS3 we observed a constitutive activation of STAT3. SOCS1 levels were not increased while pSTAT1 was suppressed in HBV-infected HuH7 cells. Our results demonstrate that STAT/SOCS-signaling is dysregulated in HBV-infected hepatocytes both in vivo and in vitro and this correlated with the severity of liver inflammatory changes. This interference of STAT/SOCS signaling by HBV may result in an ineffective immune response against HBV and potentially contributes to viral pathogenesis, malignant transformation and may represent an important mechanism of viral persistence.
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Affiliation(s)
- Bernd Koeberlein
- Department of Molecular Pathology, Institute of Pathology, University Hospital of Tuebingen, 72076 Tuebingen, Germany
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Chin R, Nachbur U, Earnest-Silveira L, Bankovacki A, Koeberlein B, Zentgraf H, Bock CT, Silke J, Torresi J. Dysregulation of hepatocyte cell cycle and cell viability by hepatitis B virus. Virus Res 2010; 147:7-16. [PMID: 19786052 DOI: 10.1016/j.virusres.2009.09.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2009] [Revised: 09/18/2009] [Accepted: 09/18/2009] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS Dysregulation of the cell cycle is frequently associated with tumor development. Hepatitis B virus (HBV) is associated with a significant risk of developing hepatocellular carcinoma but the effects of HBV on cell cycle regulation are not completely understood. METHODS We have used a recombinant adeno-HBV model system to investigate the effect of infection with HBV and the replication defective lamivudine resistant mutant rtM204I mutant on hepatocyte cell cycle and cell viability. RESULTS Huh7 cells synchronised at the G1/S phase of the cell cycle were arrested at the G2/M following infection with rAdHBV-wt and rAdHBV-M204I. This was accompanied by increased levels of p21(cip1), p-cdc2, cyclins D, A and B. Cell viability was reduced and cleaved caspase 3 levels were increased in HBV- and rtM204I-infected cells. rAdHBV-M204I-infected Huh7 cells also demonstrated significant up-regulation of phospho-ERK, phospho-Akt, p53 and phospho-Mdm2 compared to mock-infected cells. These changes were comparable to those following infection of Huh7 cells with rAdHBV-wt. CONCLUSION Our results suggest that HBV, regardless of phenotype, produces cell cycle arrest and reduced hepatocyte viability. Perturbations in these cellular processes are likely to underlie HBV-associated liver oncogenic transformation and may help explain the ongoing risk of developing hepatocellular carcinoma in individuals in whom the lamivudine resistant rtM204I mutant emerges.
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Affiliation(s)
- Ruth Chin
- Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, Victoria 3084, Australia.
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