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Niu YJ, Xia CJ, Ai X, Xu WM, Lin XT, Zhu YQ, Zhu HY, Zeng X, Cao ZL, Zhou W, Huang H, Shi XL. Sequential activation of ERα-AMPKα signaling by the flavonoid baicalin down-regulates viral HNF-dependent HBV replication. Acta Pharmacol Sin 2025; 46:653-661. [PMID: 39478159 PMCID: PMC11845607 DOI: 10.1038/s41401-024-01408-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/08/2024] [Indexed: 02/23/2025]
Abstract
Baicalin (BA), a natural component found in many traditional Chinese medicines, exerts protective effects against several viruses. Although our previous studies have revealed that the anti-hepatitis B virus (anti-HBV) activity of BA depends on hepatocyte nuclear factor (HNF) signaling, the specific mechanisms remain unclear. The present study explored the potential signaling mechanisms involved in BA-mediated HBV suppression. Transcriptomic analysis suggested that BA significantly modulates the estrogen receptor (ER) and AMPK signaling pathways in HepG2 cells. The ER alpha (ERα) binding affinity of BA and its estrogen-like agonist activity were subsequently verified through molecular docking assays, BA-ERα affinity detection experiments, ERα luciferase reporter gene assays, and qRT-PCR. ERα knockdown (shRNA) and AMPK inhibition (Compound C and doxorubicin [Dox]) experiments revealed that the sequential activation of the ERα-LKB1-AMPK-HNF signaling axis is essential for the anti-HBV effects of BA. This study indicates that BA may trigger the ERα-AMPKα-HNF pathway to inhibit HBV replication, providing insights into its potential protective mechanisms against other viruses.
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Affiliation(s)
- Yi-Jun Niu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Cheng-Jie Xia
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xin Ai
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei-Ming Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xiao-Tong Lin
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Ying-Qi Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Hai-Yan Zhu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xian Zeng
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Zhong-Lian Cao
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Wei Zhou
- Department of Chemistry, Fudan University, Shanghai, 201203, China
| | - Hai Huang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xun-Long Shi
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University School of Pharmacy, Shanghai, 201203, China.
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2
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Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
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Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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3
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Zhang L, Jiang T, Yang Y, Deng W, Lu H, Wang S, Liu R, Chang M, Wu S, Gao Y, Hao H, Shen G, Xu M, Chen X, Hu L, Yang L, Bi X, Lin Y, Lu Y, Jiang Y, Li M, Xie Y. Postpartum hepatitis and host immunity in pregnant women with chronic HBV infection. Front Immunol 2023; 13:1112234. [PMID: 36685527 PMCID: PMC9846060 DOI: 10.3389/fimmu.2022.1112234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/16/2022] [Indexed: 01/06/2023] Open
Abstract
In order to develop immune tolerant to the fetal, maternal immune system will have some modification comparing to the time before pregnancy. Immune tolerance starts and develops at the maternal placental interface. In innate immunity, decidual natural killer (dNK) cells, macrophages and dendritic cells play a key role in immue tolerance. In adaptive immunity, a moderate increase of number and immune inhibition function of regulatory T cells (Treg) are essential for immune tolerance. The trophoblast cells and immune cells expressing indoleamine 2,3-dioxygenase (IDO), the trophoblast cells expressing HLA-G, and Th1/Th2 shifting to Th2 dominant and Th17/Treg shifting to Treg domiant are in favor of maternal fetal immune tolerance. Steroids (estrogen and progesterone) and human chorionic gonadotropin (HCG) also participate in immune tolerance by inducing Treg cells or upregulating immunosuppressive cytokines. Most of the patients with chronic HBV infection are in the "HBV immune tolerance period" before pregnancy, and the liver disease is relatively stable during pregnancy. In chronic HBV infection women, after delivery, the relative immunosuppression in vivo is reversed, and Th1 is dominant in Th1/Th2 and Th17 is dominant in Th17/Treg balance. After delivery, the number of Treg decrease and NK cells increase in quantity and cytotoxicity in peripheral blood. Liver NK cells may cause liver inflammation through a non-antigen specific mechanism. After delivery, the number of CD8+ T cells will increase and HBV specific T cell response recovers from the disfunction in pregnancy. Under the background of postpartum inflammation, the rapid decrease of cortisol after delivery, and especially the enhancement of HBV specific T cell response induced by HBV DNA and cytokines, are the main reasons for postpartum hepatitis. HBeAg positive, especially HBeAg<700 S/CO, and HBV DNA>3-5Log10IU/ml are risk factors for postpartum hepatitis. Antiviral treatment in late pregnancy can reduce the incidence of mother to child transmission (MTCT) in chronic HBV infection women. Chronic HBV infection women have hepatitis both during pregnancy and more often in 12 weeks postpartum. It is generally agreed that postpartum hepatitis is mild symptoms and self-limited. Delaying drug withdrawal to 48 weeks can increase the seroconversion rate of HBeAg in delivery women with elevated alanine aminotransferase (ALT) in pregnancy.
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Affiliation(s)
- Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ying Yang
- Hepatology Department 2, Xingtai Second Hospital, Xingtai, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Huihui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Obstetrics and Gynecology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuyong Jiang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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Identification of Estradiol Benzoate as an Inhibitor of HBx Using Inducible Stably Transfected HepG2 Cells Expressing HiBiT Tagged HBx. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27155000. [PMID: 35956950 PMCID: PMC9370419 DOI: 10.3390/molecules27155000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 11/16/2022]
Abstract
HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.
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Wang CH, Lin RC, Hsu HY, Tseng YT. Hormone replacement therapy is associated with reduced hepatocellular carcinoma risk and improved survival in postmenopausal women with hepatitis B: A nationwide long-term population-based cohort study. PLoS One 2022; 17:e0271790. [PMID: 35862398 PMCID: PMC9302748 DOI: 10.1371/journal.pone.0271790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 07/07/2022] [Indexed: 11/19/2022] Open
Abstract
Postmenopausal women with hepatitis B virus (HBV) infection are more likely to have accelerated liver fibrosis, eventually advancing to liver cirrhosis or hepatocellular carcinoma (HCC). The association between sex hormones and HBV-related HCC risk is unclear. We investigated whether hormone replacement therapy (HRT) is beneficial to postmenopausal women with HBV infection. This retrospective study selected the data of 44,465patients with HBV infection between January 2000 and December 2018 from Taiwan’s National Health Insurance Research Database. After excluding patients with preexisting liver diseases, liver cirrhosis, or liver malignancies, we grouped the remaining 10,474 patients by whether they had undergone HRT for at least 3 months (n = 5,638) and whether they had not received HRT (n = 4,836). After propensity score matching, we assigned 3080 patients to an HRT cohort and matched them (1:1) with those in a non-HRT cohort. The incidence of HCC (P < 0.022) and all-cause mortality rate (P < 0.001) were lower in the HRT cohort than in the non-HRT cohort. The liver cirrhosis risk was not significantly higher in the HRT cohort (P = 0.355). HRT is associated with reduced HCC risk and improved survival outcomes but is unrelated to liver cirrhosis development in postmenopausal women.
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Affiliation(s)
- Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
- Department of Optometry, Chung Hwa Medical University, Tainan, Taiwan
| | - Ruey-Chang Lin
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
| | - Hua-Yin Hsu
- Departments of Nursing, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan City, Taiwan
| | - Yuan-Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
- * E-mail:
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Li H, Chen J, Zhang R, Xu R, Zhang Z, Ren L, Yang Q, Tian Y, Li D. Single nucleotide polymorphisms in ZNF208 are associated with increased risk for HBV in Chinese people. Oncotarget 2017; 8:112451-112459. [PMID: 29348838 PMCID: PMC5762523 DOI: 10.18632/oncotarget.19669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 05/22/2017] [Indexed: 12/26/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) in ZNF208 may be associated with susceptibility to Hepatitis B virus (HBV). In the current study, we analyzed the association between ZNF208 SNPs and risk of HBV in 242 HBV patients and 300 healthy subjects from the Xi'an area of Chinese Han Population. Of the five SNPs examined, rs2188971 (OR: 1.36, 95% CI: 1.04-1.76, P = 0.022), rs8103163 (OR: 1.40, 95% CI: 1.08-1.82, P = 0.010) and rs7248488 (OR: 1.38, 95% CI: 1.07-1.79, P = 0.014) were correlated with HBV susceptibility based on Chi-square tests. After the P-values were adjusted by Bonferroni correction, there only rs8103163 (P = 0.050) was slightly with increased HBV risk. Additionally, haplotype Ars2188972Trs2188971Ars8103163Ars7248488 (OR = 1.42; 95% C I, 1.10-1.85; P = 0.008) was found to increase susceptibility of suffering from HBV. These findings suggest that ZNF208 polymorphisms may contribute to the development of HBV.
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Affiliation(s)
- Hengxin Li
- Xi'an Center for Disease Control and Prevention, Xi'an, Shaanxi 710054, China
| | - Jun Chen
- Department of Pharmacy, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
| | - RuiZhi Zhang
- Department of Stomatology, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
| | - Ran Xu
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Zhe Zhang
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Le Ren
- Department of Stomatology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qi Yang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.,Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yumei Tian
- Xi'an Mental Health Center, Xi'an, Shaanxi 710061, China
| | - Daxu Li
- Department of Stomatology, The Ankang Central Hospital, Ankang, Shaanxi 725000, China
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Yuan L, Wang T, Zhang Y, Liu X, Zhang T, Li X, Liu P, Wu K, Shih JWK, Yuan Q, Cheng T, Xia N. An HBV-tolerant immunocompetent model that effectively simulates chronic hepatitis B virus infection in mice. Exp Anim 2016; 65:373-382. [PMID: 27264142 PMCID: PMC5111840 DOI: 10.1538/expanim.16-0013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is the leading cause of liver disease and hepatic carcinoma (HCC). Approximately 350 million people worldwide are infected with HBV and at risk of chronicity. An efficient HBV-tolerant murine model that mimics HBV infection in humans is desirable for HBV-related research. In this study, we investigated and established a murine model by hydrodynamic injection (HDI) of pAAV/HBV into the tail vein of AAVS1 site element-transgenic mice. In 80% of the injected mice, the serum level of HBsAg reached 103-4 IU/ml and persisted for more than half a year. Next, the model was used to evaluate RNA interference (RNAi)-based antiviral therapy. Data obtained using the model demonstrated that this model will facilitate the elucidation of the mechanisms underlying chronic HBV infection and will also be useful for evaluating new antiviral drugs.
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Affiliation(s)
- Lunzhi Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, Xiamen University, Xiamen, 361102, P.R. China
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8
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Correlations between ASCC3 Gene Polymorphisms and Chronic Hepatitis B in a Chinese Han Population. PLoS One 2015; 10:e0141861. [PMID: 26536629 PMCID: PMC4633062 DOI: 10.1371/journal.pone.0141861] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 10/14/2015] [Indexed: 01/01/2023] Open
Abstract
We have previously identified 8 SNPs in Han Chinese HBV carriers that are associated with disease progression. Although not well studied, genetic factors may also play a significant role in developing chronic HBV disease after exposure. We extend the effect of these eight SNPs on persistent HBV infection in this study. A total of 875 unrelated Han Chinese, 493 chronic hepatitis B subjects (CHB) and 382 HBV clearance individuals (Clear), were recruited from Hubei Province from September 2007 to March 2010. SNPs were verified by using TaqMan 7900HT Sequence Detection System. By using multiple logistic regression analysis, each of the 8 SNP associations was tested using 3 different genetic models (Dominant, Recessive and Additive model), in 4 types of analyses (full sample, men, women, age stratified). A Bonferroni correction was used to account for multiple statistical tests for each SNP association (P<0.05/8 = 0.0063). A significant correlation was observed at SNP rs10485138 located in ASCC3 gene in female patients (OR, 0.445; 95% CI, 0.253–0.784; P = 0.005). Females bearing C allele infected by HBV had an increased susceptibility to CHB compared with those T allele carriers. Our results indicated that SNP rs10485138 located in ASCC3 gene was associated with persistent HBV infection in Han Chinese.
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Wang SH, Chen PJ, Yeh SH. Gender disparity in chronic hepatitis B: Mechanisms of sex hormones. J Gastroenterol Hepatol 2015; 30:1237-45. [PMID: 25708186 DOI: 10.1111/jgh.12934] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/18/2015] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma (HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, microRNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients.
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Affiliation(s)
- Sheng-Han Wang
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
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10
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Montella M, D'Arena G, Crispo A, Capunzo M, Nocerino F, Grimaldi M, Barbieri A, D'Ursi AM, Tecce MF, Amore A, Galdiero M, Ciliberto G, Giudice A. Role of Sex Hormones in the Development and Progression of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Int J Endocrinol 2015; 2015:854530. [PMID: 26491442 PMCID: PMC4600563 DOI: 10.1155/2015/854530] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 06/29/2015] [Accepted: 07/01/2015] [Indexed: 12/25/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC) in developed countries. Epidemiological reports indicate that the incidence of HBV-related HCC is higher in males and postmenopausal females than other females. Increasing evidence suggests that sex hormones such as androgens and estrogens play an important role in the progression of an HBV infection and in the development of HBV-related HCC. While androgen is supposed to stimulate the androgen signaling pathway and cooperate to the increased transcription and replication of HBV genes, estrogen may play a protecting role against the progression of HBV infections and in the development of HBV-related HCC through decreasing HBV RNA transcription and inflammatory cytokines levels. Additionally, sex hormones can also affect HBV-related hepatocarcinogenesis by inducing epigenetic changes such as the regulation of mRNA levels by microRNAs (miRNAs), DNA methylation, and histone modification in liver tissue. This review describes the molecular mechanisms underlying the gender disparity in HBV-related HCC with the aim of improving the understanding of key factors underneath the sex disparity often observed in HBV infections. Furthermore, the review will propose more effective prevention strategies and treatments of HBV-derived diseases.
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Affiliation(s)
- Maurizio Montella
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
- *Maurizio Montella:
| | - Giovanni D'Arena
- Department of Onco-Hematology, IRCCS, Cancer Referral Center of Basilicata, 85028 Rionero in Vulture, Italy
| | - Anna Crispo
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Mario Capunzo
- Department of Medicine and Surgery, University of Salerno, 84081 Fisciano, Italy
| | - Flavia Nocerino
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Maria Grimaldi
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Antonio Barbieri
- Animal Facility, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Anna Maria D'Ursi
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Alfonso Amore
- Department of Surgery, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | | | - Gennaro Ciliberto
- National Cancer Institute “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Aldo Giudice
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
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Liu WC, Liu QY. Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2014; 20:6252-6261. [PMID: 24876746 PMCID: PMC4033463 DOI: 10.3748/wjg.v20.i20.6252] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 12/22/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the most common causes of hepatocellular carcinoma (HCC), a malignant tumor with high mortality worldwide. One remarkable clinical feature of HBV-related HCC is that its incidence is higher in males and postmenopausal females compared to other females. Increasing evidence indicates that HBV-associated HCC may involve gender disparity and that it may be a type of hormone-responsive malignant tumor. Sex hormones, such as androgen and estrogen, have been shown to play very different roles in the progression of an HBV infection and in the development of HBV-related HCC. Through binding to their specific cellular receptors and affecting the corresponding signaling pathways, sex hormones can regulate the transactivation of HBx, cause the chronic release of inflammatory cytokines in the hepatocellular microenvironment, and participate in epigenetic and genetic alternations in hepatocytes. All of these functions may be related to the initiation and progression of HBV-associated HCC. A thorough investigation of the molecular mechanisms underlying the gender-related disparity in HBV-related HCC should provide a new perspective for better understanding its pathogenesis and exploring more effective methods for the prevention and treatment of this disease.
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12
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Identification and characterization of multiple TRIM proteins that inhibit hepatitis B virus transcription. PLoS One 2013; 8:e70001. [PMID: 23936368 PMCID: PMC3731306 DOI: 10.1371/journal.pone.0070001] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 06/18/2013] [Indexed: 01/05/2023] Open
Abstract
Tripartite motif (TRIM) proteins constitute a family of over 100 members that share conserved tripartite motifs and exhibit diverse biological functions. Several TRIM proteins have been shown to restrict viral infections and regulate host cellular innate immune responses. In order to identify TRIM proteins that modulate the infection of hepatitis B virus (HBV), we tested 38 human TRIMs for their effects on HBV gene expression, capsid assembly and DNA synthesis in human hepatoma cells (HepG2). The study revealed that ectopic expression of 8 TRIM proteins in HepG2 cells potently reduced the amounts of secreted HBV surface and e antigens as well as intracellular capsid and capsid DNA. Mechanistic analyses further demonstrated that the 8 TRIMs not only reduced the expression of HBV mRNAs, but also inhibited HBV enhancer I and enhancer II activities. Studies focused on TRIM41 revealed that a HBV DNA segment spanning nucleotide 1638 to nucleotide 1763 was essential for TRIM41-mediated inhibition of HBV enhancer II activity and the inhibitory effect depended on the E3 ubiquitin ligase activity of TRIM41 as well as the integrity of TRIM41 C-terminal domain. Moreover, knockdown of endogenous TRIM41 in a HepG2-derived stable cell line significantly increased the level of HBV preC/C RNA, leading to an increase in viral core protein, capsid and capsid DNA. Our studies have thus identified eight TRIM proteins that are able to inhibit HBV transcription and provided strong evidences suggesting the endogenous role of TRIM41 in regulating HBV transcription in human hepatoma cells.
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Wang SH, Yeh SH, Lin WH, Yeh KH, Yuan Q, Xia NS, Chen DS, Chen PJ. Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4α. Gastroenterology 2012; 142:989-998.e4. [PMID: 22240483 DOI: 10.1053/j.gastro.2011.12.045] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Revised: 12/08/2011] [Accepted: 12/26/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Women with hepatitis B virus (HBV) infection usually have lower viral loads than men, reducing their risk of liver cancer. There are 2 androgen-responsive elements in the HBV enhancer I that contribute to higher viral titers in men. We investigated whether and how estrogen signaling affects progression of HBV infection. METHODS Ovariectomy and estrogen supplementation were used to evaluate the effect of estrogen on HBV titers in transgenic mice with replicating HBV in hepatocytes. The effect of estrogen signaling on transcription of HBV genes, and the mechanisms of regulation, were studied in HepG2 cells. RESULTS HBV titers increased in female mice after ovariectomy and decreased in male mice supplemented with estrogen. Hepatic expression of estrogen receptor (ER)-α was increased by estrogen exposure. In HepG2 cells, up-regulation of ER-α reduced HBV transcription, which required a specific region within enhancer I. Direct DNA binding of ER-α and histone deacetylase activity were not required for ER-α-mediated repression of HBV genes. Overexpression of hepatocyte nuclear factor (HNF)-4α, which binds to this region, overcame the repressive effect of ER-α. ER-α did not repress transcription of an HBV replicon with a mutant HNF-4α binding site within enhancer I. Coimmunoprecipitation assays showed an interaction between ER-α and HNF-4α; this interaction prevented HNF-4α binding to enhancer I and activation of HBV transcription. CONCLUSIONS Estrogen can repress transcription of HBV genes by up-regulating ER-α, which interacts with and alters binding of HNF-4α to the HBV enhancer I. These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men.
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Affiliation(s)
- Sheng-Han Wang
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
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14
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Chen J, Wang Z, Zhou B, Wang Y, Hou J. Factors associated with serum hepatitis B surface antigen levels and its on-treatment changes in patients under lamivudine therapy. Antivir Ther 2012; 17:71-79. [PMID: 22267471 DOI: 10.3851/imp1925] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
BACKGROUND We aimed to investigate factors associated with serum hepatitis B surface antigen (HBsAg) levels and its kinetics under lamivudine treatment in chronic hepatitis B patients. METHODS HBsAg levels were measured with the Architect HBsAg assay (Abbott laboratories, Abbott Park, IL, USA) in genotype B (HBV/B) or C (HBV/C) patients (n=218). Early HBsAg kinetics in 86 hepatitis B e antigen (HBeAg)-positive patients and long-term HBsAg changes in 45 patients with rapid and sustained viral suppression were further analysed. RESULTS Mean HBsAg levels were higher in male (n=181) than in female (n=37) patients (3.59 versus 3.23 log(10) IU/ml; P=0.036), and higher in 121 HBV/B than in 97 HBV/C patients (3.68 versus 3.34 log(10) IU/ml; P=0.006). In addition to HBV DNA loads (P<0.001), male gender (P=0.012) and HBV/B infection (P=0.035) were independently associated with higher HBsAg levels in antiviral-naive patients. HBsAg increases (0.00-0.87 log(10)) were found in 28/86 patients who obtained viral suppression under 12 weeks of lamivudine therapy. Higher baseline HBsAg levels (P=0.046), HBV/B infection (P=0.007) and faster HBV DNA declines (P=0.006) independently contributed to greater HBsAg decreases under 12 weeks treatment. An apparent dissociation between HBsAg and HBV DNA changes were found in 14/45 patients with rapid and sustained viral suppression, who had low baseline HBsAg levels and predominant HBV/C infection. CONCLUSIONS HBV/B and male gender were associated with higher HBsAg levels in antiviral-naive patients. Higher baseline HBsAg levels and HBV/B infection contributed to greater early HBsAg declines in HBeAg-positive patients, and might correlate with discordance between HBsAg and HBeAg or HBV DNA under long-term lamivudine treatment.
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Affiliation(s)
- Jinjun Chen
- Institute of Hepatology, Department of Infectious Diseases, Key Laboratory for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, PR China
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15
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Wu S, Kanda T, Imazeki F, Nakamoto S, Shirasawa H, Yokosuka O. Nuclear receptor mRNA expression by HBV in human hepatoblastoma cell lines. Cancer Lett 2011; 312:33-42. [PMID: 21903321 DOI: 10.1016/j.canlet.2011.07.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 07/19/2011] [Accepted: 07/21/2011] [Indexed: 02/07/2023]
Abstract
Recent studies have implicated nuclear receptors (NRs) in the development of hepatocarcinogenesis. We assumed that hepatitis B virus (HBV) alters the expression of NRs and coregulators, and compared the gene expression profiling for 84 NRs and related genes between HpeG2.2.15, which secretes complete HBV virion, and HepG2 by real-time RT-PCR with SyBr green. Forty (47.6%) genes were upregulated 2-fold or greater, and only 5 (5.9%) were downregulated 2-fold or more, in HepG2.2.15 compared to HepG2. These results suggest that HBV affects NRs and their related signal transduction, and that they play important roles in viral replication and HBV-related hepatocarcinogenesis.
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Affiliation(s)
- Shuang Wu
- Department of Medicine and Clinical Oncology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan
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Abstract
Hepatitis B and its complications are one of the major global health problems. Around 2 billion individuals are infected by hepatitis B virus (HBV) worldwide, more than 350 million are chronically infected, and approximately 15 to 40 percents of them will develop serious complications such as liver cirrhosis, hepatic failure, or hepatocellular carcinoma (HCC). The worldwide prevalence of chronic HBV infection ranges from 0.1 to 20 percent and varies widely in different geographic areas. According to the prevalence rate, WHO has classified countries into 3 levels: high areas (>8%) such as Africa, Asia, Western Pacific and Middle East; intermediate areas (2–8%) such as South America and Eastern Europe, and low areas (<2%) such as Western Europe, North America, and Australia.
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17
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Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ. Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology 2009; 50:1392-402. [PMID: 19670412 DOI: 10.1002/hep.23163] [Citation(s) in RCA: 151] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
UNLABELLED Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs more often in men than in women. Male HBV carriers usually have higher viral loads, which is a well-known risk factor for HCC. Whether and how the male androgen axis regulates HBV transcription and replication is investigated here. We used HBV transgenic mice to evaluate any sex disparity of serum hepatitis B surface antigen and HBV titers as well as the castration effect on this disparity. Compared to females, HBV transgenic male mice showed higher hepatitis B surface antigen and viral titers, which were lessened by castration of the males. In a cell culture system, HepG2 cells transfected with HBV and androgen receptor (AR) constructs were used to study the effect of the androgen pathway on viral transcription and replication. We found the ligand-stimulated AR could increase the transcription of HBV RNAs through its transcription activation domain. A genomic region within HBV enhancer I was identified that is responsible for the transcriptional activation of AR. The results from chromatin immunoprecipitation and in vitro binding assays further demonstrated a direct binding of AR to this region, in a ligand-dependent manner. Two androgen-responsive element motifs in this region were identified, and their mutations can significantly abolish the AR effects. CONCLUSION This study demonstrated that the androgen pathway can increase the transcription of HBV through direct binding to the androgen-responsive element sites in viral enhancer I. This may explain a higher HBV titer in male carriers and an increased risk of HCC.
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Affiliation(s)
- Sheng-Han Wang
- Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan
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18
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Nguyen G, Garcia RT, Nguyen N, Trinh H, Keeffe EB, Nguyen MH. Clinical course of hepatitis B virus infection during pregnancy. Aliment Pharmacol Ther 2009; 29:755-64. [PMID: 19183158 DOI: 10.1111/j.1365-2036.2009.03932.x] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND For women with hepatitis B virus (HBV) infection, little is known about the natural progression of the disease during pregnancy or its impact on pregnancy outcomes. OBJECTIVES To investigate the natural progression of HBV infection during pregnancy or its impact on pregnancy outcomes. METHODS In this retrospective cohort study, we reviewed medical records of all patients who were pregnant and presented with HBsAg-positivity between 2000 and 2008 at a community gastroenterology practice and a university hepatology clinic. Maternal characteristics were analysed according to maternal and perinatal outcomes. RESULTS A total of 29 cases with at least 2 measurements of either HBV DNA or alanine aminotransferase (ALT) levels were included. Older age was the only predictor of a trend towards higher risk of an adverse clinical outcome [OR = 1.21 (0.97-1.51), P = 0.089], defined as either a negative foetal outcome (premature delivery, spontaneous abortion), or a negative maternal outcomes (gestational diabetes mellitus, pre-eclampsia, hepatic flare, liver failure). This trend for age remained even after adjusting for baseline ALT. Baseline serum HBV DNA, ALT, hepatitis B e antigen status, gravida and parity were not significant predictors for adverse clinical outcomes. Four patients developed liver failure. CONCLUSIONS Maternal and neonatal outcomes are highly variable in this clinic-based patient cohort. Severe complications due to HBV infection can occur during pregnancy in previously asymptomatic patients. It is unclear how generalizable the results observed in this cohort would be to the general population; therefore, further studies are needed to identify reliable predictors for significant adverse outcomes and until more data are available, pregnant patients with HBV infection should be monitored with periodic serum HBV DNA and ALT levels.
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Affiliation(s)
- G Nguyen
- Albert Einstein College of Medicine, Bronx, NY, USA
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Abstract
In countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases of chronic hepatitis B. Passive-active immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine at birth is 95% efficacious in reducing the risk of HBV transmission but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. In the last 4 weeks of pregnancy lamivudine may provide additional protection in pregnant women who have high-level viremia. Further studies are needed to evaluate the use of nucleos(t)ide analogues to treat chronic hepatitis B during pregnancy.
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Affiliation(s)
- Maya Gambarin-Gelwan
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College of Cornell University, 1305 York Avenue, 4th floor, New York, NY 10021, USA.
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Epstein RJ, Leung TW. Reversing hepatocellular carcinoma progression by using networked biological therapies. Clin Cancer Res 2007; 13:11-7. [PMID: 17200333 DOI: 10.1158/1078-0432.ccr-06-1619] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The liver is distinguished from other tissues by (a) its detoxifying function, (b) its resistance to apoptosis, and (c) its regenerative response to damage. Hepatocellular carcinoma arises when chronic insults, such as hepatitis or iron overload, constitutively activate this regenerative program. Here, we propose that the proliferative response of the liver to damage underlies the resistance of hepatocellular carcinoma to cytotoxic therapy, and that hepatocellular carcinoma growth should therefore be more readily controlled by using a networked combination of noncytotoxic interventions to interrupt the damage-inducible regenerative pathway. To this end, hepatocellular carcinoma boasts a wealth of potential drug targets, including viral replication, the antiapoptotic immunosuppressant alpha-fetoprotein, hepatic iron overload, inflammatory signaling, extracellular proteases, and growth factors. By blocking these positive feedback loops in parallel, and so returning the host environment to a more normal state, epigenetic repression of tumor-suppressor gene function may be reversed and tumor dormancy restored. Noncytotoxic maneuvers that short circuit damage resistance loops may thus represent an indirect form of gene therapy meriting incorporation into hepatocellular carcinoma clinical trials.
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Affiliation(s)
- Richard J Epstein
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, China.
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Han J, Ding L, Yuan B, Yang X, Wang X, Li J, Lu Q, Huang C, Ye Q. Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res 2006; 34:3095-106. [PMID: 16757575 PMCID: PMC1475750 DOI: 10.1093/nar/gkl389] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) is considered to play a role in the development of hepatocellular carcinoma (HCC) during HBV infection. HCC was shown to be more prevalent in men than in women. Estrogen, which exerts its biological function through estrogen receptor (ER), can inhibit HBV replication. ERDelta5, an ERalpha variant lacking exon 5, was found to be preferentially expressed in patients with HCC compared with patients with normal livers. Here, we report the biological role of ERDelta5 and a novel link between HBx and ERalpha signaling in hepatoma cells. ERDelta5 interacts with ERalpha in vitro and in vivo and functions as a dominant negative receptor. Both ERalpha and ERDelta5 associate with HBx. HBx decreases ERalpha-dependent transcriptional activity, and HBx and ERDelta5 have additive effect on suppression of ERalpha transactivation. The HBx deletion mutant that lacks the ERalpha-binding site abolishes the HBx repression of ERalpha. HBx, ERalpha and histone deacetylase 1 (HDAC1) form a ternary complex. Trichostatin A, a specific inhibitor of HDAC enzyme, can restore the transcriptional activity of ERalpha inhibited by HBx. Our data suggest that HBx and ERDelta5 may play a negative role in ERalpha signaling and that ERalpha agonists may be developed for HCC therapy.
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Affiliation(s)
| | | | | | | | | | | | - Qiujun Lu
- Beijing Institute of Radiation MedicineBeijing 100850, People's Republic of China
| | | | - Qinong Ye
- To whom correspondence should be addressed. Tel: +8610 6818 0809; Fax: +8610 6824 8045;
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Li HQ, Li Z, Liu Y, Li JH, Dong JQ, Gao JR, Gou CY, Li H. Association of polymorphism of tumor necrosis factor-alpha gene promoter region with outcome of hepatitis B virus infection. World J Gastroenterol 2005; 11:5213-7. [PMID: 16127755 PMCID: PMC4320398 DOI: 10.3748/wjg.v11.i33.5213] [Citation(s) in RCA: 9] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether -238G/A and -857C/T polymor-phisms of tumor necrosis factor-alpha (TNF-α), gene promoter and hepatitis B (HB) viral genotypes were associated with outcomes of HBV infection.
METHODS: A total of 244 HBV self-limited infected subjects, 208 asymptomatic carriers, and 443 chronic HB patients were recruited to conduct a case-control study. TNF-α -238G/A and -857C/T gene promoter polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and HBV genotypes were examined by nested PCR.
RESULTS: The positive rate of HBV DNA in asymptomatic carrier group and chronic HB group was 46.6% and 49.9%, respectively. HBV genotype proportion among the asymptomatic carriers was 2.1% for genotype A, 25.8% for genotype B, 68.0% for genotype C, and 4.1% for genotype B+C mixed infection, and 0.9% for genotype A, 21.7% for genotype B, 71.5% for genotype C, 5.9% for genotype B+C mixed infection in chronic HB group. There was no significant difference in genotype distribution between the asymptomatic carrier group and chronic HB group (χ2 = 1.66, P = 0.647). The frequency of -238GG genotype in self-limited group was 95.1%, significantly higher than 90.7% in chronic HB group and 89.0% in asymptomatic carrier group (P = 0.041 and P = 0.016, respectively).The frequency of TNF-α-857 CC in chronic HB group was 79.7%, significantly higher than 64.4% in asymptomatic carrier group and 70.9% in self-limited group (P<0.001 and P = 0.023, respectively). A multiple logistic regression analysis revealed that TNF-α-238GA and -857CC were independently associated with chronic HB after gender and age were adjusted.
CONCLUSION: TNF-α promoter variants are likely to play a substantial role in the outcome of HBV infection.
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Affiliation(s)
- Hong-Quan Li
- Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
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Deng G, Zhou G, Zhai Y, Li S, Li X, Li Y, Zhang R, Yao Z, Shen Y, Qiang B, Wang Y, He F. Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004; 40:318-26. [PMID: 15368436 DOI: 10.1002/hep.20318] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Several studies have demonstrated that estrogen receptor alpha (ESR1) participates in the pathogenesis of persistent hepatitis B virus (HBV) infection. To examine whether polymorphisms at the ESR1 gene locus are associated with persistent HBV infection, we resequenced ESR1 genomic region for single nucleotide polymorphisms (SNPs) in 27 unrelated Chinese. Two haplotype-tagged SNPs (htSNP), T29C and A252966G, were selected for genotyping in 1,277 persistent HBV-infected cases, 748 spontaneously recovered controls, and 293 nuclear families using polymerase chain reaction (PCR)-restriction fragment length polymorphism (PCR-RFLP) analysis. We observed that the subjects bearing ESR1 29T/T genotype had an increased susceptibility to persistent HBV infection compared to those bearing at least one 29C allele (odds ratio 1.41; 95% CI, 1.17-1.71, P < .001). Consistent with the results of population-based association study, a significantly greater than expected transmission of the 29T allele (56.4%) from heterozygous parents to offspring with persistent HBV infection was observed (chi2 = 4.60, P = .033) using the transmission-disequilibrium test (TDT) in 293 nuclear families. Linkage disequilibrium (LD) mapping analysis indicated that the T29C polymorphism contained within a LD block located from promoter region to intron 3 of ESR1, suggesting that the strong association detected with T29C in ESR1 originated from ESR1 itself. In conclusion, our results suggest that the genetic variation at the ESR1 locus influences susceptibility to persistent HBV infection in a Chinese population.
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Affiliation(s)
- Guohong Deng
- Department of Infectious Diseases, Southwest Hospital, Chongqing, China
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Labonté P, Morin N, Bowlin T, Mounir S. Basal replication of hepatitis C virus in nude mice harboring human tumor. J Med Virol 2002; 66:312-9. [PMID: 11793382 DOI: 10.1002/jmv.2147] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) can infect and propagate in humans and chimpanzees. Whereas the chimpanzee has been used as an animal model for infection, ethical considerations, conservation, and the prohibitively high cost preclude progress for experimental research on the biology of the virus. The development of a small animal model for HCV infection is thus desirable to facilitate studies on the infectious cycle of the virus and for the evaluation of drugs for the treatment of HCV infections in humans. As an alternative to the chimpanzee model, we have established a model based on ex vivo infection of orthotopically-implanted human hepatocellular carcinoma cells (HCC) in athymic nude mice. The results show that up to 42 days post-infection, HCV RNA was present in the tumor cells as well as in the liver and serum of infected mice. Furthermore, a direct correlation between size of the tumor and the presence of HCV RNA in the liver was observed, which is concordant with the finding that HCV RNA was detectable only in mice harboring human tumor. Immunohistochemistry analysis of infected liver specimens showed cells expressing the HCV encoded NS5B protein. A few mice developed a humoral response against the nonstructural viral proteins, providing further evidence for expression of these proteins during viral infection. In summary, these results suggest that mice harboring orthotopic tumors support a basal level of HCV replication in vivo.
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Komukai Y, Amao H, Goto N, Kusajima Y, Sawada T, Saito M, Takahashi KW. Sex differences in susceptibility of ICR mice to oral infection with Corynebacterium kutscheri. Exp Anim 1999; 48:37-42. [PMID: 10067204 DOI: 10.1538/expanim.48.37] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Sex difference in susceptibility to oral infection with Corynebacterium (C.) kutscheri was experimentally studied in ICR mice. Immature (4-week-old) and adult (14-week-old) mice were inoculated with two infecting doses of C. kutscheri, and necropsied for bacteriological and serological survey 4 weeks after the bacterial infection. No macroscopic lesions at necropsy were demonstrated, except for one adult male given 10(9) bacteria. In immature mice, C. Kutscheri isolated from the oral cavity and cecum with FNC agar, were recovered in only 40.0% of female mice but in 90.0% of male mice given 10(6) bacteria (p < 0.05), and in only 55.6% of female mice but in 80.0% male mice given 10(8) bacteria. In adult mice given 10(9) bacteria, the organism were recovered in only 45.5% of female mice but in 90.9% of male mice (p < 0.05), furthermore, the mean number of organisms in the cecum of male mice harboring the organism was significantly higher than that in females (p < 0.01). Castration caused an increase in host resistance in adult male mice. These results indicated that ICR male mice were more susceptible than females, in terms of bacterial colonization in the cecum and the oral cavity, to oral infection with C. kutscheri.
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Affiliation(s)
- Y Komukai
- Division of Laboratory Animal Science, Nippon Veterinary and Animal Science University, Tokyo, Japan
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