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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Hao L, Li S, Hu X. New insights into T-cell exhaustion in liver cancer: from mechanism to therapy. J Cancer Res Clin Oncol 2023; 149:12543-12560. [PMID: 37423958 DOI: 10.1007/s00432-023-05083-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 06/29/2023] [Indexed: 07/11/2023]
Abstract
Liver cancer is one of the most common malignancies. T-cell exhaustion is associated with immunosuppression of tumor and chronic infection. Although immunotherapies that enhance the immune response by targeting programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) have been applied to malignancies, these treatments have shown limited response rates. This suggested that additional inhibitory receptors (IRs) also contributed to T-cell exhaustion and tumor prognosis. Exhausted T-cells (Tex) in the tumor immune microenvironment (TME) are usually in a dysfunctional state of exhaustion, such as impaired activity and proliferative ability, increased apoptosis rate, and reduced production of effector cytokines. Tex cells participate in the negative regulation of tumor immunity mainly through IRs on the cell surface, changes in cytokines and immunomodulatory cell types, causing tumor immune escape. However, T-cell exhaustion is not irreversible and targeted immune checkpoint inhibitors (ICIs) can effectively reverse the exhaustion of T-cells and restore the anti-tumor immune response. Therefore, the research on the mechanism of T-cell exhaustion in liver cancer, aimed at maintaining or restoring the effector function of Tex cells, might provide a new method for the treatment of liver cancer. In this review, we summarized the basic characteristics of Tex cells (such as IRs and cytokines), discussed the mechanisms associated with T-cell exhaustion, and specifically discussed how these exhaustion characteristics were acquired and shaped by key factors within TME. Then new insights into the molecular mechanism of T-cell exhaustion suggested a potential way to improve the efficacy of cancer immunotherapy, namely to restore the effector function of Tex cells. In addition, we also reviewed the research progress of T-cell exhaustion in recent years and provided suggestions for further research.
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Affiliation(s)
- Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, No. 37 Shi-Er-Qiao Road, Chengdu, 610075, Sichuan Province, People's Republic of China
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-Er-Qiao Road, Chengdu, 610072, Sichuan Province, People's Republic of China.
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Tang Y, Jiang M, Jiang HM, Ye ZJ, Huang YS, Li XS, Qin BY, Zhou RS, Pan HF, Zheng DY. The Roles of circRNAs in Liver Cancer Immunity. Front Oncol 2021; 10:598464. [PMID: 33614486 PMCID: PMC7890029 DOI: 10.3389/fonc.2020.598464] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
Circular RNAs (circRNAs) are stable covalently closed non-coding RNAs (ncRNAs). Many studies indicate that circRNAs are involved in the pathological and physiological processes of liver cancer. However, the functions of circRNAs in liver cancer immunity are less known. In this review, we summarized the functions of circRNAs in liver cancer, including proliferative, metastasis and apoptosis, liver cancer stemness, cell cycle, immune evasion, glycolysis, angiogenesis, drug resistance/sensitizer, and senescence. Immune escape is considered to be one of the hallmarks of cancer development, and circRNA participates in the immune escape of liver cancer cells by regulating natural killer (NK) cell function. CircRNAs may provide new ideas for immunotherapy in liver cancer.
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Affiliation(s)
- Ying Tang
- Department of Oncology, Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Mei Jiang
- Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hai-Mei Jiang
- Department of Oncology, Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zeng Jie Ye
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yu-Sheng Huang
- Department of Oncology, Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiu-Shen Li
- Department of Oncology, Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin-Yu Qin
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Rui-Sheng Zhou
- Department of Oncology, Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hua-Feng Pan
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Da-Yong Zheng
- Department of Oncology, Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Hepatopancreatobiliary, Cancer Center, Southern Medical University, Guangzhou, China
- Department of Hepatology, TCM-Integrated Hospital of Southern Medical University, Guangzhou, China
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Wagner M, Jasek M, Karabon L. Immune Checkpoint Molecules-Inherited Variations as Markers for Cancer Risk. Front Immunol 2021; 11:606721. [PMID: 33519815 PMCID: PMC7840570 DOI: 10.3389/fimmu.2020.606721] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/25/2020] [Indexed: 12/13/2022] Open
Abstract
In recent years, immunotherapy has been revolutionized by a new approach that works by blocking receptors called immune checkpoints (IC). These molecules play a key role in maintaining immune homeostasis, mainly by suppressing the immune response and by preventing its overactivation. Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response. This therapeutic approach has brought spectacular clinical effects. The ICs present heterogeneous expression patterns on immune cells, which may affect the effectiveness of immunotherapy. The inherited genetic variants in regulatory regions of ICs genes can be considered as potential factors responsible for observed inter-individual differences in ICs expression levels on immune cells. Additionally, polymorphism located in exons may introduce changes to ICs amino acid sequences with potential impact on functional properties of these molecules. Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development. Inherited genetic markers such as SNPs may also be useful in stratification patients into groups which will benefit from particular immunotherapy. In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations of CTLA-4, PDCD1, PD-L1, BTLA, TIM-3, and LAG-3 genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.
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Affiliation(s)
| | - Monika Jasek
- Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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Wu JL, Zhao J, Zhang HB, Zuo WW, Li Y, Kang S. Genetic variants and expression of the TIM-3 gene are associated with clinical prognosis in patients with epithelial ovarian cancer. Gynecol Oncol 2020; 159:270-276. [PMID: 32694063 DOI: 10.1016/j.ygyno.2020.07.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 07/06/2020] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Polymorphisms of T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) were reported to be associated with cancer risk and patients' survival. This study aims to investigate the correlation of TIM-3 polymorphisms with susceptibility to epithelial ovarian cancer (EOC) and patients' outcomes. METHODS A total of 700 EOC patients and 710 healthy controls from North China were included. The polymorphisms (rs10053538, rs10515746 and rs1036199) were genotyped using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. Survival data were available for 339 patients after cytoreductive surgery. The expression level of TIM-3 was detected by real-time quantitative PCR (RT-qPCR). The prognostic value of TIM3 in EOC patients was assessed using the Kaplan-Meier plotter database. RESULTS The results showed that none of the TIM3 polymorphisms were associated with the risk of developing EOC. Patients with the rs10053538 CA + AA genotype had worse PFS and OS than those with the CC genotype (HR = 1.49, 95% CI = 1.05-2.09, P = 0.024 and HR = 1.57, 95%CI = 1.09-2.26, P = 0.017, respectively). The RT-qPCR results showed that the expression levels of TIM-3 mRNA in EOC tissues with the rs10053538CA + AA genotypes were significantly higher than those with the CC genotype (P = 0.006). Analysis using the Kaplan-Meier plotter database showed that high expression of TIM-3 mRNA was significantly associated with shorter PFS and OS in EOC patients (HR = 1.57, 95%CI = 1.29-1.91, P < 0.001 and HR = 1.31, 95% CI = 1.06-1.63, P = 0.013, respectively). CONCLUSIONS TIM-3 polymorphisms were not associated with risk of developing EOC. Both rs10053538 and the expression level of TIM-3 mRNA may be associated with its clinical outcome in EOC patients.
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Affiliation(s)
- Jian-Lei Wu
- Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
| | - Jian Zhao
- Department of Obstetrics and Gynaecology, First Hospital of Shijiazhuang, Shijiazhuang, China
| | - Hai-Bo Zhang
- Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
| | - Wei-Wei Zuo
- Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China
| | - Yan Li
- Department of Molecular Biology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China.
| | - Shan Kang
- Department of Obstetrics and Gynaecology, Hebei Medical University, Fourth Hospital, Shijiazhuang, China.
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6
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Lu C, Rong D, Zhang B, Zheng W, Wang X, Chen Z, Tang W. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol Cancer 2019; 18:130. [PMID: 31464625 PMCID: PMC6714090 DOI: 10.1186/s12943-019-1047-6] [Citation(s) in RCA: 298] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/18/2019] [Indexed: 12/14/2022] Open
Abstract
Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.
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Affiliation(s)
- Chen Lu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dawei Rong
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.,Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China
| | - Betty Zhang
- Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Wubin Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xuehao Wang
- Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. .,Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China.
| | - Ziyi Chen
- Department of General Surgery, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China.
| | - Weiwei Tang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
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Liu F, Liu Y, Chen Z. Tim-3 expression and its role in hepatocellular carcinoma. J Hematol Oncol 2018; 11:126. [PMID: 30309387 PMCID: PMC6182863 DOI: 10.1186/s13045-018-0667-4] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, and its mortality is still on the rise. Limited treatments and low chemotherapy sensitivity of HCC make new therapeutic strategies urgently needed. With the rise of immune checkpoint blockade, anti-CTLA-4 antibodies and anti-PD-1 antibodies have shown therapeutic effects in various tumors. T cell immunoglobulin mucin-3 (Tim-3), a newly discovered immune checkpoint molecule, plays a major role in the development of HCC. Tim-3 can be used to evaluate the prognosis and therapeutic effects in HCC, and Tim-3 intervention has shown anti-tumor effects in preclinical experiments. This review summarizes findings regarding Tim-3 and HCC in recent years and discusses the rationale of Tim-3 as a therapeutic target for HCC.
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Affiliation(s)
- Feifei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79# Qingchun Road, 6A-17, Hangzhou, 310003, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79# Qingchun Road, 6A-17, Hangzhou, 310003, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, 79# Qingchun Road, 6A-17, Hangzhou, 310003, China.
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Gao X, Yang J, He Y, Zhang J. Quantitative assessment of TIM-3 polymorphisms and cancer risk in Chinese Han population. Oncotarget 2017; 7:35768-35775. [PMID: 27008699 PMCID: PMC5094960 DOI: 10.18632/oncotarget.8157] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 03/04/2016] [Indexed: 12/31/2022] Open
Abstract
Previous studies have investigated the associations of TIM-3 polymorphisms (−1516G/T, −574G/T, and +4259T/G) with cancer risk in Chinese Han population, but the results remain conflicting. Therefore, we conducted a meta-analysis to derive a more precise estimation of the associations. The pooled data showed that TIM-3 polymorphisms (−1516G/T, −574G/T, and +4259T/G) were significantly associated with an increased risk of overall cancer in Chinese Han population. Subgroup analyses based on cancer system showed that TIM-3 −1516G/T polymorphism was only associated with an increased risk of digestive system cancer in Chinese Han population. TIM-3 −574G/T polymorphism was associated with an increased risk of digestive system cancer and other cancer in Chinese Han population. TIM-3 +4259T/G polymorphism was only associated with an increased risk of other cancer in Chinese Han population. In summary, our results indicated that TIM-3 polymorphisms (−1516G/T, −574G/T, and +4259T/G) were associated with the increased risk of cancer in Chinese Han population.
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Affiliation(s)
- Xueren Gao
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Jiaojiao Yang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Youji He
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China
| | - Jianqiong Zhang
- Department of Microbiology and Immunology, Medical School of Southeast University, Nanjing, Jiangsu, China.,Jiangsu Key Laboratory of Molecule Imaging and Functional Imaging, Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Medical School of Southeast University, Nanjing, Jiangsu, China
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Lin H, Yang B, Teng M. T-cell immunoglobulin mucin-3 as a potential inducer of the epithelial-mesenchymal transition in hepatocellular carcinoma. Oncol Lett 2017; 14:5899-5905. [PMID: 29113224 PMCID: PMC5661575 DOI: 10.3892/ol.2017.6961] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 04/26/2017] [Indexed: 12/13/2022] Open
Abstract
T-cell immunoglobulin mucin (TIM)-3 is an important member of the TIM gene family, which was thought to contribute to the progression of numerous types of cancer, including hepatocellular carcinoma (HCC); however, the mechanism underlying TIM-3 functions in HCC progression has not yet been extensively investigated. The present study aimed to investigate the function of TIM-3 in the metastasis of HCC and to determine whether the alteration of TIM-3 expression levels regulated the epithelial-mesenchymal transition (EMT) occurrence of HCC, using epithelial (E)-cadherin, neuronal (N)-cadherin, matrix metallopeptidase-9 (MMP-9), Twist 1, Slug, Snail, and Smad as EMT biomarkers. The results demonstrated that upregulation of TIM-3 using TIM-3 lentiviral activation particles (5 µl) increased cell migration and invasion, which was decreased in TIM-3 short interfering RNA-infected cells (10 µM, 3 µl) correspondingly. SMMC-7721 HCC cells were used as the control. EMT was aggravated in TIM-3 upregulated SMMC-7721 cells, which was attenuated in the TIM-3 interference group, accompanied by an alteration of E-cadherin, N-cadherin, MMP-9, Twist 1, Slug, Snail and Smad expression levels. The data presented suggests that TIM-3 serves an essential role in the metastasis of HCC, the mechanism of which was associated with EMT occurrence. Interference of TIM-3 is expected to be an effective means to prevent and control EMT, and further the metastasis of HCC.
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Affiliation(s)
- Huapeng Lin
- Department of Hepatobiliary Surgery, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China.,Department of Hepatobiliary Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272001, P.R. China
| | - Bin Yang
- Department of Hepatobiliary and Vascular Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272001, P.R. China
| | - Mujian Teng
- Department of Hepatobiliary Surgery, Qianfoshan Hospital Affiliated to Shandong University, Jinan, Shandong 250014, P.R. China
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唐 映, 徐 加. Tim-3在肝脏疾病中的调节作用. Shijie Huaren Xiaohua Zazhi 2017; 25:2080-2087. [DOI: 10.11569/wcjd.v25.i23.2080] [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
T淋巴细胞免疫球蛋白黏蛋白分子(T-cell immunoglobulin domain and mucin domain-containing molecule, Tim)-3是Tim家族中的一员, 为近年来新发现的一种在辅助Ⅰ型T淋巴细胞(Help T cell 1, Th1)上特异性表达的Ⅰ型细胞表面分子. Tim-3作为负性调节因子通过与其配体Galectin-9结合引起细胞死亡, 进而调控Th1型细胞功能. Tim-3还表达于其他类型细胞表面, 如自然杀伤细胞、树突状细胞和单核细胞, 对自身免疫性疾病和其他免疫介导的疾病进行免疫调控. 对Tim-3在不同细胞不同免疫条件下的功能以及如何调节进行研究, 将有利于研发Tim-3的潜在治疗作用. 近年来大量研究显示Tim-3通道与肝脏疾病发生发展有着密切关系, 本文就其在肝脏疾病中的调节作用做一总结.
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Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis. Int J Mol Sci 2017; 18:ijms18071517. [PMID: 28703774 PMCID: PMC5536007 DOI: 10.3390/ijms18071517] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/03/2017] [Accepted: 07/04/2017] [Indexed: 12/21/2022] Open
Abstract
Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.
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12
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Li Z, Li N, Li F, Zhou Z, Sang J, Chen Y, Han Q, Lv Y, Liu Z. Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma. Medicine (Baltimore) 2016; 95:e5749. [PMID: 28033288 PMCID: PMC5207584 DOI: 10.1097/md.0000000000005749] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 11/30/2016] [Accepted: 12/02/2016] [Indexed: 12/27/2022] Open
Abstract
Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.
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Affiliation(s)
- Zhu Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Jiao Sang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Yanping Chen
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
- Department of Infectious Diseases, Yanan University Affiliated Hospital, Yanan
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
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13
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Pei JP, Jiang LF, Ji XW, Xiao W, Deng XZ, Zhou ZX, Zhu DY, Ding WL, Zhang JH, Wang CJ, Jing K. The relevance of Tim-3 polymorphisms and F protein to the outcomes of HCV infection. Eur J Clin Microbiol Infect Dis 2016; 35:1377-86. [PMID: 27230511 DOI: 10.1007/s10096-016-2676-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 05/09/2016] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus (HCV) is one of the major causes of liver inflammation. The aim of this study was to investigate the associations of T-cell immunoglobulin and mucin domain-3 (Tim-3) polymorphisms and the alternate reading frame protein (F protein) with the outcomes of HCV infection. Three single-nucleotide polymorphisms (SNPs; rs10053538, rs12186731, and rs13170556) of Tim-3 were genotyped in this study, which included 203 healthy controls, 558 hepatitis C anti-F-positive patients, and 163 hepatitis C anti-F-negative patients. The results revealed that the rs12186731 CT and rs13170556 TC and CC genotypes were significantly less frequent in the anti-F-positive patients [odds ratio (OR) = 0.54, 95 % confidence interval (CI) = 0.35-0.83, p = 0.005; OR = 0.26, 95 % CI = 0.18-0.39, p < 0.001; and OR = 0.19, 95 % CI = 0.10-0.35, p < 0.001, respectively), and the rs13170556 TC genotype was more frequent in the chronic HCV (CHC) patients (OR = 1.70, 95 % CI = 1.20-2.40, p = 0.002). The combined analysis of the rs12186731 CT and rs13170556 TC/CC genotypes revealed a locus-dosage protective effect in the anti-F-positive patients (OR = 0.22, 95 % CI = 0.14-0.33, p trend < 0.001). Stratified analyses revealed that the frequencies of the rs12186731 (CT + TT) genotypes were significantly lower in the older (OR = 0.31, 95 % CI = 0.15-0.65, p = 0.002) and female (OR = 0.30, 95 % CI = 0.17-0.52, p < 0.001) subgroups, and rs13170556 (TC + CC) genotypes exhibited the same effect in all subgroups (all p < 0.001) in the anti-F antibody generations. Moreover, the rs13170556 (TC + CC) genotypes were significantly more frequent in the younger (OR = 1.86, 95 % CI = 1.18-2.94, p = 0.007) and female (OR = 2.38, 95 % CI = 1.48-3.83, p < 0.001) subgroups of CHC patients. These findings suggest that the rs12186731 CT and rs13170556 TC/CC genotypes of Tim-3 provide potential protective effects with the F protein in the outcomes of HCV infection and that these effects are related to sex and age.
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Affiliation(s)
- J P Pei
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - L F Jiang
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210002, China
| | - X W Ji
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - W Xiao
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China.
| | - X Z Deng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Nanjing Medical University, Nanjing, 210029, China.
- Huadong Research Institute for Medicine and Biotechnics, No. 293, Zhongshan East Road, Nanjing, 210002, China.
| | - Z X Zhou
- Department of Clinical Laboratory, Nanjing Second Hospital, Nanjing, China
| | - D Y Zhu
- Department of Infectious Diseases at Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471000, China
| | - W L Ding
- Department of Clinical Laboratory, Yixing People's Hospital, Yixing, 214200, China
| | - J H Zhang
- Huadong Research Institute for Medicine and Biotechnics, No. 293, Zhongshan East Road, Nanjing, 210002, China
| | - C J Wang
- Huadong Research Institute for Medicine and Biotechnics, No. 293, Zhongshan East Road, Nanjing, 210002, China
| | - K Jing
- Faculty of Chemical Engineering, Huaiyin Institute of Technology, Meicheng Road East, Huai'an, 223003, China
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14
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Li Z, Li N, Li F, Zhou Z, Sang J, Jin Z, Liu H, Han Q, Lv Y, Liu Z. Genetic polymorphisms of immune checkpoint proteins PD-1 and TIM-3 are associated with survival of patients with hepatitis B virus-related hepatocellular carcinoma. Oncotarget 2016; 7:26168-26180. [PMID: 27034168 PMCID: PMC5041972 DOI: 10.18632/oncotarget.8435] [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: 02/03/2016] [Accepted: 03/14/2016] [Indexed: 12/17/2022] Open
Abstract
Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 -1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0.001, respectively). In multivariate analysis, PD1 +8669 G allele-containing genotypes and TIM3 -1516 genotype GG were independently associated with longer OS (hazard ratio (HR), 1.835; 95% confidence interval (CI), 1.342-2.509; P < 0.001 and HR, 2.070; 95%CI, 1.428-3.002; P < 0.001, respectively). PD1 +8669 G allele-containing genotypes were significantly associated with longer OS in patients receiving surgical (resection or radiofrequency) treatment, transcatheter arterial chemoembolization (TACE) or supportive and symptomatic treatment. TIM3 -1516 genotype GG was significantly associated with longer OS in TACE patients. In multivariate analysis, PD1 +8669 G allele-containing genotypes were independently associated with longer OS in each treatment population. TIM3 -1516 genotype GG was independently associated with longer OS in patients receiving surgical treatment or TACE. These findings suggest that PD1 +8669 A/G and TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients.
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Affiliation(s)
- Zhu Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Jiao Sang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Zhao Jin
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
- Xi'an Medical University, Xi'an, 710021, Shaanxi, China
| | - Huihui Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
- Xi'an Medical University, Xi'an, 710021, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China
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15
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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16
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Liu Y, Gao LF, Liang XH, Ma CH. Role of Tim-3 in hepatitis B virus infection: An overview. World J Gastroenterol 2016; 22:2294-2303. [PMID: 26900291 PMCID: PMC4735003 DOI: 10.3748/wjg.v22.i7.2294] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/08/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection has received increasing public attention. HBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the above-mentioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of HBV-related liver disease and suggest new therapeutic methods for intervention.
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17
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Peng H, Li QL, Hou SH, Hu J, Fan JH, Guo JJ. Association of genetic polymorphisms in CD8+ T cell inhibitory genes and susceptibility to and progression of chronic HBV infection. INFECTION GENETICS AND EVOLUTION 2015; 36:467-474. [PMID: 26296604 DOI: 10.1016/j.meegid.2015.08.018] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 07/16/2015] [Accepted: 08/11/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND Previous studies have shown that multiple inhibitory genes play an important role in HBV-specific CD8+ T cell exhaustion and dysfunction in the setting of chronic HBV infection. Polymorphic variants of these genes are thought to be predisposing factors for HBV susceptibility, clearance, and disease progression. The aim of this retrospective study was to identify variants affecting chronic HBV infection in a Chinese Han population. METHODS We chose 28 tgSNPs from HapMap data on 5 key genes. They were genotyped on a total of 858 chronic HBV patients, 429 patients who underwent spontaneous recovery, and 239 healthy controls. We evaluated the correlation between the polymorphisms and HBV susceptibility, spontaneous clearance, and disease progression. RESULTS The association of rs3827537 of BIM genotype TA and allele A was significantly different (P=0.016, OR=2.049; P=0.031, OR=1.925) between HBV patients and healthy controls. The rs36084323 of PD-1, as well as rs3766377, rs485618, rs4656942 of CD244 showed significant associations with the risk for HBV-related cirrhosis and hepatocellular carcinoma (HCC) (P=0.009, OR=0.482; P=0.009, OR=4.573; P=0.015, OR=0.580; P=0.028, OR=2.855). MDR analysis revealed that the four SNPs (rs36084323, rs3766377, rs485618, rs4656942) modulated the predisposition to cirrhosis and HCC in patients with chronic HBV infection (P=0.006). Using a luciferase reporter assay, we demonstrated that various alleles of rs3766377 had differential effects, and rs3766377 and rs485618 might have interactive effects. CONCLUSIONS The present study reveals genetic associations among PD-1 and CD244 variants that may be involved in the development of cirrhosis and HCC in patients with chronic HBV infection. The BIM variant was associated with HBV susceptibility.
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Affiliation(s)
- Hong Peng
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing-Ling Li
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Si-Hui Hou
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Hu
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jia-Hao Fan
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jin-Jun Guo
- Department of Gastroenterology and Hepatology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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18
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Zhang P, Li N, Zhu Q, Li F, Yang C, Zeng X, Lv Y, Zhou Z, Han Q, Liu Z. Association between TNFAIP3 nonsynonymous single-nucleotide polymorphism rs2230926 and chronic hepatitis B virus infection in a Chinese Han population. Virol J 2015; 12:33. [PMID: 25890346 PMCID: PMC4359777 DOI: 10.1186/s12985-015-0268-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 02/18/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNPs) in tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) gene have been linked to inflammatory, immunological and malignant diseases. Hepatitis B virus (HBV) infection is characterized by immunopathogenesis. This study investigated the association of rs2230926, a nonsynonymous SNP in TNFAIP3 gene, with chronic HBV infection. METHODS Four hundred and fifty-five patients with chronic HBV infection with clinical diseases of chronic hepatitis (n = 183), liver cirrhosis (n = 167) and hepatocellular carcinoma (n = 105), 92 HBV infection resolvers and 171 healthy controls were included. All subjects were of Chinese Han ethnicity. Genotyping of rs2230926 was carried out by polymerase chain reaction-restriction fragment length polymorphism method. RESULTS The gender and age between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotypes of rs2230926 in HBV patients, HBV infection resolvers and healthy controls are in Hardy-Weinberg equilibrium. The genotype and allele frequencies of TNFAIP3 rs2230926 polymorphism between HBV patients, HBV infection resolvers and healthy controls had no significant difference. The genotype and allele frequencies of TNFAIP3 rs2230926 polymorphism between HBV patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma also showed no significant difference. CONCLUSIONS The TNFAIP3 rs2230926 polymorphism is not suggested to be associated with the susceptibility of chronic HBV infection or the progression of HBV-related diseases in this study. Replicative studies and studies in large control and HBV patient populations of different ethnicity by genotyping more polymorphisms in TNFAIP3 gene are needed.
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Affiliation(s)
- Pingping Zhang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Qianqian Zhu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Cuiling Yang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Xiaoyan Zeng
- Department of Laboratory Medicine, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China.
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, China.
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China.
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi Province, China.
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, 710061, Shaanxi, China.
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19
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Wirth TC. Spontaneous and therapeutic immune responses in hepatocellular carcinoma: implications for current and future immunotherapies. Expert Rev Gastroenterol Hepatol 2014; 8:101-10. [PMID: 24410473 DOI: 10.1586/17474124.2014.862497] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) represents a major health problem in the world, ranking fifth in incidence and third in cancer-related deaths. Due to the unique immunosuppressive microenvironment of the liver, HCC develops in an immunotolerant niche posing an important obstacle to immunotherapy. A number of studies, however, have shown immunogenic properties of HCC by demonstrating spontaneous adaptive immune responses during tumor formation and progression. Furthermore, studies examining immune responses during HCC therapy have revealed that conventional treatments such as surgical resection, locoregional therapy and systemic therapy with antibodies, small molecules or chemotherapy induce adaptive immune responses that contribute to therapeutic effects. These observations have provided a basis for clinical trials involving adoptive transfers of T cells or natural killer cells, peptide and dendritic cell vaccinations or, more recently, virotherapy and inhibition of co-inhibitory molecules. Here, spontaneous and therapeutic immune responses in HCC and their implication for current and future immunotherapies are discussed.
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Affiliation(s)
- Thomas C Wirth
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, 30625 Hannover, Germany
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20
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Yu J, Xie Y. Role of Tim-3 in pathogenesis of inflammatory diseases of the digestive system. Shijie Huaren Xiaohua Zazhi 2013; 21:2169-2175. [DOI: 10.11569/wcjd.v21.i22.2169] [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
T cell immunoglobulin mucin domain-containing molecules (Tim)-3 is a type I cell membrane glycoprotein that is expressed on the surface of cells involved in innate and adaptive immunity. As the first discovered member of Tim family, Tim-3 participates in T cell-induced immune responses. By interacting with its ligands galectin-9 or PtdSer, Tim-3 induces cell apoptosis and clearance of apoptotic cells in autoimmune disorders, allergic diseases and virus infection-associated diseases. Tim-3 can act as a negative regulator of Th1/Th17 immune responses. Current research has shown that Tim-3 is involved in the pathogenesis of inflammatory diseases of the digestive system. Here we will review the progress in understanding the role of Tim-3 in the pathogenesis of inflammatory diseases of the digestive system.
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21
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Zakeri Z, Hashemi M, Ebrahim Pourhosseini SM, Eskandari-Nasab E, Baharic G, Taheri M. Associação entre o polimorfismo rs7700944 no gene TIM-4 e artrite reumatoide em Zahedan, sudeste do Irã. REVISTA BRASILEIRA DE REUMATOLOGIA 2013. [DOI: 10.1590/s0482-50042013000400005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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22
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Li Z, Li N, Zhu Q, Zhang G, Han Q, Zhang P, Xun M, Wang Y, Zeng X, Yang C, Liu Z. Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2013; 14:240-246. [PMID: 23291409 DOI: 10.1016/j.meegid.2012.12.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 12/08/2012] [Accepted: 12/13/2012] [Indexed: 12/11/2022]
Abstract
Cooperation or interaction of programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) molecules is more relevant than either molecule alone to immune dysfunction in chronic viral infection and cancers. This study simultaneously investigated polymorphisms at PD1 +8669 and TIM3 -1516 loci in 845 hepatitis B virus (HBV) chronically infected patients [151 asymptomatic carriers, 202 chronic hepatitis, 221 cirrhosis and 271 hepatocellular carcinoma (HCC)], 141 HBV infection resolvers and 318 healthy controls. Multivariate analysis showed that, in addition to gender, age, ALT, albumin and HBV DNA, PD1 +8669 genotype AA was associated with cirrhosis compared with patients without cirrhosis (OR, 2.410; P=0.001). TIM3 -1516 genotypes GT+TT, together with gender, age, ALT, AST, direct bilirubin, albumin and HBeAg status, were associated with HCC compared with cirrhosis patients without HCC (OR, 2.142; P=0.011). The combined carriage of PD1 +8669 AA/TIM3 -1516 GT or TT was higher in cirrhosis and HCC pooled patients than in patients without cirrhosis (OR, 2.326; P=0.020) and in HCC patients than in cirrhosis patients (OR, 2.232; P=0.013). These data suggest that PD1 and TIM3 polymorphisms may differentially and interactively predispose cirrhosis and HCC in chronic HBV infection.
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Affiliation(s)
- Zhu Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 710061 Shaanxi, PR China
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Saitoh H, Ashino Y, Chagan-Yasutan H, Niki T, Hirashima M, Hattori T. Rapid decrease of plasma galectin-9 levels in patients with acute HIV infection after therapy. TOHOKU J EXP MED 2013; 228:157-61. [PMID: 23038209 DOI: 10.1620/tjem.228.157] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Acute HIV-1 infection is often diagnosed as infectious mononucleosis and the symptoms resolve spontaneously after varying periods of time. After the infection of HIV-1 through the mucosa, the characteristic clinical symptoms and laboratory markers of acute HIV-1 infection appear in each patient through a complicated virus-host interaction. To understand the host responses, we measured two unique proinflammatory cytokines, galectin-9 (Gal-9) and osteopontin (OPN). A β-galactoside-binding mammalian lectin, Gal-9, reduces pro-inflammatory type-1 helper T (Th1) cells and Th17 cells and increases anti-inflammatory regulatory T cells. The plasma level of Gal-9 is known to be associated with HIV-1 viral load in chronic HIV-1 infection. On the contrary, osteopontin induces Th1/Th17 cells and promotes tissue inflammation. OPN is synthesized by variety of cells in the body, and dendritic cells are known to synthesize OPN in HIV-1 infected individuals. It was hypothesized that Gal-9 and/or OPN could be not only immune-modulators but also novel biomarkers of acute HIV-1 infection. We experienced 3 patients with acute HIV-1 and measured the levels of Gal-9 and OPN periodically before and after antiretroviral treatment. The results showed that the plasma levels of Gal-9 were extremely elevated [more than 2,300 pg/ml (normal range < 46 pg/ml)] in all three acute HIV-1 infected individuals and decreased rapidly after treatment. The changes in the OPN levels were less marked. In conclusion, the plasma levels of Gal-9 may be predictive of a severe inflammation status during the acute phase of HIV-1 infection and could be a potential biomarker during acute infection.
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Affiliation(s)
- Hiroki Saitoh
- Division of Emerging Infectious Diseases, Department of Internal Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
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