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Gramantieri L, Fornari F, Giovannini C, Trerè D. MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma. Biomolecules 2022; 12:biom12070930. [PMID: 35883486 PMCID: PMC9313100 DOI: 10.3390/biom12070930] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/23/2022] [Accepted: 06/30/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary In recent years, treatments enhancing the antitumor immune response have revealed a new promising approach for advanced hepatocellular carcinoma (HCC). Beside favorable results in about one third of patients, much still remains to be done to face primary nonresponse, early, and late disease reactivation. Understanding the mechanisms underneath immune system modulation by immune checkpoint inhibitors in HCC might give additional opportunities for patient selection and combined approaches. MicroRNAs have emerged as relevant modulators of cancer cell hallmarks, including aberrant proliferation, invasion and migration capabilities, epithelial-to-mesenchymal transition, and glycolytic metabolism. At the same time, they contribute to the immune system development, response, and programs activation, with particular regard towards regulatory functions. Thus, miRNAs are relevant not only in cancer cells’ biology, but also in the immune response and interplay between cancer, microenvironment, and immune system. Abstract Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their ‘dual’ role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments.
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Affiliation(s)
- Laura Gramantieri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Francesca Fornari
- Department for Life Quality Studies (QuVi), University of Bologna, 47921 Rimini, Italy
- Centre for Applied Biomedical Research-CRBA, University of Bologna, IRCCS St. Orsola Hospital, 40138 Bologna, Italy
| | - Catia Giovannini
- Centre for Applied Biomedical Research-CRBA, University of Bologna, IRCCS St. Orsola Hospital, 40138 Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
| | - Davide Trerè
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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Jiang Y, Zhao L, Wu Y, Deng S, Cao P, Lei X, Yang X. The Role of NcRNAs to Regulate Immune Checkpoints in Cancer. Front Immunol 2022; 13:853480. [PMID: 35464451 PMCID: PMC9019622 DOI: 10.3389/fimmu.2022.853480] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 03/07/2022] [Indexed: 01/07/2023] Open
Abstract
At present, the incidence of cancer is becoming more and more common, but its treatment has always been a problem. Although a small number of cancers can be treated, the recurrence rates are generally high and cannot be completely cured. At present, conventional cancer therapies mainly include chemotherapy and radiotherapy, which are the first-line therapies for most cancer patients, but there are palliatives. Approaches to cancer treatment are not as fast as cancer development. The current cancer treatments have not been effective in stopping the development of cancer, and cancer treatment needs to be imported into new strategies. Non-coding RNAs (ncRNAs) is a hot research topic at present. NcRNAs, which include microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), participate in all aspects of cancer biology. They are involved in the progression of tumors into a new form, including B-cell lymphoma, glioma, or the parenchymal tumors such as gastric cancer and colon cancer, among others. NcRNAs target various immune checkpoints to affect tumor proliferation, differentiation, and development. This might represent a new strategy for cancer treatment.
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Affiliation(s)
- Yicun Jiang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China
| | - Leilei Zhao
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China
| | - Yiwen Wu
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China
| | - Sijun Deng
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China
| | - Pu Cao
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China
| | - Xiaoyong Lei
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
| | - Xiaoyan Yang
- School of Pharmacy, Hengyang Medical College, University of South China, Hengyang, China.,Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, Hengyang, China
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Sukowati CHC, El-Khobar KE, Tiribelli C. Immunotherapy against programmed death-1/programmed death ligand 1 in hepatocellular carcinoma: Importance of molecular variations, cellular heterogeneity, and cancer stem cells. World J Stem Cells 2021; 13:795-824. [PMID: 34367478 PMCID: PMC8316870 DOI: 10.4252/wjsc.v13.i7.795] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/25/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous malignancy related to diverse etiological factors. Different oncogenic mechanisms and genetic variations lead to multiple HCC molecular classifications. Recently, an immune-based strategy using immune checkpoint inhibitors (ICIs) was presented in HCC therapy, especially with ICIs against the programmed death-1 (PD-1) and its ligand PD-L1. However, despite the success of anti-PD-1/PD-L1 in other cancers, a substantial proportion of HCC patients fail to respond. In this review, we gather current information on biomarkers of anti-PD-1/PD-L1 treatment and the contribution of HCC heterogeneity and hepatic cancer stem cells (CSCs). Genetic variations of PD-1 and PD-L1 are associated with chronic liver disease and progression to cancer. PD-L1 expression in tumoral tissues is differentially expressed in CSCs, particularly in those with a close association with the tumor microenvironment. This information will be beneficial for the selection of patients and the management of the ICIs against PD-1/PD-L1.
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Affiliation(s)
| | | | - Claudio Tiribelli
- Centro Studi Fegato, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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Tang F, Huang G, Lin L, Yin H, Shao L, Xu R, Cui X. Anti-HBV Activities of Polysaccharides from Thais clavigera (Küster) by In Vitro and In Vivo Study. Mar Drugs 2021; 19:md19040195. [PMID: 33808126 PMCID: PMC8066037 DOI: 10.3390/md19040195] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a major global health problem. It is therefore imperative to develop drugs for anti-hepatitis B with high-efficiency and low toxicity. Attracted by the observations and evidence that the symptoms of some patients from the Southern Fujian, China, suffering from hepatitis B were alleviated after daily eating an edible marine mollusk, Thais clavigera (Küster 1860) (TCK). Water-soluble polysaccharide from TCK (TCKP1) was isolated and characterized. The anti-HBV activity of TCKP1 and its regulatory pathway were investigated on both HepG2.2.15 cell line and HBV transgenic mice. The data obtained from in vitro studies showed that TCKP1 significantly enhanced the production of IFN-α, and reduced the level of HBV antigens and HBV DNA in the supernatants of HepG2.2.15 cells in a dose-dependent manner with low cytotoxicity. The result of the study on the HBV transgenic mice further revealed that TCKP1 significantly decreased the level of transaminases, HBsAg, HBeAg, and HBV DNA in the serum, as well as HBsAg, HBeAg, HBV DNA, and HBV RNA in the liver of HBV transgenic (HBV-Tg) mice. Furthermore, TCKP1 exhibited equivalent inhibitory effect with the positive control tenofovir alafenamide (TAF) on the markers above except for HBV DNA even in low dosage in a mouse model. However, the TCKP1 high-dose group displayed stronger inhibition of transaminases and liver HBsAg, HBeAg, and HBV RNA when compared with those of TAF. Meanwhile, inflammation of the liver was, by pathological observation, relieved in a dose-dependent manner after being treated with TCKP1. In addition, elevated levels of interleukin-12 (IL-12) and interferon γ (IFN-γ), and reduced level of interleukin-4 (IL-4) in the serum were observed, indicating that the anti-HBV effect of TCKP1 was achieved by potentiating immunocyte function and regulating the balance of Th1/Th2 cytokines.
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Affiliation(s)
- Fei Tang
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
- Fujian Key Laboratory of Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen Key Laboratory of Marine and Gene Drugs, Xiamen 361021, China
| | - Guanghua Huang
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
- Fujian Key Laboratory of Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen Key Laboratory of Marine and Gene Drugs, Xiamen 361021, China
| | - Liping Lin
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
- Fujian Key Laboratory of Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen Key Laboratory of Marine and Gene Drugs, Xiamen 361021, China
| | - Hong Yin
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
| | - Lili Shao
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
| | - Ruian Xu
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
- Fujian Key Laboratory of Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen Key Laboratory of Marine and Gene Drugs, Xiamen 361021, China
- Correspondence: (R.X.); (X.C.)
| | - Xiuling Cui
- Engineering Research Center of Molecular Medicine, Ministry of Education, School of Medicine, Huaqiao University, Xiamen 361021, China; (F.T.); (G.H.); (L.L.); (H.Y.); (L.S.)
- Fujian Key Laboratory of Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Xiamen Key Laboratory of Marine and Gene Drugs, Xiamen 361021, China
- Correspondence: (R.X.); (X.C.)
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Zhen S, Qiang R, Lu J, Tuo X, Yang X, Li X. Enhanced antiviral benefit of combination therapy with anti-HBV and anti-PD1 gRNA/cas9 produces a synergistic antiviral effect in HBV infection. Mol Immunol 2021; 130:7-13. [PMID: 33340931 DOI: 10.1016/j.molimm.2020.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/16/2020] [Accepted: 12/02/2020] [Indexed: 02/08/2023]
Abstract
Targeted therapy for patients with hepatitis B virus (HBV) infection can lead to objective responses, although response times may be short. At the same time, the response rate to programmed cell death-1 (PD-1) treatment was more durable. It is speculated that HBV targeted therapy can synergistically enhance the antitumor activity with PD-1 blockade. To test this hypothesis, we evaluated the effect of crispr-cas9 on HBV and PD-1 in vitro and in vivo. We found that HBV targeting gRNA/cas9 induced a decrease in the expression of HBsAg, while the PD-1 gene could be knocked out by electroporation targeting gRNA / cas9 by polymerase chain reaction. In HBV transgenic mice, the immunophenotype and cytokine expression of human dendritic cells (DCS) were detected by crispr-cas9 system stimulation, flow cytometry and polymerase chain reaction. These results indicate that gRNA/cas9 treatment upregulates the expression of CD80, CD83 and CD86, and significantly increases the mRNA levels of IL-6, IL-12, IL-23 and tumor necrosis factor alpha. The combination of anti HBV and anti PD-1 therapy can inhibit HBV expression and significantly improve the survival of HBV transgenic mice. In addition, the combination therapy increased the production of interferon by T cells, and then enhanced the expression of Th1 related immunostimulatory genes, thereby reducing the transcription of regulatory / inhibitory immune genes. In general, this response can reshape the tumor microenvironment from immunosuppression to immune stimulation. Finally, anti HBV therapy can induce the expression of interferon dependent programmed cell death ligand-1 in HBV transgenic mice in vivo. To sum up, these results demonstrate that the combination of HBV targeted therapy and PD-1 immune checkpoint block has a strong synergistic effect, thus supporting the transformation potential of this combined therapy strategy in clinical treatment of HBV infection.
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Affiliation(s)
- Shuai Zhen
- Medical Heredity Research Center, Northwest Women's and Children's Hospital, Shaanxi, PR China.
| | - Rong Qiang
- Medical Heredity Research Center, Northwest Women's and Children's Hospital, Shaanxi, PR China
| | - Jiaojiao Lu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China
| | - Xiaoqian Tuo
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China
| | - Xiling Yang
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China
| | - Xu Li
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China
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Wang T, Wang X, Zhuo Y, Si C, Yang L, Meng L, Zhu B. Antiviral activity of a polysaccharide from Radix Isatidis (Isatis indigotica Fortune) against hepatitis B virus (HBV) in vitro via activation of JAK/STAT signal pathway. JOURNAL OF ETHNOPHARMACOLOGY 2020; 257:112782. [PMID: 32217096 DOI: 10.1016/j.jep.2020.112782] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 05/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hepatitis B virus (HBV) infection frequently results in both acute and chronic hepatitis and poses serious threats to human health worldwide. Despite the availability of effective HBV vaccine and anti-HBV drugs, apparently inevitable side effects and resistance have limited its efficiency, thus prompt the search for new anti-HBV agents. The traditional Chinese medicine Radix Isatidis has been used for thousands of years, mainly for the treatment of viral and bacterial infection diseases including hepatitis. AIM OF THE STUDY In this study, antiviral activities of a Radix Isatidis (Isatis indigotica Fortune) polysaccharide (RIP) were evaluated in vitro model using the HepG2.2.15 cell line and the underlying mechanism was elucidated with the aim of developing a novel anti-HBV therapeutic agent. MATERIALS AND METHODS Structure features of the purified polysaccharide RIP were investigated by a combination of chemical and instrumental analysis. Drug cytotoxicity was assessed using the MTT assay. The contents of HBsAg, HBeAg, intracellular and extracellular IFN-α level were measured using respective commercially available ELISA kit. The HBV DNA expression was evaluated by real-time quantitative polymerase chain reaction (PCR) and the relevant proteins involved in TFN/JAK/STAT signaling pathways were examined by western blot assay. RESULTS MTT assay showed that RIP had no toxicity on HepG2.2.15 cell line below the concentration 400 μg/ml at Day 3, 6 and 9. Furthermore, RIP at the concentration of 50, 100 and 200 μg/ml significantly reduced extracellular and intracellular level of HBsAg, HBeAg and HBV DNA in HepG2.2.15 cells in a time and dose-dependent manner. Moreover, RIP also enhanced the production of IFN-α in HepG2.2.15 cell via activation of JAK/STAT signal pathway and induction of antiviral proteins, as evidenced by the increased protein expression of p-STAT-1, p-STAT-2, p-JAK1, p-TYK2, OAS1, and Mx in HepG2.2.15 cells. In addition, the over expression of SOCS-1 and SOCS-3 was significantly abolished under same conditions. CONCLUSIONS These results suggested that the HBV inhibitory effect of RIP was possibly due to the activation of IFN-α-dependent JAK/STAT signal pathway and induction of the anti-HBV protein expression.
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Affiliation(s)
- Tianbao Wang
- Infectious Disease Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Xinwei Wang
- Infectious Disease Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Ya Zhuo
- Infectious Disease Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Changyun Si
- Infectious Disease Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Lu Yang
- Gastroenterology Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Lijun Meng
- Gastroenterology Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China
| | - Bin Zhu
- Infectious Disease Department of the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
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Li J, Li A. Role of microRNA 4717, its effects on programmed cell death protein-1 in hepatitis B infection, and interaction between PDCD1 and miR-4717. EUR J INFLAMM 2020. [DOI: 10.1177/2058739220934604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
It is suggested that programmed cell death protein-1 (PD-1) is involved in hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma globally. This study was multi-aimed, that is, to investigate the role of microRNA (miR) 4717 and its target, PD-1 and to determine how the rs10204525 polymorphism in the 3′ untranslated region (3′UTR) of PD-1 affects its interaction with miR-4717. The expression levels of miR-4717 with various single-nucleotide polymorphisms were measured by reverse transcription–quantitative polymerase chain reaction (RT-qPCR). A total of 54 tissue samples from HBV-infected individuals were collected, genotyped, and categorized into three groups; AA (n = 32), AG (n = 18), and GG (n = 4). The expression levels of gene PDCD1 and its corresponding PD-1 protein were significantly declined in the AA group as compared to AG and GG groups. There was a negative linear association between PDCD1 and miR-4717 in the tissue samples. HEPG2 cells transfected with an miR-4717 mimic or PD-1 small interfering (si)RNA exhibited significantly reduced expression levels of PDCD1 and PD-1, whereas cells transfected with an inhibitor of miR-4717 demonstrated greater expression levels of PDCD1 and PD-1 compared with the scramble control. In addition, cell viability and apoptosis were assessed in cells transfected with an miR-4717 mimic, PD-1 siRNA, or an miR-4717 inhibitor. Results revealed that treatment with the miR-4717 mimic or PD-1 siRNA enhanced viability of cells and reduced apoptosis. The results of this study suggest that rs10204525 polymorphism interferes with the interaction between PD-1 and miR-4717 and therefore induces apoptosis in liver cancer cells.
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Affiliation(s)
- Junhua Li
- Department of Laboratory, Kuling District People’s Hospital, Dezhou, China
| | - Andong Li
- Department of Laboratory, Dezhou City Hospital, Dezhou, China
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Huang C, Ge T, Xia C, Zhu W, Xu L, Wang Y, Wu F, Liu F, Zheng M, Chen Z. Association of rs10204525 genotype GG and rs2227982 CC combination in programmed cell death 1 with hepatitis B virus infection risk. Medicine (Baltimore) 2019; 98:e16972. [PMID: 31464942 PMCID: PMC6736136 DOI: 10.1097/md.0000000000016972] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/23/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022] Open
Abstract
Single nuclear polymorphism (SNP) of programmed cell death 1 (PD-1) was reported associated with hepatitis B virus (HBV) infection, but the SNP sites studied were limited. Whether the combination of 2 or more SNP sites could better represent the relationship between PD-1 SNP and HBV infection was not studied.Eight hundred ninety-eight HBV-infected patients (222 asymptomatic carriers [AsC], 276 chronic hepatitis B, 105 acute-on-chronic liver failure, and 295 liver cirrhosis) and 364 health controls of South China were enrolled in this study. Four PD-1 SNPs (rs10204525, rs2227982, rs41386349, and rs36084323) were selected and detected by TaqMan probe. The frequency of allele, genotype, and combination of different SNPs were compared between different groups.For allele frequency analysis, G allele of rs10204525 was protective factor (odds ratio (OR) = 0.823, 95% confidence interval (CI) = 0.679-0.997, P = .046) and T allele of rs2227982 was predisposing factor (OR = 1.231, 95% CI = 1.036-1.463, P = .018) in HBV infection. When analyzed in genotype frequency, the genotype GG of rs10204525 and CC of rs2227982 were protective factor of HBV infection. Combination of rs10204525 GG and rs2227982 CC was potent protective factor of HBV infection (OR = 0.552, 95% CI = 0.356-0.857, P = .007) and was also associated with lower HBV load (OR = 0.201, 95% CI = 0.056-0.728, P = .008) in AsC. The 4 SNP sites were not associated with progression of HBV-related liver disease.Rs10204525 and rs2227982 of PD-1 associate with HBV infection and combination of the 2 SNP sites can better predict host susceptibility in HBV infection.
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Affiliation(s)
- Chunhong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Tiantian Ge
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Caixia Xia
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital
| | - Wei Zhu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lichen Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Yunyun Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Fengtian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Feifei Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital
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Chihab H, Jadid FZ, Foka P, Zaidane I, El Fihry R, Georgopoulou U, Marchio A, Elhabazi A, Chair M, Pineau P, Ezzikouri S, Benjelloun S. Programmed cell death-1 3'-untranslated region polymorphism is associated with spontaneous clearance of hepatitis B virus infection. J Med Virol 2018; 90:1730-1738. [PMID: 30016557 DOI: 10.1002/jmv.25265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 06/18/2018] [Indexed: 12/29/2022]
Abstract
Hepatitis B virus (HBV)-specific CD8+ T cells play an important role in the clearance of HBV infection. Programmed cell death-1 (PD-1), an immunosuppressive molecule that regulates T-cell activation and peripheral immune tolerance, is increasingly shown to influence the outcome of HBV infection. rs10204525, a single-nucleotide polymorphism in the 3'-untranslated region (3'-UTR) of PD-1, has been associated with susceptibility and disease progression of chronic HBV infection in far-eastern patients. The aim of our study was to assess the impact of rs10204525 variation on HBV infection in Moroccan patients. A total of 236 patients with chronic HBV infection and 134 individuals with spontaneous HBV resolution were genotyped using a Taqman assay. In addition, PD-1 mRNA expression in peripheral blood nuclear cells was determined by quantitative reverse-transcription polymerase chain reaction. We found that the AA genotype is protective (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.97; P = 0.038) against HBV infection. Interestingly, PD-1 messenger RNA (mRNA) expression analysis has revealed that chronic HBV carriers with GG and GA displayed higher levels of PD-1 mRNA compared with corresponding genotypes in resolved subjects (P = 0.031 and 0.014, respectively). Our data suggest that Mediterranean HBV-infected patients carrying PD-1 GG and GA genotypes at rs10204525 have high PD-1 mRNA expression and may be more prone to installation of chronicity.
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Affiliation(s)
- Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.,Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Fatima-Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Pelagia Foka
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia El Fihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | | | - Agnes Marchio
- Unité Organisation Nucléaire et Oncogenèse, INSERM U2993, Institut Pasteur, Paris, France
| | - Abdellah Elhabazi
- Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Mohammed Chair
- Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Pascal Pineau
- Unité Organisation Nucléaire et Oncogenèse, INSERM U2993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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Hepatoprotective and inhibiting HBV effects of polysaccharides from roots of Sophora flavescens. Int J Biol Macromol 2017; 108:744-752. [PMID: 29111266 DOI: 10.1016/j.ijbiomac.2017.10.171] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/25/2017] [Accepted: 10/26/2017] [Indexed: 11/21/2022]
Abstract
Roots of Sophora flavescens is an important herbal medicine for treatment of HBV and hepatic carcinoma in China. Alkaloids in the root were well known for exhibiting good hepato-protective and anti-HBV effects. However, polysaccharides as main components in the root remained unknown. In the studies, we investigated the chemical features and hepatoprotective effects of Sophora flavescens polysaccharides (SFP-100 and its active fractions) with ConA-induced hepatitis mice, human liver LO2 cells and HepG2.2.15 cells. The results showed that SFP-100 was composed of arabinose, glucose, galactose and galacturonic acid, SFP-100-A mainly contained glucose. SFP-100-B and SFP-100-C were acidic polysaccharides. SFP-100 significantly decreased hepatocytes apoptosis, inhibited the infiltration of neutrophils and macrophages into liver, and improved the production of IFN-γ and IL-6 of splenocytes in ConA-induced hepatitis mice. SFP-100 and its two sugar fractions increased LO2 cell proliferation and reduced cell apoptosis induced by ConA. SFP-100, SFP-100-A and SFP-100-C remarkedly inhibited the secretion of HBsAg and HBeAg by HepG2.2.15 cells.These results suggested Sophora flavescens polysaccharides exerts significant hepatoprotective and anti-HBV roles, and further is used for treatment of immune-mediated liver disease in the future.
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11
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Association of TNF-Alpha gene polymorphisms and susceptibility to hepatitis B virus infection in Egyptians. Hum Immunol 2017; 78:739-746. [PMID: 29054398 DOI: 10.1016/j.humimm.2017.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 09/25/2017] [Accepted: 10/16/2017] [Indexed: 12/15/2022]
Abstract
Tumor necrosis factor alpha (TNF-α) is one of the important cytokine in generating an immune response against hepatitis B virus (HBV). Genetic polymorphisms might influence gene transcription, leading to disturbance in cytokine production. We hypothesized that single nucleotide polymorphism (SNPs) in TNF-α gene could affect the pathogenesis of HBV. To test this hypothesis, we investigated the role of TNF-α polymorphism [-863C/A (rs1800630), -308G/A (rs1800629), -376G/A (rs1800750), -857C/T (rs1799724) and +489G/A (rs1800610)] in the susceptibility to chronic hepatitis B (CHB) infection. Polymorphisms of the TNF-α (-863C/A (rs1800630), -308G/A) were analyzed by Polymerase chain reaction sequence specific primer (PCR-SSP) while TNF-α (-376G/A, -857C/T and +489G/A) by PCR-restriction fragment length polymorphism (PCR-RFLP) in 104 patients with CHB and 104 healthy controls. The plasma level of TNF-α was measured using Enzyme-linked immunosorbent assay (ELISA). The study showed a significant increase in the frequency of -863CC, -376GA, -857CC, -857TT and +489GA genotypes and -863C, -376A, -857C, and +489A alleles in CHB patients compared to controls. In addition, CAGCG haplotype had a highest frequency in CHB patients. A strong Linkage Disequilibrium (LD) between TNF-α -863C/A (rs1800630) and -376G/A (D' = 0.7888, r2 = 0.0200); -308G/A and -857C/T (D' = 0.9213, r2 = 0.1770); -308G/A and +489G/A (D' = 0.9088, r2 = 0.1576) was demonstrated. CHB patients had significantly lower levels of TNF-α compared to controls. In conclusion, our preliminary results suggest that -863C/A (rs1800630), -308G/A, -376G/A, and +489G/A of the TNF-α gene may play a role in HBV susceptibility in Egyptians. The significant reduction in TNF-α in CHB patient was independent of any particular genotype/haplotype in TNF-α.
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Kansy BA, Concha-Benavente F, Srivastava RM, Jie HB, Shayan G, Lei Y, Moskovitz J, Moy J, Li J, Brandau S, Lang S, Schmitt NC, Freeman GJ, Gooding WE, Clump DA, Ferris RL. PD-1 Status in CD8 + T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 2017; 77:6353-6364. [PMID: 28904066 DOI: 10.1158/0008-5472.can-16-3167] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Revised: 05/10/2017] [Accepted: 08/24/2017] [Indexed: 12/21/2022]
Abstract
Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T-cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T-cell function and prognostic impact, because PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (P = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TILs were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease-free survival and higher hazard ratio for recurrence (P < 0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1-based immunotherapy. Cancer Res; 77(22); 6353-64. ©2017 AACR.
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Affiliation(s)
- Benjamin A Kansy
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Otorhinolaryngology, University Hospital Essen, Germany
| | | | | | - Hyun-Bae Jie
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Yu Lei
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jessica Moskovitz
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jennifer Moy
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Jing Li
- School of Medicine, Tsinghua University, Beijing, China
| | - Sven Brandau
- Department of Otorhinolaryngology, University Hospital Essen, Germany
| | - Stephan Lang
- Department of Otorhinolaryngology, University Hospital Essen, Germany
| | - Nicole C Schmitt
- Department of Otolaryngology, Johns Hopkins University, Baltimore, Maryland, and National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland
| | - Gordon J Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - William E Gooding
- Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
| | - David A Clump
- Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. .,Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
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13
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Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem, with approximately one third of populations have been infected, among which 3-5% of adults and more than 90% of children developed to chronic HBV infection. Host immune factors play essential roles in the outcome of HBV infection. Thus, ineffective immune response against HBV may result in persistent virus replications and liver necroinflammations, then lead to chronic HBV infection, liver cirrhosis, and even hepatocellular carcinoma. Cytokine balance was shown to be an important immune characteristic in the development and progression of hepatitis B, as well as in an effective antiviral immunity. Large numbers of cytokines are not only involved in the initiation and regulation of immune responses but also contributing directly or indirectly to the inhibition of virus replication. Besides, cytokines initiate downstream signaling pathway activities by binding to specific receptors expressed on the target cells and play important roles in the responses against viral infections and, therefore, might affect susceptibility to HBV and/or the natural course of the infection. Since cytokines are the primary causes of inflammation and mediates liver injury after HBV infection, we have discussed recent advances on the roles of various cytokines [including T helper type 1 cells (Th1), Th2, Th17, regulatory T cells (Treg)-related cytokines] in different phases of HBV infection and cytokine-related mechanisms for impaired viral control and liver damage during HBV infection. We then focus on experimental therapeutic applications of cytokines to gain a better understanding of this newly emerging aspect of disease pathogenesis.
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Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2016; 44:94-105. [DOI: 10.1016/j.meegid.2016.06.043] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/15/2022]
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Olaniyan SA, Amodu OK, Bakare AA, Troye-Blomberg M, Omotade OO, Rockett KA. Tumour necrosis factor alpha promoter polymorphism, TNF-238 is associated with severe clinical outcome of falciparum malaria in Ibadan southwest Nigeria. Acta Trop 2016; 161:62-7. [PMID: 27178813 DOI: 10.1016/j.actatropica.2016.05.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 05/03/2016] [Accepted: 05/09/2016] [Indexed: 01/24/2023]
Abstract
Tumour necrosis factor (TNF) - α has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p=0.007; TNF-238: p=0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI=1.43-6.02, OR=2.94, p=0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI=1.99-18.17, OR=6.02, p<0.001 and 95% CI=1.78-8.23, OR=3.84, p<0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection.
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Zhou RM, Li Y, Wang N, Huang X, Cao SR, Shan BE. Association of programmed death-1 polymorphisms with the risk and prognosis of esophageal squamous cell carcinoma. Cancer Genet 2016; 209:365-375. [PMID: 27751353 DOI: 10.1016/j.cancergen.2016.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 05/19/2016] [Accepted: 06/11/2016] [Indexed: 12/23/2022]
Abstract
Programmed death-1 (PD-1) is an immunoinhibitory receptor belonging to the CD28 family. This study was designed to investigate the association of PD-1 rs36084323:A>G, rs2227981:C>T, rs2227982:C>T and rs10204525:A>G single nucleotide polymorphisms (SNPs) with the risk and prognosis of esophageal squamous cell carcinoma (ESCC) in a high-incidence population from Northern China. These four SNPs were genotyped by polymerase chain reaction ligase detection reaction (PCR-LDR) method in 584 ESCC patients and 585 healthy controls. The rs2227981:C>T SNP C/T genotype increased the risk of ESCC for the smokers (OR = 1.483, 95% CI = 1.018-2.160) and rs2227982:C>T SNP C/T genotype enhanced susceptibility to ESCC for the females (OR = 1.708, 95% CI = 1.056-2.762). For rs10204525:A>G SNP, A/A genotype was related to increased risk of ESCC (OR = 1.735, 95% CI = 1.086-2.771) overall. Among the 584 ESCC patients, the survival information of 204 ESCC patients was collected. The rs36084323:A>G SNP A/G genotype was associated with lower risk of death in ESCC patients with upper gastrointestinal cancer (UGIC) family history (HR = 0.339, 95%CI = 0.115-0.996). The rs2227982:C>T SNP C/T genotype was associated with lower risk of death in smoker ESCC patients and ESCC patients with UGIC family history (HR = 0.409 and 0.292, 95%CI = 0.194-0.863 and 0.101-0.847). PD-1 rs2227981:C>T, rs2227982:C>T and rs10204525:A>G SNPs might be used as predictive markers of the susceptibility to ESCC for the Han nationality in a high-incidence population from Northern China. PD-1 rs36084323:A>G and rs2227982:C>T SNPs were associated with the prognosis of the Han ESCC patients in this high-incidence region.
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Affiliation(s)
- Rong-Miao Zhou
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Yan Li
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Na Wang
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Xi Huang
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Shi-Ru Cao
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Bao-En Shan
- Hebei Provincial Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
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Sun YY, Fan YC, Wang N, Xia HHX, Xiao XY, Wang K. Increased A20 mRNA Level in Peripheral Blood Mononuclear Cells is Associated With Immune Phases of Patients With Chronic Hepatitis B. Medicine (Baltimore) 2015; 94:e2428. [PMID: 26717404 PMCID: PMC5291645 DOI: 10.1097/md.0000000000002428] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 12/05/2015] [Accepted: 12/10/2015] [Indexed: 02/07/2023] Open
Abstract
The zinc finger protein A20 is a newly identified negative regulator of immune response and mediates signal pathway of NF-κB in liver inflammation. However, the role of A20 in the natural history of patients with chronic hepatitis B (CHB) has not been demonstrated. In this present study, we aimed to investigate the dynamic expression of A20 and determine the potential association of A20 in the progression of chronic hepatitis B virus infection.This retrospective study contained 136 patients with chronic hepatitis B and 30 healthy controls (HCs). The mRNA level of A20, TNF-α, NF-κB p65 and toll-like receptor (TLR) 4 in peripheral blood mononuclear cells (PBMCs) was determined using a relative quantitative real-time polymerase chain reaction. The hepatic A20 protein expression was determined by immunohistochemistry. Clinical and laboratory parameters were obtained.In the present study, the relative expression of A20 mRNA was significantly increased in CHB patients compared with HCs and was positively associated with alanine aminotransferase, aspartate aminotransferase, and total bilirubin. In CHB patients, the levels of A20 mRNA in the immune clearance (IC) phase and hepatitis B negative (ENH) phase were significantly higher than that in immune tolerance (IT) phase and low-replicative (LR) phase (P < 0.001). Furthermore, the A20 mRNA level was significantly correlated with TNF-α/ NF-κB p65/TLR4 mRNA levels in CHB patients. Of note, we reported that cutoff values of 4.19 and 3.97 for the level of A20 mRNA have significant power in discriminating IC from IT, and ENH from LR in CHB patients respectively.In conclusion, our results suggested that increased levels of A20 mRNA and protein contribute to disease progression of chronic hepatitis B virus infection.
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Affiliation(s)
- Yan-Yan Sun
- From the Department of Hepatology, Qilu Hospital of Shandong University (Y-YS, Y-CF, NW, KW); Institute of Hepatology, Shandong University, Jinan (Y-CF, KW); Department of Gastroenterology, The first Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou (HH-XX); and Department of Nephrology, Qilu Hospital of Shandong University, Jinan, China (X-YX)
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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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Zhang G, Li N, Li Z, Zhu Q, Li F, Yang C, Han Q, Lv Y, Zhou Z, Liu Z. microRNA-4717 differentially interacts with its polymorphic target in the PD1 3' untranslated region: A mechanism for regulating PD-1 expression and function in HBV-associated liver diseases. Oncotarget 2015; 6:18933-18944. [PMID: 25895129 PMCID: PMC4662465 DOI: 10.18632/oncotarget.3662] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 02/26/2015] [Indexed: 12/14/2022] Open
Abstract
Programmed cell death-1 (PD-1) is involved in hepatitis B virus (HBV) infection, the leading cause of hepatocellular carcinoma (HCC) worldwide. Single-nucleotide polymorphism, rs10204525, located in the PD1 3' untranslated regions (UTR), is associated with chronic HBV infection. MicroRNAs (miRNAs) regulate gene expression via specific binding to the target 3'UTR of mRNA. In this study, three miRNAs were predicted to putatively interact with PD1 rs10204525 polymorphic site of allele G. One of them, miRNA-4717, was demonstrated to allele-specifically affect luciferase activity in a dose-dependent manner in cells transfected with vectors containing different rs10204525 alleles. In lymphocytes from chronic HBV patients withrs10204525 genotype GG, miR-4717 mimics significantly decreased PD-1 expression and increased (TNF)-α and interferon (IFN)-γ production. miR-4717 inhibitor significantly increased PD-1 expression and decreased TNF-α and IFN-γ production although not significantly. In lymphocytes from chronic HBV patients with rs10204525 genotype AA, no similar effects were observed. miR-4717 levels in peripheral lymphocytes from patients with HBV-related chronic hepatitis, cirrhosis and HCC were significantly decreased. In conclusion, miR-4717 may allele-specifically regulate PD-1 expression through interaction with the 3' UTR of PD1 mRNA, leading to the alteration of immune regulation and affecting the susceptibility and disease course of chronic HBV infection.
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Affiliation(s)
- Guoyu Zhang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Zhu Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Qianqian Zhu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Cuiling Yang
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi' an, Shaanxi, China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi' an, Shaanxi, China
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20
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Li N, Zhu Q, Li Z, Han Q, Zhang G, Chen J, Lv Y, Xing F, Chen Y, Zeng X, Liu Z. IL17A gene polymorphisms, serum IL-17A and IgE levels, and hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection. Mol Carcinog 2014; 53:447-457. [PMID: 23280722 DOI: 10.1002/mc.21992] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 10/08/2012] [Accepted: 11/27/2012] [Indexed: 12/15/2022]
Abstract
Interleukin (IL)-17A plays important roles in hepatitis B virus (HBV)-induced liver diseases. This study aims to investigate IL17A single nucleotide polymorphisms (SNPs) and the predispositions to chronic HBV infection and hepatocellular carcinoma (HCC) risk and the correlations to IL-17A and IgE levels. Three hundred ninety-five chronic HBV patients, 75 HBV infection resolvers, and 174 healthy controls were included. IL17A SNPs rs8193036 (C/T) and rs2275913 (A/G) and serum IL-17A and IgE levels were determined. HBV infection resolvers had higher rs8193036 allele T and allele T-containing genotypes than HBV patients or controls. Compared with chronic hepatitis, HCC patients had more frequent rs2275913 genotype GG (odds ratios [OR] 3.317, 95% confidence interval [CI] 1.663-6.617, P = 0.001) and allele G (OR 1.844, 95% CI 1.311-2.595, P < 0.001), and more frequent haplotypes CG (OR 1.868, 95% CI 1.256-2.778, P = 0.002) and TG (OR 1.788, 95% CI 1.031-3.101, P = 0.037) of rs8193036 and rs2275913. Comparison of HCC patients with cirrhosis yielded similar findings. Apart from male gender and older ages, IL-17A level (OR 1.020, 95% CI 1.003-1.036, P = 0.019) and rs2275913 genotypes AG and GG (OR 1.704, 95% CI 1.214-2.390, P = 0.006) were factors significantly associated with HCC risk in multivariate analysis in comparison with HBV patients without HCC. These factors remained significant in multivariate analysis in relation to cirrhosis. IL17A rs2275913 genotype GG was associated with significantly increased IL-17A and IgE levels. IL17A polymorphisms may influence HCC risk in chronic HBV infection via regulating IL-17A production.
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Affiliation(s)
- Na Li
- Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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Tunçbilek S. Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection. World J Gastroenterol 2014; 20:6226-6235. [PMID: 24876743 PMCID: PMC4033460 DOI: 10.3748/wjg.v20.i20.6226] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 12/09/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still a public health problem worldwide, being endemic in some parts of the world. It can lead to serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular cancer. The differences in host immune response can be one of the reasons for the various clinical presentations of HBV infection. Polymorphisms of genes encoding the proinflammatory and antiinflammatory cytokines, which are responsible for regulation of the immune response, can affect the clinical presentation of the infection. Particularly, the polymorphisms of the genes encoding cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, IL-28B, interferon-γ, tumor necrosis factor-α, tumor growth factor-β1, and regulatory molecules like vitamin D receptor and chemokine receptor 5 can be responsible for different clinical presentations of HBV infections. The genomic information about cytokines and other mediators can be important for determining high-risk people for developing chronic hepatitis or hepatocellular cancer and may be used to plan treatment and preventive approaches for these people. In this review, the current knowledge in the literature on the association between cytokine/regulatory molecule gene polymorphisms and clinical course of chronic HBV infection is summarized, and the clinical implementations and future prospects regarding this knowledge are discussed.
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Iravani-Saadi M, Karimi MH, Yaghobi R, Geramizadeh B, Ramzi M, Niknam A, Pourfathollah A. Polymorphism of costimulatory molecules (CTLA4, ICOS, PD.1 and CD28) and allogeneic hematopoietic stem cell transplantation in Iranian patients. Immunol Invest 2014; 43:391-404. [DOI: 10.3109/08820139.2013.879594] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zhang TC, Zhao YQ, Hu GL, Liu XQ, Huang XK. The relationship between tumour necrosis factor-α gene polymorphism and susceptibility and clearance of the persistent hepatitis B virus infection in a Chinese population: a meta-analysis. Clin Microbiol Infect 2013; 20:227-34. [PMID: 23701172 DOI: 10.1111/1469-0691.12257] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 04/16/2013] [Accepted: 04/25/2013] [Indexed: 01/30/2023]
Abstract
To date, many studies conducted in the Chinese population have determined the correlation between the tumour necrosis factor-α (TNF-α)-238G/A, -308G/A, -857C/T and -863C/A polymorphisms and persistent hepatitis B virus (HBV) infection. However, their results remain inconclusive. With the aim of confirming this correlation, we performed a meta-analysis of 19 studies. The dichotomous data are presented as the OR with a 95% CI. The results of our study indicate that carriers of the TNF-α-857T allele among the pooled Chinese population were more likely to show spontaneous clearance of HBV (T vs C: OR = 0.824, 95% CI = 0.713-0.953, p 0.009; TT vs CC: OR = 0.701, 95% CI = 0.507-0.970, p 0.032; TC vs CC: OR = 0.804, 95% CI = 0.683-0.947, p 0.009; TT + TC vs CC: OR = 0.835, 95% CI = 0.716-0.974, p 0.021). The TNF-α-308A allele was associated with significantly reduced persistent HBV infection risk in the Chinese (A vs G: OR = 0.585, 95% CI = 0.456-0.751, p 0.002; AG vs GG: OR = 0.519, 95% CI = 0.341-0.789, p <0.000; AA + AG vs GG: OR = 0.512, 95% CI = 0.339-0.772, p 0.001). Persistent HBV infection susceptibility is associated with the TNF-α-308G/A gene polymorphism in the Chinese population, whereas HBV clearance is associated with the TNF-α-857C/T gene polymorphism.
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Affiliation(s)
- T-C Zhang
- Jiangxi Province Centre For Disease Control And Prevention, Nanchang, China
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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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Dirks J, Egli A, Sester U, Sester M, Hirsch HH. Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells. Transpl Infect Dis 2012; 15:79-89. [PMID: 23176118 DOI: 10.1111/tid.12025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 07/16/2012] [Accepted: 07/24/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Programmed death receptor-1 (PD-1) compromises cytomegalovirus (CMV)-specific T-cell responses and has been linked to CMV viremia after transplantation. An impaired functional and proliferative capacity of PD-1-positive CMV-specific T cells may be reversed by the antibody-mediated blockade of PD-1 signaling. However, knowledge is limited on changes in "cytokinome" expression profiles associated with reversal of functional exhaustion. METHODS The "cytokinome" was analyzed by 27-plex Luminex technology comparing renal transplant recipients with low (n = 5) and high (n = 5) PD-1 expression on CMV-specific T cells. The effect of blocking PD-1 by PD-ligand (PD-L) antibodies on restoration of cytokine expression was examined. RESULTS CMV-specific cytokine release and proliferation was lower in patients with high PD-1 expression on CMV-specific T cells. Antibody-mediated blockade of PD-L in CMV-stimulated samples restored expression levels of interleukin (IL)-1β, IL-2, IL-6, IL-9, IL-10, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1α, and tumor necrosis factor-α. By contrast, no profound effect was observed for controls or patients with low PD-1 expression, or in staphylococcal enterotoxin B-stimulated cells. CONCLUSION Taken together, this pilot study provides evidence that a high PD-1 expression on CMV-specific T cells actively impairs proliferation and "cytokinome" responses in an antigen-specific manner. Importantly, blockade of PD-L restores CMV-specific T-cell proliferation and expression of a panel of different proinflammatory and/or type 1 cytokines, suggesting a common but as yet unknown regulatory principle. We conclude that PD-1 exhaustion is reversible and potentially amenable to therapeutic ex vivo and possibly in vivo manipulation. However, detailed knowledge of the differential effects on the "cytokinome" will be necessary to increase the safety and the efficacy of such manipulations.
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Affiliation(s)
- J Dirks
- Department of Transplant and Infection Immunology, Institute of Virology, Saarland University, Homburg, Germany
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