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1.
Nat Commun ; 12(1): 1658, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712578

RESUMO

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.


Assuntos
Relógios Biológicos/fisiologia , Ritmo Circadiano/fisiologia , Vírus da Hepatite B/fisiologia , Replicação Viral/fisiologia , Animais , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/genética , Ritmo Circadiano/genética , DNA Circular , DNA Viral/metabolismo , Regulação da Expressão Gênica , Genoma Viral , Células Hep G2 , Hepatite B/virologia , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatócitos/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Fígado/metabolismo , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Regiões Promotoras Genéticas , Simportadores/metabolismo , Transcriptoma , Vírion/metabolismo , Internalização do Vírus
2.
Viruses ; 13(2)2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557409

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions.


Assuntos
Carcinoma Hepatocelular/genética , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Integração Viral , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , DNA Viral/genética , Frequência do Gene , Genoma Humano/genética , Genoma Viral/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Software
3.
Viruses ; 13(2)2021 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-33573130

RESUMO

Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.


Assuntos
DNA Viral/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/virologia , Hepatócitos/virologia , Animais , Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Hepatócitos/imunologia , Humanos , Fígado/imunologia , Fígado/virologia , Integração Viral
4.
BMC Infect Dis ; 21(1): 111, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485302

RESUMO

BACKGROUND: T cells play an important role in the prognosis of hepatitis B virus (HBV) infection, and are involved in the seroconversion of a patient from HBsAb negative to positive. To compare the T-cell receptor ß-chain variable region (TcRBV) complementarity-determining region 3 (CDR3) in subjects with or without hepatitis B surface antigen (HBsAg) convert to hepatitis B surface antibody (HBsAb), the TcRBV was determined using high throughput sequencing (HTS). METHODS: The clonotype and diversity of CDR3 in peripheral blood mononuclear cells of subjects with resolved acute hepatitis B (AHB, HBsAb+, HBsAg-) (n = 5), chronic hepatitis B (CHB, HBsAb-, HBsAg+) (n = 5), and healthy controls (HC, HBsAb-, HBsAg-) (n = 3) were determined and analyzed using HTS (MiSeq). RESULTS: The overlapping rate of CDR3 clones of any two samples in AHB group was 2.00% (1.74% ~ 2.30%), CHB group was 1.77% (1.43% ~ 2.61%), and HC group was 1.82% (1.62% ~ 2.12%), and there was no significant difference among the three groups by Kruskal-Wallis H test. However, among the top 10 cumulative frequencies of clonotypes, only the frequency of clonotype (TcRBV20-1/BD1/BJ1-2) in AHB group was lower than that of HC group (P < 0.001). Moreover, exclude the 10 top clonotypes, there are 57 markedly different frequency of clones between AHB and CHB groups (18 clones up, 39 clones down), 179 (180-1) different clones between AHB and HC groups, and 134 different clones between CHB and HC groups. With regard to BV and BJ genotypes, there was no significant different frequency among the groups. Furthermore, there was no significant difference in the diversity of TcRBV CDR3 among the three groups (P > 0.05). CONCLUSIONS: Thus, there are 57 TcRBV clonotypes that may be related to HBsAg seroconversion of AHB subjects, but the diversity of TcRBV CDR3 is not significantly related to the HBsAb positive status.


Assuntos
Regiões Determinantes de Complementaridade/genética , Hepatite B/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Adulto , Feminino , Hepatite B/sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/genética , Hepatite B Crônica/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Soroconversão , Adulto Jovem
5.
BMC Med Genet ; 21(1): 241, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334325

RESUMO

BACKGROUND: Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B (CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population. METHODS: A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls. RESULTS: A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P = 5.91 × 10- 10). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS. CONCLUSIONS: rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.


Assuntos
Fator B do Complemento/genética , Éxons , Predisposição Genética para Doença , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Casos e Controles , Fator B do Complemento/deficiência , Fator B do Complemento/imunologia , Expressão Gênica , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , República da Coreia , Risco
8.
Aliment Pharmacol Ther ; 52(4): 682-691, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32573827

RESUMO

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. AIMS: To explore genetic variants associated with chronic HBV infection. METHODS: The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as having chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA) imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of different HLA allele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed for HLA alleles using NetMHCIIpan method. RESULTS: Located within a cluster of 450 single nucleotide polymorphisms in HLA class II, rs7770370 (P = 2.73 × 10-35 ) was significantly associated with HBV chronicity (Pcorrected  < 8.6 × 10-8 ). Imputation analyses showed that HLA-DPA1*02:02 and HLA-DPB1*05:01 were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05). HLA-DRB1*13:02, HLA-DQA1* 01:02 and HLA-DQB1*06:09 associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). These HLA alleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein. CONCLUSIONS: HLA class II variants are relevant for chronicity after HBV acquisition.


Assuntos
Genes MHC da Classe II/genética , Estudo de Associação Genômica Ampla , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Bancos de Espécimes Biológicos/estatística & dados numéricos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Hepatite B Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Taiwan/epidemiologia
9.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(6): 924-928, 2020 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-32564561

RESUMO

Objective: To analyze the association of two single-nucleotide polymorphisms (SNP) [Calcitonin gene related peptide (CGRP) rs155209 and receptor activity modifying protein 1 (RAMP1) rs3754701] and the prognosis of chronic hepatitis B patients who were under interferon therapy. Methods: A total of 317 patients and their anticoagulant blood samples were collected in this study. The SNPs in the CGRP and region RAMP1 were genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Logistic regression method was used to assess the results from different phenotypic outcomes between cases and controls, after adjusted for sex and age in co-dominant, dominant and recessive genetic models. Results: Data from this study clearly demonstrated the relevance of CGRP rs155209 and RAMP1 rs3754701 with DNA response and ALT response. RAMP1 rs3754701T was strongly associated with both DNA response and ALT response (OR=2.277, 95%CI: 1.386-3.741, P=0.001; OR=1.694, 95%CI: 1.073-2.675, P=0.024). However, CGRP rs155209C was less prone to DNA response and ALT response (OR=0.150, 95%CI: 0.083-0.271, P<0.001; OR=0.583, 95%CI: 0.367-0.925, P=0.022). Conclusions: Results from our study suggested that both RAMP1 rs3754701 and CGRP rs155209 were associated with the prognosis of patients under interferon therapy in Han population, from the northern parts of China while RAMP1 rs3754701T was a protective factor for both ALT response and DNA response, but CGRP rs155209C carriers were less prone to DNA and ALT responses.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Interferons/uso terapêutico , Proteína 1 Modificadora da Atividade de Receptores/genética , China , Humanos , Polimorfismo Genético , Prognóstico
10.
Cell Prolif ; 53(7): e12833, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32525231

RESUMO

OBJECTIVES: The current study aimed to investigate the mechanism by which exosomes secreted by CHB patients with PNALT and liver inflammation grade (≥A2) affected the development of liver cancer. MATERIALS AND METHODS: Gene expression was assessed by RT-PCR, Western blotting and immunohistochemistry. CCK-8, colony formation, transwell, scratch-wound and flow cytometry assays were used to detect cell viability, proliferation, apoptosis and metastasis. The interaction of TCF21 and HHIP was assessed by co-immunoprecipitation assay. Luciferase reporter was used to detect the combination of TCF21/HHIP and miR-25-3p. Xenograft studies in nude mice manifested tumour growth ability of miR-25-3p. Bioinformatics analyses were conducted using TargetScan, EVmiRNA, TCGA, GEO, DAVID, COEXPEDIA, UALCAN, UCSC and the Human Protein Atlas databases. RESULTS: CHB-PNALT-Exo (≥A2) promoted the proliferation and metastasis of HepG2.2.15 cells. miR-25-3p was upregulated in CHB-PNALT-Exo (≥A2). miR-25-3p overexpression promoted cell proliferation and metastasis and was related to poor survival in patients with CHB-PNALT (≥A2). The cell proliferation- and metastasis-promoting functions of CHB-PNALT-Exo (≥A2) were abolished by miR-25-3p inhibitors. TCF21 directly interacted with HHIP. Inhibition of TCF21 or HHIP promoted cell proliferation and metastasis. Knockdown of TCF21 or HHIP counteracted the effects of CHB-PNALT-Exo (≥A2) containing miR-25-3p inhibitor on cell proliferation, metastasis and the expression of Ki67, E-cadherin and caspase-3/-9. CONCLUSIONS: Transfer of miR-25-3p by CHB-PNALT-Exo promoted the development of liver cancer by inhibiting the co-expression of TCF21 and HHIP.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte/genética , Exossomos/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Fígado/patologia , Glicoproteínas de Membrana/genética , MicroRNAs/genética , Adulto , Animais , Apoptose/genética , Proliferação de Células/genética , Sobrevivência Celular , Progressão da Doença , Regulação para Baixo/genética , Exossomos/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Hepatite B Crônica/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Regulação para Cima/genética , Adulto Jovem
11.
Mol Immunol ; 123: 32-39, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413787

RESUMO

At present, most studies on the relationship between hepatitis B virus (HBV) and IL-33/ST2 axis focus on clinical detection, but the underlying molecular mechanisms of HBx and IL-33/ST2 axis regulation and Th cell function regulation have not been explored. In this study, serum samples of patients with chronic hepatitis B (CHB) and HBV-related liver cancer (HBV-HCC), and healthy controls, as well as the supernatant solutions of HL7702-WT, HL7702-NC, and HL7702-HBx cells were collected to detect the content of soluble ST2 (sST2). The contents of Th1 cytokines (TNF-α and TNF-γ) and Th2 cytokines (IL-6 and IL-10) in the supernatant of different co-culture groups were detected. The effects of GATA2 on ST2 promoter transcription were investigated by upregulation or interference with GATA2 expression, dual-luciferase reporting, and ChIP experiments. The combined detection of sST2 and FIB-4 was beneficial to the non-invasive diagnosis of liver fibrosis. HBx promotes sST2 expression in liver cells, upregulates Th2 cell function, and inhibits Th1 cell function through IL-33/ST2 axis. HBx interacts with GATA2 to influence the activity of ST2 promoter. Serum sST2 detection is an invaluable indicator for the assessment of the progress of HBV infectious diseases, and the IL-33/ST2 axis plays an important role in changing the cellular immune function caused by HBV infection.


Assuntos
Fator de Transcrição GATA2/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Transativadores/farmacologia , Adulto , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Células Cultivadas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/genética , Hepatite B Crônica/patologia , Humanos , Interleucina-33/fisiologia , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Proteínas Virais Reguladoras e Acessórias
12.
Int J Infect Dis ; 96: 541-547, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32422377

RESUMO

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/genética , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Receptores KIR/genética , Adulto , Idoso , Alelos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Receptores KIR/imunologia , Receptores KIR2DL2/imunologia , Receptores KIR2DL3/imunologia , Vietnã , Adulto Jovem
13.
Int J Infect Dis ; 96: 260-265, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32387446

RESUMO

OBJECTIVES: The outcomes of hepatitis B virus (HBV) infection vary substantially among affected individuals, providing evidence of the role of host genetic background in the susceptibility to HBV persistence and the dynamics of liver injury progression to cirrhosis and hepatocellular carcinoma (HCC). METHODS: Six single-nucleotide polymorphisms within the interleukin 10 gene (IL10) were genotyped by MALDI-TOF mass spectrometry in 857 patients with chronic HBV infection (CHB), 48 patients with resolved HBV infection, and 100 healthy volunteers. Associations of the selected polymorphisms with susceptibility to chronic HBV infection, liver injury progression, and outcomes were investigated. RESULTS: IL10 -819T (rs1800871), -592A (rs1800872), and +504T (rs3024490) alleles were associated with treatment-induced hepatitis B surface antigen (HBsAg) seroclearance. Additionally, IL10 ATAC haplotype increased the chance of HBsAg loss and was significantly more frequent in patients with less liver injury. Moreover rs1800871TT, rs1518110TT, rs1800872AA, and rs3024490TT genotypes were identified as predictors of a lower FIB-4 score (<0.5). CONCLUSIONS: This study indicates that polymorphisms within the promoter region and intronic sequences of IL10 are associated with chronicity of hepatitis B and with HBV-induced liver damage.


Assuntos
Hepatite B Crônica/genética , Interleucina-10/genética , Adulto , Alelos , Progressão da Doença , Feminino , Genótipo , Antígenos de Superfície da Hepatite B/metabolismo , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
PLoS One ; 15(4): e0232211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330203

RESUMO

BACKGROUND: Circulating microRNAs (miRNAs) have been shown to dysregulate in many cancer types including hepatocellular carcinoma (HCC). The purpose of this study was to examine the potential diagnostic or prognostic roles of circulating miRNAs in patients with hepatitis B virus (HBV)-related HCC. METHODS: Paired cancerous and adjacent non-cancerous liver tissue specimens of patients with HBV-related HCC were used as a discovery set for screening 800 miRNAs by a Nanostring quantitative assay. Differentially expressed miRNAs were then examined by SYBR green quantitative RT-PCR in a validation cohort of serum samples obtained from 70 patients with HBV-related HCC, 70 HBV patients without HCC and 50 healthy controls. RESULTS: The discovery set identified miR-223-3p, miR-199a-5p and miR-451a significantly lower expressed in cancerous tissues compared with non-cancerous tissues. In the validated cohort, circulating miR-223-3p levels were significantly lower in the HCC group compared with the other groups. The combined use of serum alpha-fetoprotein and miR-223-3p displayed high sensitivity for detecting early HCC (85%) and intermediate/advanced stage HCC (100%). Additionally, serum miR-223-3p had a negative correlation with tumor size and BCLC stage. On multivariate analysis, serum miR-223-3p was identified as an independent prognostic factor of overall survival in patients with HCC. In contrast, circulating miRNA-199a-5p and miR-451a did not show any clinical benefit for the diagnosis and prognostic prediction of HCC. CONCLUSIONS: Our results demonstrated that miR-223-3p was differentially expressed in cancerous compared with paired adjacent non-cancerous tissues. In addition, circulating miRNA-223-3p could represent a novel diagnostic and prognostic marker for patients with HBV-related HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , MicroRNA Circulante/genética , Hepatite B Crônica/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , MicroRNAs/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico
15.
Gene ; 742: 144585, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173542

RESUMO

The association between rs738409 (C>G, I148M) with patatin-like phospholipase domain-containing 3 (PNPLA3) gene and the risk of hepatocellular carcinoma (HCC) was controversial in different ethnic populations. Our study aimed to explore the effect of PNPLA3 rs738409 on the risk of HCC and persistent infection of Hepatitis B virus (HBV) in a Chinese HBV-related population, and further evaluate its role in HCC risk among Asians. First, we performed a case-control study by recruiting 786 HBV-related HCC cases, 695 HBV persistent carriers and 719 HBV natural clearance subjects. PNPLA3 rs738409 was genotyped by MassARRAY platform. Second, we conducted a systematic review and meta-analysis on Asians to further validate our results. Our case-control study demonstrated that PNPLA3 rs738409 was not associated with HCC risk or persistent HBV infection (All P > 0.05). The subsequent meta-analysis included 13 Asian studies with 9,802 subjects. Results showed that PNPLA3 rs738409 might increase HCC risk among healthy subjects (pooled odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.11-1.95), but it had no influence on the development of HCC among HBV-related subjects (pooled OR = 1.07, 95%CI = 0.89-1.30). Our case-control study highlights that PNPLA3 rs738409 is probably not associated with the risk of HCC or persistent HBV infection in a Chinese HBV-related population. Besides, our systematic review and meta-analysis on Asians further suggest that PNPLA3 rs738409 may confer an increased risk of HCC among healthy people, but contribute little to the development of HCC among HBV-related subjects. Future studies are required to confirm these results.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Hepatocelular/genética , Hepatite B Crônica/genética , Lipase/genética , Neoplasias Hepáticas/genética , Proteínas de Membrana/genética , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/patologia , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
16.
Sci Rep ; 10(1): 2797, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071406

RESUMO

SMYD3 (SET and MYND domain-containing protein 3) is involved in histone modification, which initiates oncogenesis by activating transcription of multiple downstream genes. To investigate associations of variable numbers of tandem repeats (VNTR) variants in the SMYD3 gene promoter, SMYD3 serum levels and SMYD3 mRNA expression in hepatitis B virus (HBV) infection and clinical progression of related liver disease. SMYD3 VNTRs were genotyped in 756 HBV patients and 297 healthy controls. SMYD3 serum levels were measured in 293 patients and SMYD3 mRNA expression was quantified in 48 pairs of hepatocellular tumor and adjacent non-tumor liver tissues. Genotype SYMD3 VNTR 3/3 was more frequent among HCC patients than in controls (Padjusted = 0.037). SMYD3 serum levels increased according to clinical progression of liver diseases (P = 0.01); HCC patients had higher levels than non-HCC patients (P = 0.04). Among patients with SMYD3 VNTR 3/3, HCC patients had higher SMYD3 levels than others (P < 0.05). SMYD3 mRNA expression was up-regulated in HCC tumor tissues compared to other tissues (P = 0.008). In conclusion, upregulation of SMYD3 correlates with the occurrence of HCC and SMYD3 VNTR 3/3 appears to increase the risk of HCC through increasing SMYD3 levels. SMYD3 may be an indicator for HCC development in HBV patients.


Assuntos
Carcinoma Hepatocelular/genética , Hepatite B Crônica/genética , Histona-Lisina N-Metiltransferase/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/etiologia , Estudos de Casos e Controles , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Hepatite B Crônica/complicações , Humanos , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Repetições Minissatélites , Polimorfismo Genético , Regiões Promotoras Genéticas , Fatores de Risco , Adulto Jovem
17.
Mikrobiyol Bul ; 54(1): 66-78, 2020 Jan.
Artigo em Turco | MEDLINE | ID: mdl-32050879

RESUMO

It has been estimated that currently 350-400 million people have been chronically infected with the hepatitis B virus (HBV) worldwide and approximately one million people die each year due to HBV related diseases. It has been suggested that the viral and host factors, especially the host immune system, may play a role in the chronicity of the HBV infection. Stimulator of interferon genes (STING) is one of the members of the pattern recognition receptor (PRR) that detects the presence of DNA in a human cell, activate synthesis of various cytokines and this protein is thought to be an important member of the immune system against HBV infection. Based on the assumption that there may be a relationship between the differences of STING expression in individuals and HBV chronicity, the aim of this study was to investigate STING gene expression levels in individuals naturally immunized against HBV, in chronic hepatitis B infected patients and in normal individuals who have not been exposed to HBV. A total of 90 volunteers have been included in the study from the age range of 18 to 65, in which the first group consists of 30 individuals naturally immunized against HBV, the second group consists of 30 chronically hepatitis B infected patients while the third group consists of 30 healthy population members who have not been exposed to HBV. Whole blood samples were taken from each participant and peripheral blood mononuclear cells (PBMC) were isolated afterwards. Total RNA was isolated from PBMC. After the synthesis of cDNA from the total RNA, STING gene expression levels were determined by real time polymerase chain reaction (Rt-PCR) method. Normalization was performed by applying the 2-ΔΔCT formula after Rt-PCR procedure. STING expression level of the naturally immunized group was calculated as 0.084 ± 0.026 on average, average STING expression level of healthy population group was 0.082 ± 0.032 and STING expression level of chronically infected patients group was 0.075 ± 0.022 on average. There was no statistically significant difference between the groups (p> 0.05). To our knowledge, this is the first study investigating the role of STING expression in the chronicity of HBV. Although there was no statistically significant difference between the groups, the data that showed STING expression levels in naturally immunized individuals were approximately 10% higher than those in chronic hepatitis B patients and was considered as an important finding.


Assuntos
Hepatite B Crônica , Hepatite B , Imunidade Inata , Proteínas de Membrana , DNA Viral , Hepatite B/genética , Vírus da Hepatite B , Hepatite B Crônica/genética , Humanos , Imunidade Inata/genética , Interferons , Leucócitos Mononucleares , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , RNA Mensageiro/genética
18.
Virus Genes ; 56(2): 168-173, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897927

RESUMO

Integration of HBV DNA into host chromosomes was found in most of the patients with chronic hepatitis B (CHB). In this study, using inverse nested PCR (invPCR), we found the integration site chrX: 111,009,033, which inserted into the p21-activated kinase 3 (PAK3) gene in HepG2.2.15 cells. The viral-human chimeric transcripts were also observed and, significant differences of the copy numbers of integration site chrX: 111,009,033 (P = 0.012) and intra-cell HBV DNA levels (P = 0.027) were found between the cells with and without H2O2 treatment, respectively. This study may provide a novel insight into the elucidation of etiology of HBV integration.


Assuntos
Vírus da Hepatite B/genética , Hepatite B Crônica/genética , Integração Viral/genética , Quinases Ativadas por p21/genética , DNA Viral/genética , DNA Viral/isolamento & purificação , Células Hep G2 , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/transmissão , Hepatite B Crônica/virologia , Hepatócitos/virologia , Humanos , Replicação Viral/genética
19.
Hum Immunol ; 81(2-3): 79-84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31955869

RESUMO

There is growing evidence that the non-classical HLA-G has a role in the process of the immune response against pathogens, including HBV and HIV. Previous studies demonstrated that a 14-bp insertion/deletion (indel) polymorphism at 3'-untranslated region of HLA-G gene interferes in the mRNA stability and expression. The present study aimed to evaluate the association of the 14-bp indel polymorphism (rs371194629) with HBV infection in chronic hepatitis B (CHB) mono-infected and HBV/HIV co-infected patients from Southern Brazil. A total of 817 individuals were analyzed, including 357 CHB patients, 134 HBV/HIV co-infected patients and 326 healthy controls. The 14-bp indel polymorphism was analyzed by DNA amplification using PCR. Logistic regression models were performed to compute adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs). To control for multiple comparisons, the Bonferroni correction was applied to the p-values. The 14-bp Ins allele was observed in 47.6% of the CHB mono-infected patients and in 41.6% of the controls (aOR = 1.33; 95% CI: 1.05-1.60; p = 0.02; pcorrected = 0.08). The results also showed that the 14-bp Ins/Ins genotype was present in 21.8% of the CHB mono-infected patients and in 12.9% of the controls (aOR = 1.91; 95% CI: 1.21-3.01; p < 0.01; pcorrected = 0.02). There was significant association between the 14-bp indel and CHB monoinfection, but not in HBV/HIV co-infection. In conclusion, the 14-bp indel polymorphism was associated with CHB in this specific population.


Assuntos
Antígenos HLA-G/genética , Hepatite B Crônica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Brasil , Estudos de Casos e Controles , Coinfecção , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Antígenos HLA-G/imunologia , Hepatite B Crônica/imunologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade
20.
Anticancer Res ; 40(1): 245-252, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892573

RESUMO

AIM: It has been shown that the integration of hepatitis B virus (HBV) gene into the host genome is a high-risk factor for development of hepatocellular carcinoma (HCC). However, the relationship between HBV S-integrated human extra spindle pole bodies-like 1 (ESPL1) gene and HCC is unknown. This study was designed to detect HBV S-integrated human ESPL1 fusion gene in patients with HCC for potentially using this fusion gene as a biomarker for HCC diagnosis. PATIENTS AND METHODS: Nineteen and 70 patients with chronic hepatitis B (CHB) were recruited to the experimental and control groups, respectively, and both groups underwent an effective nucleoside/nucleotide analog therapy and follow-up for HCC occurrence for up to 11 years. HCC tissues were obtained by surgical resection from the experimental group, while liver tissues were collected by liver biopsy in the control group prior to treatment with nucleoside/nucleotide analogs. Alu polymerase chain reaction was used to assess HBV S gene integration in the liver tissues from both groups. HBV S-integrated human ESPL1 fusion gene was then detected in patients with HBV S gene integration using a gene database. RESULTS: All patients in the experimental group developed HCC, whereas no HCC was diagnosed in the control group. HBV S gene integration was identified in 12 out of 19 HCC tissues in the experimental group, giving a detection rate of 63.2%, which was significantly greater than that of 15.7% (11/70) in the control group (p<0.001). We further showed that HBV S-integrated human ESPL1 fusion gene was detected in eight patients (rate of 66.7%) among the 12 patients with HCC with HBV S gene integration in the experimental group, whereas the fusion gene was not detectable in any of the patients in the control group (p=0.001). CONCLUSION: This research demonstrates a high detection rate of HBV S-integrated human ESPL1 fusion gene in patients with HBV-related HCC and shows that this fusion gene appears to be associated with HCC development in patients with CHB. These findings suggest that HBV S-integrated human ESPL1 fusion gene may potentially serve as a biomarker for early detection of HCC in HBV-infected populations.


Assuntos
Grupo com Ancestrais do Continente Asiático , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Proteínas de Fusão Oncogênica/genética , Separase/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatite B Crônica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Separase/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo
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