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1.
Hepatology ; 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34626132

RESUMO

BACKGROUND & AIMS: The mechanism underlying hepatocellular carcinoma (HCC) metastasis remains unclear, many oncogenes are known to regulate this process. However, the role of alternative splicing (AS) in pro-metastatic HCC is poorly understood. APPROACH & RESULTS: By performing RNA-seq of 9 pairs of primary HCC tissues with extrahepatic metastasis (EHMH) and 9 pairs of metastasis-free HCC tissues (MFH), we depicted the AS landscape in HCC and found that a higher frequency of AS events in EHMH compared with MFH. Moreover, 28 differentially expressed splicing regulators were identified in EHMH compared with MFH. Among these, DEAD-box RNA helicase 17 (DDX17) was significantly upregulated in EHMH and was also strongly associated with patient outcome. Functional studies indicated that DDX17 knockout inhibited the degradation of the extracellular matrix, and diminished the invasive ability of HCC cells. A significant reduction in lung metastasis induced by DDX17 deficiency was also demonstrated in a diethylnitrosamine (DEN)-induced DDX17HKO mouse model. Mechanistically, high DDX17 induced intron 3 retention of PXN-AS1 and produced a novel transcript (termed PXN-AS1-IR3). The novel transcript PXN-AS1-IR3 acted as an important promoter of HCC metastasis by inducing MYC transcription activation via recruitment the complex of Tex10 and p300 to MYC enhancer region, which leading to transcriptional activation of several metastasis-associated downstream genes. Finally, the PXN-AS1-IR3 level was significantly higher in serum and HCC tissues with extrahepatic metastasis. CONCLUSIONS: DDX17 and PXN-AS1-IR3 act as important metastatic promoters by modulating MYC signaling, suggesting that DDX17 and PXN-AS1-IR3 may be potential prognostic markers for metastatic HCC.

2.
Pediatr Pulmonol ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559474

RESUMO

OBJECTIVE: Few studies have explored the clinical features in children infected with SARS-CoV-2 and other common respiratory viruses, including respiratory syncytial virus (RSV), Influenza virus (IV), and adenovirus (ADV). Herein, we reported the clinical characteristics and cytokine profiling in children with COVID-19 or other acute respiratory tract infections (ARTI). METHODS: We enrolled 20 hospitalized children confirmed as COVID-19 positive, 58 patients with ARTI, and 20 age and sex-matched healthy children. The clinical information and blood test results were collected. A total of 27 cytokines and chemokines were measured and analyzed. RESULTS: The median age in the COVID-19 positive group was 14.5 years, which was higher than that of the ARTI groups. Around one-third of patients in the COVID-19 group experienced moderate fever, with a peak temperature of 38.27°C. None of the patients displayed wheezing or dyspnea. In addition, patients in the COVID-19 group had lower white blood cells, platelet counts as well as a neutrophil-lymphocyte ratio. Lower serum concentrations of 14 out of 27 cytokines were observed in the COVID-19 group than in healthy individuals. Seven cytokines (IL-1Ra, IL-1ß, IL-9, IL-10, TNF-α, MIP-1α, and VEGF) changed serum concentration in COVID-19 compared with other ARTI groups. CONCLUSION: Patients with COVID-19 were older and showed milder symptoms and a favorable prognosis than ARTI caused by RSV, IV, and ADV. There was a low grade or constrained innate immune reaction in children with mild COVID-19.

4.
Clin Sci (Lond) ; 135(12): 1505-1522, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34128977

RESUMO

Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.


Assuntos
Catálise , DNA Circular/metabolismo , Histona Metiltransferases/genética , Histonas/metabolismo , Sirtuínas/metabolismo , DNA Viral/genética , Hepatite B/prevenção & controle , Hepatite B/terapia , Hepatite B/virologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/prevenção & controle , Humanos , Sirtuínas/genética , Transcrição Genética/genética , Replicação Viral/genética
5.
Cell Discov ; 7(1): 18, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767156

RESUMO

It is important to evaluate the durability of the protective immune response elicited by primary infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we systematically evaluated the SARS-CoV-2-specific memory B cell and T cell responses in healthy controls and individuals recovered from asymptomatic or symptomatic infection approximately 6 months prior. Comparatively low frequencies of memory B cells specific for the receptor-binding domain (RBD) of spike glycoprotein (S) persisted in the peripheral blood of individuals who recovered from infection (median 0.62%, interquartile range 0.48-0.69). The SARS-CoV-2 RBD-specific memory B cell response was detected in 2 of 13 individuals who recovered from asymptomatic infection and 10 of 20 individuals who recovered from symptomatic infection. T cell responses induced by S, membrane (M), and nucleocapsid (N) peptide libraries from SARS-CoV-2 were observed in individuals recovered from coronavirus disease 2019 (COVID-19), and cross-reactive T cell responses to SARS-CoV-2 were also detected in healthy controls.

9.
Clin Infect Dis ; 73(3): e531-e539, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-32745196

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic with no licensed vaccine or specific antiviral agents for therapy. Little is known about the longitudinal dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing antibodies (NAbs) in patients with COVID-19. METHODS: Blood samples (n = 173) were collected from 30 patients with COVID-19 over a 3-month period after symptom onset and analyzed for SARS-CoV-2-specific NAbs using the lentiviral pseudotype assay, coincident with the levels of IgG and proinflammatory cytokines. RESULTS: SARS-CoV-2-specific NAb titers were low for the first 7-10 days after symptom onset and increased after 2-3 weeks. The median peak time for NAbs was 33 days (interquartile range [IQR], 24-59 days) after symptom onset. NAb titers in 93.3% (28/30) of the patients declined gradually over the 3-month study period, with a median decrease of 34.8% (IQR, 19.6-42.4%). NAb titers increased over time in parallel with the rise in immunoglobulin G (IgG) antibody levels, correlating well at week 3 (r = 0.41, P < .05). The NAb titers also demonstrated a significant positive correlation with levels of plasma proinflammatory cytokines, including stem cell factor (SCF), TNF-related apoptosis-inducing ligand (TRAIL), and macrophage colony-stimulating factor (M-CSF). CONCLUSIONS: These data provide useful information regarding dynamic changes in NAbs in patients with COVID-19 during the acute and convalescent phases.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , Pandemias
10.
Nat Med ; 27(1): 86-93, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33257893

RESUMO

The effectiveness of control measures to contain coronavirus disease 2019 (COVID-19) in Wanzhou, China was assessed. Epidemiological data were analyzed for 183 confirmed COVID-19 cases and their close contacts from five generations of transmission of severe acute respiratory syndrome coronavirus 2 throughout the entire COVID-19 outbreak in Wanzhou. Approximately 67.2% and 32.8% of cases were symptomatic and asymptomatic, respectively. Asymptomatic and presymptomatic transmission accounted for 75.9% of the total recorded transmission. The reproductive number was 1.64 (95% confidence interval: 1.16-2.40) for G1-to-G2 transmission, decreasing to 0.31-0.39 in later generations, concomitant with implementation of rigorous control measures. Substantially higher infection risk was associated with contact within 5 d after the infectors had been infected, frequent contact and ≥8 h of contact duration. The spread of COVID-19 was effectively controlled in Wanzhou by breaking the transmission chain through social distancing, extensive contact tracing, mass testing and strict quarantine of close contacts.


Assuntos
COVID-19/epidemiologia , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , Adulto , Número Básico de Reprodução , COVID-19/transmissão , Portador Sadio , Criança , China/epidemiologia , Busca de Comunicante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia
11.
J Hepatol ; 74(3): 522-534, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32987030

RESUMO

BACKGROUND & AIMS: Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS: We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS: Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS: Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY: Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.

12.
Clin Sci (Lond) ; 134(22): 3007-3022, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33103728

RESUMO

Hepatitis B virus (HBV) infection remains a global public health problem. Nearly 257 million people worldwide have been infected with HBV, resulting in 887,000 people dying of cirrhosis or liver cancer caused by chronic hepatitis B (CHB) annually. Therefore, identification of new targets against HBV is urgently needed. Long noncoding RNAs (LncRNAs) have gained widespread attention in recent years due to their function in cancer, inflammation and other diseases. Notably, a growing number of lncRNAs have been found to play a role in HBV development. In the present study, we first identified a famous lncRNA, HOTAIR, which was significantly up-regulated in HBV-infected cells and PBMCs from CHB patients. Furthermore, we evaluated the clinical relevance of HOTAIR in 20 CHB patients and found that higher levels of HOTAIR expression were associated with higher ALT/AST levels and were positively correlated with HBsAg and HBV DNA levels. In addition, functional analysis showed that HOTAIR promoted HBV transcription and replication by elevating the activities of HBV promoters via modulation of the levels of cccDNA-bound SP1. In conclusion, our study reveals that HOTAIR expression is correlated with the clinicopathological and physiological characteristics of HBV. Thus, HOTAIR may serve as a novel HBV diagnostic and therapeutic biomarker based on its ability to facilitate HBV transcription and replication.


Assuntos
Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , RNA Longo não Codificante/metabolismo , Fator de Transcrição Sp1/metabolismo , Transcrição Viral/genética , Replicação Viral/genética , Adulto , Feminino , Redes Reguladoras de Genes , Inativação Gênica , Células Hep G2 , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Humanos , Masculino , Regiões Promotoras Genéticas/genética
13.
Nat Med ; 26(8): 1200-1204, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32555424

RESUMO

The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.


Assuntos
Infecções Assintomáticas , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Imunidade Inata , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Criança , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Hospitalização , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , SARS-CoV-2 , Adulto Jovem
14.
Genes Dis ; 7(4): 535-541, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32363222

RESUMO

In December 2019, the corona virus disease 2019 (COVID-19) caused by novel coronavirus (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide. Few information on clinical features and immunological profile of COVID-19 in paediatrics. The clinical features and treatment outcomes of twelve paediatric patients confirmed as COVID-19 were analyzed. The immunological features of children patients was investigated and compared with twenty adult patients. The median age was 14.5-years (range from 0.64 to 17), and six of the patients were male. The average incubation period was 8 days. Clinically, cough (9/12, 75%) and fever (7/12, 58.3%) were the most common symptoms. Four patients (33.3%) had diarrhea during the disease. As to the immune profile, children had higher amount of total T cell, CD8+ T cell and B cell but lower CRP levels than adults (P < 0.05). Ground-glass opacity (GGO) and local patchy shadowing were the typical radiological findings on chest CT scan. All patients received antiviral and symptomatic treatment and the symptom relieved in 3-4 days after admitted to hospital. The paediatric patients showed mild symptom but with longer incubation period. Children infected with SARS-CoV-2 had different immune profile with higher T cell amount and low inflammatory factors level, which might ascribed to the mild clinical symptom. We advise that nucleic acid test or examination of serum IgM/IgG antibodies against SARS-CoV-2 should be taken for children with exposure history regardless of clinical symptom.

15.
J Infect Dis ; 222(2): 189-193, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32382737

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. METHODS: In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. RESULTS: To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. CONCLUSIONS: Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.


Assuntos
Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Técnicas Imunoenzimáticas/métodos , Pneumonia Viral/diagnóstico , Testes Sorológicos/métodos , Adulto , COVID-19 , Teste para COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Pandemias , Peptídeos/imunologia , Pneumonia Viral/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Sensibilidade e Especificidade , Proteínas Virais/imunologia
16.
Cell Commun Signal ; 17(1): 168, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842909

RESUMO

BACKGROUND: Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. METHODS: Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. RESULTS: We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. CONCLUSIONS: Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sirtuínas/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , NAD(P)H Desidrogenase (Quinona)/deficiência , Fosforilação , Estabilidade Proteica , Transdução de Sinais , Regulação para Cima
17.
EBioMedicine ; 49: 232-246, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31680002

RESUMO

BACKGROUND: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed. METHODS: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model. FINDINGS: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production. INTERPRETATION: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent.


Assuntos
6-Aminonicotinamida/farmacologia , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Replicação Viral/efeitos dos fármacos , 6-Aminonicotinamida/química , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Células Hep G2 , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Regiões Promotoras Genéticas/genética , Transcrição Genética/efeitos dos fármacos , Viremia/sangue
18.
Front Pharmacol ; 10: 1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31708789

RESUMO

Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.

19.
BMC Med Genet ; 20(1): 59, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947687

RESUMO

BACKGROUND: Several studies have focused on the association between KIF1B rs17401966 polymorphism and susceptibility to hepatitis B virus-related (HBV-related) hepatocellular carcinoma (HCC), but the conclusions have been inconsistent. We have conducted this updated meta-analysis to explore the association between KIF1B rs17401966 polymorphism and HCC susceptibility. METHODS: Eligible studies were identified through systematic searches in PubMed, OVID, ISI Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases. The quality of evidence was systematically assessed by use of the Newcastle-Ottawa Scale for case control studies in meta-analyses. RESULTS: Ten studies containing 18 independent case-control studies were included. The results revealed a significant association between KIF1B rs17401966 polymorphism and susceptibility to HCC under a random-effect allelic model (OR = 0.85, 95% CI 0.76-0.94, P = 0.003); HBV-positive subgroup (OR = 0.82, 95% CI 0.72-0.95, P = 0.007); and Chinese-subgroup (OR = 0.82, 95% CI 0.72-0.93, P = 0.002). CONCLUSIONS: G-allele appears to be a protective allele of KIF1B for HCC, especially in HBV-positive and Chinese populations. More well-designed studies with larger sample size and various ethnic groups and risk factors are needed to establish that KIF1B rs17401966 polymorphism is significantly associated with risk of HCC.


Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Cinesina/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Humanos
20.
Cancer Lett ; 452: 90-102, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-30914208

RESUMO

Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.


Assuntos
Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Lectinas de Ligação a Manose/genética , Glicoproteínas de Membrana/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-ets/genética , Receptores de Superfície Celular/genética , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Células Hep G2 , Humanos , Fígado/citologia , Fígado/patologia , Neoplasias Hepáticas/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/biossíntese , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/genética
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