RESUMEN
BACKGROUND: Although nucleos(t)ide analogues (NAs) are thought to reduce the risk of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), the effect of NA discontinuation on the prognosis of HBV-related HCC after hepatectomy is rarely reported. We aimed to investigate the potential for hepatitis B virus e antigen (HBeAg)-negative HBV-related HCC patients to discontinue NAs based on preoperative hepatitis B virus surface antigen (HBsAg) status. METHODS: This historical cohort study involved 1232 NA-treated HBeAg-negative patients who underwent curative hepatectomy for HBV-related HCC from 2014 to 2019. The recurrence-free survival (RFS) and overall survival (OS) of patients discontinuing NAs before surgery were compared with those continuing NAs. Propensity score matching (PSM) was used to balance baseline characteristics. RESULTS: Of all enrolled patients, 839 (68.1%) patients continued NAs, and 393 (31.9%) patients discontinued NAs. Continuation of NAs was identified as an independent risk factor for RFS (HR 2.047, 95% CI 1.348-3.109, p < 0.001 before PSM and HR 2.756, 95% CI 1.537-4.942, p < 0.001 after PSM) in HBsAg-negative patients. Similarly, subgroup survival analyses showed that NA discontinuation was associated with better RFS (p = 0.029 before PSM and p < 0.001 after PSM) and comparable OS (p = 0.935 before PSM and p = 0.115 after PSM) than NA continuation in HBsAg-negative patients. The interaction between HBsAg status and continuation or discontinuation of NAs was significant (p for interaction <0.001). CONCLUSIONS: These findings demonstrate the potential for HBeAg-negative HBV-related HCC patients who have achieved HBsAg seroclearance to discontinue NAs under strict monitoring.
Asunto(s)
Carcinoma Hepatocelular , Hepatectomía , Antígenos e de la Hepatitis B , Virus de la Hepatitis B , Neoplasias Hepáticas , Puntaje de Propensión , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Masculino , Femenino , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/etiología , Persona de Mediana Edad , Antígenos e de la Hepatitis B/sangre , Pronóstico , Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B/sangre , Nucleósidos/uso terapéutico , Estudios Retrospectivos , Adulto , Anciano , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virologíaRESUMEN
Background: To identify the risk factors and construct a predictive model for early recurrence of hepatitis B virus(HBV-)- related hepatocellular carcinomas(HCCs) after radical resection. Data and methods: A total of 465 HBV-related HCC patients underwent radical resections between January 1, 2012 and August 31, 2018.Their data were collected through the inpatient information management system of the First Affiliated Hospital of University of Science and Technology of China. Survival and subgroup analyses of early recurrence among male and female patients were performed using Kaplan-Meier curves. The independent risk factors associated with early postoperative tumor recurrence were analyzed using multivariate Cox proportional hazards regression model. Based on these independent risk factors, a risk function model for early recurrence was fitted, and a column chart for the prediction model was drawn for internal and external validation. Results: A total of 181 patients developed early recurrences, including 156 males and 25 females. There was no difference in the early recurrence rates between males and females. Tumor diameters>5cm, microvascular invasion and albumin level<35 g/L were independent risk factors for early recurrence. A nomogram for the early recurrence prediction model was drawn; the areas under the curve for the model and for external verification were 0.638 and 0.655, respectively. Conclusion: Tumor diameter>5 cm, microvascular invasion, and albumin level<35 g/L were independent risk factors for early recurrence. The prediction model based on three clinical indicators could predict early recurrence, with good discrimination, calibration, and extrapolation.
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Carcinoma Hepatocelular , Hepatectomía , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Nomogramas , Humanos , Masculino , Femenino , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/patología , Persona de Mediana Edad , Adulto , Factores de Riesgo , Virus de la Hepatitis B , Estudios Retrospectivos , Hepatitis B/complicaciones , China/epidemiología , Anciano , PronósticoRESUMEN
Currently, chronic hepatitis B virus infection is still one of the most serious public health problems in the world. Though current strategies are effective in controlling infection and slowing down the disease process, it remains a big challenge to achieve a functional cure for chronic hepatitis B in a majority of patients due to the inability to clear the cccDNA pool. The mammalian target of rapamycin (mTOR) integrates nutrition, energy, growth factors, and other extracellular signals, participating in gene transcription, protein translation, ribosome synthesis, and other biological processes. Additionally, mTOR plays an extremely important role in cell growth, apoptosis, autophagy, and metabolism. More and more evidence show that HBV infection can activate the mTOR pathway, suggesting that HBV uses or hijacks the mTOR pathway to facilitate its own replication. Therefore, mTOR signaling pathway may be a key target for controlling HBV infection. However, the role of the central cytokine mTOR in the pathogenesis of HBV infection has not yet been systematically addressed. Notably, mTOR is commonly activated in hepatocellular carcinoma, which can progress from chronic hepatitis B. This review systematically summarizes the role of mTOR in the life cycle of HBV and its impact on the clinical progression of HBV infection.
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Carcinoma Hepatocelular , Virus de la Hepatitis B , Neoplasias Hepáticas , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virología , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virología , Virus de la Hepatitis B/fisiología , Hepatitis B/metabolismo , Animales , Hepatitis B Crónica/metabolismoRESUMEN
Despite recent advances in systemic therapy for hepatocellular carcinoma (HCC), the prognosis of hepatitis B virus (HBV)-induced HCC patients remains poor. By screening a sgRNA library targeting human deubiquitinases, we find that ubiquitin-specific peptidase 26 (USP26) deficiency impairs HBV-positive HCC cell proliferation. Genetically engineered murine models with Usp26 knockout confirm that Usp26 drives HCC tumorigenesis. Mechanistically, we find that the HBV-encoded protein HBx binds to the promoter and induces the production of USP26, which is an X-linked gene exclusively expressed in the testis. HBx consequently promotes the association of USP26 with SIRT1 to synergistically stabilize SIRT1 by deubiquitination, which promotes cell proliferation and impedes cell apoptosis to accelerate HCC tumorigenesis. In patients with HBV-positive HCC, USP26 is robustly induced, and its levels correlate with SIRT1 levels and poor prognosis. Collectively, our study highlights a causative link between HBV infection, deubiquitinase induction and development of HCC, identifying a druggable target, USP26.
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Carcinoma Hepatocelular , Proliferación Celular , Epigénesis Genética , Virus de la Hepatitis B , Neoplasias Hepáticas , Sirtuina 1 , Transactivadores , Proteínas Reguladoras y Accesorias Virales , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Humanos , Animales , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Virus de la Hepatitis B/genética , Ratones , Sirtuina 1/metabolismo , Sirtuina 1/genética , Transactivadores/metabolismo , Transactivadores/genética , Masculino , Proliferación Celular/genética , Proteínas Reguladoras y Accesorias Virales/metabolismo , Carcinogénesis/genética , Hepatitis B/virología , Hepatitis B/complicaciones , Hepatitis B/genética , Hepatitis B/metabolismo , Línea Celular Tumoral , Ratones Noqueados , Regulación Neoplásica de la Expresión Génica , Enzimas Desubicuitinizantes/metabolismo , Enzimas Desubicuitinizantes/genética , Apoptosis/genética , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Regiones Promotoras Genéticas/genéticaRESUMEN
Objective: To examine the effects of peripheral blood eosinophil (EOS) count and its dynamic alterations on the treatment efficacy and prognosis of patients with advanced hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) receiving camrelizumab combined with lenvatinib (C + L) therapy. Methods: A retrospective analysis was performed on 200 patients with advanced HBV-HCC who were admitted to two centers from January 2018 to August 2023 and treated with C + L. EOS, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were determined before C + L treatment (EOS0, NLR0, and PLR0) and after three cycles of treatment (EOS3, NLR3, and PLR3). The area under the curve was calculated using the receiver operating characteristic (ROC) curve. NLR and PLR served as references to analyze the effect of differences in EOS in predicting the survival efficacy of patients with HBV-HCC treated using C + L. The independent risk factors affecting progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate Cox proportional risk models. Results: The ROC curve revealed that the predictive value of EOS3 was better than those of NLR3 and PLR3 for the long-term treatment efficacy of patients with intermediate and advanced HBV-HCC receiving C + L. Statistically significant differences were observed between groups with different levels of EOS0 and EOS3 and the evaluation of treatment efficacy after 3 weeks (P < 0.05). The median PFS of the high-EOS0 group was higher than that of the low-EOS0 group (P = 0.027); median PFS of the high EOS3 group was higher than that of the low EOS3 group (P = 0.018); median OS of the high EOS0 group was higher than that of the low EOS0 group (P = 0.032); median OS of the high EOS3 group was higher than that of the low EOS3 group (P < 0.0001). Multifactorial Cox analysis revealed that EOS3 was an independent predictor of PFS and that EOS0 was an independent predictor of OS (P < 0.05). Conclusion: EOS may be an ideal indicator for predicting the treatment efficacy and prognosis of patients with advanced HBV-HCC receiving C + L.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular , Eosinófilos , Hepatitis B , Neoplasias Hepáticas , Compuestos de Fenilurea , Quinolinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/sangre , Femenino , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Curva ROC , Anciano , Recuento de Leucocitos , Adulto , Virus de la Hepatitis B/aislamiento & purificación , Resultado del TratamientoRESUMEN
Hepatitis B virus is one of the leading causes behind the neoplastic transformation of liver tissue and associated mortality. Despite the availability of many therapies and vaccines, the pathogenic landscape of the virus remains elusive; urging the development of novel strategies based on the fundamental infectious and transformative modalities of the virus-host interactome. Ubiquitination is a widely observed post-translational modification of several proteins, which either regulates the proteins' turnover or impacts their functionalities. In recent years, ample amount of literature has accumulated regarding the ubiquitination dynamics of the HBV proteins as well as the host proteins during HBV infection and carcinogenesis; with direct and detailed characterization of the involvement of HBV in these processes. Interestingly, while many of these ubiquitination events restrict HBV life cycle and carcinogenesis, several others promote the emergence of hepatocarcinoma by putting the virus in an advantageous position. This review sums up the snowballing literature on ubiquitination-mediated regulation of the host-HBV crosstalk, with special emphasis on its influence on the establishment and progression of hepatocellular carcinoma on a molecular level. With the advent of cutting-edge ubiquitination-targeted therapeutic approaches, the findings emanating from this review may potentiate the identification of novel anti-HBV targets for the formulation of novel anticancer strategies to control the HBV-induced hepato-carcinogenic process on a global scale.
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Carcinoma Hepatocelular , Virus de la Hepatitis B , Interacciones Huésped-Patógeno , Neoplasias Hepáticas , Ubiquitina , Ubiquitinación , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/metabolismo , Humanos , Virus de la Hepatitis B/fisiología , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Ubiquitina/metabolismo , Hepatitis B/virología , Hepatitis B/complicaciones , AnimalesRESUMEN
Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer often associated with chronic hepatitis B virus infection (CHB) and liver cirrhosis (LC), underscoring the critical need for biomarker discovery to improve patient outcomes. Emerging as a promising avenue for biomarker development, proteomic technology leveraging liquid biopsy from small extracellular vesicles (sEV) offers new insights. Here, we evaluated various methods for sEV isolation and identified polysaccharide chitosan (CS) as an optimal approach. Subsequently, we employed optimized CS-based magnetic beads (Mag-CS) for sEV separation from serum samples of healthy controls, CHB, LC, and HBV-HCC patients. Leveraging data-independent acquisition mass spectrometry coupled with machine learning, we uncovered potential vesicular protein biomarker signatures (KNG1, F11, KLKB1, CAPNS1, CDH1, CPN2, NME2) capable of distinguishing HBV-HCC from CHB, LC, and non-HCC conditions. Collectively, our findings highlight the utility of Mag-CS-based sEV isolation for identifying early detection biomarkers in HBV-HCC.
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Carcinoma Hepatocelular , Quitosano , Virus de la Hepatitis B , Neoplasias Hepáticas , Proteómica , Humanos , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/virología , Proteómica/métodos , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/sangre , Vesículas Extracelulares/metabolismo , Hepatitis B Crónica/sangre , Biomarcadores de Tumor/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/virología , Masculino , FemeninoRESUMEN
BACKGROUND: This study investigates the molecular mechanisms of CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and sorafenib (SF) for improving hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). METHODS: A dataset of 44 HBV-HCC patients and their survival information was selected from the TCGA database. Immune genes related to survival status were identified using the ImmPort database and WGCNA analysis. A prognostic risk model was constructed and analyzed using Lasso regression. Differential analysis was performed to screen key genes, and their significance and predictive accuracy for HBV-HCC were validated using Kaplan-Meier survival curves, ROC analysis, CIBERSORT analysis, and correlation analysis. The correlation between AC099850.3 and the gene expression matrix was calculated, followed by GO and KEGG enrichment analysis using AC099850.3 and its co-expressed genes. HepG2.2.15 cells were selected for in vitro validation, and lentivirus interference, cell cycle determination, CCK-8 experiments, colony formation assays, Transwell experiments, scratch experiments, and flow cytometry were performed to investigate the effects of key genes on HepG2.2.15 cells. A subcutaneous transplanted tumor model in mice was constructed to verify the inhibitory effect of key genes on HBV-HCC tumors. Subsequently, pH-triggered drug release NPs (CC@AC&SF@PP) were prepared, and their therapeutic effects on HBV-HCC in situ tumor mice were studied. RESULTS: A prognostic risk model (AC012313.9, MIR210HG, AC099850.3, AL645933.2, C6orf223, GDF10) was constructed through bioinformatics analysis, showing good sensitivity and specificity in diagnostic prediction. AC099850.3 was identified as a key gene, and enrichment analysis revealed its impact on cell cycle pathways. In vitro cell experiments demonstrated that AC099850.3 promotes HepG2.2.15 cell proliferation and invasion by regulating immune checkpoint CD276 expression and cell cycle progression. In vivo, subcutaneously transplanted tumor experiments showed that AC099850.3 promotes the growth of HBV-HCC tumors in nude mice. Furthermore, pH-triggered drug release NPs (CC@AC&SF@PP) loaded with AC099850.3 siRNA and SF were successfully prepared and delivered to the in situ HBV-HCC, enhancing the effectiveness of combined therapy for HBV-HCC. CONCLUSIONS: AC099850.3 accelerates the cell cycle progression and promotes the occurrence and development of HBV-HCC by upregulating immune checkpoint CD276 expression. CC@AC&SF@PP NPs loaded with AC099850.3 siRNA and SF improve the effectiveness of combined therapy for HBV-HCC.
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Antígenos B7 , Carcinoma Hepatocelular , Proliferación Celular , Virus de la Hepatitis B , Neoplasias Hepáticas , Invasividad Neoplásica , Sorafenib , Humanos , Sorafenib/farmacología , Sorafenib/uso terapéutico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/virología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/virología , Proliferación Celular/efectos de los fármacos , Animales , Antígenos B7/metabolismo , Antígenos B7/genética , Células Hep G2 , Virus de la Hepatitis B/efectos de los fármacos , Ratones Desnudos , Ratones , Quitosano/química , Quitosano/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Ratones Endogámicos BALB CRESUMEN
Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.
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Metilación de ADN , Epigénesis Genética , Hepacivirus , Hepatitis C , Humanos , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/genética , Hepatitis C/virología , Metilación de ADN/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/etiología , AnimalesRESUMEN
BACKGROUND AND AIMS: Antiviral therapy (AVT) is required in patients with newly diagnosed hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), if HBV DNA is detectable. We compared the risk of recurrence according to HBV replication activity at the curative treatment of HBV-related HCC. METHODS: Patients with HBV-related HCC who underwent surgical resection or radiofrequency ablation between 2013 and 2018 were enrolled in this retrospective cohort study. Patients were categorized into two groups according to HBV replication activity at the curative treatment of HBV-related HCC (group 1: patients who met the AVT indication for HBV-related HCC due to detectable HBV DNA but did not meet the AVT indication if without HCC; group 2: patients who met the AVT indication, regardless of HCC). RESULTS: In the entire cohort (n = 911), HCC recurred in 303 (33.3%) patients during a median follow-up of 4.7 years. After multivariate adjustment, group 2 showed a statistically similar risk of HCC recurrence (adjusted hazard ratio [aHR] = 1.18, P = 0.332) compared to that of group 1. In addition, group 2 showed statistically similar risks of early (< 2 years; aHR = 1.31) and late (≥ 2 years; aHR = 0.83) recurrence than that of group 1 (all P>0.05). Propensity score matching and inverse probability of treatment weighting analysis also yielded similar risks of HCC recurrence between the two groups (all P>0.05, log-rank tests). CONCLUSIONS: The risk of HCC recurrence in patients who received curative treatment for newly diagnosed HBV-related HCC was similar regardless of HBV replication activity, if AVT was properly initiated.
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Carcinoma Hepatocelular , Virus de la Hepatitis B , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Replicación Viral , Humanos , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/patología , Masculino , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/patología , Femenino , Virus de la Hepatitis B/fisiología , Persona de Mediana Edad , Recurrencia Local de Neoplasia/virología , Estudios Retrospectivos , ADN Viral/genética , Anciano , Antivirales/uso terapéutico , Hepatitis B/complicaciones , Hepatitis B/virologíaRESUMEN
BACKGROUND: In this study, we comprehensively profiled the T-cell receptor (TCR) repertoire of the tumor and adjacent normal tissue in patients with HBV-associated hepatocellular carcinoma (HCC) and determined the baseline characteristics and clinical significance of TCR. METHODS: High-throughput sequencing was used to determine the profile of complementarity-determining region 3 (CDR3) of the TCR-ß chain variable (TRBV) in the tumor and normal tissue samples of 14 HCC patients. At the same time, TRBV diversity and differences in expression between tumor and normal tissues were investigated. The cumulative frequency of top 100 CDR3 (CF100), clonality, and Shannon entropy as indices to evaluate diversity, RESULTS: The diversity of TRBV CDR3 showed no significant difference between tumor and normal tissues. Of the 58 V gene segments in TRBV, TRBV16 and TRBV7-6 had a significantly higher frequency in the tumor group than in the normal group (p < 0.05). The frequency of 14 J gene segments showed no significant difference between tumor and normal tissues. In contrast, the frequency of 22 TRBVx/BJx combinations was significantly higher in the tumor than in the normal tissue. In addition, the length and type of TRBV CDR3 were similar in tumor and normal tissues, and a Gaussian distribution was observed in both groups. CONCLUSION: This study provided a large amount of information about the TCR lineage in HBV-associated HCC, laying the foundation for further research. In addition, the fact that the immune repertoire (TRBV CDR3) hardly differs between tumor and adjacent normal tissue provides a new clue for exploring the mechanism of the liver as an organ with immune privileges.
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Carcinoma Hepatocelular , Regiones Determinantes de Complementariedad , Neoplasias Hepáticas , Receptores de Antígenos de Linfocitos T alfa-beta , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Regiones Determinantes de Complementariedad/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , AncianoRESUMEN
Hepatitis B virus (HBV) X protein (HBx) plays a key role in hepatocellular carcinoma (HCC). HBx may alter the expression of multiple microRNAs (miRs), which are important in hepatocarcinogenesis. This study aimed to investigate the importance of HBx protein in the expression of miR-21, miR-22, miR-122, miR-132, and miR-222. A recombinant vector expressing HBx was developed. The Huh-7 cell line was transfected with the HBx-pcDNA3.1+ recombinant plasmid. A Real-Time Polymerase Chain Reaction was used to evaluate the expression of miR-21, miR-22, miR-122, miR-132, and miR-222 in the cell line. It was found that the expression of miR-21 and miR-222 was upregulated at all points of time after HBx transfection. The expression of miR-21 was 4.24-fold 72 h after transfection. The miR-22 had a 7.69-fold downregulation after 24 h, and the miR-122 had a significant downregulation after 48 h (10-fold). The miR-132 expression reached its lowest rate 12 h after HBx transfection (8.33-fold), and the miR-222 expression was upregulated in transfected cells but was not significantly different (1.18- to 2.45-fold). The significant downregulation of miR-22, miR-122, and miR-132 implicates their inhibitory roles in the progression of HBV-associated HCC. The expression of these microRNAs could be used as a prognostic marker for the progression of HBV-associated liver disease.
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MicroARNs , Transactivadores , Proteínas Reguladoras y Accesorias Virales , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Reguladoras y Accesorias Virales/genética , Proteínas Reguladoras y Accesorias Virales/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Línea Celular Tumoral , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/genética , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/fisiologíaRESUMEN
BACKGROUND: The progression of tumours is related to abnormal phospholipid metabolism. This study is anticipated to present a fresh perspective for disease therapy targets of hepatocarcinoma caused by hepatitis B virus in the future by screening feature genes related to phospholipid metabolism. METHODS: This study analysed GSE121248 to pinpoint differentially expressed genes (DEGs). By examining the overlap between the metabolism-related genes and DEGs, the research focused on the genes involved in phospholipid metabolism. To find feature genes, functional enrichment studies were carried out and a network diagram was proposed. These findings were validated via data base of The Cancer Genome Atlas (TCGA). Further analyses included immune infiltration studies and metabolomics. Finally, the relationships between differentially abundant metabolites and feature genes were confirmed by molecular docking, providing a thorough comprehension of the molecular mechanisms. RESULTS: The seven genes with the highest degree of connection (PTGS2, IGF1, SPP1, BCHE, NR1I2, NAMPT, and FABP1) were identified as feature genes. In the TCGA database, the seven feature genes also had certain diagnostic efficiency. Immune infiltration analysis revealed that feature genes regulate the infiltration of various immune cells. Metabolomics successfully identified the different metabolites of the phospholipid metabolism pathway between patients and normal individuals. The docking study indicated that different metabolites may play essential roles in causing disease by targeting feature genes. CONCLUSIONS: In this study, for the first time, it reveals the possible involvement of genes linked to phospholipid metabolism-related genes using bioinformatics analysis. Identifying genes and probable therapeutic targets could provide clues for the further treatment of disease.
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Carcinoma Hepatocelular , Virus de la Hepatitis B , Hepatitis B , Neoplasias Hepáticas , Simulación del Acoplamiento Molecular , Fosfolípidos , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/metabolismo , Hepatitis B/genética , Hepatitis B/complicaciones , Hepatitis B/metabolismo , Hepatitis B/virología , Virus de la Hepatitis B/genética , Fosfolípidos/metabolismo , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Metabolómica/métodos , Perfilación de la Expresión GénicaRESUMEN
Hepatocellular carcinoma (HCC) is a malignant tumor. It is estimated that approximately 50-80% of HCC cases worldwide are caused by hepatitis b virus (HBV) infection, and other pathogenic factors have been shown to promote the development of HCC when coexisting with HBV. Understanding the molecular mechanisms of HBV-induced hepatocellular carcinoma (HBV-HCC) is crucial for the prevention, diagnosis, and treatment of the disease. In this study, we analyzed the molecular mechanisms of HBV-induced HCC by combining bioinformatics and deep learning methods. Firstly, we collected a gene set related to HBV-HCC from the GEO database, performed differential analysis and WGCNA analysis to identify genes with abnormal expression in tumors and high relevance to tumors. We used three deep learning methods, Lasso, random forest, and SVM, to identify key genes RACGAP1, ECT2, and NDC80. By establishing a diagnostic model, we determined the accuracy of key genes in diagnosing HBV-HCC. In the training set, RACGAP1(AUC:0.976), ECT2(AUC:0.969), and NDC80 (AUC: 0.976) showed high accuracy. They also exhibited good accuracy in the validation set: RACGAP1(AUC:0.878), ECT2(AUC:0.731), and NDC80(AUC:0.915). The key genes were found to be highly expressed in liver cancer tissues compared to normal liver tissues, and survival analysis indicated that high expression of key genes was associated with poor prognosis in liver cancer patients. This suggests a close relationship between key genes RACGAP1, ECT2, and NDC80 and the occurrence and progression of HBV-HCC. Molecular docking results showed that the key genes could spontaneously bind to the anti-hepatocellular carcinoma drugs Lenvatinib, Regorafenib, and Sorafenib with strong binding activity. Therefore, ECT2, NDC80, and RACGAP1 may serve as potential biomarkers for the diagnosis of HBV-HCC and as targets for the development of targeted therapeutic drugs.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Biología Computacional , Neoplasias Hepáticas , Aprendizaje Automático , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/diagnóstico , Humanos , Biomarcadores de Tumor/genética , Virus de la Hepatitis B/genética , Proteínas Activadoras de GTPasa/genética , Hepatitis B/complicaciones , Hepatitis B/diagnóstico , Hepatitis B/virología , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Bases de Datos GenéticasRESUMEN
Hepatitis C virus (HCV) infection is a major health problem worldwide. It can cause liver cirrhosis and hepatocellular carcinoma (HCC), making it a cause of morbidity from liver disease. Thus, there is an urgent need for a prophylactic HCV vaccine. Fortunately, modern medicine has transformed the therapy for HCV infection through development of direct-acting antiviral agents (DAAs), achieving high rates of sustained virologic response and giving significant relief from HCC and associated mortality, but unfortunately it fails to eradicate the risk of HCC, especially in HCV-cleared patients with already advanced liver disease. Additionally, DAA-cured patients do not develop sufficient antiviral immunity and are susceptible to reinfection. A comprehensive strategy to control HCV infection must include a vaccine development approach in which the host can develop humoral and cellular immunity to eradicate HCV successfully; however, this remains a challenge as HCV has developed systems to evade immune attacks from its host. This review highlights the current understanding of HCV's effect on liver disease and cancer progression, the nature of immune responses from cell populations interacting with HCV, and the current strategies for vaccine development. The information in this review will advance prophylactic intervention strategies for HCV infection, with the end goal being to prevent chronicity and subsequent liver disease leading to HCC.
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Hepacivirus , Hepatitis C Crónica , Desarrollo de Vacunas , Humanos , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Hepatitis C Crónica/prevención & control , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/etiología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/etiología , Vacunas contra Hepatitis Viral/inmunología , Vacunas contra Hepatitis Viral/uso terapéutico , Animales , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: The efficacy of coronavirus disease 2019 (COVID-19) vaccines in preventing SARS-CoV-2 infection in patients with hepatocellular carcinoma (HCC) is not clear. METHODS: From January 2022 to October 2022, patients diagnosed with HCC in a prospective, multicenter, observational cohort were analyzed. RESULTS: One hundred and forty-one patients with (n = 107) or without COVID-19 vaccination (n = 34) were included. The number of patients with severe or very severe infection was relatively lower in the vaccinated group (3.7% vs. 11.8%, p = 0.096). Median infection-free survival in the vaccinated group (14.0 vs. 8.3 months, p = 0.010) was significantly longer than that in the unvaccinated group. COVID-19 vaccination (hazard ratio (HR) HR = 0.47), European Cooperative Oncology Group performance score = 0 (HR = 2.06), and extrahepatic spread (HR = 0.28) were found to be the independent predictive factors for infection-free survival. CONCLUSION: COVID-19 vaccines could effectively reduce the SARS-Cov-2 infection in patients with HCC.
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Vacunas contra la COVID-19 , COVID-19 , Carcinoma Hepatocelular , Neoplasias Hepáticas , SARS-CoV-2 , Humanos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/virología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/uso terapéutico , Femenino , Masculino , COVID-19/prevención & control , COVID-19/complicaciones , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Pronóstico , SARS-CoV-2/inmunologíaRESUMEN
BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third leading cause of cancer-related mortality. Extensive literature suggests that long noncoding RNAs play a role in the progression of HCC and hold potential as diagnostic biomarkers for this disease. MATERIALS AND METHODS: We examined the serum levels of HOX antisense intergenic RNA (HOTAIR) in 49 hepatitis patients, 31 liver cirrhosis (LC), and 37 HCC patients using quantitative real-time polymerase chain reaction. Correlations between serum HOTAIR levels and clinical data were evaluated in HCC patients. The receiver operating characteristic curve was utilized to analyze the diagnostic potency of HOTAIR. RESULTS: The HOTAIR levels in serum were significantly higher in HCC patients compared to those with hepatitis (P = .003) and LC patients (P = .048). There was a significant association between the serum levels of HOTAIR and positivity of hepatitis B e antigen (HBeAg) (P = .039) as well as portal vein tumor thrombus (P = .040) in HCC patients. The area under the curve (AUC) for HOTAIR for distinguishing HCC from hepatitis and LC was 0.697. The combined AUC for HOTAIR, HBeAg, and alpha-fetoprotein (AFP) was 0.777. CONCLUSION: Serum HOTAIR functions as a potential diagnostic marker for hepatitis B virus-related HCC. Combining HOTAIR with clinical data and AFP can reinforce the diagnostic precision on HCC.
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Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/diagnóstico , ARN Largo no Codificante/sangre , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Adulto , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/virología , Cirrosis Hepática/genética , Curva ROC , Anciano , Virus de la Hepatitis B/genética , Hepatitis B Crónica/sangre , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Antígenos e de la Hepatitis B/sangre , Hepatitis B/complicaciones , Hepatitis B/sangre , Hepatitis B/diagnósticoRESUMEN
N6-methyladenosine (m6A) is a dynamic and reversible modification process involving in a series of important biological and pathophysiological processes, including the progression of cancers. Herein, we aimed to assess the relationships of genetic variants in m6A modification genes with the survival of hepatitis B virus -related hepatocellular carcinoma (HBV-HCC). We performed a two-stage survival analysis to investigate the associations of 4425 single nucleotide polymorphisms (SNPs) in 36 m6A modification genes with the overall survival (OS) of HBV-HCC patients. Then, the identified SNPs were further used to functionally annotate. We identified that METTL3 rs1263790 (A > G) and ADARB1 rs57884102 (C > T) were significantly associated with the HBV-HCC OS (hazard ratios [HR] = 0.68, 95% confidence interval [CI] = 0.52-0.89, p = 0.004; and HR = 1.70, 95% CI = 1.33-2.18, p < 0.001, respectively). Combined analysis revealed that patients carrying more risk genotypes of two variants had a progressively poorer OS. Moreover, the expression quantitative trait loci (eQTL) analysis indicated that rs1263790 G allele decreased mRNA expression levels of METTL3 in 483 cell-cultured fibroblasts samples. And we found the mRNA expression levels of METTL3 and ADARB1 in HCC tissues were higher than in normal tissues, and the higher METTL3 and the lower ADARB1 were associated with poorer HCC OS. Our results demonstrated that two novel genetic variants (METTL3 rs1263790 and ADARB1 rs57884102) may be potential prognostic markers for HBV-HCC, but these results need larger different ethnic cohorts and functional experiments to validate in the future.
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Adenosina , Carcinoma Hepatocelular , Virus de la Hepatitis B , Neoplasias Hepáticas , Polimorfismo de Nucleótido Simple , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Polimorfismo de Nucleótido Simple/genética , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/patogenicidad , Masculino , Femenino , Persona de Mediana Edad , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferasas/genética , Pronóstico , Hepatitis B/genética , Hepatitis B/complicaciones , Hepatitis B/virología , Genotipo , Predisposición Genética a la EnfermedadRESUMEN
A substantial body of literature, including our own, points to a connection between hepatitis B virus (HBV) infection and the development of drug resistance in hepatocellular carcinoma (HCC), particularly against sorafenib. However, the influence of HBV on resistance to regorafenib, another therapeutic agent, has been less studied. In this study, we used the GEO database (GSE87630) and clinical samples to demonstrate that C-C motif chemokine receptor 9 (CCR9) was highly expressed in HBV-related HCC and predicted poor overall survival. Its overexpression correlated with HBsAg-positive HCC patients. Both univariate and multivariable Cox regression analysis elucidated CCR9 was an independent risk factor for poor overall survival in HCC patients. Our in vitro findings further revealed that HBV structural proteins, small HBV surface antigen (SHBs), triggered an upregulation of CCR9. Functional assays showed that SHBs enhanced HCC cell proliferation, migration, and invasion, increased ABCB1 and ABCC1 expression, and promoted regorafenib resistance via CCR9. Intriguingly, overexpression of HBV plasmid and an AAV-HBV mouse model both exhibited a significant elevation in global N6-methyladenosine (m6A) levels. Further investigations revealed that SHBs elevated these m6A levels, upregulated CCR9 and stabilized CCR9 mRNA through KIAA1429-mediated m6A modification, with sites 1373 and 1496 on CCR9 mRNA being critical for modification. In conclusion, SHBs promoted HCC progression and regorafenib resistance via KIAA1429-mediated m6A modification of CCR9. Our findings suggested that CCR9 could be a potential prognostic biomarker and a valuable molecular therapeutic target of regorafenib resistance in HBV-related HCC.
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Carcinoma Hepatocelular , Resistencia a Antineoplásicos , Antígenos de Superficie de la Hepatitis B , Neoplasias Hepáticas , Compuestos de Fenilurea , Piridinas , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Animales , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Ratones , Masculino , Femenino , Receptores CCR/genética , Receptores CCR/metabolismo , Línea Celular Tumoral , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/efectos de los fármacos , Persona de Mediana Edad , Hepatitis B/virología , Hepatitis B/complicaciones , Hepatitis B/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Adenosina/análogos & derivadosRESUMEN
It is generally acknowledged that antiviral therapy can reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), there remains a subset of patients with chronic HBV infection who develop HCC despite receiving antiviral treatment. This study aimed to develop a model capable of predicting the long-term occurrence of HCC in patients with chronic HBV infection before initiating antiviral therapy. A total of 1450 patients with chronic HBV infection, who received initial antiviral therapy between April 2006 and March 2023 and completed long-term follow-ups, were nonselectively enrolled in this study. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis was used to construct the model. The results were validated in an external cohort (n = 210) and compared with existing models. The median follow-up time for all patients was 60 months, with a maximum follow-up time of 144 months, during which, 32 cases of HCC occurred. The nomogram model for predicting HCC based on GGT, AFP, cirrhosis, gender, age, and hepatitis B e antibody (TARGET-HCC) was constructed, demonstrating a good predictive performance. In the derivation cohort, the C-index was 0.906 (95% CI = 0.869-0.944), and in the validation cohort, it was 0.780 (95% CI = 0.673-0.886). Compared with existing models, TARGET-HCC showed promising predictive performance. Additionally, the time-dependent feature importance curve indicated that gender consistently remained the most stable predictor for HCC throughout the initial decade of antiviral therapy. This simple predictive model based on noninvasive clinical features can assist clinicians in identifying high-risk patients with chronic HBV infection for HCC before the initiation of antiviral therapy.