HBV-related Hepatocellular Carcinoma Research Articles

Hepatitis B virus-related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures.

Emerging evidence supports a high prevalence of cancer type-specific microbiota residing within tumor tissues. The intratumoral microbiome in hepatocellular carcinoma (HCC), especially in viral (hepatitis B virus [HBV]/hepatitis C virus [HCV]) HCC, has not been well characterized for their existence, composition, distribution, and biological functions. We report herein a finding of specific microbial signature in viral HCC as compared to non-HBV/non-HCV (NBNC) HCC. However, the significantly diverse tumor microbiome was only observed in HBV-related HCC, and Cutibacterium was identified as the representative taxa biomarker. Biological function of the unique tumor microbiota in modulating tumor microenvironment (TME) was characterized by using formalin-fixed paraffin-embedded (FFPE) tissue-based multiplex immunofluorescence histochemistry (mIFH) allowing simultaneous in situ detection of the liver cancer cells surrounded with high/low density of microbiota, and the infiltrating immune cells. In HBV_HCC, the intratumoral microbiota are positively associated with increased tumor-infiltrating CD8+ T lymphocytes, but not the CD56+ NK cells. Two subtypes of myeloid-derived suppressor cells (MDSCs): monocytic MDSCs and polymorphonuclear MDSCs, were also found to be positively correlated with the intratumoral microbiota in HBV_HCC, indicating an inhibitory role of these microbial species in antitumor immunity and the contribution to the liver TME in combination of chronic viral hepatitis during HCC development.

Huaier granule improves liver inflammation and fibrosis and prevents recurrence in hepatitis B virus related hepatocellular carcinoma.

There is basic research suggesting that Huaier granule can inhibit liver cirrhosis and hepatocellular carcinoma (HCC), but this conclusion has not been clinically verified. We analyzed the distant cancer tissue of two groups of hepatitis B virus (HBV) related HCC with/without Huaier granule, to clarify the effect of Huaier granule on liver inflammation, liver fibrosis, and postoperative recurrence. We collected clinicopathological data of HCC patients who received two surgery procedures at Mengchao Hepatobiliary Hospital of Fujian Medical University in China from January 2014 to December 2020. Patients according to taking/not taking Huaier granule after the first hepatectomy were divided into two groups, 51 patients with Huaier granule for more than 6 months after operation (Group A); 56 patients without Huaier granule (Group B). The effects on liver inflammation, fibrosis grade, and postoperative recurrence were compared between two groups. The results showed that liver inflammation improved significantly in the Group A [19 (37.3%) cases improved, 31 (60.8%) cases remained unchanged, and 1 (2.0%) case deteriorated] was significantly more than that in the Group B [7 (12.5%) cases improved, 32 (57.1%) cases remained unchanged, and 17 (30.4%) cases deteriorated] (P<0.001). The liver fibrosis in the Group A [17 (33.3%) cases improved, 32 (62.7%) cases remained unchanged, and 2 (3.9%) cases deteriorated] was significantly improved in the Group B [5 (8.9%) cases improved, 45 (80.4%) cases remained unchanged, and 6 (10.7%) cases deteriorated] (P=0.005). The recurrence interval (27.0±21.2 months) in the Group A was significantly longer than that in the Group B (19.0±14.2 months) (P=0.026). Huaier granule can improve liver inflammation, fibrosis, and liver function and prolong the time to recurrence in HBV-related HCC. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Hepatitis B Virus X Protein Induces Expression Changes of miR-21, miR-22, miR-122, miR-132, and miR-222 in Huh-7 Cell Line.

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). Thesignificant 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.

Overexpression of tousled-like kinase 2 predicts poor prognosis in HBV-related hepatocellular carcinoma patients after radical resection.

Background: Tousled-like kinase 2 (TLK2) is integral to DNA repair, replication, and cell cycle regulation, crucial for maintaining genome stability and integrity. However, the expression and prognostic value of TLK2 in hepatitis B viral (HBV) -related hepatocellular carcinoma (HCC) remains unclear. Methods: We examined TLK2 expression and prognostic implications in pan-cancer by using diverse databases. Subsequently, TLK2 expression in HBV-related HCC tissues and adjacent tissues was assessed using quantitative real-time PCR and immunohistochemistry. The prognostic value of TLK2 was assessed through ROC curves, time-dependent ROC curves, Cox regression, Kaplan-Meier curve, and decision curve analysis. Additionally, analyses of immune infiltration, protein-protein interactions, key molecules of tumor-related signaling pathways, molecular subtypes, and TLK2-associated differentially expressed genes (DEGs) were conducted, along with GO/KEGG and GSEA enrichment analyses. Results: TLK2 expression was significantly higher in HCC tissues compared to adjacent tissues and correlated with gender, AFP levels, albumin-bilirubin (ALBI) grade, microvascular invasion (MVI), maximum tumor diameter, tumor number, and TNM stage. TLK2 overexpression emerged as an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in HBV-related HCC patients. An integrated OS nomogram model, incorporating TLK2, age, ALBI grade, MVI, and tumor number, displayed enhanced prognostic capability (C-index: 0.765, 95% CI: 0.732-0.798) in predicting OS and has a higher net benefit than the TNM stage. Moreover, TLK2 expression correlated closely with immune cell infiltration and key molecules of signaling pathways. Functional enrichment analyses highlighted significant associations with DNA duplex unwinding, double-strand break repair, DNA replication, cell cycle, E2F targets, G2M checkpoint, and MYC targets V1. Conclusion: TLK2 is notably overexpressed in HBV-related HCC and emerges as a promising prognostic biomarker, necessitating further validation.

The co-existence of NAFLD and CHB is associated with suboptimal viral and biochemical response to CHB antiviral therapy: a systematic review and meta-analysis

Background and aimsChronic hepatitis B (CHB) and non-alcoholic fatty liver disease (NAFLD) are leading causes of liver-related morbidity and mortality. The interaction between these two disease processes is poorly defined and the impact of NAFLD on HBV-related cirrhosis and HCC remains unclear. The aim of this study was to evaluate the impact of NAFLD on response to antiviral CHB therapy to inform the debate on changing CHB treatment thresholds for these comorbid patients.MethodsStudies with a minimum of 50 adult CHB patients on nucleoside analogue therapy with or without concurrent NAFLD were identified from PubMed/Medline and EMBASE to February 21, 2023. Data extraction from each study included HBeAg and treatment status, diagnostic method of NAFLD, frequency of monitoring intervals, patient age, gender, grade of hepatic steatosis, BMI and metabolic comorbidities. The outcomes of interest, complete virological response (CVR), biochemical response (BR) and HBeAg loss/seroconversion, were recorded at each available monitoring interval. Comparing CHB-NAFLD and CHB-only groups, pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using random- or fixed-effects models depending on heterogeneity.ResultsFrom a search of 470 citations, we identified 32 potentially relevant papers. Overall, 11 studies, comprising 2580 unique patients, met the inclusion criteria of the meta-analysis. CHB-NAFLD patients exhibited significantly lower rates of CVR compared to CHB-only patients. This was demonstrated by an OR of 0.59 (0.38-0.93, p=0.001, I2 = 72%) at 12 months, which tapered off to an OR of 0.67 (0.48-0.95, p=0.02) at 60 months. CHB-NAFLD patients also exhibited significantly lower rates of BR compared to CHB-only patients, as demonstrated by ORs of 0.39 (0.24-0.62, p&amp;lt;0.0001, I2 = 53%) at 12 months and 0.33 (0.17-0.63, p=0.0008) at 24 months.ConclusionPatients with concurrent CHB and NAFLD experience delayed CVR to antiviral therapy and more persistent biochemical abnormalities in comparison to patients with CHB only. This supports the argument for earlier antiviral therapy in order to avert CHB complications in these multi-morbid patients, as the global disease burden of NAFLD continues to increase.

Analytical and Clinical Evaluation of a Chemiluminescent Immunoassay to Detect Serum Chitinase-3-like Protein 1 in HBV-Related Liver Diseases.

Serum chitinase-3-like protein 1 (CHI3L1) is a diagnostic marker for liver diseases, such as hepatocellular carcinoma (HCC). Herein, we aimed to evaluate the analytical performance of a chemiluminescent immunoassay (CLIA) for the quantitative detection of CHI3L1 and its application in hepatitis B virus (HBV)-related liver diseases. The CLIA for CHI3L1 detection presented good analytical performance, with a linear range of 1.50-2000.00 ng/mL and a detection limit of 0.98 ng/mL. To evaluate its clinical application, serum CHI3L1 levels were detected in 82 patients with chronic hepatitis B (CHB) and in 21 healthy controls. The patients with CHB and HCC had higher CHI3L1 levels than the healthy controls and the patients with CHB without HCC. However, CHI3L1 levels did not change significantly with the increase in liver fibrosis stages. The area under the receiver operating characteristic curve for the diagnosis of HBV-related HCC was 0.808, representing a moderate diagnostic value. Correlation analysis revealed a significant association between CHI3L1 and alpha-fetoprotein (AFP) levels, the fibrosis-4 (FIB-4) index, and the aspartate aminotransferase-to-platelet ratio index (APRI). In conclusion, compared with currently reported methods for CHI3L1 detection, the CLIA has a high sensitivity, a wide linear range, and an acceptable accuracy, precision, and reference intervals, making it valuable in the diagnosis of HBV-related HCC.

NAMPT promotes the malignant progression of HBV-associated hepatocellular carcinoma through activation of SREBP1-mediated lipogenesis.

Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.

The Influence of ESR2 Gene Polymorphisms on Susceptibility to Hepatitis B Virus-Related Chronic Hepatitis, Liver Cirrhosis, and Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents an estrogen-dependent tumor. The action of estrogen is regulated via estrogen receptor (ER). Polymorphisms in ERα gene, ESR1, are known to be related to HCC susceptibility among people carrying chronic hepatitis B (CHB). But the effect of ERβ on HCC is still largely unclear, and studies about the genetic variability of ESR2 and HCC are rare. For understanding ESR2's effect on HCC, this work tested two polymorphisms in the ESR2 gene promoter as well as the associations with CHB, HCC, and hepatitis B virus (HBV)-related liver cirrhosis (LC) among the Guangxi population. This work enrolled a total of 137 CHB, 136 LC, and 149 HBV-related HCC patients, together with 146 normal subjects. ESR2 polymorphisms rs3020449 and rs2978381 were examined using the SNaPshot genotyping technique. The AG genotype and dominant model of rs3020449 were related to the decreased CHB susceptibility. In both the overall and subgroup analyses, no associations were observed with the remaining models in all patient groups (those with CHB, HBV-related LC, and HCC), but associations were found between the dominant (TC+CC vs TT) and allele models (C vs T) of rs2978381 and increased HBV-related LC and HCC susceptibility, but not CHB. These findings suggest that rs3020449 polymorphism of ESR2 gene makes great contribution to the decreased CHB risk and that rs2978381 significantly contributed to higher risks of HBV-related LC and HCC.

5-FU promotes HBV replication through oxidative stress-induced autophagy dysfunction

Background & aimsHepatitis B virus (HBV) reactivation is a major problem that must be overcome during chemotherapy for HBV-related hepatocellular carcinoma (HCC). However, the mechanism underlying chemotherapy-associated HBV reactivation is still not fully understood, hindering the development of improved HBV-related HCC treatments. MethodsA meta-analysis was performed to assess the HBV reactivation risk during transcatheter arterial chemoembolization (TACE). To investigate the regulatory effects and mechanisms of 5-FU on HBV replication, an HBV mouse model was established by pAAV-HBV1.2 hydrodynamic injection followed by intraperitoneal 5-FU injection, and different in vitro models (HepG2.2.15 or Huh7 cells) were established. Realtime RT‒qPCR, western blotting, luciferase assays, and immunofluorescence were used to determine viral parameters. We also explored the underlying mechanisms by RNA-seq, oxidative stress evaluation and autophagy assessment. ResultsThe pooled estimated rate of HBV reactivation in patients receiving TACE was 30.3 % (95 % CI, 23.1%–37.4 %). 5-FU, which is a chemotherapeutic agent commonly used in TACE, promoted HBV replication in vitro and in vivo. Mechanistically, 5-FU treatment obviously increased autophagosome formation, as shown by increased LC3-II levels. Additionally, 5-FU impaired autophagic degradation, as shown by marked p62 and mCherry-GFP-LC3 upregulation, ultimately promoting HBV replication and secretion. Autophagy inhibition by 3-methyladenine or chloroquine significantly altered 5-FU-induced HBV replication. Furthermore, 5-FU-induced autophagy and HBV replication were markedly attenuated with a reactive oxygen species (ROS) scavenger. ConclusionsTogether, our results indicate that ROS-induced autophagosome formation and autophagic degradation play a critical role in 5-FU-induced HBV reactivation.

Identification of CD8+ T-cell exhaustion signatures for prognosis in HBV-related hepatocellular carcinoma patients by integrated analysis of single-cell and bulk RNA-sequencing

BackgroundHBV infection is the leading risk factor for HCC. HBV infection has been confirmed to be associated with the exhaustion status of CD8+ T cells and immunotherapeutic efficacy in HCC. In this study, we aimed to investigate the prognostic value of the CD8+ T-cell exhaustion signature and immunotherapy response in patients with HBV-related HCC.MethodsWe identified different clusters of HBV-related HCC cells by single-cell RNA sequencing (scRNA-seq) and identified CD8+ T-cell exhaustion-related genes (TERGs) by pseudotime analysis. We conducted differential expression analysis and LASSO Cox regression to detect genes and construct a CD8+ T-cell exhaustion index (TEI). We next combined the TEI with other clinicopathological factors to design a prognostic nomogram for HCC patients. We also analysed the difference in the TEI between the non-responder and responder groups during anti-PD-L1 therapy. In addition, we investigated how HBV induces CD8+ T lymphocyte exhaustion through the inhibition of tyrosine metabolism in HCC using gene set enrichment analysis and RT‒qPCR.ResultsA CD8+ T-cell exhaustion index (TEI) was established with 5 TERGs (EEF1E1, GAGE1, CHORDC1, IKBIP and MAGOH). An AFP level > 500 ng, vascular invasion, histologic grade (G3-G4), advanced TNM stage and poor five-year prognosis were related to a higher TEI score, while HBV infection was related to a lower TEI score. Among those receiving anti-PD-L1 therapy, responders had lower TEIs than non-responders did. The TEI also serves as an independent prognostic factor for HCC, and the nomogram incorporating the TEI, TNM stage, and vascular invasion exhibited excellent predictive value for the prognosis in HCC patients. RT‒qPCR revealed that among the tyrosine metabolism-associated genes, TAT (tyrosine aminotransferase) and HGD (homogentisate 1,2 dioxygenase) were expressed at lower levels in HBV-HCC than in non-HBV HCC.ConclusionGenerally, we established a novel TEI model by comprehensively analysing the progression of CD8+ T-cell exhaustion, which shows promise for predicting the clinical prognosis and potential immunotherapeutic efficacy in HBV-related HCC patients.

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

Entecavir versus tenofovir for prevention of hepatitis B virus-associated hepatocellular carcinoma after curative resection: study protocol for a randomized, open-label trial

BackgroundEntecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection.MethodsThis study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery.DiscussionThis study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study.Trial registrationClinicalTrials.gov NCT02650271. Registered on January 7, 2016.

Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma.

There are limited data on antiviral treatment utilization and its impact on long-term outcomes of hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after hepatic resection. We aimed to determine the utilization and impact of antivirals in HBV- and HCV-related HCC. This cohort study included 1,906 participants (1,054 HBV-related HCC and 852 HCV-related HCC) from 12 international sites. All participants had HBV- or HCV-related HCC and underwent curative surgical resection. The primary outcome was the utilization of antiviral therapy, and the secondary outcome was long-term overall survival (OS). The mean (±standard deviation [SD]) age was 62.1 (±11.3) years, 74% were male, and 84% were Asian. A total of 47% of the total cohort received antiviral therapy during a mean (±SD) follow-up of 5.0 (±4.3) years. The overall antiviral utilization for participants with HBV-related HCC was 57% and declined over time, from 65% before 2010, to 60% from 2010 to 2015, to 47% beyond 2015, P < .0001. The overall utilization of antivirals for HCV-related HCC was 35% and increased over time, from 24% before 2015 to 74% from 2015 and beyond, P < .0001. The 10-year OS was lower in untreated participants for both HBV (58% v 61%) and HCV participants (38% v 82%; both P < .0001). On multivariable Cox regression analysis adjusted for relevant confounders, antiviral therapy initiated before or within 6 months of HCC diagnosis was independently associated with lower mortality in both HBV- (adjusted hazard ratio [aHR], 0.60 [95% CI, 0.43 to 0.83]; P = .002) and HCV-related HCC (aHR, 0.18 [95% CI, 0.11 to 0.31]; P < .0001). Antiviral therapy is associated with long-term survival in people with HBV- or HCV-related HCC who undergo curative resection but is severely underutilized.

ARID1A deficiency promotes progression and potentiates therapeutic antitumour immunity in hepatitis B virus-related hepatocellular carcinoma.

Exploring predictive biomarkers and therapeutic strategies of ICBs has become an urgent need in clinical practice. Increasing evidence has shown that ARID1A deficiency might play a critical role in sculpting tumor environments in various tumors and might be used as pan-cancer biomarkers for immunotherapy outcomes. The current study aims to explored the immune-modulating role of ARID1A deficiency in Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC) and its potential immunotherapeutic implications. In the current study, we performed a comprehensive analysis using bioinformatics approaches and pre-clinical experiments to evaluate the ARID1A regulatory role on the biological behavior, and immune landscape of Hepatitis B virus (HBV) related hepatocellular carcinoma (HBV-HCC). A total of 425 HBV-related hepatocellular carcinoma patients from TCGA-LIHC, AMC and CHCC-HBV cohort were enrolled in bioinformatics analysis.Immunohistochemical staining of HBV-HCC specimens and ARID1A deficiency cellular models were used to validate the results of the analysis. Our results have shown that ARID1A deficiency promoted tumor proliferation and metastasis. More importantly, ARID1A deficiency in HBV-HCC was associated with the higher TMB, elevated immune activity, and up-regulated expression of immune checkpoint proteins, especially TIM-3 in HBV-HCC. Further, the expression of Galectin-9, which is the ligand of TIM-3, was elevated in the ARID1A knockout HBV positive cell line. To conclude, we have shown that the ARID1A deficiency was correlated with more active immune signatures and higher expression of immune checkpoints in HBV-HCC. Additionally, the present study provides insights to explore the possibility of the predictive role of ARID1A in HBV-HCC patients responsive to immunotherapy.

Interferon therapy improves survival in patients with hepatitis B virus-related hepatocellular carcinoma after curative surgery: a meta-analysis.

A novel study found interferon enhanced antitumor activity of anti-PD-1-based immunotherapy and played a crucial role in improving efficacy on HCC, but the opposite results about the efficacy of interferon on HBV-related HCC were obtained from previous clinical studies and meta-analyses. Thus, this meta-analysis aimed to re-evaluate whether interferon could improve survival and reduce recurrence of patients with HBV-related HCC after curative surgery. MEDLINE/PubMed, Cochrane Library, EMBASE, Web of Science and CNKI were searched for eligible studies from inception to November 2022 and a meta-analysis was done. 10 trials with a total of 2062 subjects were screened.Interferon significantly improved 1-, 2-, 3- and 5-year OS and 1-, 2- and 3-year DFS, and reduced 2-, 3- and 5-year recurrence rates of patients with HBV-related HCC after curative surgery. However, interferon did not improve 8-year OS and 5-year DFS, did not reduce 1-year recurrence rate. Interferon may significantly reduce recurrence and improve DFS of patients with HBV-related HCC after curative surgery, and finally improve the OS. However, the efficacy advantage may gradually weaken as time goes on. The clinical application of interferon combined with NAs recommended in this meta-analysis is needed to be further studied.

TEP SNORD12B, SNORA63, and SNORD14E as novel biomarkers for hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC)

PurposeThe alterations of RNA profile in tumor-educated platelets (TEPs) have been described as a novel biosource for cancer diagnostics. This study aimed to explore the potential snoRNAs in TEP as biomarkers for diagnostics of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC).MethodsPlatelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection.ResultsDown-regulated SNORD12B and SNORD14E as well as up-regulated SNORA63 were identified in TEP from HBV-related HCC, which could act as diagnostic biomarkers for HBV-related HCC as well as the early disease. Besides, TEP SNORD12B, SNORD14E, and SNORA63 facilitate the diagnostic performance of AFP and achieve favorable diagnostics efficiency for HBV-related HCC when combined with platelet parameters.ConclusionsAberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis.

The preliminary data of gene expressions and bioinformatics analysis of miR-146b-5p and miR-4510 in the Turkish population in HBV-related hepatocellular carcinoma.

It is reported that miRNAs play an important role in hepatocellular carcinogenesis and may serve as non-invasive biomarkers for hepatocellular carcinoma (HCC). MiR-4510 and miR-146b-5p expression levels have been found to be associated with HCC. However, their associations with hepatitis B virus (HBV)-related HCC (HBV-HCC) are yet to be explored. We aimed to assess the predictive value of expression levels of serum miR-4510 and miR-146b-5p in patients with HBV-HCC and performed bioinformatics analyses based on the miRNA expression profile. This cross-sectional study used the serum of 16 patients with Chronic Hepatitis B (CHB), 15 hepatitis B virus-related cirrhosis (HBV-cirrhosis), 15 HBV-HCC, and 16 healthy subjects. The total RNA was isolated from serum, and the expression of miRNAs was measured by qRT-PCR, calculated using the 2-ΔΔCt methods. MIENTURNET was used to predict miRNA-target gene interactions. The Network Analyst was used to build protein-protein interactions. There was a significant difference in miR-146b-5p between study groups (p=0.009). MiR-146b-5p expression was found to be significantly reduced in HBV-HCC compared to the HBV-cirrhosis group and healthy controls (p=0.005 and p=0.006, respectively). The serum miR-146b-5p levels might be a promising tool to be used as a non-invasive diagnostic biomarker for HCC. Our findings shed light on potential biomarkers for the diagnosis of HBV-HCC in terms of selected miRNAs. The target pathways of miR-146b-5p identified by our in-silico analysis to reveal the functional mechanism are "MAPK signaling pathways" and "Pathways in cancer."

Unveiling disulfidptosis-related genes in HBV-associated hepatocellular carcinoma: an integrated study incorporating transcriptome and Mendelian randomization analyses.

Disulfidptosis, a recently unveiled mechanism of demise, has been linked to an unfavorable prognosis in the context of hepatocellular carcinoma (HCC). However, few studies have focused on the causal link between disulfidptosis and HBV-related HCC (HBV-HCC). In this study, the Mendelian randomization (MR) analysis demonstrated that the risk of HCC increased with increasing genetic susceptibility to HBV, and the genetic changes of disulfidptosis were significantly associated with the increased risk of HBV-HCC. Within both the TCGA and GEO cohorts, it is possible to accurately forecast the prognosis of HBV-HCC by utilizing a risk score that is derived from a combination of GYS1, RPN1, SLC7A11, LRPPRC and CAPZB genes. GYS1, a potential therapeutic target for HBV-HCC, exhibits a remarkable positive correlation with immune infiltration and MSI when compared to other molecules. Furthermore, we demonstrated that silencing GYS1 effectively inhibits the tumor proliferation and metastasis of HBV-HCC in vitro and in vivo. Overall, this study expands the understanding of the potential roles of disulfidptosis in HBV-HCC and highlights GYS1 as a promising target for HBV-HCC.

Predictive Value of Peripheral Blood Eosinophil Count on the Efficacy of Treatment with Camrelizumab in Combination with Lenvatinib in Patients with Advanced Hepatitis B-Associated Hepatocellular Carcinoma.

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.

HBV viral load and tumor and non-tumor factors in patients with HBV-associated HCC.

Several tumor and non-tumor factors affect the prognosis of hepatocellular carcinoma (HCC) patients. This study aimed to investigate the effects of hepatitis B virus (HBV) viral load on tumor and non-tumor factors in patients with HBV-associated HCC. Patients with hepatitis B and HCC who presented to the HCC council at the Faculty of Medicine, Marmara University Liver Transplantation Institute, were included in our study. Patients were divided into two groups according to the presence or absence of HBV-DNA, and it was determined whether there were differences between these two groups with respect to tumor and non-tumor parameters. Comparison of serum alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), hepatitis B surface antigen (HBsAg), and C-reactive protein (CRP) levels between HBV-DNA negative and positive patients showed significant differences (respectively p<0.01, p<0.01, p<0.05, and p<0.05). A major finding was a very significant difference between the two patient groups in terms of portal vein invasion (PVI) and venous invasion (p<0.001 and p<0.01, respectively). However, there was no significant difference in metastasis or lymph node involvement between HBV-DNA negative and positive patients. Our findings suggest that HBV viral load plays an important role in PVI in HCC patients, and there is a significant relationship between HBV viral load and inflammation.