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HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC. [ABSTRACT FROM AUTHOR]

Background: To explore the anti‐tumor and anti‐virus key active ingredients of Sini Decoction Plus Ginseng Soup (SNRS) and their mechanisms. Methods: The main ingredients of SNRS were analyzed by network pharmacology, and quercetin was identified as the key active ingredient. Then, we obtained the targets of quercetin by using Drugbank, PharmMapper, and SwissTargetPrediction databases. Then, the targets of HBV‐related hepatocellular carcinoma (HBV‐related HCC) were obtained by using Genecards database. In addition, using the gene expression profiles of HBV‐related HCC patients in GEO database and the genes with the greatest survival difference in GEPIA 2 database identified the potential targets of quercetin. In addition, the mechanism of potential genes was studied through GO, KEGG analysis, and PPI network. Using AUC and survival analysis to evaluate the diagnostic and prognostic value of cyclin‐dependent kinase 1 (CDK1) and CCNB1. Finally, the effects of quercetin on proliferation of Hep3B and HepG2215 cells and the level of CDK1 and CCNB1 were verified in vitro. ELISA was used to measure the expression levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) after the intervention by quercetin for 24 h and 48 h in HepG2215 cell. Results: The first 10 key ingredients of SNRS were identified, and quercetin was the most key ingredient. The 101 potential quercetin targets were identified for the treatment of HBV‐related HCC. GO and KEGG showed that 101 potential target enrichment in cancer and cell cycle regulation. By Venn analysis, CDK1 and CCNB1 were intersection targets, which could be used as potential targets for the action of quercetin on HBV‐related HCC. Moreover, the expression of CDK1 and CCNB1 was highly expressed in the high‐risk group, while the OS rate was low. The 1‐year, 3‐year and 5‐year area under the curve (AUC) curves of CDK1 and CCNB1 were 0.724, 0.676, 0.622 and 0.745, 0.678, 0.634, respectively. Moreover, experimental results also showed that quercetin inhibited cell proliferation and reduced CDK1 expression in Hep3B and HepG2215 cells. The expressions of HBsAg and HBeAg in HepG2215 cell supernatant and cell gradually decreased with the increase of intervention time of quercetin and CDK1 inhibitor. Conclusions: Quercetin is a key ingredient of anti‐HBV‐related HCC activity and inhibits HBV replication in SNRS by inhibiting CDK1. [ABSTRACT FROM AUTHOR]

HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC.

Background: Ferroptosis and lncRNAs both play crucial roles in cancers. But the roles of ferroptosis-related lncRNAs (FRLncs) in HBV-related HCC (HBV-HCC) remain ambiguous. Methods: The gene expression profile and clinical data were originated from the Cancer Genome Atlas (TCGA) database. The risk signature was constructed by FRLncs based on the Cox regression analysis. The survival curve, Cox regression analysis, and time-dependent receiver operating characteristic (ROC) curve were adopted to verify the independence and reliability of the signature. A nomogram was established. Immune-infiltrating cells, immune functions, and checkpoints were analyzed. Results: A risk signature composed of 7 FRLncs (LINC00942, AC131009.1, POLH-AS1, AC090772.3, MKLN1-AS, AC009403.1, AL031985.3) was constructed and divided HBV-HCC patients into high- and low-risk groups. Patients in the high-risk group showed a poor prognosis. The area under curves (AUC) of the signature for 1-, 3-, and 5-year was satisfactory. A nomogram composed of gender, stage, age, grade, and risk signature was established. The risk signature and nomogram displayed appreciable independence and reliability in HBV-HCC patients. The T-cell CD8 + , monocyte, and macrophage M1 were expressed differently significantly in HCC patients, while macrophage M2 showed an obvious difference in the HBV-HCC patients between the different risk groups. PDCD1 and CTL4 were expressed higher in the high-risk group of HCC patients. Conclusion: A 7-lncRNA signature was identified as a potential prognostic predictor for HBV-HCC patients. Immune therapy may be a promising strategy for HCC patients, especially HBV-HCC patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose The 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). Methods Platelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection. Results Down-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. Conclusions Aberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis.

Jiaming Shen,1,2,* Xia Wang,2,* Guangde Yang,2,* Li Li,2 Juanjuan Fu,2 Wei Xu,3 Qingqiao Zhang,3 Xiucheng Pan2 1Department of Gastroenterology, People’s Hospital of Jingjiang, Taizhou, People’s Republic of China; 2Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 3Department of Interventional Radiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiucheng Pan, Tel +8618052268129, Email xzpxc68@126.comPurpose: Recently, the triple therapy of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs) has become a new treatment option for advanced or unresectable hepatocellular carcinoma (HCC) patients. We aimed to explore the liver injury and its effect on overall survival (OS) in patients treated with this combination therapy.Patients and Methods: Patients with HBV-related HCC who were treated with TACE-TKIs-ICIs from January 2020 to December 2021 were enrolled. Liver injury and survival time were the main endpoints of the study. Logistic regression analysis was used to analyze the factors associated with liver injury. Cox regression and Kaplan–Meier analysis were used to determine prognostic factors for OS.Results: As of March 2022, 52 of the 119 enrolled patients developed any grade hepatotoxicity: 15 cases with grade 1, 19 cases with grade 2, 16 cases with grade 3 and 2 cases with grade 4. Our analysis indicated that lack of antiviral prevention was a risk factor for liver injury (OR = 0.149; 95% CI: 0.050– 0.442; P = 0.001). The findings suggested that liver injury events (HR = 1.912; 95% CI: 1.031– 3.546; P = 0.040) was associated with patient death. The median OS of patients without liver injury, grade 1– 2 and grade 3– 4 liver injury were undefined, 13.7 months and 11.1 months, respectively (log-rank P = 0.034).Conclusion: Liver injury adverse events are common in HBV-related HCC patients treated with TACE-TKIs-ICIs. Patients who developed liver injury had a poor prognosis. For HBV-related HCC patients, effective prophylactic antiviral therapy and regular liver function testing are required before and during this triple therapy. Keywords: HBV-related HCC, TACE, TKI, ICI, liver injury, survival time

Bang Liu,1,2,* Jia Liu,3,* Xuan Mei,1,* Zhi-Qiang Zhang,1,2 Jian Fang,4 Li-Li Zhou,2 Jiao-Long Zheng,2 Hai-Yan Lin,2 Xiu-Ling Zhu,2 Dong-Liang Li1,2 1Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, 350025, People’s Republic of China; 2Department of Hepatobiliary Disease, 900TH Hospital of Joint Logistics Support Force, Fuzhou, 350025, People’s Republic of China; 3Department of Hepatobiliary Surgery, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 4Department of Hepatobiliary Medicine, The Third Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong-Liang Li, Department of Hepatobiliary Disease, Fuzong Clinical Medical College of Fujian Medical University & 900TH Hospital of Joint Logistics Support Force, Fuzhou, 350025, People’s Republic of China, Email ldliang900@163.comBackground: PVTT is a hallmark of advanced hepatocellular carcinoma (HCC). We aim to explore the influence of non-invasive biomarkers on the occurrence of PVTT and develop and validate models for predicting prognosis in HBV-related HCC patients without PVTT.Methods: A total of 1026 HBV-related HCC patients without PVTT were enrolled, with 515 in the training cohort, 216 in the internal validation cohort, and 295 in the external validation cohort. We conducted Cox regression analyses to discern the independent risk factors associated with PVTT events, PFS, and OS, then constructed and validated predictive models. The predictive and discriminatory capabilities of models were assessed using the calibration, time-dependent ROC, and DCA curves.Results: In our study, 136 patients (13.3%) experienced PVTT events during the follow-up period. The Cox regression analysis unveiled that male gender, AAPR ≤ 0.49, APRI > 0.48, extrahepatic metastasis, and multiple tumors were independent risk factors for PVTT. In the training cohort, non-invasive biomarkers (AAR and APRI), AFP, ascites, and tumor-related characteristics (extrahepatic metastasis, tumor diameter, tumor number, and PVTT event) were independent risk factors for both OS and PFS, whereas age and ALBI grade independently correlated with OS. The C-indexes of OS and PFS nomogram models were 0.795 and 0.733 in the training cohort, 0.765 and 0.716 in the internal validation cohort, and 0.780 and 0.722 in the external validation cohort, respectively. Our models demonstrated strong predictive and discriminative abilities in all cohorts and yielded a greater net benefit compared to three traditional staging systems.Conclusion: Non-invasive biomarkers are expected to be reliable predictors for assessing PVTT risk and predicting prognosis among HBV-related HCC patients without PVTT.Keywords: non-invasive biomarker, portal vein tumor thrombosis, HBV-related HCC, nomogram, prognosis

Han Chen,1,2 Dan Cao,1,2 Ning Han,1,2 Mingming Zhang,1,2 Wei Jiang,1,2 Xin Wang,1,2 Qinmin Zeng,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Hong Tang, Email tanghong6198@wchscu.cnIntroduction: Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1).Results: By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3’-UTR of FIH-1 mRNA by luciferase activity assay.Conclusion: HBV-miR-3 was related to HCC patients’ overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC. Keywords: HBV-miR-3, FIH-1, HBV-related HCC, angiogenesis

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 pancancer 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, proteinprotein 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. [ABSTRACT FROM AUTHOR]

Purpose: The 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). Methods: Platelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection. Results: Down-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. Conclusions: Aberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Background Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. Methods We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case–control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. Results Through a case–control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032–2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. Conclusion The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Abstract Background N6A methylation (m6A) is a significant epigenetic modification that critically impacts post-transcriptional regulation and tumor occurrence and development. While previous studies have identified a role for epigenetic regulation in hepatocellular carcinoma (HCC), the potential function of the m6A cluster in Hepatitis B virus (HBV)-related HCC remains unclear. Methods The related information was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Based on the expression of 20 m6A regulators, we comprehensively evaluated the m6A clusters and systematically explored the correlation between these clusters and immune cell infiltration characteristics of the tumor microenvironment (TME). The patients were divided into low- and high-m6A score groups. Then, the immune cell infiltration, chemokines, and cytokines levels, and drug sensitivity were further explored between the two groups. Results The m6A cluster predicted a better prognosis that was accompanied by increased immune cell infiltration. Using these results, an m6A score was established that could predict overall survival, immune checkpoints, and clinical treatments for patients with HBV-related HCC. This study demonstrated that m6A modifications affected tumorigenesis, TME, and the prognosis of patients with HBV-related HCC. Conclusion A comprehensive assessment of m6A patterns could improve the current understanding of immune cell infiltration patterns and inform the development of individualized cancer treatments.

Background: Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. Methods: We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case–control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. Results: Through a case–control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032–2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. Conclusion: The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a rapidly progressing cancer and the main reason for cancer-related deaths. There are numerous risk factors for HCC, of which hepatitis B virus (HBV) infection is recognized as a high risk. HBV infection is accompanied by gene integration, and the liver has undergone the process of continuous and repeated damage and repair. However, predictive factors of HBV-related HCC are still limited, and the prognostic regulatory genes have not been fully elucidated. This study aims to use bioinformatics analysis to search potential prognostic genes of HBV-related HCC. Based on the full utilization of the GEO database, we screened out prognostic-related genes by performing systematic Kaplan-Meier survival analysis. The differences of the transcriptional information and protein expression were verified in the TCGA and HPA databases respectively, and the clinical characteristics of the screened genes were described by the boxplot. Five prognostic-related genes we screened, including CDK1, MAD2L1, SPP1, TYMS, and CCNA2, are strongly linked with poor prognosis in HBV-related HCC. The five prognostic-related genes have realistic clinical significance and potential as prognostic markers, and may provide new directions for basic research and clinical diagnosis.

Background. Chronic hepatitis B virus (HBV) infection is the main pathogen of hepatocellular carcinoma. However, the mechanisms of HBV-related hepatocellular carcinoma (HCC) progression are practically unknown. Materials and Methods. The results of RNA-sequence and clinical data for GSE121248 and GSE17548 were accessed from the Gene Expression Omnibus data library. We screened Sangerbox 3.0 for differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was employed to select core modules and hub genes, and protein-protein interaction network module analysis also played a significant part in it. Validation was performed using RNA-sequence data of cancer and normal tissues of HBV-related HCC patients in the cancer genome atlas-liver hepatocellular cancer database (TCGA-LIHC). Results. 787 DEGs were identified from GSE121248 and 772 DEGs were identified from GSE17548. WGCNA analysis indicated that black modules (99 genes) and grey modules (105 genes) were significantly associated with HBV-related HCC. Gene ontology analysis found that there is a direct correlation between DEGs and the regulation of cell movement and adhesion; the internal components and external packaging structure of plasma membrane; signaling receptor binding, calcium ion binding, etc. Kyoto Encyclopedia of Genes and Genomes pathway analysis found out the association between cytokine receptors, cytokine-cytokine receptor interactions, and viral protein interactions with cytokines were important and HBV-related HCC. Finally, we further validated 6 key genes including C7, EGR1, EGR3, FOS, FOSB, and prostaglandin-endoperoxide synthase 2 by using the TCGALIHC. Conclusions. We identified 6 hub genes as candidate biomarkers for HBV-related HCC. These hub genes may act as an essential part of HBV-related HCC progression.

Background: N6A methylation (m6A) is a significant epigenetic modification that critically impacts post-transcriptional regulation and tumor occurrence and development. While previous studies have identified a role for epigenetic regulation in hepatocellular carcinoma (HCC), the potential function of the m6A cluster in Hepatitis B virus (HBV)-related HCC remains unclear. Methods: The related information was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Based on the expression of 20 m6A regulators, we comprehensively evaluated the m6A clusters and systematically explored the correlation between these clusters and immune cell infiltration characteristics of the tumor microenvironment (TME). The patients were divided into low- and high-m6A score groups. Then, the immune cell infiltration, chemokines, and cytokines levels, and drug sensitivity were further explored between the two groups. Results: The m6A cluster predicted a better prognosis that was accompanied by increased immune cell infiltration. Using these results, an m6A score was established that could predict overall survival, immune checkpoints, and clinical treatments for patients with HBV-related HCC. This study demonstrated that m6A modifications affected tumorigenesis, TME, and the prognosis of patients with HBV-related HCC. Conclusion: A comprehensive assessment of m6A patterns could improve the current understanding of immune cell infiltration patterns and inform the development of individualized cancer treatments. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs). Methods: In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation. Results: A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P=0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P=0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P=0.614). Conclusion: HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy. [ABSTRACT FROM AUTHOR]

Background: The functional ramifications of internal N7-methylguanosine (m7G) modification on RNAs have recently come to light, yet its regulatory influence on long noncoding RNAs (lncRNAs) during the inflammatory-carcinogenesis transformation process in hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC) remains largely unexplored. Methods: Clinical surgical samples encompassing HBV-related HCC, comprising both HCC tissue (tumor group, HBV+) and corresponding adjacent liver tissue (paracancerous group, HBV+), were collected for analysis. Additional adjacent normal liver tissues (normal group, HBV-) were acquired from patients with hepatic hemangioma, serving as controls. Employing MeRIP-seq, differential m7G levels of lncRNAs across these groups were compared to identify a subset of lncRNAs exhibiting continuous and dynamic changes in m7G modification. Subsequently, in vitro validation was conducted. Results: A total of 856 lncRNAs exhibited alterations in m7G modification when compared to paracancerous tissue and normal tissue. Similarly, 1775 lncRNAs displayed changes in m7G modification when comparing HCC tissue to paracancerous tissue. For intergroup comparison, orthogonal analysis revealed that 6 lncRNAs consistently demonstrated hyper-m7G modification. In vitro validation confirmed that among these 6 lncRNAs, TEKT4P2 and DNM1P41 exhibited m7G modification-dependent expression. Conclusions: This study provides a comprehensive analysis of lncRNA m7G modification during the inflammatory-carcinogenesis transformation process in HBV-mediated HCC. The findings highlight the potential for multiple lncRNAs to undergo m7G modification changes, with TEKT4P2 and DNM1P41 identified as promising molecular targets within this intricate regulatory landscape.

Objective To elucidate the impact of acute-phase protein serum amyloid A (aSAA) on microvascular invasion (MVI) and early recurrence in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods HBV-related HCC patients (n = 192) undergoing liver resection were included in the study. The protein levels of aSAA were analyzed by immunohistochemical staining in 172 tumor specimens, and further detected via western blotting in HCC and their corresponding portal vein tumor thrombus (PVTT) (n = 20). Cox and logit regression analysis was performed. Exploratory subgroup analysis was used to balance the potential confounders. Results HBV-related HCC patients with high aSAA levels tended to have high HBV-DNA loads. Logit and Cox regression analyses revealed high expression of aSAA is an independent risk factor not only for MVI (OR 5.384, 95% CI 2.286–13.301, P

Huasheng Huang,* Xiwen Liao,* Guangzhi Zhu, Chuangye Han, Xiangkun Wang, Chengkun Yang, Xin Zhou, Tianyi Liang, Ketuan Huang, Tao Peng Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Peng; Xiwen Liao, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Road 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China, Tel +86-771-5356528, Fax +86-771-5350031, Email pengtaogmu@163.com; LXWen1991@hotmail.comBackground: The aim of our study was to evaluate the potential of expression and single nucleotide polymorphism of Acyl-CoA binding domain containing 4 (ACBD4) gene as prognosis biomarkers in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after hepatectomy.Methods: HBV-related HCC patients from the First Affiliated Hospital of Guangxi Medical University and GSE14520 were included in the current study, as well as The Cancer Genome Atlas (TCGA) HCC verification cohort. Prognostic analysis and multiple functional enrichment analysis methods were used to evaluate the prognostic value and potential biological functions of the ACBD4 gene in HBV-related HCC.Results: We found that ACBD4 gene is highly expressed in normal liver tissues and markedly down-regulated in HBV-related HCC tissues. ACBD4 gene was significantly related to overall survival (OS) of HCC in TCGA and GSE14520 cohorts, and patients with low ACBD4 expression were markedly related to poor OS. Rs4986172 was observed as an OS biomarker after hepatectomy in the Guangxi HBV-related HCC cohort. The OS of rs4986172 GG genotype was worse than that of HCC patients with A allele (AA and AG genotypes). Multifunctional enrichment analysis suggested that ACBD4 gene is closely related to the metabolic, peroxisome proliferator-activated receptor and cytochrome P450 pathway. Through connectivity map, we also identified eight compounds that may be used as targeted therapeutic agents for ACBD4 gene in HBV-related HCC; these compounds were scopoletin, alfaxalone, bephenium hydroxynaphthoate, apramycin, 4,5-dianilinophthalimide, DL-thiorphan, aminohippuric acid and quinidine. Immune microenvironment analysis revealed that there were significant differences in immune scores of HBV-related HCC tumor tissues with different ACBD4 expression levels.Conclusion: Our study reveals that ACBD4 expression and rs4986172 can be serve as biomarkers of OS in HBV-related HCC patients after hepatectomy.Keywords: rs4986172, ACBD4, HBV-related HCC, overall survival, hepatectomy

Abstract Aims Hepatitis B Virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC) in East Asia. Here we aimed to further investigate the abundance of viral antigen and DNA within HBV-related HCC and surrounding tissues at histological level. Method In addition to routine histopathology, in situ hybridization (ISH) of HBV DNA and immunohistochemistry (IHC) of HBsAg were performed in tissues from 131 HBsAg-positive HCC patients undergoing liver resection. Serum α-fetoprotein together with basic biochemical and immunological parameter was also measured. Results Overall, the ISH of HBV DNA and IHC of HBsAg showed 31.3% and 92.9% positive rate respectively (p

HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Khan, Mao, Hu, Shi, Wang, Rehman and Li.)

To elucidate the impact of acute-phase protein serum amyloid A (aSAA) on microvascular invasion (MVI) and early recurrence in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). HBV-related HCC patients (n = 192) undergoing liver resection were included in the study. The protein levels of aSAA were analyzed by immunohistochemical staining in 172 tumor specimens, and further detected via western blotting in HCC and their corresponding portal vein tumor thrombus (PVTT) (n = 20). Cox and logit regression analysis was performed. Exploratory subgroup analysis was used to balance the potential confounders. HBV-related HCC patients with high aSAA levels tended to have high HBV-DNA loads. Logit and Cox regression analyses revealed high expression of aSAA is an independent risk factor not only for MVI (OR 5.384, 95% CI 2.286–13.301, P < 0.001) but also for early recurrence (HR 6.040, 95% CI 1.970–18.540, P = 0.002), overall recurrence (HR 3.720, 95% CI 2.140–6.450, P < 0.001), and overall survival (HR 4.15, 95% CI 2.380–7.230, P < 0.001). Subgroup analysis showed that the effects of aSAA were consistent across all subgroups examined. Additionally, the aSAA protein level was significantly higher in PVTT than that in its corresponding tumor specimen. A high HBV-DNA level and large tumor size were the independent risk factors for early HCC recurrence in patients with high levels of aSAA. High expression of aSAA was an independent risk factor for MVI and early tumor recurrence in HBV-related HCC patients after liver resection. The aSAA protein level could thus be a promising biomarker for predicting MVI and early recurrence in these patients. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is a life‐threatening cancer. Long noncoding RNAs participate in HBV‐related HCC progression. Based on the bioinformatics analysis, LINC00924 downregulation is positively related to unfavorable outcomes in patients with HBV‐related HCC. Herein, we detected the biological functions and regulatory system of LINC00924 in HCC. The LINC00924 downregulation in HBV‐related HCC tissues and cells was revealed by reverse transcription‐quantitative polymerase chain reaction. Functionally, as Transwell assays and western blotting indicated, LINC00924 elevation inhibited HCC cell invasion and epithelial‐mesenchymal transition (EMT). The binding site between LINC00924 and miR‐6755‐5p was determined by luciferase reporter assays. miR‐6755‐5p was confirmed to target NDRG2. miR‐6755‐5p upregulation decreased NDRG2 messenger RNA (mRNA) and protein levels. The mRNA and protein levels of NDRG2 were downregulated in tissues and cells. NDRG2 knockdown attenuated the inhibition induced by LINC00924 overexpression on invasion and EMT of HCC cells. In summary, LINC00924 increases NDRG2 expression to inhibit EMT by targeting miR‐6755‐5p in HBV‐related HCC. HIGHLIGHTS: LINC00924 upregulation inhibits the epithelial‐mesenchymal transition of HBV‐related HCC cellsLINC00924 sponges miR‐6755‐5p that targets NDRG2NDRG2 inhibition reverses the inhibitory effects of LINC00924 elevation on cell malignancy [ABSTRACT FROM AUTHOR]

Infection with the hepatitis B virus (HBV) continues to pose a major threat to public health as approximately 292 million people worldwide are currently living with the chronic form of the disease, for which treatment is non-curative. Chronic HBV infections often progress to hepatocellular carcinoma (HCC) which is one of the world's leading causes of cancer-related deaths. Although the process of hepatocarcinogenesis is multifaceted and has yet to be fully elucidated, several studies have implicated numerous long non-coding RNAs (lncRNAs) as contributors to the development of HCC. These host-derived lncRNAs, which are often dysregulated as a consequence of viral infection, have been shown to function as signals, decoys, guides, or scaffolds, to modulate gene expression at epigenetic, transcriptional, post-transcriptional and even post-translational levels. These lncRNAs mainly function to promote HBV replication and oncogene expression or downregulate tumor suppressors. Very few lncRNAs are known to suppress tumorigenesis and these are often downregulated in HCC. In this review, we describe the mechanisms by which lncRNA dysregulation in HBV-related HCC promotes tumorigenesis and cancer progression. [ABSTRACT FROM AUTHOR]

Aims: Hepatitis B Virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC) in East Asia. Here we aimed to further investigate the abundance of viral antigen and DNA within HBV-related HCC and surrounding tissues at histological level. Method: In addition to routine histopathology, in situ hybridization (ISH) of HBV DNA and immunohistochemistry (IHC) of HBsAg were performed in tissues from 131 HBsAg-positive HCC patients undergoing liver resection. Serum α-fetoprotein together with basic biochemical and immunological parameter was also measured. Results: Overall, the ISH of HBV DNA and IHC of HBsAg showed 31.3% and 92.9% positive rate respectively (p < 0.0001). The level of correlation between these two markers was much more significant in tumor (p < 0.0001) than in tumor-surrounding tissue (p = 0.01). HBsAg exhibited a much higher positive rate in tumor-adjacent tissue than in tumor tissue (86.6% versus 29.9%, p < 0.0001) with significantly different staining pattern. By contrast, the positive rate of HBV DNA ISH was comparable in tumor and surrounding tissue (17.6% versus 22.9%, p = 0.36). Yet the HBV DNA signal in tumor tissue showed predominant nuclear localization (87.0%) whereas staining pattern in adjacent tissue was mixed (43.3% nuclear localization, p = 0.0015). Finally, no significant association between intra-tumor HBV DNA/HBsAg positivity and major histological markers (microvascular invasion, tumor differentiation, etc.) or recurrence after surgery was observed. Conclusions: These data confirmed the largely integrated state of HBV DNA, weaker expression and altered localization of surface antigen in tumor compared with surrounding tissue. The strikingly different prevalence and localization of HBsAg and HBV DNA reflected the complex and heterogeneous mechanisms leading to HBV-induced tumorigenesis. [ABSTRACT FROM AUTHOR]

Infection with the hepatitis B virus (HBV) continues to pose a major threat to public health as approximately 292 million people worldwide are currently living with the chronic form of the disease, for which treatment is non-curative. Chronic HBV infections often progress to hepatocellular carcinoma (HCC) which is one of the world’s leading causes of cancer-related deaths. Although the process of hepatocarcinogenesis is multifaceted and has yet to be fully elucidated, several studies have implicated numerous long non-coding RNAs (lncRNAs) as contributors to the development of HCC. These host-derived lncRNAs, which are often dysregulated as a consequence of viral infection, have been shown to function as signals, decoys, guides, or scaffolds, to modulate gene expression at epigenetic, transcriptional, post-transcriptional and even post-translational levels. These lncRNAs mainly function to promote HBV replication and oncogene expression or downregulate tumor suppressors. Very few lncRNAs are known to suppress tumorigenesis and these are often downregulated in HCC. In this review, we describe the mechanisms by which lncRNA dysregulation in HBV-related HCC promotes tumorigenesis and cancer progression.

Despite the effectiveness of hepatitis B virus (HBV) vaccination in reducing the prevalence of chronic HBV infection as well as the incidence of acute hepatitis B, fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), there was still a large crowd of chronically infected populations at risk of developing cirrhosis or HCC. In this study, we established a comprehensive prognostic system covering multiple signatures to elevate the predictive accuracy for overall survival (OS) of hepatitis B virus carriers with HCC development. Weighted Gene Co-Expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and multivariate COX analysis, along with a suite of other online analyses were successfully applied to filtrate a three-gene signature model (TP53, CFL1, and UBA1). Afterward, the gene-based risk score was calculated based on the Cox coefficient of the individual gene, and the prognostic power was assessed by time-dependent receiver operating characteristic (tROC) and Kaplan–Meier (KM) survival analysis. Furthermore, the predictive power of the nomogram, integrated with the risk score and clinical parameters (age at diagnosis and TNM stage), was revealed by the calibration plot and tROC curves, which was verified in the validation set. Taken together, our study may be more effective in guiding the clinical decision-making of personalized treatment for HBV carriers.

Despite the effectiveness of hepatitis B virus (HBV) vaccination in reducing the prevalence of chronic HBV infection as well as the incidence of acute hepatitis B, fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), there was still a large crowd of chronically infected populations at risk of developing cirrhosis or HCC. In this study, we established a comprehensive prognostic system covering multiple signatures to elevate the predictive accuracy for overall survival (OS) of hepatitis B virus carriers with HCC development. Weighted Gene Co-Expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and multivariate COX analysis, along with a suite of other online analyses were successfully applied to filtrate a three-gene signature model (TP53 , CFL1 , and UBA1). Afterward, the gene-based risk score was calculated based on the Cox coefficient of the individual gene, and the prognostic power was assessed by time-dependent receiver operating characteristic (tROC) and Kaplan–Meier (KM) survival analysis. Furthermore, the predictive power of the nomogram, integrated with the risk score and clinical parameters (age at diagnosis and TNM stage), was revealed by the calibration plot and tROC curves, which was verified in the validation set. Taken together, our study may be more effective in guiding the clinical decision-making of personalized treatment for HBV carriers. [ABSTRACT FROM AUTHOR]

Background: Long non‐coding RNA (lncRNA) plays an essential role in hepatitis B virus‐related hepatocellular carcinoma (HBV‐related HCC) occurrence and development. Single nucleotide polymorphism (SNP) may affect HBV‐related HCC susceptibility by altering the function of lncRNA. However, the relationship between lncRNA SNPs and HBV‐related HCC occurrence and development is still unclear. Methods: In the present study, based on HBV‐related HCC genome‐wide association studies, eight potentially functional SNPs from two lncRNAs were predicted using a set of bioinformatics strategies. In 643 HBV‐related HCC patients, 549 CHB carriers, and 553 HBV natural clearance subjects from Southern Chinese, we evaluated associations between SNPs and HBV‐related HCC occurrence or development with odds ratio (OR) and 95% confidence interval (CI) under credible genetic models. Results: In HBV‐related HCC patients, rs9908998 was found to significantly increase the risk of lymphatic metastasis under recessive model (Adjusted OR = 1.95, 95% CI = 1.20–3.17). Lnc‐RP11‐150O12.3 rs2275959, rs1008547, and rs11776545 with cancer family history may show significant multiplicative and additive interactions on HBV‐related HCC susceptibility (all pAdjusted <.05). The associations of rs2275959, rs1008547, and rs11776545 with distant metastasis of HBV‐related HCC patients were observed in additive model (Adjusted OR = 1.45, 95% CI = 1.06–1.97 for rs2275959; Adjusted OR = 1.45, 95% CI = 1.06–1.98 for rs1008547; Adjusted OR = 1.40, 95% CI = 1.03–1.91 for rs11776545). Conclusion: Taken together, lnc‐ACACA‐1 rs9908998, lnc‐RP11‐150O12.3 rs2275959, rs1008547, and rs11776545 might be predictors for HBV‐related HCC risk or prognosis. [ABSTRACT FROM AUTHOR]

Chengkun Yang,1,* Hao Su,1,* Xiwen Liao,1 Chuangye Han,1 Tingdong Yu,1 Guangzhi Zhu,1 Xiangkun Wang,1 Cheryl Ann Winkler,2 Stephen J O’Brien,3–5 Tao Peng1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China; 2Basic Research Laboratory, CCR, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD, USA; 3Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, MD, USA; 4Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St Petersburg, Russia; 5Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL, USA *These authors contributed equally to this work Abstract: Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver. Transforming growth factor beta 1 (TGFB1) and marker of proliferation Ki-67 (MKI67) regulate cell proliferation, differentiation, and growth. The association between MKI67 and TGFB1 expression and its clinical implications in HCC remain unknown.Methods: Public databases were used to analyze TGFB1 and MKI67 expression in different pathologic grades/stages and tissue types of HCC. The association between MKI67 and TGFB1 expression was explored using pathway analysis and in a HepG2 cell line treated with TGFB1. Survival analysis was performed to evaluate the prognostic value of TGFB1 and MKI67 expression in patients with hepatitis B virus (HBV)-related HCC. Results: We identified that MKI67 expression was upregulated in liver cancer tissues. MKI67 and TGFB1 expression levels were different in various stages and tissue types of liver cancer. Furthermore, MKI67 expression was associated with TGFB1 expression in liver cancer tissues and HepG2 cells. Patients with HBV-related HCC and a higher level of MKI67 expression had a worse prognosis. Moreover, a nomogram was conducted to predict the clinical outcomes of patients with HBV-related HCC. Conclusion: MKI67 expression level was associated with TGFB1 expression in liver cancer tissues and a HepG2 cell line. MKI67 expression level can predict the clinical outcomes of patients with HBV-related HCC. Keywords: MKI67, TGFB1, HBV-related HCC, nomogram

Background/Aims: Hepatocellular carcinoma (HCC) is a common malignant tumor with a high rate of recurrence. Immunohistochemical analysis of the marker of proliferation Ki-67 (MKI67) is used to assess proliferation activity of HCC The regulation of MKI67 expression remains unclear in HCC This study aims to explore the association between MKI67 expression and gene variants. Methods: A total of 195 hepatitis B virus (HBV)-related HCC patients were genotyped using Illumina HumanExome BeadChip-12-1_A (242,901 markers). An independent cohort (97 subjects) validated the association of polymorphism determinants and candidate genes with MKI67 expression. The relationships between MKI67 with p53 and variants of candidate genes in the clinical outcomes of HCC patients were analyzed. Results: We found that MKI67 combined with p53 was associated with a 3-year recurrence-free survival and five variants near TTN and CCDC8 were associated with MKI67 expression. TTN harboring rs2288563-TT and rs2562832-AA+CA indicated a favorable outcome for HCC patients. Conclusion: Variants near TTN and CCDC8 were associated with MKI67 expression, and rs2288563 and rs2562832 in TTN are potential biomarkers for the prediction of clinical outcomes in HBV-related HCC patients.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Lu, Yu, Mei, Liu, Zheng, Zhou, Lin, Zhu and Li.)

Background: The functional ramifications of internal N7-methylguanosine (m7G) modification on RNAs have recently come to light, yet its regulatory influence on long noncoding RNAs (lncRNAs) during the inflammatory-carcinogenesis transformation process in hepatitis B virus (HBV)-mediated hepatocellular carcinoma (HCC) remains largely unexplored., Methods: Clinical surgical samples encompassing HBV-related HCC, comprising both HCC tissue (tumor group, HBV+) and corresponding adjacent liver tissue (paracancerous group, HBV+), were collected for analysis. Additional adjacent normal liver tissues (normal group, HBV-) were acquired from patients with hepatic hemangioma, serving as controls. Employing MeRIP-seq, differential m7G levels of lncRNAs across these groups were compared to identify a subset of lncRNAs exhibiting continuous and dynamic changes in m7G modification. Subsequently, in vitro validation was conducted., Results: A total of 856 lncRNAs exhibited alterations in m7G modification when compared to paracancerous tissue and normal tissue. Similarly, 1775 lncRNAs displayed changes in m7G modification when comparing HCC tissue to paracancerous tissue. For intergroup comparison, orthogonal analysis revealed that 6 lncRNAs consistently demonstrated hyper-m7G modification. In vitro validation confirmed that among these 6 lncRNAs, TEKT4P2 and DNM1P41 exhibited m7G modification-dependent expression., Conclusions: This study provides a comprehensive analysis of lncRNA m7G modification during the inflammatory-carcinogenesis transformation process in HBV-mediated HCC. The findings highlight the potential for multiple lncRNAs to undergo m7G modification changes, with TEKT4P2 and DNM1P41 identified as promising molecular targets within this intricate regulatory landscape., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer mortality in New Zealand due to endemic hepatitis B virus (HBV) infection and recent hepatitis C virus (HCV) and obesity epidemics. Aim: To describe the changing landscape of HCC referred to a national HCC service over a 20‐year period, including trends in underlying liver disease, screening uptake and access to curative treatments, and to determine the impact of screening on outcomes with a comparison between screened detected and non‐screened detected cases. Methods: All newly diagnosed cases of HCC referred to New Zealand Liver Transplant Unit between 1998 and 2017 were included. Data on patient demographics, liver disease aetiology, screening status and treatment modalities were collected. Results: HCC diagnosis rates have increased from 24 cases in 1998 to 250 in 2017, an increase of 20% per annum. The total of 1985 HCC cases was divided into three cohorts (Era 1: 1998–2009; Era 2: 2009–2014; Era 3: 2014–2017), each comprising 661–662 patients. During the study period, overall survival improved (P = 0.005). The proportion with screen‐detected HCC was similar across the three cohorts (44% in Era 1, 42% in Era 2 and 47% in Era 3). Five‐ and 10‐year survival was higher in screen‐detected cases (49 and 43%) than in non‐screen detected cases (14 and 10%), P < 0.0001. Survival was higher in patients with HCV and HBV than in those with non‐alcoholic steatohepatitis (NASH) or alcoholic liver disease (ALD) – 5 and 10‐year survival was 40 and 34% in HCV‐HCC, 30 and 26% in HBV–HCC, 15 and 14% in NASH‐HCC, 13 and 10% in ALD‐HCC, P < 0.0001. Conclusion: Better outcomes in patients with HBV‐ or HCV‐related HCC than in those with NASH‐related or ALD‐related HCV may reflect better screening uptake and better access to curative therapies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. Hepatitis B virus (HBV) is one of the leading causes of HCC, but the precise mechanisms by which this infection promotes cancer development are not fully understood. Recently, miR‐340‐5p, a microRNA (miRNA) that has been identified as a cancer suppressor gene, was found to inhibit the migration and invasion of liver cancer cells. However, the effect of miR‐340‐5p on cell proliferation and apoptosis in HBV‐associated HCC remains unknown. In our study, we show that miR‐340‐5p plays an important role during HBV infection and hepatocellular carcinoma development. Specifically, this miRNA directly binds to the mRNA encoding activating transcription factor 7 (ATF7), a protein that both promotes cell proliferation and suppresses apoptosis through its interaction with heat shock protein A member 1B (HSPA1B). We further found that miR‐340‐5p is downregulated by HBV, which enhances ATF7 expression, leading to enhanced cell proliferation and inhibition of apoptosis. Notably, ATF7 is upregulated in HCC tissue, suggesting that HBV may target miR‐340‐5p in vivo to promote ATF7/HSPA1B‐mediated proliferation and apoptosis and regulate liver cancer progression. This work helps to elucidate the complex interactions between HBV and host miRNAs and further suggests that miR‐340‐5p may represent a promising candidate for the development of improved therapeutic strategies for HCC. [ABSTRACT FROM AUTHOR]

The nuclear factor E2-related factor 2 (NRF2) signaling pathway is one of the most important cell defense pathways. However, it is unclear whether genetic variants in NRF2 signaling pathway genes are associated with the survival of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). In the present study, we utilized a new hypothesis-driven approach based on biological pathways to investigate the associations between 17919 single nucleotide polymorphisms (SNPs) in 137 NRF2 signaling pathway genes and the overall survival (OS) of 866 patients with HBV-related HCC. As a result, two independent SNPs with potential biological function were identified to be significantly associated with HBV-related HCC OS: [ SLC2A9 rs28643326 T>C: hazard ratio (HR) = 0.74, 95% confidence interval (95% CI) = 0.62-0.89, P < 0.001 and SLC5A10 rs2472711 G>T: HR = 0.81, 95% CI = 0.71-0.93, P = 0.003, respectively]. The expression quantitative trait loci (eQTL) analysis further revealed that the rs28643326 C allele was significantly associated with increased levels of SLC2A9 mRNA expression ( P < 0.001), and higher mRNA expression levels of SLC2A9 in adjacent normal liver tissues were associated with better survival. Although the association between the rs2472711 T allele and the mRNA expression of SLC5A10 was not statistically significant ( P = 0.200), the fact that rs2472711 is located at the DNase I hypersensitivity site and is a marker for promoter and enhancer histones also suggests that it may have the function of regulating its corresponding gene expression. In conclusion, genetic variants of NRF2 signaling pathway genes may serve as potential prognostic biomarkers for HBV-related HCC and also provide a solid basis for further mechanistic exploration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/Aims. Hepatocellular carcinoma (HCC) is a common malignant tumor with a high rate of recurrence. Immunohistochemical analysis of the marker of proliferation Ki-67 (MKI67) is used to assess proliferation activity of HCC. The regulation of MKI67 expression remains unclear in HCC. This study aims to explore the association between MKI67 expression and gene variants. Methods: A total of 195 hepatitis B virus (HBV)-related HCC patients were genotyped using Illumina HumanExome BeadChip-12-l_A (242,901 markers). An independent cohort (97 subjects) validated the association of polymorphism determinants and candidate genes with MKI67 expression. The relationships between MKI67 with p53 and variants of candidate genes in the clinical outcomes of HCC patients were analyzed. Results: We found that MKI67 combined with p53 was associated with a 3-year recurrence-free survival and five variants near TTN and CCDC8 were associated with MKI67 expression. TTN harboring rs2288563-TT and rs2562832-AA+CA indicated a favorable outcome for HCC patients. Conclusion: Variants near TTN and CCDC8 were associated with MKI67 expression, and rs2288563 and rs2562832 in TTN are potential biomarkers for the prediction of clinical outcomes in HBV-related HCC patients. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection is a major risk factor which can lead to development of hepatocellular carcinoma (HCC). Tissue transglutaminase-2 (TG2) has been shown to be critical for cancer progression. However, how TG2 promotes the progression of HBV-related HCC remains unknown. In this study, we aimed to explore the expression and function of TG2 on HBV-related HCC progression. The expression levels of TG2 were examined in a series of HBV-related HCC tissues and a panel of HCC cell lines. The effects of TG2 knockdown on the proliferation and migration of HBV-related cells were determined. TG2 expression was found to be significantly upregulated in HBV-related HCC tissues. TG2 expression was higher in HBV-related HCC cell lines than HBV-unrelated HCC cell lines. Moreover, inhibition of TG2 in HCC cell lines HepG2.2.15 and Hep3B could inhibit cell proliferation, migration, and invasion in vitro. Our results indicated that TG2 could serve as a promising target for treatment of HBV-related HCC patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to access hepatitis B virus (HBV) reactivation and its effect on survival in HBV-related hepatocarcinoma (HCC) patients who underwent transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitors (ICIs)., Methods: In this single-center retrospective study, we enrolled 119 HBV-related unresectable advanced HCC patients receiving TACE combined with TKIs plus ICIs. Risk factors for HBV reactivation were analyzed by logistic regression. Kaplan-Meier method was applied to draw the survival curve, and log-rank test was used to compare survival between patients with and without HBV reactivation., Results: A total of 12 patients (10.1%) encountered HBV reactivation in our study, of which only 4 patients received antiviral prophylaxis. The incidence of HBV reactivation was 1.8% (1/57) in patients with detectable baseline HBV DNA and 4.2% (4/95) in patients with antiviral prophylaxis respectively. Lack of prophylactic antiviral treatment (OR=0.047, 95%CI 0.008-0.273, P =0.001) and undetectable HBV DNA (OR=0.073, 95%CI 0.007-0.727, P =0.026) were independent risk factors for HBV reactivation. The median survival time (MST) for all patients was 22.4 months. No survival difference was observed in patients with or without HBV reactivation. (MST: undefined vs 22.4 months, log-rank test: P =0.614)., Conclusion: HBV reactivation could occur in HBV-related HCC patients who treated with TACE in combination with TKIs plus ICIs. Before and during the combination treatment, it is necessary to routinely monitor HBV DNA and to take effective prophylactic antiviral therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shen, Wang, Wang, Wen, Yang, Li, Fu and Pan.)

IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95 % CI 0.35-0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95 % CI 0.99-1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95 % CI 1.10-1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95 % CI 0.45-0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development. [ABSTRACT FROM AUTHOR]

Background: DNA methylation mainly affects tumor suppressor genes in the development of hepatocellular carcinoma (HCC). However, sera methylation of specific genes in hepatitis B virus (HBV)-related HCC remains unknown.Aims: The purpose of this study was to identify methylation frequencies of sera E-cadherin (CDH1), DNA methyltransferase 3b (DNMT3b) and estrogen receptor 1 (ESR1) promoter in HBV-related HCC and analyze the associated clinical significance.Methods: Methylation-specific PCR was used to determine the frequencies of DNA methylation for CDH1, DNMT3b and ESR1 genes in sera from 183 patients with HCC, 47 liver cirrhosis (LC), 126 chronic hepatitis B (CHB), and 50 normal controls (NCs).Results: Significantly higher frequencies of methylation of CDH1, DNMT3b and ESR1 were found in HBV-related HCC compared with LC, CHB and NCs. Nodule numbers, tumor size and the presence of liver cirrhosis were significantly associated with gene methylation status in HBV-related HCC. Moreover, HBV may have a strong and enhanced effect on the concurrent methylation of CDH1, DNMT3b and ESR1 in HBV-related HCC. More importantly, combined methylation as a biomarker displayed significantly higher diagnostic value than AFP to discriminate HCC from CHB and LC.Conclusions: Aberrant sera DNA methylation of CDH1, DNMT3b and ESR1 gene promoters could be a biomarker in the early diagnosis of HBV-related HCC. [ABSTRACT FROM AUTHOR]

Circulating microRNAs (miRNAs) are emerging as promising biomarkers for cancer; however, the significance of circulating miRNAs in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains largely unknown. Based on our prior observations that miRNA-101 (miR-101) is downregulated by HBV and induces epigenetic modification, we sought to test whether circulating miR-101 may serve as a potential biomarker for HCC. The expression of miR-101 in HCCs and serum was evaluated by real-time polymerase chain reaction. Tissue and serum miR-101 levels were assessed in samples from patients with HBV-related HCC and healthy controls. A potential correlation was also evaluated between miR-101 expression and the clinicopathological features and prognosis of HCC patients. miR-101 was downregulated in HBV-related HCC tissues compared with adjacent noncancerous tissues. Furthermore, the miR-101 levels in these tissues from HCC patients were signiicantly lower than those in tissues from control subjects. Notably, serum miR-101 levels were found to have an inverse correlation with tissue miR-101 expression levels. The expression of serum miR-101 in patients with HBV-related HCC was signiicantly higher than that in the healthy controls, and this increase correlated with hepatitis B surface antigen positivity, HBV DNA levels and tumor size. These results indicate that different factors govern the levels of miR-101 in the tissue and serum of HCC patients. Given the marked and consistent increase in serum miR-101 levels in HCC patients, circulating miR-101 may serve as a promising biochemical marker for monitoring the progression of tumor development in HBV-related HCC. [ABSTRACT FROM AUTHOR]

Abstract: Hepatitis B virus x (HBx) protein is involved in the initiation and progression of HBV-related hepatocellular carcinoma (HCC) by regulating host protein-coding genes. However, the role of HBx in the epigenetic repression of miRNAs, which play important roles in gene regulation during hepatocarcinogenesis, remains largely unknown. In this study, the expression of miR-132 in HCC cells, HBV-related HCC tissues, and serum were determined using real-time PCR. The level of DNA methylation on the promoter of miR-132 was examined using methylation-specific PCR (MSP). MiR-132 was functionally characterized in HCC cells with transiently altered miR-132 expression. HBx-induced DNA hypermethylation of the promoter of miR-132 was found to be more prevalent in HBx-expressing HepG2 cells than in control cells. Consistently, MiR-132 expression was also more frequently down-regulated in HBV-related HCC tissues than in adjacent noncancerous hepatic tissues and had a significant inverse correlation with HBx expression in HBV-related HCCs. Serum miR-132 levels were found to be significantly correlated with levels in tumor tissue. Finally, proliferation and colony formation of HCC cells were found to be suppressed by miR-132-mediated inhibition of the Akt-signaling pathway in miR132 transfected cells. Our study has demonstrated the epigenetic repression of miR-132 expression through DNA methylation induced by HBx. This work provides novel mechanistic insights into HBV-mediated hepatocarcinogenesis and suggests that miR-132 may be a promising biochemical marker and may have therapeutic applications in HBV-related HCC. [Copyright &y& Elsevier]

Abstract: The hepatitis B virus x (HBx) protein has been implicated in HBV-related hepatocellular carcinoma (HCC) pathogenesis. However, whether HBx regulates miRNA expression that plays important roles in gene regulation during hepatocarcinogenesis remains unknown. The expression of microRNA-101 (miR-101) in HBV-related HCC tissues and HCC cells was evaluated by real-time PCR. The direct target of miR-101, DNA methyltransferase 3A (DNMT3A), was identified in silico and validated using a 3′-UTR reporter assay. miR-101 was functionally characterized in cells with transiently altered miR-101 expression. HBx expression was found to have a significant inverse correlation with miR-101 expression in HBx-expressing HepG2 compared to control HepG2 cells. miR-101 expression was frequently down-regulated in HBV-related HCC tissues compared to adjacent noncancerous hepatic tissues and had a significant inverse correlation with DNMT3A expression in HBV-related HCCs. Further characterization of miR-101 revealed that it negatively regulated DNA methylation partly through targeting DNMT3A. HBx-mediated miR-101 down-regulation and DNMT3A up-regulation supported the enhanced DNA methylation of several tumor-suppressor genes in HBx-expressing cells. Our studies demonstrating the deregulation of miR-101 expression by HBx may provide novel mechanistic insights into HBV-mediated hepatocarcinogenesis and identify a potential miRNA-based targeted approach for treating HBV-related HCC. [Copyright &y& Elsevier]