• Epstein–Barr virus
• episome
• genome integration
• hepatitis B virus
• latency
• oncogenic viruses
• papillomavirus
• persistence
• retrovirus

• Virus Integration
• Humans
• Carcinogenesis/genetics
• Genome, Viral
• Virus Replication
• Animals
• Virus Diseases/virology
• Virus Diseases/genetics

• Ricerca Corrente linea 3 epatiti Ministero della Salute

• HBV
• HBV x-protein
• HBx
• HCC
• Hepatitis B
• Hepatocellular carcinoma
• STAT3

• HBV-specific T-cell response
• hepatitis B virus
• hepatocellular carcinoma
• immune response

• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/virology
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/virology
• Hepatitis B virus/immunology
• Adaptive Immunity
• T-Lymphocytes, Regulatory/immunology
• Programmed Cell Death 1 Receptor/immunology
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/pharmacology
• Hepatitis B/immunology
• Hepatitis B/virology
• Hepatitis B/complications
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/virology
• Hepatitis B, Chronic/complications
• CD4-Positive T-Lymphocytes/immunology
• T-Lymphocytes/immunology
• Immunotherapy

• Clinical Trials
• Curcuma longa L
• Gut–Liver Axis
• Hepatobiliary Diseases
• Pharmacotherapeutic Properties

• Humans
• Curcuma/chemistry
• Liver
• Digestive System Diseases/drug therapy
• Digestive System Diseases/pathology

• Animal model
• Hepatocellular carcinoma
• Immunotherapy

• 21377772D; H2022406034 Natural Science Foundation of Hebei Province
• 81672700 National Natural Science Foundation of China
• Award for Liaoning Distinguished Professor

• CtDNA
• HBV
• HCC
• chronic hepatitis B (CHB)
• circulatory tumor DNA (ctDNA)
• ddPCR
• driver mutation

• Humans
• CD8-Positive T-Lymphocytes
• Carcinoma, Hepatocellular
• Killer Cells, Natural
• Liver Neoplasms

Liver cancer is one of the most common cancers in the world, and the rate of liver cancer is high due to the of its illness. The main risk factor for liver cancer is infection with the hepatitis B virus (HBV), but a considerable number of genetic and epigenetic factors are also directly or indirectly involved in the underlying pathogenesis of liver cancer. In particular, the apolipoprotein B mRNA editing enzyme, catalytic peptide-like protein (APOBEC) family (DNA or mRNA editor family), which has been the focus of virology research for more than a decade, has been found to play a significant role in the occurrence and development of various cancers, providing a new direction for the research of liver cancer. APOBEC3B is a cytosine deaminase that controls a variety of biological processes, such as protein expression, innate immunity, and embryonic development, by participating in the process of cytidine deamination to uridine in DNA and RNA. In humans, APOBEC3B has long been known as a DNA editor for limiting viral replication and transcription. APOBEC3B is widely expressed at low levels in a variety of normal tissues and organs, but it is significantly upregulated in different types of tumor tissues and tumor lines. Thus, APOBEC3B has received increasing attention in various cancers, but the role of APOBEC3B in the occurrence and development of liver cancer due to infection with HBV remains unclear. This review provides a brief introduction to the pathogenesis of hepatocellular carcinoma induced by HBV, and it further explores the latest results of APOBEC3B research in the development of HBV and liver cancer, thereby providing new directions and strategies for the treatment and prevention of liver cancer.

• CD24
• cluster of differentiation 24
• polymorphism
• single nucleotide
• viral hepatitis

• hepatocellular carcinoma
• nano-delivery systems
• nanoparticles
• target therapy
• tumor microenvironment

• Antiviral Agents/therapeutic use
• Hepatitis B
• Hepatitis B virus
• Hepatitis B, Chronic/drug therapy
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Neoplasms/etiology

• covalently closed circular DNA
• hepatitis B virus
• interferon
• interferon-induced protein 44-like
• primary human hepatocyte

• MTA1
• biomarker
• chronic hepatitis
• hepatitis B virus
• hepatocarcinogenesis
• hydrodynamic injection
• oncogene
• splice variant
• transgenic mice

• Animals
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Hepatitis B/complications
• Hepatitis B/pathology
• Hepatitis B virus/genetics
• Hepatitis B virus/pathogenicity
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Liver Neoplasms, Experimental/virology
• Marmota
• Mice
• Mice, Transgenic
• Repressor Proteins/chemistry
• Repressor Proteins/metabolism
• Trans-Activators/chemistry
• Trans-Activators/metabolism

• MOST 105-2314-B-002-115-MY2 Ministry of Science and Technology, Taiwan
• MOST 106-2622-B-002-007-CC3 Ministry of Science and Technology, Taiwan
• MOST 107-2314-B-002-028-MY3 Ministry of Science and Technology, Taiwan
• MOST 108-2321-B-002-039 Ministry of Science and Technology, Taiwan
• NTUH 108-S4124 National Taiwan University Hospital

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

• adaptive immunity
• hepatitis B virus
• hepatocellular carcinoma
• immune balance
• immune cells
• innate immunity

• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/pathology
• Carcinogenesis/immunology
• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/pathology
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology

• HR21C1003, HI19C0872 Korea Health Industry Development Institute

This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.

• Woodchuck
• Hepatitis B virus
• Chronic infection
• Liver disease
• Hepatocellular carcinoma
• Cancer treatment

• HBV DNA integration
• HBV RNA
• HBV surface antigen (HBsAg)
• HBcr antigen
• biomarkers
• hepatitis B
• hepatocellular carcinoma

Chronic hepatitis B and C viral infections are major risk factors for hepatocellular carcinoma (HCC) in the United States and worldwide. Direct and indirect mechanisms of viral infection lead to the development of HCC. Chronic viral infection leads to inflammation and liver damage, culminating in cirrhosis, the penultimate step in the progression toward HCC. Host, viral, and environmental factors likely interact to promote oncogenesis. Clinical considerations include recommendations for screening for HCC in persons at risk, treatment with antivirals, and an emerging role for immunotherapy in HCC. We pose unanswered questions regarding HCC susceptibility and pathogenesis in the setting of chronic hepatitis B and C.

• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/therapy
• Endoplasmic Reticulum Stress
• Hepatitis B/complications
• Hepatitis C/complications
• Humans
• Immunotherapy
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Sustained Virologic Response

• K08 DK106478 NIDDK NIH HHS

• HDAC inhibitor
• cGMP phosphodiesterase inhibitor
• hepatobiliary carcinogenesis
• histone deacetylases
• liver fibrosis
• precision medicine

• PI16/01126, PI16/00598, PI19/00819, PI15/01132, PI18/01075 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
• Miguel Servet Program CON14/00129 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
• CPII19/00008 Instituto de Salud Carlos III (ISCIII) co-financed by Fondo Europeo de Desarrollo Regional (FEDER) Una manera de hacer Europa
• Rare Cancers 2017 Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation)
• 58/17 Gobierno de Navarra Salud
• HEPACARE La Caixa Foundation
• 06119JB AMMF
• ESCALON project, grant number H2020-SC1-BHC-2018-2020 Horizon 2020 (H2020)
• EiTB Maratoia : BIO15/CA/016/BD, BIO15/CA/011 BIOEF (Basque Foundation for Innovation and Health Research
• 2017111010 Department of Health of the Basque Country
• 2016222001, 2017222014, 2018222029, 2019222054, 2020333010 Euskadi RIS3
• KK-2020/00008 Elkartek
• SA063P17 Junta de Castilla y Leon
• LCF/PR/HP17/52190004 La Caixa Foundation
• SAF2016-75197-R, SAF2017-88933-R, SAF2017-87301-R, PID2019-104878RB-100, PID2019-104265RB-100 Mineco-Feder
• Ayudas a Equipos de Investigación Científica Umbrella 2018 Fundación BBVA
• Severo Ochoa Excellence Accreditation SEV-2016-0644 MCIU
• Centro Internacional sobre el Envejecimiento MCIU
• OLD-HEPAMARKER, 0348_CIE_6_E Centro Internacional sobre el Envejecimiento
• PC-TCUE18-20_051 University of Salamanca Foundation
• 201916-31 Fundació Marato TV3
• RYC2018-024475-1 Ramón y Cajal Program

• biomarker
• chronic liver disease
• extracellular vesicles
• hepatic fibrosis
• therapy

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

• Carcinoma, Hepatocellular
• Hepatocytes
• Hippo
• Liver
• YAP/TAZ

• Hepatitis B virus (HBV)
• Hepatocellular carcinoma (HCC)
• Immune checkpoint inhibitors
• Immunotherapy

• 2′-5′-oligoadenylate synthase 2
• apolipoprotein B mRNA editing enzyme catalytic subunit 3G
• covalently closed circular DNA
• hepatitis B virus
• interferon-gamma
• signal transducer and activator of transcription 1

An effective prophylactic hepatitis B virus (HBV) vaccine has long been available but is ineffective for chronic infection. The primary cause of chronic hepatitis B (CHB) and greatest impediment for a therapeutic vaccine is the direct and indirect effects of immune tolerance to HBV antigens. The resulting defective CD4⁺/CD8⁺ T cell response, poor cytokine production, insufficient neutralizing antibody (nAb) and poor response to HBsAg vaccination characterize CHB infection. The objective of this study was to develop virus-like-particles (VLPs) that elicit nAb to prevent viral spread and prime CD4⁺/CD8⁺ T cells to eradicate intracellular HBV. Eight neutralizing B cell epitopes from the envelope PreS1 region were consolidated onto a species-variant of the HBV core protein, the woodchuck hepatitis core antigen (WHcAg). PreS1-specific B cell epitopes were chosen because of preferential expression on HBV virions. Because WHcAg and HBcAg are not crossreactive at the B cell level and only partially cross-reactive at the CD4⁺/CD8⁺ T cell level, CD4⁺ T cells specific for WHcAg-unique T cell sites can provide cognate T-B cell help for anti-PreS1 Ab production that is not curtailed by immune tolerance. Immunization of immune tolerant HBV transgenic (Tg) mice with PreS1-WHc VLPs elicited levels of high titer anti-PreS1 nAbs equivalent to wildtype mice. Passive transfer of PreS1 nAbs into human-liver chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV in a model of CHB. At the T cell level, PreS1-WHc VLPs and hybrid WHcAg/HBcAg DNA immunogens elicited HBcAg-specific CD4⁺ Th and CD8⁺ CTL responses.

• Hbv
• immune tolerance
• neutralizing antibody
• pres1
• therapeutic vaccine

• HBV
• HBsAg-specific CTL
• HCC

We aimed to evaluate soluble CD25 (sCD25) as a marker for hepatocellular carcinoma (HCC) diagnosis.

Eighty-eight subjects were enrolled in our study in the years 2017-2018. They were divided into three groups as follows: group 1 – HCC group (n = 44) patients, represented by BCLC stage A (n = 16) patients, stage B (n = 14) patients and stage C (n = 14) patients for each stage. All HCC patients were on top of cirrhosis. Group 2 – group of cirrhotic patients without HCC (n = 32); 50% of them were Child-Turcotte-Pugh class A (n = 16) while class B was represented only by 43.7% (n = 14) of patients. Group 3 – control group (n = 12) of healthy subjects.

The levels of sCD25 and AFP were higher in HCC patients than cirrhotic and control groups without a statistically significant difference between the three groups (p-value > 0.05). For HCC presence, sensitivity and specificity of sCD25 were 86.4% and 29.5% respectively at a cut-off value of 1.1 × 10³ pg/ml (AUC = 0.619, p-value = 0.054, PPV = 33.2%, NPV = 68.44%). For early detection of HCC, sCD25 had a sensitivity of 70.5% and a specificity of 30.9% at a cut-off value of 1.575 × 10³ pg/ml (AUC = 0.577, p-value = 0.251, PPV = 58.5%, NPV = 43.1%), while the sensitivity and specificity of AFP were 75% and 62.5% respectively at a cut-off value of 9.5 ng/ml (AUC = 0.828, p = 0.000, PPV = 73.4%, NPV = 64.4%) in the same settings.

sCD25 seems to offer no better detection rate of HCC compared to AFP with lower sensitivity and specificity.

• HCC markers
• alpha-fetoprotein
• hepatocellular carcinoma
• soluble CD25

Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8⁺ T cells, and also CD4⁺ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.

• HBV
• HCC
• adaptive immunity
• immune dysfunction
• innate immunity

Hepatocellular carcinoma (HCC), one of the leading causes of death worldwide, has a causal nexus with liver injury, inflammation, and regeneration that accumulates over decades. Observations from recent studies have accounted for the involvement of the gut–liver axis in the pathophysiological mechanism responsible for HCC. The human intestine nurtures a diversified colony of microorganisms residing in the host ecosystem. The intestinal barrier is critical for conserving the normal physiology of the gut microbiome. Therefore, a rupture of this barrier or dysbiosis can cause the intestinal microbiome to serve as the main source of portal-vein endotoxins, such as lipopolysaccharide, in the progression of hepatic diseases. Indeed, increased bacterial translocation is a key sign of HCC. Considering the limited number of clinical studies on HCC with respect to the microbiome, we focus on clinical as well as animal studies involving the gut microbiota, with the current understandings of the mechanism by which the intestinal dysbiosis promotes hepatocarcinogenesis. Future research might offer mechanistic insights into the specific phyla targeting the leaky gut, as well as microbial dysbiosis, and their metabolites, which represent key pathways that drive HCC-promoting microbiome-mediated liver inflammation and fibrosis, thereby restoring the gut barrier function.

• gut microbiota
• gut–liver axis
• hepatocellular carcinoma
• intestinal dysbiosis

Hepatocellular carcinoma (HCC) is the sixth most common type of cancer, and is the third leading cause of cancer-related deaths each year. It involves a multi-step progression and is strongly associated with chronic inflammation induced by the intake of environmental toxins and/or viral infections (i.e., hepatitis B and C viruses). Although several genetic dysregulations are considered to be involved in disease progression, the detailed regulatory mechanisms are not well defined. Homeobox genes that encode transcription factors with homeodomains control cell growth, differentiation, and morphogenesis in embryonic development. Recently, more aberrant expressions of Homeobox genes were found in a wide variety of human cancer, including HCC. In this review, we summarize the currently available evidence related to the role of Homeobox genes in the development of HCC. The objective is to determine the roles of this conserved transcription factor family and its potential use as a therapeutic target in future investigations.

• EMT
• HCC
• Homeobox
• IL6
• immunosuppression

• nf-κb
• apoptosis
• hepatic stellate cells
• er stress
• immune checkpoint inhibitor

• Apoptosis
• Carcinogenesis
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/pathology
• Female
• Hepatic Stellate Cells/metabolism
• Hepatitis, Viral, Human/complications
• Humans
• Inflammation/immunology
• Inflammation/metabolism
• Liver Cirrhosis, Alcoholic/complications
• Liver Neoplasms/etiology
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Male
• NF-kappa B/metabolism
• Non-alcoholic Fatty Liver Disease/complications
• Sex Distribution
• Tumor Necrosis Factor-alpha/metabolism

• R01 AA027036 NIAAA NIH HHS
• R01 DK085252 NIDDK NIH HHS
• R21 AA025841 NIAAA NIH HHS
• T32 HL134637 NHLBI NIH HHS

Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8⁺ T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8⁺ T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8⁺ T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.

Chronic hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) and is associated with immune tolerance to HBV. Here the authors show, in a transgenic mouse model, that rescuing T cells function via inhibition of co-inhibitory receptor TIGIT results in HCC development via supporting inflammation.

• Adolescent
• Adult
• Aged
• Alaska
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/virology
• Child
• Child, Preschool
• Genotype
• Hepatitis B virus/classification
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/complications
• Humans
• Indigenous Peoples
• Infant
• Liver Neoplasms/complications
• Liver Neoplasms/virology
• Middle Aged
• Mutation
• Young Adult

• H26-Bsou-kanen-ippan-013 Ministry of Health, Labor, and Welfare of Japan
• 17fk0310101h0001 Japan Agency for Medical Research and Development
• JP16fk0310512h0005 Japan Agency for Medical Research and Development
• JP18fk0310101h0002 Japan Agency for Medical Research and Development
• 16K19360 Ministry of Education, Culture, Sports, Science, and Technology
• 16H05288 Ministry of Education, Culture, Sports, Science, and Technology
• IN-US-334-2090 Gilead Sciences
• H26-Bsou-kanen-ippan-013 The Ministry of Health, Labor, and Welfare of Japan
• 17fk0310101h0001 The Japan Agency for Medical Research and Development
• JP16fk0310512h0005 The Japan Agency for Medical Research and Development
• JP18fk0310101h0002 The Japan Agency for Medical Research and Development
• 16K19360 The Ministry of Education, Culture, Sports, Science, and Technology
• 16H05288 The Ministry of Education, Culture, Sports, Science, and Technology

• T cell priming
• cross-presentation
• endogenous antigen presentation
• hepatitis B virus
• intrahepatic lymphocytes
• liver
• tolerance

• Animals
• Antigen Presentation/immunology
• CD8-Positive T-Lymphocytes/immunology
• Cross-Priming/immunology
• Dendritic Cells/immunology
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/immunology
• Histocompatibility Antigens Class I/immunology
• Liver/immunology
• Lymphocyte Activation/immunology
• Male
• Mice
• Mice, Knockout

• R01 AI079060 NIAID NIH HHS
• HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
• Japan Agency for Medical Research and Development (AMED)
• Ministry of Education, Culture, Sports, Science and Technology (MEXT)

• E-cadherin
• Src kinase
• hepatitis B virus (HBV)
• hepatocellular carcinoma (HCC)
• β-catenin

• cell cycle
• hepatitis B virus
• hepatocellular carcinoma
• primary human hepatocytes
• transforming growth factor

• Lung cancer
• NLR
• PLR
• Prognosis

• DC-CIK
• dendritic cell vaccine
• hepatocellular carcinoma
• immunotherapy
• meta-analysis

Glypican-3 (GPC3) is a glycosylphosphatidylinositol-anchored cell surface protein overexpressed in hepatocellular carcinoma(HCC), and its overexpression is associated with poor prognosis. The diagnostic potential of GPC3 as a serum marker has been reported. In the present study, we evaluated the usefulness of plasma GPC3 as a predictor for recurrence after surgical resection in stage I HCC patients by newly developed an enzyme-linked immunosorbent assay (ELISA) system. Current study demonstrated that high levels of preoperative plasma GPC3 patients tended to experience postoperative recurrence. On the other hand, pre- and postoperative plasma GPC3 positivity of non-recurrence patients was very low. Moreover, even after surgery, approximately half of patients who experienced recurrence were positive for plasma GPC3. Postoperative plasma GPC3 positivity was significantly correlated with worse recurrence-free survival. Immuohistochemical analysis also showed positive rate of GPC3-expression in HCC was higher in recurrence patients than in non-recurrence patients. These results suggested that both pre- and postoperative plasma GPC3 levels may be accurate predictors for recurrence after curative resection of early-stage HCC. It should be noted that the current study only examined a small number of cases; thus, a larger sample size is necessary to validate GPC3 as a predictor for HCC recurrence.

• enzyme-linked immunosorbent assay
• glypican-3
• hepatocellular carcinoma
• recurrence
• tumor marker

Hepatitis B and C viruses are a global health problem causing acute and chronic infections that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). These infections are the leading cause for HCC worldwide and are associated with significant mortality, accounting for more than 1.3 million deaths per year. Owing to its high incidence and resistance to treatment, liver cancer is the second leading cause of cancer-related death worldwide, with HCC representing approximately 90% of all primary liver cancer cases. The majority of viral-associated HCC cases develop in subjects with liver cirrhosis; however, hepatitis B virus infection can promote HCC development without prior end-stage liver disease. Thus, understanding the role of hepatitis B and C viral infections in HCC development is essential for the future design of treatments and therapies for this cancer. In this review, we summarize the current knowledge on hepatitis B and C virus hepatocarcinogenesis and highlight direct and indirect risk factors.