• Schistosoma japonicum
• cirrhosis
• granuloma
• inflammation
• liver cancer

• Humans
• Liver Neoplasms/etiology
• Animals
• Schistosomiasis japonica/complications
• Schistosoma japonicum
• Carcinogenesis
• Liver/parasitology
• Liver/pathology

• Connexin 43
• Gap junctions
• Hemichannels
• Human adenovirus type 5
• Human immunodeficiency virus
• Human papillomavirus
• Severe acute respiratory syndrome coronavirus 2

• Connexin 43/metabolism
• Connexin 43/genetics
• Humans
• Gap Junctions/metabolism
• Virus Diseases/immunology
• Virus Diseases/metabolism
• Virus Diseases/genetics
• Animals
• RNA Viruses/immunology
• RNA Viruses/physiology

• IPSE/alpha-1
• Schistosoma mansoni
• fibrosis
• granuloma
• liver cancer

• Animals
• Humans
• Liver Neoplasms/parasitology
• Liver Neoplasms/etiology
• Carcinoma, Hepatocellular/parasitology
• Schistosoma mansoni/physiology
• Schistosomiasis mansoni/complications
• Schistosomiasis mansoni/parasitology
• Carcinogenesis

• Elderly
• Hepatocellular carcinoma
• Radiofrequency ablation
• Surgery
• Treatment

• Aged
• Humans
• Carcinoma, Hepatocellular/pathology
• Liver Neoplasms/pathology
• Treatment Outcome
• Retrospective Studies
• Radiofrequency Ablation
• Hepatectomy
• Propensity Score
• Catheter Ablation/adverse effects

• NA22-006 National Evidence-based Healthcare Collaborating Agency

• COVID-19
• HCC
• Hepatocellular carcinoma
• SARS-CoV-2
• pregnancy

• complete remission
• hepatocellular carcinoma
• recurrence after resection
• sequential therapy
• two-stage hepatectomy

• work was supported in part by the Natural Science Foundation of Guangxi Province of China

• hepatitis C
• hepatocellular carcinoma
• noninvasive biomarker
• overall survival C
• progression
• ribonucleic acids

• Alpha-fetoprotein
• Hepatocellular carcinoma
• Loco-regional therapy
• Protein Induced by Vitamin-K Absence-II
• Radiological response

• Adult
• Humans
• Male
• Middle Aged
• alpha-Fetoproteins/analysis
• Carcinoma, Hepatocellular/diagnostic imaging
• Liver Neoplasms/diagnostic imaging
• Prospective Studies

• Anticancer
• Cancer
• Curcumin
• Hepatocellular Carcinoma

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Curcumin/pharmacology
• Curcumin/therapeutic use
• Liver Neoplasms/drug therapy
• Curcuma
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use

• antiviral therapy
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• lenvatinib

• BTR
• Fischer’s ratio
• aromatic amino acids
• branched chain amino acids
• triple quadrupoletandem mass spectrometry
• ultra-performance liquid chromatography

• Apoptosis
• DEN
• Hepatocellular carcinoma
• Oxidative stress
• Sodium tetraborate decahydrate
• Tumor markers

• Animals
• Antioxidants/metabolism
• Apoptosis
• Boron/metabolism
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/drug therapy
• Caspase 3/metabolism
• Diethylnitrosamine
• Liver Neoplasms/chemically induced
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Male
• Mice
• Mice, Inbred C3H
• Oxidative Stress
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Reactive Oxygen Species/metabolism
• Trace Elements/metabolism
• Tumor Suppressor Protein p53/metabolism
• bcl-2-Associated X Protein/genetics
• bcl-2-Associated X Protein/metabolism
• bcl-2-Associated X Protein/pharmacology

• hepatocellular carcinoma (HCC)
• microvessel density (MVD)
• vessels that encapsulate tumor clusters (VETC)

• AASLD, American Association of Study of Liver Disease
• AFP, Alpha fetoprotein
• ALP, Alkaline phosphatase
• ALT, Alanine transaminase
• AST, Aspartate transaminase
• BCLC, Barcelona Clinic Liver Cancer staging
• BCS, Budd Chiari syndrome
• CT, Computed tomography
• EASL, European Association for Study of Liver
• GGT, Gamma glutamyl transpeptidase
• HBV, Hepatitis B virus
• HCC, Hepatocellular carcinoma
• HCV, Hepatitis C virus
• HKLC, Hong-Kong Liver Cancer staging
• HVPG, Hepatic venous pressure gradient
• INR, International normalized ratio
• MDT, Multidisciplinary team
• MRI, Magnetic resonance imaging
• NAFLD, Non-alcoholic fatty liver disease
• PHT, Portal hypertension
• PVTT, Portal venous tumor thrombosis
• clinical profile
• hepatocellular carcinoma
• milan criteria
• multicenter

• Asia
• epidemiology
• hepatocellular carcinoma

• hepatocellular carcinoma
• metastasis
• miR-122
• molecular targets
• signaling pathways

• 2016R1D-1A1B01012515 Ministry of Education
• 2010-0025409 Ministry of Education

With the advent of combination antiretroviral therapy (cART), overall survival has been improved, and the incidence of acquired immunodeficiency syndrome (AIDS)-defining cancers has also been remarkably reduced. However, non-AIDS-defining cancers among human immunodeficiency virus-1 (HIV-1)-associated malignancies have increased significantly so that cancer is the leading cause of death in people living with HIV in certain highly developed countries, such as France. However, it is currently unknown how HIV-1 infection raises oncogenic virus-mediated cancer risks in the HIV-1 and oncogenic virus co-infected patients, and thus elucidation of the molecular mechanisms for how HIV-1 expedites the oncogenic viruses-triggered tumorigenesis in the co-infected hosts is imperative for developing therapeutics to cure or impede the carcinogenesis. Hence, this review is focused on HIV-1 and oncogenic virus co-infection-mediated molecular processes in the acceleration of non-AIDS-defining cancers.

• F31 DA053151 NIDA NIH HHS
• F31DA053151 NIDA NIH HHS

To systematically compare the performance of liver imaging reporting and data system treatment response (LR-TR) with the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for diagnosing viable hepatocellular carcinoma (HCC) treated with locoregional therapy (LRT).

Original studies of intra-individual comparisons between the diagnostic performance of LR-TR and mRECIST using dynamic contrast-enhanced CT or MRI were searched in MEDLINE and EMBASE, up to August 25, 2021. The reference standard for tumor viability was surgical pathology. The meta-analytic pooled sensitivity and specificity of the viable category using each criterion were calculated using a bivariate random-effects model and compared using bivariate meta-regression.

For five eligible studies (430 patients with 631 treated observations), the pooled per-lesion sensitivities and specificities were 58% (95% confidence interval [CI], 45%–70%) and 93% (95% CI, 88%–96%) for the LR-TR viable category and 56% (95% CI, 42%–69%) and 86% (95% CI, 72%–94%) for the mRECIST viable category, respectively. The LR-TR viable category provided significantly higher pooled specificity (p < 0.01) than the mRECIST but comparable pooled sensitivity (p = 0.53).

The LR-TR algorithm demonstrated better specificity than mRECIST, without a significant difference in sensitivity for the diagnosis of pathologically viable HCC after LRT.

• Forkhead box P1
• hepatitis C virus
• hepatocellular carcinoma
• single-nucleotide polymorphism

Our meta-analysis aimed to evaluate the diagnostic performance of surveillance magnetic resonance imaging (sMRI) for detecting hepatocellular carcinoma (HCC), and to compare the diagnostic performance of sMRI between different protocols. Original articles about the diagnostic accuracy of sMRI for detecting HCC were found in major databases. The meta-analytic pooled sensitivity and specificity of sMRI for detecting HCC were determined using a bivariate random effects model. The pooled sensitivity and specificity of full MRI and abbreviated MRI protocols were compared using bivariate meta-regression. In the total seven included studies (1830 patients), the pooled sensitivity of sMRI for any-stage HCC and very early-stage HCC were 85% (95% confidence interval, 79–90%; I² = 0%) and 77% (66–85%; I² = 32%), respectively. The pooled specificity for any-stage HCC and very early-stage HCC were 94% (90–97%; I² = 94%) and 94% (88–97%; I² = 96%), respectively. The pooled sensitivity and specificity of abbreviated MRI protocols were 87% (80–94%) and 94% (90–98%), values that were comparable with those of full MRI protocols (84% [76–91%] and 94% [89–99%]; p = 0.83). In conclusion, sMRI had good sensitivity for detecting HCC, particularly very early-stage HCC. Abbreviated MRI protocols for HCC surveillance had comparable diagnostic performance to full MRI protocols.

• hepatocellular carcinoma
• liver
• magnetic resonance imaging
• meta-analysis
• surveillance
• systematic review

• hepatitis virus
• hepatocellular carcinoma
• kinase inhibitor

• Sorafenib
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma

Hepatitis virus is a major risk factor for liver cancer. We analyzed possible synergism between momelotinib and sorafenib in hepatitis virus-associated liver cancer. The combined effect of momelotinib and sorafenib both at in vitro and in vivo synergistically sup-presses the proliferation of vHCC cells and effectively reduces the tumor burden. Our results showed that momelotinib effectively suppressed the expression of the IFNGR-JAK-STAT-PARP1 pathway, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes and inhibiting the DNA repair gene in vHCC cells, thus maximizing its therapeutic potential for patients with HCC.

Background: Hepatitis virus is a major risk factor for liver cancer. The mitochondrial dysfunction IFN gamma-related pathways are activated after virus infection. Jak family-related protein is involved in the downstream of IFN gamma-related pathways. However, the effect of the IFNGR-JAK-STAT pathway acting as functional regulators of their related protein expression on virus infection and hepatocellular carcinoma (HCC) remains unclear. Interestingly, the role of the DNA repair gene (PARP1) in therapy resistant cancers also has not been studied and explored well. In this study, we hypothesized that momelotinib could suppress the progression of HCC by targeting Jak family related and PARP1 DNA repair protein. Based on this observation, we link the relevant targets of the JAK family and the potential applications of targeted therapy inhibitors. Methods: We analyzed possible synergism between momelotinib and sorafenib in hepatitis virus-associated liver cancer. Immunostaining, colony formation assay, cell invasion, migration, and tumorsphere-formation assay were used for drug cytotoxicity, cell viability, and possible molecular mechanism. Result: We first demonstrated that the expression of Jak1 and 2 is significantly upregulated in vHCC than in nvHCC/normal liver tissues. In addition, the gene expression of IFN gamma-related pathways is activated after virus infection. Additionally, we found that momelotinib significantly inhibited the growth of HCC cells and reduces the expression of Jak2, which showed the importance of momelotinib in targeting Jak2 and reducing tumorigenesis in HCC. Meanwhile, momelotinib effectively inhibited the IFNGR-JAK-STAT pathway and reduced the migratory/invasive ability of vHCC cells through down-regulating EMT biomarkers (E-cadherin and vimentin), transcription factor (Slug), and significantly inhibits the DNA damage repair enzyme PARP1. It also induced cell apoptosis of vHCC cells. Furthermore, the combined effect of momelotinib and sorafenib both at in vitro and in vivo synergistically suppresses the proliferation of vHCC cells and effectively reduces the tumor burden. Conclusions: Our results showed that momelotinib effectively suppressed the expression of the IFNGR-JAK-STAT-PARP1 pathway, which results in the downregulation of cancer stem cell genes and enhances the antitumor efficacy of sorafenib by initiating the expression of apoptosis-related genes and inhibiting the DNA repair gene in vHCC cells, thus maximizing its therapeutic potential for patients with HCC.

• EMT
• IFNGR-JAK-STAT-PARP1 axis pathway
• hepatocellular carcinoma
• momelotinib
• stemness

• Hepatocellular carcinoma
• Liver
• Meta-analysis
• Systematic review
• Treatment outcome

• hepatocellular carcinoma (HCC)
• metabolic vulnerability
• metabolism
• targeted therapy

• P01 HL131477 NHLBI NIH HHS
• R35 CA197697 NCI NIH HHS
• Genome Institute of Singapore Innovation Fellow Award
• Agency for Science, Technology, and Research A*ccelerate Gap Award
• Singapore Ministry of Health's National Medical Research Council Singapore Translational Research
• Singapore Ministry of Education
• Research Centres of Excellence initiative
• National Institutes of Health
• National Heart, Lung, and Blood Institute
• Xiu Research Fund

This study aims at evaluating the symptom response, response duration, and toxicity of single dose palliative liver radiotherapy (RT) for symptomatic HCC patients. We reviewed unresectable HCC patients treated with palliative RT in our institution. Eligible patients were unsuitable or refractory to trans-arterial chemoembolization (TACE) and stereotactic body radiotherapy (SBRT), with an index symptom of pain or abdominal discomfort. The primary outcome was the percentage of patients with clinical improvement of index symptom at 1 month. Secondary outcomes were response duration, toxicities, alpha-feto protein (AFP) response, and radiological response. Fifty-two patients were included in the study. The index symptom was pain in 34 patients (65.4%), and abdominal discomfort (34.6%) in 18 patients. At 1 month, 51.9% of patients had improvement of symptoms. Median time to symptom progression was 89 days (range: 12–392 days). Treatment was well tolerated with only 2 patients (3.8%) developing grade 3 GI toxicities. AFP response, radiological response rate, and disease control rate at 3 months were 48.6%, 15.1%, and 54.5% respectively. Half of the patients had improvement of index symptoms after receiving palliative liver RT with median response duration of 3 months. The treatment was well tolerated with minimal toxicities.

• exosome
• microRNA-146
• viral infection

Background: Tumor-infiltrating leukocytes (TILs) are immune cells surrounding tumor cells, and several studies have shown that TILs are potential survival predictors in different cancers. However, few studies have dissected the differences between hepatitis B- and hepatitis C-related hepatocellular carcinoma (HBV−HCC and HCV−HCC). Therefore, we aimed to determine whether the abundance and composition of TILs are potential predictors for survival outcomes in HCC and which TILs are the most significant predictors. Methods: Two bioinformatics algorithms, ESTIMATE and CIBERSORT, were utilized to analyze the gene expression profiles from 6 datasets, from which the abundance of corresponding TILs was inferred. The ESTIMATE algorithm examined the overall abundance of TILs, whereas the CIBERSORT algorithm reported the relative abundance of 22 different TILs. Both HBV−HCC and HCV−HCC were analyzed. Results: The results indicated that the total abundance of TILs was higher in non-tumor tissue regardless of the HCC type. Alternatively, the specific TILs associated with overall survival (OS) and recurrence-free survival (RFS) varied between subtypes. For example, in HBV−HCC, plasma cells (hazard ratio [HR] = 1.05; 95% CI 1.00–1.10; p = 0.034) and activated dendritic cells (HR = 1.08; 95% CI 1.01–1.17; p = 0.03) were significantly associated with OS, whereas in HCV−HCC, monocytes (HR = 1.21) were significantly associated with OS. Furthermore, for RFS, CD8+ T cells (HR = 0.98) and M0 macrophages (HR = 1.02) were potential biomarkers in HBV−HCC, whereas neutrophils (HR = 1.01) were an independent predictor in HCV−HCC. Lastly, in both HBV−HCC and HCV−HCC, CD8+ T cells (HR = 0.97) and activated dendritic cells (HR = 1.09) had a significant association with OS, while γ delta T cells (HR = 1.04), monocytes (HR = 1.05), M0 macrophages (HR = 1.04), M1 macrophages (HR = 1.02), and activated dendritic cells (HR = 1.15) were highly associated with RFS. Conclusions: These findings demonstrated that TILs are potential survival predictors in HCC and different kinds of TILs are observed according to the virus type. Therefore, further investigations are warranted to elucidate the role of TILs in HCC, which may improve immunotherapy outcomes.

• CIBERSORT
• ESTIMATE
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• immune cell
• tumor-infiltrating lymphocytes

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Gene Expression Regulation, Neoplastic
• Hepacivirus/pathogenicity
• Hepatitis B virus/pathogenicity
• Humans
• Leukocytes/classification
• Leukocytes/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Lymphocytes, Tumor-Infiltrating/classification
• Lymphocytes, Tumor-Infiltrating/metabolism
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism

To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).

A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients’ serum before RT and in surgical specimens was correlated with response to RT.

In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group (P < .001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% (P < .001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; P < .001] and 0.45 [95% CI, 0.31 to 0.64; P < .001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT.

For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients.

Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as “cancer-eliminating agents” or as products to improve one’s health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis.

• antioxidant
• cancer
• oxidative stress
• reactive oxygen species

• BCLC stage B-C
• Hepatocellular carcinoma
• Initial therapy
• Stereotactic body radiotherapy
• Transarterial chemoembolization

Lactate dehydrogenase (LDH), which was an indirect marker of hypoxia, was a potentially prognostic factor in several malignancies. There is a lack of evidence about the prognostic value of serum LDH level in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment from hepatitis B virus endemic areas.

A total of 119 HBV-related HCC patients treated by sorafenib from a Chinese center were included into the study. They were categorized into 2 groups according to the cut-off value of pre-treatment LDH, which was determined by the time dependent receiver operating characteristics (ROC) curve for the overall survival. The prognostic value of LDH was evaluated. The relationships between LDH and other clinicopathological factors were also assessed.

The cut-off value was 221 U/L. With a median follow up of 15 (range, 3-73) months, 91 patients reached the endpoint. Multivariate analysis proved that pre-treatment serum LDH level was an independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). For patients whose pre-treatment LDH ≥ 221 U/L, increased LDH value after 3 months of sorafenib treatment predicted inferior OS and PFS. And patients with elevated pre-treatment LDH level predisposed to be featured with lower serum albumin, presence of macroscopic vascular invasion, advanced Child-Pugh class, advanced T category, higher AFP, and higher serum total bilirubin.

Serum LDH level was a potentially prognostic factor in HCC patients treated by sorafenib in HBV endemic area. More relevant studies with reasonable study design are needed to further strengthen its prognostic value.

• HBV endemic area
• LDH
• hepatocellular carcinoma
• prognosis
• sorafenib

Hepatitis C infection is one of the main causes of chronic liver disorders worldwide. Nearly three percent (3%) of the world population has an HCV infection. Prevalence of HCV infection was higher in some groups such as injected drug users (IDUs) and HIV positive populations. Acute hepatitis has proven asymptomatic in most cases, and delay of diagnosis might lead to late onset of hepatocellular carcinoma and cirrhosis. Some host characteristics such as age, gender, body mass index, and viral properties are associated with HCV outcome hepatitis. Although disease progression is typically slow, some risk factors such as alcohol abuse and coinfection of patients with HBV and HIV can worsen the disease. On the other hand, viral overload is one of the main causes of prediction of HCV infection outcome. Prevalence of HCV infection will increase if we do not consider means of transmission, virus behaviors, and immunologic responses. Rapid diagnostic tests can help us to create preventive strategies among undeveloped villages and prisoners. Screening and training of the high-risk population such as IV drug users, dialysis patients, and hemophiliacs must be one of main HCV preventive programs. The present review is intended to help health policymakers to design suitable preventive and management programs.

• Epidemiology
• Hepatitis C
• Outcome
• Prevalence

• GAGE6
• hepatocellular carcinoma
• long interspersed nuclear element 1
• polypyrimidine tract-binding protein-associated splicing factor
• proliferation
• tumor formation

• cachexia
• cancer
• carcinogenesis
• chemotherapy
• immunotherapy
• metabolism and cancer
• microbiota

• Asian versus non-Asian
• East versus West
• hepatocellular carcinoma
• liver cancer
• regional differences

• HBx
• hepatocellular carcinoma cell
• maspin
• metastasis
• microRNA

• CTNNB1
• TERT
• TP53

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Disease-Free Survival
• Female
• Follow-Up Studies
• Hepatitis B/complications
• Hepatitis B Surface Antigens/blood
• Hepatitis C/complications
• High-Throughput Nucleotide Sequencing
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Male
• Middle Aged
• Mutation
• Promoter Regions, Genetic
• Survival Rate
• Telomerase/genetics
• Tumor Suppressor Protein p53/genetics
• Virus Integration
• beta Catenin/genetics

• Chemoprevention
• Esophageal adenocarcinoma
• Innate immunity
• Microbiome

Oxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma.

• Liver cancer
• Liver cirrhosis
• Hepatitis B
• Hepatitis C
• Non-alcoholic steatohepatitis
• Reactive oxygen species

The underlying mechanisms of carcinogenesis and gender disparity in hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) remain unclear. Recently, we reported a novel HCC-related W4P/R mutation in the large surface protein (LHB) of HBV genotype C, which was found exclusively in male HCC patients.

LHB sequences from a carrier (wild type; WT) and W4P variant LHB sequence from an HCC patient were cloned and used to generate NIH3T3 and Huh7 cell lines. Cell proliferation and in vitro tumorigenicity were assessed by cell growth and transformation assays. Male and female nude mice were injected with the cells to determine in vivo tumorigenicity. To confirm the effect of estrogen in W4P-mediated tumorigenicity, male mice were injected with estrogen and challenged with W4P-expressing cells. The serum levels of different cytokines from the mouse model and patients were analyzed by ELISA. A critical role of interleukin (IL)-6 signaling in W4P-mediated tumorigenicity was tested by inhibition of Jak2.

Although both WT and W4P variant LHBs enhanced cell proliferation by regulating the cell cycle and facilitated cell colony formation, the W4P variant demonstrated significantly higher activity. NIH3T3 cells expressing variant LHB, but not the WT, induced tumor in a nude mouse model. Tumor masses produced by variant LHB were significantly larger in male than female mice, and significantly reduced by estrogen. IL-6, but not tumor necrosis factor-α, was elevated in male mice harboring W4P-induced tumor, and was reduced by estrogen. IL-6 levels of HCC patients with the W4P variant were significantly higher than those of patients with WT LHB. W4P LHB induced higher production of IL-6 than WT LHB in cell lines, and the level was reduced by estrogen. The ability to reduce cell proliferation and colony formation of W4P LHB was hampered by inhibition of IL-6 signaling.

This study suggests that the W4P mutation during the natural course of chronic hepatitis B infection may contribute to HCC development, particularly in male patients, in an IL-6-dependent manner.

The online version of this article (doi:10.1186/s12943-015-0303-7) contains supplementary material, which is available to authorized users.