• DBB1
• HBV DNA integration
• HCC
• cancer evolution
• cccDNA
• hepadnavirus
• hepatocellular carcinoma
• transcriptional regulation

• Viral Regulatory and Accessory Proteins/metabolism
• Viral Regulatory and Accessory Proteins/genetics
• Humans
• Trans-Activators/metabolism
• Trans-Activators/genetics
• Hepatitis B virus/physiology
• Hepatitis B virus/genetics
• Virus Replication
• Liver Neoplasms/virology
• Liver Neoplasms/metabolism
• Animals
• Carcinogenesis
• Carcinoma, Hepatocellular/virology
• Carcinoma, Hepatocellular/metabolism
• Hepatitis B/virology
• Hepatitis B/complications
• Hepatitis B, Chronic/virology
• Hepatitis B, Chronic/complications

• Precision Medicine fellowship Paul and Valeria Ainsworth

• HBx protein
• TGF-β signaling
• hepatitis B virus
• hepatocellular carcinoma
• pro-tumorigenic
• tumor suppressor

• cancer
• molecular biology

• Humans
• Hepatitis B virus/genetics
• Carcinoma, Hepatocellular/pathology
• Hepatitis B, Chronic
• Liver Neoplasms/pathology
• Hepatitis B/complications
• Hepatitis B/genetics
• Gene Expression
• Virus Replication
• DNA-Binding Proteins/genetics

• 2020CFB619 Natural Science Foundation of Hubei Province
• WX21Z36 Wuhan Municipal Health Research Foundation
• TGQB20210109 Chinese foundation for the hepatitis prevention and control-TianQing liver disease research fund subject
• 2023KF004 Open Research Program of the State Key Laboratory of Virology of China
• 2022KF003 Open Research Program of the State Key Laboratory of Virology of China
• 2021KF002 Open Research Program of the State Key Laboratory of Virology of China
• 2021KF006 Open Research Program of the State Key Laboratory of Virology of China
• 202140407 The Clinical Research Project of Health Industry of Shanghai Municipal Health Commission
• PWZxq2022-08 Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai
• KFJJ-202005 Open Funds of Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province
• KFJJ-201907 Open Funds of Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province

• HBx
• Keap1/Nrf2/ARE
• hepatitis B virus

• Humans
• Antioxidant Response Elements
• Hepatitis B/genetics
• Hepatitis B virus/physiology
• Kelch-Like ECH-Associated Protein 1/metabolism
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress
• Signal Transduction
• Virus Replication

• 23fk0310507h0002 Japan Agency for Medical Research and Development (AMED)
• 21K07040 MEXT | Japan Society for the Promotion of Science (JSPS)

• carcinogenesis
• hepatitis B
• hepatitis D
• hepatocellular carcinoma
• oncogenesis

• Humans
• Carcinoma, Hepatocellular
• Liver Neoplasms
• Hepatitis B/complications
• Hepatitis Delta Virus/genetics
• Hepatitis B virus/genetics
• Inflammation
• DNA
• Carcinogenesis
• Coinfection

• HBV
• HBx
• HCC
• chronic infection
• host factors
• pathogenesis
• signaling

• hepatitis B virus X gene
• hepatocellular carcinoma
• microcystins-LR
• redox balance

• HBx
• Yarrowia lipolytica
• hepatitis B virus
• hepatocellular carcinoma
• heterologous expression
• mitochondria-targeted antioxidants
• mitochondrial dysfunction
• oxidative stress
• yeast

In recent years, the role of oxidative stress has been investigated in an increasing number of infections. There is a close link between the inflammation that accompanies infections and oxidative stress. Excessive reactive oxygen species induce harmful effects on cell components, including lipids, proteins, and nucleic acids. A growing body of evidence attests to the role of oxidative stress in the pathogenesis of viral liver infections, especially in hepatitis C virus (HCV) infection. Regarding hepatitis B virus (HBV) infection, the data are limited, but important progress has been achieved in recent years. This review presents the latest advances pertaining to the role of the oxidative stress byproducts in the pathogenesis of chronic hepatitis B, constituting a source of potential new markers for the evaluation and monitoring of patients with chronic hepatitis B.

Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.

• HBx protein
• cancer hallmarks
• hepatitis B virus
• hepatocellular carcinoma
• therapeutics

Accumulating evidence indicates that hepatitis B virus X protein (HBx) plays a key role in HBV-related hepatocellular carcinoma (HCC) aggressiveness; however, the underlying mechanisms are not entirely clear. Long non-coding RNAs (lncRNAs), which participate in the regulation of diverse biological processes, may be critical for the function of HBx. Our research indicated that HBx induced changes in the expression of numerous lncRNAs and implicated the novel lncRNA RP11-241J12.3 in HBx-mediated HCC aggressiveness. Although RP11-241J12.3 expression was downregulated in transient HBx-expressing HCC cells (similar to the early stage of HBV infection), its oncogenic properties remained. The results showed that RP11-241J12.3 not only accelerated DNA synthesis and upregulated the expression of pyruvate carboxylase (PC) and MSH3, which is a key protein in pyruvate metabolism and DNA mismatch repair (MMR), but also promoted tumor growth in vitro and in vivo, thus promoting HCC aggressiveness. More importantly, we revealed that RP11-241J12.3 may interact with PC and identified its location in the cytoplasm close to the nucleus using fluorescence in situ hybridization (FISH). We also observed RP11-241J12.3 expression was upregulated in HCC tissues compared with the paracarcinomatous tissues. Furthermore, RP11-241J12.3 expression levels showed a close relationship with clinical stage and tumor size and that low RP11-241J12.3 expression was significantly correlated with longer HCC patient survival. These results further our understanding of the lncRNAs regulated by HBx in HCC, and provide evidence that dysregulation of RP11-241J12.3 contributes to HCC aggressiveness.

• DNA MMR
• HBx
• Hepatocellular carcinoma
• LncRNAs
• Pyruvate metabolism
• RP11-241J12.3

• ER stress
• HCC
• anti-oxidants
• free radicals
• kaempferol
• oxidative stress

• Alcoholic liver disease
• cirrhosis
• hepatitis B
• hepatitis C
• hepatocellular carcinoma
• nonalcoholic steatohepatitis

• HepG2 cells
• Hepatocellular carcinoma
• MAPK signaling Pathway
• ctHBx

• Carcinogenesis
• Hepatitis B virus
• Hepatitis C virus
• Hepatocellular carcinoma
• Molecular pathways
• Viral hepatitis.

• Bioavailability
• Hepatocellular carcinoma
• Immunomodulatory
• Selenium

• Carcinoma, Hepatocellular/virology
• DNA Repair
• Hepatitis B/complications
• Hepatitis B/genetics
• Hepatitis B virus/genetics
• Hepatitis B virus/pathogenicity
• Humans
• Liver Neoplasms/virology
• Oncogenes

• R01 HL144790 NHLBI NIH HHS
• R01 AI129540 NIAID NIH HHS
• R01 AI066020 NIAID NIH HHS
• R01 ES025786 NIEHS NIH HHS
• R01 HL151493 NHLBI NIH HHS
• R01 AI148304 NIAID NIH HHS
• R01 ES021801 NIEHS NIH HHS

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.

• Chronic viral infection
• Hallmarks of cancer
• Hepatocellular carcinoma
• Hepatitis B virus
• Hepatitis C virus
• Hepatitis delta virus co-infection
• Molecular mechanisms
• Viral hepatitis

• Carcinoma, Hepatocellular
• Hepatitis B/complications
• Hepatitis B virus/genetics
• Hepatitis, Viral, Human
• Humans
• Liver Neoplasms

Chronic viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) have been widely acknowledged to be the leading causes of liver cirrhosis and hepatocellular carcinoma. As anti-viral treatment progresses, the impact of NAFLD is increasing. NAFLD can coexist with chronic viral hepatitis and exacerbate its progression. Oxidative stress has been recognized as a chronic liver disease progression-related and cancer-initiating stress response. However, there are still many unresolved issues concerning oxidative stress, such as the correlation between the natural history of the disease and promising treatment protocols. Recent findings indicate that oxidative stress is also an anti-cancer response that is necessary to kill cancer cells. Oxidative stress might therefore be a cancer-initiating response that should be down regulated in the pre-cancerous stage in patients with risk factors for cancer, while it is an anti-cancer cell response that should not be down regulated in the post-cancerous stage, especially in patients using anti-cancer agents. Antioxidant nutrients should be administered carefully according to the patients’ disease status. In this review, we will highlight these paradoxical effects of oxidative stress in chronic liver diseases, pre- and post-carcinogenesis.

• chronic hepatitis
• hepatocellular carcinoma
• oxidative stress

• Antioxidants/administration & dosage
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/therapy
• Chronic Disease
• Disease Progression
• Eating/physiology
• Female
• Humans
• Liver Diseases/etiology
• Liver Diseases/therapy
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Male
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/therapy
• Nutritional Physiological Phenomena/physiology
• Oxidative Stress/physiology
• Risk Factors

About 20% of total cancer cases are associated to infections. To date, seven human viruses have been directly linked to cancer development: high-risk human papillomaviruses (hrHPVs), Merkel cell polyomavirus (MCPyV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-lymphotropic virus 1 (HTLV-1). These viruses impact on several molecular mechanisms in the host cells, often resulting in chronic inflammation, uncontrolled proliferation, and cell death inhibition, and mechanisms, which favor viral life cycle but may indirectly promote tumorigenesis. Recently, the ability of oncogenic viruses to alter autophagy, a catabolic process activated during the innate immune response to infections, is emerging as a key event for the onset of human cancers. Here, we summarize the current understanding of the molecular mechanisms by which human oncogenic viruses regulate autophagy and how this negative regulation impacts on cancer development. Finally, we highlight novel autophagy-related candidates for the treatment of virus-related cancers.

• Epstein–Barr virus (EBV)
• Kaposi’s sarcoma-associated herpesvirus (KSHV)
• Merkel cell polyomavirus (MCPyV)
• autopaghy
• hepatitis B and C viruses (HBV and HCV)
• human T-lymphotropic virus 1 (HTLV–1)
• human papillomavirus (HPV)
• oncogenic (or carcinogenic) viruses

The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11–18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.

• Hepatic fibrosis
• Hepatic glucose
• Hepatic steatosis
• Hepatitis B virus (HBV)
• Hepatitis B virus X (HBx)
• Hepatocellular carcinoma (HCC)
• Oxidative stress
• Reactive oxygen species (ROS)
• Transgenic mice

Hepatitis B virus × protein (HBx) serves an important role in the pathogenesis of the hepatitis B virus infection. Previous studies have reported that the interaction between HBx and hepatocyte mitochondria is an important factor leading to liver cell injury and apoptosis, ultimately inducing the formation of liver cancer. In the present study, a mouse model expressing HBx was constructed using hydrodynamic in vivo transfection based on the interaction between HBx and cytochrome c oxidase (COX) subunit III. The specific mechanism of HBx-induced oxidative stress in mouse hepatocytes and the subsequent effect on mitochondrial function and inflammatory injury was assessed. The results demonstrated that HBx reduced the activity of COX and the expression of superoxide dismutase and upregulated the expression of malondialdehyde, NF-κB and phospho-AKT, thus increasing oxidative stress. In addition, HBx induced an increase in interleukin (IL)-6, IL-1β and IL-18 expression levels, which created an inflammatory microenvironment in the liver, further promoting hepatocyte inflammatory injury. Therefore, it was proposed that HBx may affect hepatocyte mitochondrial respiration by reducing the activity of cytochrome c oxidase, leading to mitochondrial dysfunction and inducing hepatocyte inflammation and injury.

• cytochrome c oxidase
• hepatitis B virus × protein
• inflammation injury
• mitochondrion
• oxidative stress

• Hepatitis B virus (HBV), mitochondria
• interaction
• proteins/signaling

• Animals
• Antiviral Agents/therapeutic use
• Hepatitis B/drug therapy
• Hepatitis B virus/genetics
• Hepatitis B virus/metabolism
• Humans
• Mice
• Mitochondria/metabolism
• Mitochondria/virology
• Mitochondrial Proteins/genetics
• Mitochondrial Proteins/metabolism
• Signal Transduction
• Viral Proteins/genetics
• Viral Proteins/metabolism
• Virus Replication/drug effects

Infection of hepatitis B virus (HBV) increase the incidence of chronic liver disease and hepatocellular carcinoma (HCC). The hepatitis B viral x (HBx) protein encoded by the HBV genome contributes to the pathogenesis of HCC and thus, negative regulation of HBx is beneficial for the alleviation of the disease pathogenesis. MARCH5 is a mitochondrial E3 ubiquitin ligase and here, we show that high MARCH5 expression levels are correlated with improved survival in HCC patients. MARCH5 interacts with HBx protein mainly accumulated in mitochondria and targets it for degradation. The N-terminal RING domain of MARCH5 was required for the interaction with HBx, and MARCH5^H43W lacking E3 ligase activity failed to reduce HBx protein levels. High expression of HBx results in the formation of protein aggregates in semi-denaturing detergent agarose gels and MARCH5 mediates the elimination of protein aggregates through the proteasome pathway. HBx-induced ROS production, mitophagy, and cyclooxygenase-2 gene expression were suppressed in the presence of high MARCH5 expression. These results suggest MARCH5 as a target for alleviating HBV-mediated liver disease.

Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx.

With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis.

• Hepatitis C virus
• Hepatits B virus
• Nrf2
• liver regeneration
• reactive oxygen species

• Animals
• Hepacivirus/pathogenicity
• Hepacivirus/physiology
• Hepatitis B/metabolism
• Hepatitis B/pathology
• Hepatitis B virus/pathogenicity
• Hepatitis B virus/physiology
• Hepatitis C/metabolism
• Hepatitis C/pathology
• Humans
• Kelch-Like ECH-Associated Protein 1/metabolism
• NF-E2-Related Factor 2/metabolism
• Signal Transduction
• Virus Replication/physiology

• HBV infection
• autophagy
• pathogenesis

• HBV
• Hepatocellular carcinoma
• Liver injury
• Oxidative stress
• STING
• mtDNA

Reactive oxygen species- (ROS-) mediated autophagy physiologically contributes to management of cell homeostasis in response to mild oxidative stress. Cancer cells typically engage autophagy downstream of ROS signaling derived from hypoxia and starvation, which are harsh environmental conditions that need to be faced for cancer development and progression. Hepatocellular carcinoma (HCC) is a solid tumor for which several environmental risk factors, particularly viral infections and alcohol abuse, have been shown to promote carcinogenesis via augmentation of oxidative stress. In addition, ROS burst in HCC cells frequently takes place after administration of therapeutic compounds that promote apoptotic cell death or even autophagic cell death. The interplay between ROS and autophagy (i) in the disposal of dysfunctional mitochondria via mitophagy, as a tumor suppressor mechanism, or (ii) in the cell survival adaptive response elicited by chemotherapeutic interventions, as a tumor-promoting event, will be depicted in this review in relation to HCC development and progression.

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

Hepatitis B virus X protein (HBx) participates in the occurrence and development processes of hepatocellular carcinoma (HCC) as a multifunctional regulation factor. However, the underlying molecular mechanism remains obscure. Here, we describe the use of p21^HBx/+ mouse and SILAM (Stable Isotope Labeling in Mammals) strategy to define the pathological mechanisms for the occurrence and development of HBx induced liver cancer. We systematically compared a series of proteome samples from regular mice, 12- and 24-month old p21^HBx/+ mice representing the inflammation and HCC stages of liver disease respectively and their nontransgenic wild-type (WT) littermates. Totally we identified 22 and 97 differentially expressed proteins out of a total of 2473 quantified proteins. Bioinformatics analysis suggested that the lipid metabolism and CDC42-induced cytoskeleton remodeling pathways were strongly activated by the HBx transgene. Interestingly, the protein-protein interaction MS study revealed that HBx directly interacted with multiple proteins in these two pathways. The same effect of up-regulation of cytoskeleton and lipid metabolism related proteins, including CDC42, CFL1, PPARγ and ADFP, was also observed in the Huh-7 cells transfected with HBx. More importantly, CFL1 and ADFP were specifically accumulated in HBV-associated HCC (HBV-HCC) patient samples, and their expression levels were positively correlated with the severity of HBV-related liver disease. These results provide evidence that HBx induces the dysregulation of cytoskeleton remodeling and lipid metabolism and leads to the occurrence and development of liver cancer. The CFL1 and ADFP might be served as potential biomarkers for prognosis and diagnosis of HBV-HCC.

• ADFP
• CDC42
• CFL1
• HBx
• SILAM

Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.

• carcinogenesis
• hepatitis B virus
• hepatitis C virus
• pathogenesis
• reactive oxygen species

• EBV
• HBV
• HCV
• HIV
• HPV
• Mitochondria
• Oncovirus

• Animals
• Carcinogenesis/pathology
• Hepatocytes/pathology
• Humans
• Liver Neoplasms/etiology
• Liver Neoplasms/therapy
• Models, Biological
• Molecular Targeted Therapy
• Oxidative Stress

Chronic hepatitis B virus (HBV) infection is one of the most associated factors in hepatocarcinogenesis. HBV is able to integrate into the host genome and encode the multi-functional hepatitis B virus x protein (HBx). Although the mechanism between HBx and carcinogenesis is still elusive, recent studies have shown that HBx was able to influence various signaling pathways, as well as epigenetic and genetic processes. This review will examine and summarize recent literature about HBx’s role in these various processes.

• HBx protein
• hepatocarcinogenesis
• hepatocellular carcinoma

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• Epigenesis, Genetic
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• Signal Transduction
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

The hepatitis B virus (HBV) infection is accompanied by the induction of oxidative stress, especially mediated by HBV X protein (HBx). Oxidative stress has been implicated in a series of pathological states, such as DNA damage, cell survival and apoptosis. However, the host factor by which cells protect themselves under this oxidative stress is poorly understood.

In this study, we first confirmed that HBV infection significantly induced oxidative stress. Moreover, viral protein HBx plays a major role in the oxidative stress induced by HBV. Importantly, we found that mitochondrial protein SIRT3 overexpression could decrease reactive oxygen species (ROS) induced by HBx while SIRT3 knockdown increased HBx-induced ROS. Importantly, SIRT3 overexpression abolished oxidative damage of HBx-expressing cells as evidenced by γH₂AX and AP sites measurements. In contrast, SIRT3 knockdown promoted HBx-induced oxidative damage. In addition, we also observed that oxidant H₂O₂ markedly promoted HBV replication while the antioxidant N-acetyl-L-cysteine (NAC) inhibited HBV replication. Significantly, SIRT3 overexpression inhibited HBV replication by reducing cellular ROS level.

Collectively, these data suggest HBx expression induces oxidative stress, which promotes cellular oxidative damage and viral replication during HBV pathogenesis. Mitochondrial protein SIRT3 protected HBx expressing-cells from oxidative damage and inhibited HBV replication possibly by decreased cellular ROS level. These studies shed new light on the physiological significance of SIRT3 on HBx-induced oxidative stress, which can contribute to the liver pathogenesis.

Many factors are considered to contribute to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signaling pathways associated with cell proliferation and invasion, and HBx C-terminal truncation has been suggested to impact the development of HCC. This review focuses on the pathological functions of HBx in HBV-induced hepatocarcinogenesis. As a transactivator, HBx can affect regulatory non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs. HBx is also involved in epigenetic modification and DNA repair. HBx interacts with various signal-transduction pathways, such as the p53, Wnt, and nuclear factor-κB pathways. We conclude that HBx hastens the development of hepatoma.

• Hepatocellular carcinoma
• Hepatitis B virus
• Hepatitis B virus X protein
• Hepatocarcinogenesis

• Animals
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• Cell Movement
• Cell Proliferation
• DNA Methylation
• DNA Repair
• Humans
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• MicroRNAs/genetics
• RNA, Untranslated/genetics
• Signal Transduction
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

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

Liver cancer in men is the second leading cause of cancer death and hepatocellular carcinoma (HCC) accounts for 70%-85% of the total liver cancer worldwide. Chronic infection with hepatitis B virus (HBV) is the major cause of HCC. Chronic, intermittently active inflammation provides “fertile field” for “mutation, selection, and adaptation” of HBV and the infected hepatocytes, a long-term evolutionary process during HBV-induced carcinogenesis. HBV mutations, which are positively selected by insufficient immunity, can promote and predict the occurrence of HCC. Recently, advanced sequencing technologies including whole genome sequencing, exome sequencing, and RNA sequencing provide opportunities to better under-stand the insight of how somatic mutations, structure variations, HBV integrations, and epigenetic modifications contribute to HCC development. Genomic variations of HCC caused by various etiological factors may be different, but the common driver mutations are important to elucidate the HCC evolutionary process. Genome-wide analyses of HBV integrations are helpful in clarifying the targeted genes of HBV in carcinogenesis and disease progression. RNA sequencing can identify key molecules whose expressions are epigenetically modified during HCC evolution. In this review, we summarized the current findings of next generation sequencings for HBV-HCC and proposed a theory framework of Cancer Evolution and Development based on the current knowledge of HBV-induced HCC to characterize and interpret evolutionary mechanisms of HCC and possible other cancers. Understanding the key viral and genomic variations involved in HCC evolution is essential for generating effective diagnostic, prognostic, and predictive biomarkers as well as therapeutic targets for the interventions of HBV-HCC.

• Deep sequencing.
• Epigenetic modification
• Hepatitis B virus
• Hepatocellular carcinoma
• Integration
• Somatic mutation

• Amino Acid Sequence
• Animals
• Apoptosis
• Carcinoma, Hepatocellular/chemically induced
• Carcinoma, Hepatocellular/virology
• Cell Proliferation
• Diethylnitrosamine/toxicity
• Gene Expression Regulation, Viral
• Hepatitis B virus/pathogenicity
• Hepatocytes/cytology
• Hepatocytes/physiology
• Hepatocytes/virology
• Liver Neoplasms/chemically induced
• Liver Neoplasms/virology
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

• ROS
• mitochondria
• mitophagy
• oncogenes
• virus

Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, and of its long-term complications. It is the most variable among DNA viruses, mostly because of its unique life cycle which includes the activity of error-prone enzyme, reverse transcriptase, and the very high virion production per day. In last two decades, numerous research studies have shown that the speed of disease progression, reliability of diagnostic methods and the success of antiviral therapy and immunization are all influenced by genetic variability of this virus. It was shown that mutations in specific regions of HBV genome could be responsible for unwanted clinical outcomes or evasion of detection by diagnostic tools, thus making the monitoring for these mutations a necessity in proper evaluation of patients. The success of the vaccination programs has now been challenged by the discovery of mutant viruses showing amino acid substitutions in hepatitis B surface antigen (HBsAg), which may lead to evasion of vaccine-induced immunity. However, the emergence of these mutations has not yet raised concern since it was shown that they develop slowly. Investigations of HBV genetic variability and clinical implications of specific mutations have resulted in significant advances over the past decade, particularly in regard to management of resistance to antiviral drugs. In the era of drugs with high genetic barrier for resistance, on-going monitoring for possible resistance is still essential since prolonged therapy is often necessary. Understanding the frequencies and clinical implications of viral mutations may contribute to improvement of diagnostic procedures, more proper planning of immunization programs and creating the most efficient therapeutic protocols.

• Hepatitis B virus
• Hepatitis B virus variability
• Mutation
• Drug resistance
• Vaccine escape

• Acute Disease
• Antiviral Agents/therapeutic use
• Drug Resistance, Viral/genetics
• Genotype
• Hepatitis B/diagnosis
• Hepatitis B/drug therapy
• Hepatitis B/virology
• Hepatitis B Antigens/genetics
• Hepatitis B virus/drug effects
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Hepatitis B virus/pathogenicity
• Hepatitis B, Chronic/virology
• Humans
• Mutation
• Phenotype
• Trans-Activators/genetics
• Treatment Outcome
• Viral Core Proteins/genetics
• Viral Regulatory and Accessory Proteins

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered (“cis” effect); and (2) the HBV genome becomes altered (“trans” effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.

• Hepatitis B virus
• Integration
• Hepatocarcinogenesis
• Cis effect
• Trans effect
• Whole genome sequencing

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/virology
• Genome, Viral
• Genome-Wide Association Study
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/virology
• Humans
• Inflammation
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• Mutation
• Sequence Analysis, DNA
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins
• Virus Integration

• Citric Acid Cycle
• Energy Metabolism
• Host-Pathogen Interactions
• Mitochondria/metabolism
• Oxidation-Reduction
• Oxidative Phosphorylation
• Virus Replication
• Viruses/growth & development

• Carcinogenesis
• HBV
• HBVx
• HCC