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.

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

• Hepatitis B virus
• Lamivudine
• Liver cancer
• Sorafenib resistance
• cIAP2

• 81960443 National Natural Science Foundation of China
• 81360338 National Natural Science Foundation of China
• 20195422 The Foundation of Jiangxi Provincial Health Department

Hepatitis B virus (HBV) is causally linked to hepatocellular injury and cell death, which are followed by hepatocellular carcinoma (HCC) after a long latent period. The HBV derived X protein (HBX) is the most potent carcinogenic factor for HCC, however, the molecular mechanism of HBX-induced transformation of hepatic cells in HCC is poorly understood. We have shown that nuclear receptor co-repressor (NCoR) is essential for the spatial repression of global transcription by the promyelocytic leukemia oncogenic domains (PODs), a frequent target of viral oncoproteins like HBX and that disintegration of PODs due to misfolded conformation dependent loss (MCDL) of NCoR is linked to promyelocytic and monocytic acute myeloid leukemia (AML). Given the key role of NCoR in cellular homeostasis across various tissue subtypes, we hypothesized that HBX-induced MCDL of NCoR might be linked to HCC through similar mechanism. Based on this hypothesis, the conformation of NCoR in HCC derived tumor cells and primary human tissue sections were analyzed and a selective MCDL of NCoR in HBX positive HCC cells was identified. HBX triggered the misfolding of NCoR through ubiquitination, followed by its degradation by autophagy, thus suggesting a cross talk between ubiquitin proteasome system (UPS) and autophagy lysosomal pathway (ALP) in MCDL of NCoR in HBX positive HCC cells. SiRNA-induced NCoR ablation selectively impaired the growth and survival of HBX positive HCC cells, suggesting a role of MCDL in the growth and survival of HBX positive HCC cells. These finding identify a possible crosstalk between UPS and ALP in the misfolding and loss of NCoR in HBX positive HCC cells and suggest a role of autophagic recycling of misfolded NCoR in the activation of oncogenic metabolic signaling in HCC. The misfolded NCoR reported in this study represents a novel conformation based molecular target which could be valuable in the design and development of tumor cell specific diagnostic and therapeutic approach for HBX positive HCC.

• HBX
• HCC
• NCoR
• autophagy
• misfolded protein

Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancer, is a lethal malignancy that is tightly associated with chronic hepatitis B virus (HBV) infection. HBV encodes a viral onco-protein, transactivator protein X (HBx), which interacts with proteins of hepatocytes to promote oncogenesis. Our current study focused on the interaction of HBx with a transcription factor, hypoxia-inducible factor-1α (HIF-1α), which is stabilized by low O₂ condition (hypoxia) and is found to be frequently overexpressed in HCC intra-tumorally due to poor blood perfusion. Here, we showed that overexpression of HBx by tetracycline-inducible systems further stabilized HIF-1α under hypoxia in HBV-negative HCC cell lines. Reversely, knockdown of HBx reduced HIF-1α protein stabilization under hypoxia in HBV-positive HCC cell lines. More intriguingly, overexpression of HBx elevated the mRNA and protein expression of a family of HIF-1α target genes, the lysyl oxidase (LOX) family in HCC. The LOX family members function to cross-link collagen in the extracellular matrix (ECM) to promote cancer progression and metastasis. By analyzing the collagens under scanning electron microscope, we found that collagen fibers were significantly smaller in size when incubated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells in vitro. Transwell invasion assay further revealed that less cells were able to invade through the matrigel which was pre-treated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells. Orthotopic and subcutaneous HCC models further showed that knockdown of HBx in HCC cells reduced collagen crosslinking and stiffness in vivo and repressed HCC growth and metastasis. Taken together, our in vitro and in vivo studies showed the HBx remodeled the ECM through HIF-1α/LOX pathway to promote HCC metastasis.

Tumor relapse after chemotherapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive initial treatment. Chronic infection with hepatitis B virus (HBV) has long been linked to the development of HCC. Upon infection, random HBV genome integration can lead to truncation of hepatitis B virus X (HBx) protein at the C-terminus. The resulting C-terminal-truncated HBx (HBx-ΔC) was previously shown to confer enhanced invasiveness and diminished apoptotic response in HCC cells. Here, we found HBx-ΔC to promote the appearance of a CD133 liver CSC subset and confer cancer and stem cell-like features in HCC. HBx-ΔC was exclusively detected in HCC cell lines that were raised from patients presented with a HBV background with concomitant CD133 expression. Stable overexpression of the naturally occurring HBx-ΔC mutants, HBx-Δ14 or HBx-Δ35, in HCC cells Huh7 and immortalized normal liver cells MIHA resulted in a significant increase in the cells ability to self-renew, resist chemotherapy and targeted therapy, migrate and induce angiogenesis. MIHA cells with the mutants stably overexpressed also resulted in the induction of CD133, mediated through STAT3 activation. RNA sequencing profiling of MIHA cells with or without HBx-ΔC mutants stably overexpressed identified altered FXR activation. This, together with rescue experiments using a selective FXR inhibitor suggested that C-terminal truncated HBx can mediate cancer stemness via FXR activation. Collectively, we find C-terminal truncated HBx mutants to confer cancer and stem cell-like features in vitro and to play an important role in driving tumor relapse in HCC.

• HBx
• HCC
• RNA-Seq
• cancer stem cells
• tumor-initiating cells

• Hepatitis B virus
• Hepatitis B virus X protein
• Hepatocellular carcinoma
• Inflammation
• Tumor microenvironment

• Special National International Technology Cooperation of China
• National Natural Sciences Foundation of China
• National Major Sciences research Program of China(973 Program)
• National Natural Sciences Foundation of China

• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Hepatitis B/complications
• Hepatitis B/virology
• Hepatitis B virus/genetics
• Hepatitis B virus/pathogenicity
• Histone Deacetylases/genetics
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Liver Neoplasms/virology
• Precision Medicine
• Prognosis
• Repressor Proteins/genetics
• Trans-Activators/genetics
• Viral Regulatory and Accessory Proteins

Hepatocellular carcinoma (HCC) is one of the leading causes of death induced by cancer in the modern world and majority of the cases are related to chronic hepatitis B virus (HBV) infection. HBV-encoded X protein (HBx) is known to play a pivotal role in the pathogenesis of viral induced HCC. HBx is a multifunctional protein of 17 kDa which modulates several cellular processes by direct or indirect interaction with a repertoire of host factors resulting in HCC. HBX might interfere with several cellular processes such as oxidative stress, DNA repair, signal transduction, transcription, protein degradation, cell cycle progression and apoptosis. A number of reports have indicated that HBx is one of the most common viral ORFs that is often integrated into the host genome and its sequence variants play a crucial role in HCC. By mutational or deletion analysis it was shown that carboxy terminal of HBx has a likely role in protein-protein interactions, transcriptional transactivation, DNA repair, cell, signaling and pathogenesis of HCC. The accumulated evidence thus far suggests that it is difficult to understand the mechanistic nature of HBx associated HCC, and HBx mediated transcriptional transactivation and signaling pathways may be a major determinant. This article addresses the role of HBx in the development of HCC with particular emphasis on HBx mutants and their putative targets.

• Hepatitis B virus
• Hepatocellular carcinoma
• Transcription factors
• Apoptosis
• Epigenetics
• Mutants
• Tumor necrosis factor
• Activating protein
• Transforming growth factor
• Mitogen activated protein kinase

• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Transformation, Viral
• Gene Expression Regulation, Neoplastic
• Gene Expression Regulation, Viral
• Genotype
• Hepatitis B/complications
• Hepatitis B/virology
• Hepatitis B virus/genetics
• Hepatitis B virus/metabolism
• Hepatitis B virus/pathogenicity
• Host-Pathogen Interactions
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• MicroRNAs/metabolism
• Mutation
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

• Adipose most abundant 2
• Differential gene expression
• Gene expression signature
• Hepatitis B virus
• Hepatocellular carcinoma

• Apoptosis
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• DNA Repair
• Epigenesis, Genetic
• Hepatitis B virus/genetics
• Hepatitis B virus/metabolism
• Hepatitis B, Chronic/complications
• Humans
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• Mutation
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

AIM: To investigate the effect of hepatitis B virus X protein (HBx) on COX-2 expression in human liver cell line L-02.

METHODS: HBx expression vector pIRES2-AcGFP-HBx was constructed and transfected into L-02 cells. The expression of COX-2 mRNA and protein was detected by RT-PCR and Western blot, respectively. The effect of HBx protein on cell division and proliferation was evaluated by plotting cell growth curve and analyzing cell cycle. Moreover, pGL3-COX-2 plasmid, in which the COX-2 promoter has been linked to the luciferase reporter gene, was transfected into L-02 cells and luciferase activities were measured.

RESULTS: RT-PCR results revealed that HBx mRNA was expressed only in cells transfected with the HBx gene, and that COX-2 mRNA expression in cells transfected with the HBx gene was higher than that in cells untranfected or transfected with an empty vector (0.76 ± 0.12 vs 0.28 ± 0.04, 0.25 ± 0.03, both P < 0.01). Western blot analysis showed that HBx protein was expressed only in cells transfected with the HBx gene, and COX-2 protein expression in this group was higher than that in the two control groups. The proliferation of cells transfected with the HBx gene was faster than that of control cells (both P < 0.05). The numbers of cells in S and G2-M phases significantly increased while those in G₀-G₁ phase decreased in cells transfected with the HBx gene compared to control cells (all P < 0.05). The luciferase activity in cells transfected with the HBx gene was higher than that in control cells (1 675.2 ± 84.9 vs 657.7 ± 34.7, 739.3 ± 45.3, both P < 0.05).

CONCLUSION: HBx protein can enhance COX-2 expression by up-regulating the activity of COX-2 promoter and promote cell growth, division and proliferation in human liver cell line L-02.

• Hepatitis B virus
• Hepatitis B virus X protein
• Cyclooxygenase-2
• Liver cancer

AIM: To investigate the biological features of hepatitis B virus (HBV)-transfected HepG2.2.15 cells.

METHODS: The cell ultrastructure, cell cycle and apoptosis, and the abilities of proliferation and invasion of HBV-transfected HepG2.2.15 and the parent HepG2 cells were examined by electron microscopy, flow cytometry, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and trans-well assay. Oncogenicity of the two cell lines was compared via subcutaneous injection and orthotopic injection or implantation in nude mice, and the pathological analysis of tumor formation was performed. Two cytoskeletal proteins were detected by Western blotting.

RESULTS: Compared with HepG2 cells, HepG2.2.15 cells showed organelle degeneration and filopodia disappearance under electron microscope. HepG2.2.15 cells proliferated and migrated slowly in vitro, and hardly formed tumor and lung metastasis in nude mice. Flow cytometry showed that the majority of HepG2.2.15 cells were arrested in G1 phase, and apoptosis was minor in both cell lines. Furthermore, the levels of cytoskeletal proteins F-actin and Ezrin were decreased in HepG2.2.15 cells.

CONCLUSION: HepG2.2.15 cells demonstrated a lower proliferation and invasion ability than the HepG2 cells due to HBV transfection.

• HepG2.2.15
• HepG2
• Hepatitis B virus
• Biological feature
• Tumor

Hepatocellular carcinoma (HCC) is a fatal disease that represents the fifth most common human cancer. Although remarkable progress has been achieved in HCC treatment in China, the overall incidence and mortality rates of HCC show no obvious changes. Pharmacological treatment can not improve the prognosis of patients with unresectable HCC. This emphasizes the need to identify new targets for early diagnosis, chemoprevention, and treatment of the disease. An effort to understand the molecular mechanisms responsible for tumor initiation and progression has led to the identification of several potential molecular targets for HCC. The majority of these targets are involved in receptor tyrosine kinase-activated pathways, such as the Raf/MEK/ERK, PI-3K/Akt/mTOR, and Jak/Stat pathways. Sorafenib is a multikinase inhibitor that has attracted wide attention. This review describes the potential targets for HCC and recent progress in targeted therapy of the disease.

• Hepatocellular carcinoma
• Molecularly targeted therapy
• Sorafenib
• Sunitinib

The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NF-κB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NF-κB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2β expression. Thus, we proposed that HBx activates MAT2A expression through NF-κB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC.

• Animals
• Apoptosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Proliferation
• DNA Repair
• Gene Expression Regulation, Neoplastic
• Hepatitis B/complications
• Hepatitis B virus/genetics
• Hepatitis B virus/metabolism
• Hepatitis B virus/pathogenicity
• Humans
• Insulin-Like Growth Factor II/metabolism
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Signal Transduction
• Telomerase/metabolism
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins

AIM: To investigate the expression of nuclear-transcription factor-κB (NF-κB) in different tissues of hepatocellular carcinoma (HCC) and its correlation with the clinicopathological features of HCC.

METHODS: Immunohistochemistry was used to detect NF-κB expression in 35 HCC tissues and in their corresponding non-cancerous tissues. Liver HBV-DNA was detected by in situ molecular hybridization technique. The relationship between NF-κB expression and HBV replication, and clinical pathological characteristics was analyzed. Fisher's exact test was used to analyze the numeration data, and rank sum test was used to analyze the ranked data.

RESULTS: The positive NF-κB material was brown granule-like stained substance, the NF-κB with dot-nest-like staining was localized in nucleus and cytoplasm in HCC, and only in cytoplasm in its surrounding tissues. Its expression in HCC was well-distributed and stronger than its surrounding tissues. The incidence of NF-κB positive expression was 100% in HCC tissues, and 68.6% in its surrounding tissues, respectively. Significant difference was found between the two groups (Fisher's exact = 0.000). No positive relationship presented itself between NF-κB expression and histological differentiation grading, the number of tumor, the size of tumor or the level of AFP and ALT. The expression level of NF-κB was significantly higher in HBV-DNA-positive HCC group than that in HBV-DNA- negative ones (t = 4.7347, P = 0.000).

CONCLUSION: The overexpression of hepatic NF-κB was closely associated with the occurrence and development of HCC, and it could be a marker for early diagnosis and prognosis of HCC.

• Hepatocellular carcinoma
• Nuclear-transcription factor-κB
• Immunohistochemistry

AIM: To investigate the biological impact of hepatitis B virus X- hepatitis C virus core (HBV X-HCV C) fusion gene on hepatoma cells.

METHODS: The recombinant adenoviruses Ad-XC, Ad-X and Ad-C expressing HBV X-HCV C fusion gene, HBV X gene and HCV C gene were constructed, respectively. Hepatoma cells were infected with different recombinant adenoviruses. MTT, colony-forming experiment, FCM, TUNEL assay were performed to observe the biological impact of the HBV X-HCV C fusion gene on liver cells.

RESULTS: MTT showed that the Ad-XC group cells grew faster than the other group cells. Colony-forming experiment showed that the colony-forming rate for the Ad-XC group cells was significantly higher than that for the other group cells. FCM analysis showed that Ad-XC/Ad-X/Ad-C infection enhanced the progression of G1→S phase in the HepG2 cell cycle. The apoptosis index of the Ad-XC, Ad-X, Ad-C group cells was significantly lower than that of the Ad0 and control group cells. Semi-quantitative RT-PCR showed that the expression level of c-myc was the highest in Ad-XC infected cells. Tumor formation was found at the injected site of mice inoculated with Ad-XC-infected LO2 cells, but not in control mice.

CONCLUSION: Ad-XC, Ad-X and Ad-C facilitate the proliferation activity of HepG2 cells and inhibit their apoptosis in vitro. The effect of Ad-XC is significantly stronger than that of Ad-X and Ad-C. Up-regulation of c-myc may be one of the mechanisms underlying the synergism of HBV X and HCV C genes on hepatocarcinogenesis in athymic nude mice.

• Hepatitis B virus X gene
• Hepatitis C virus core gene
• Hepatocellular carcinoma
• Proliferation
• Apoptosis

Hepatocellular carcinoma (HCC) is a common hepatic malignancy worldwide. Its nature of rapid growth results in a grave prognosis. Its treatment is challenging because the mechanisms underlying tumor progression are still largely unknown. Recently, new molecular targets have been confirmed and various targeted agents are now being investigated for the treatment of HCC. The progression of HCC is closely associated with expression of hepatic growth factors that may be molecular targets for HCC treatment. This paper concludes the expression characters and dynamic changes of several hepatoma-related growth factors such as IGF-Ⅱ, VEGF, TGF-β1 and HGF.

• Hepatocellular carcinoma
• Insulin-like growth factor-Ⅱ
• Vascular endothelial growth factor
• Transforming growth factor-β1
• Hepatocyte growth factor

• Acetylation
• Animals
• Blotting, Western
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Hypoxia
• Gene Expression
• Histone Deacetylase 1
• Histone Deacetylase 2
• Histone Deacetylases/genetics
• Histone Deacetylases/metabolism
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Immunoenzyme Techniques
• Immunoprecipitation
• Liver/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Retrospective Studies
• Signal Transduction
• Trans-Activators/physiology
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Cells, Cultured
• Viral Regulatory and Accessory Proteins

Abnormal expression of total γ-glutamyl transferase (GGT, EC 2.3.2.2) activity can be found in patients with different liver diseases and extrahepatic tumors. Circulating GGT from hepatocellular carcinoma (HCC) patients can be divided into different isoforms (Ⅰ, Ⅰ', Ⅱ, Ⅱ', β, δ, ε, φA, ⅦB, φC, γA, γB) by using PAGE. Some of these isoforms (Ⅰ', Ⅱ and Ⅱ', and hepatoma-specific GGT, HS-GGT) can be detected in sera of HCC patients. Hepatic GGT gene expression may be closely related to the development of HCC. The human cDNA sequences from fetal liver, placenta and HepG2 cells (H) were investigated. The genotype H was predominant in cancerous tissues of HCC. Both HS-GGT and genotype H were confirmed as useful specific HCC markers, with higher specificity and sensitivity, and their analysis may be useful for HCC diagnosis and differentiation.

• Hepatocellular carcinoma
• γ-glutamyl transferase
• Gene
• Genotyping

• APOBEC Deaminases
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/physiopathology
• Cytidine Deaminase
• Cytosine Deaminase/metabolism
• Hepatitis B Antigens/genetics
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/physiopathology
• Mutation
• Trans-Activators/genetics
• Viral Regulatory and Accessory Proteins

• R01 AI062644 NIAID NIH HHS
• R01 AI062644-03 NIAID NIH HHS
• AI062644 NIAID NIH HHS

• Aflatoxin B1/toxicity
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/genetics
• Genetic Predisposition to Disease
• Hepatitis Viruses
• Hepatitis, Chronic/complications
• Humans
• Incidence
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Liver Neoplasms/genetics
• Mutagenesis
• Mutation
• Tumor Suppressor Protein p53/genetics

• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/metabolism
• Calcium-Binding Proteins/physiology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• Cell Line, Tumor
• Gene Expression
• Humans
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Intercellular Signaling Peptides and Proteins/physiology
• Jagged-1 Protein
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Membrane Proteins/physiology
• Serrate-Jagged Proteins
• Trans-Activators/metabolism
• Trans-Activators/physiology
• Viral Regulatory and Accessory Proteins

• Amino Acid Motifs
• Animals
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Hepatitis B/complications
• Hepatitis B/genetics
• Hepatitis B/metabolism
• Hepatitis B/pathology
• Hepatitis B/virology
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• Liver Neoplasms, Experimental/metabolism
• Liver Neoplasms, Experimental/pathology
• Liver Neoplasms, Experimental/virology
• Mice
• Mice, Nude
• NIMA-Interacting Peptidylprolyl Isomerase
• Peptidylprolyl Isomerase/genetics
• Peptidylprolyl Isomerase/metabolism
• Phosphorylation
• Proline
• Protein Binding
• Proto-Oncogene Proteins c-myc/genetics
• Proto-Oncogene Proteins c-myc/metabolism
• RNA, Messenger/metabolism
• Reproducibility of Results
• Serine
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Transcription Factor RelA/genetics
• Transcription Factor RelA/metabolism
• Transcription, Genetic
• Transcriptional Activation
• Transfection
• Transplantation, Heterologous
• Up-Regulation
• Viral Regulatory and Accessory Proteins
• bcl-X Protein/genetics
• bcl-X Protein/metabolism

• Apoptosis
• Base Sequence
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Proliferation
• Cisplatin/pharmacology
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Molecular Sequence Data
• RNA Interference
• Trans-Activators
• Transfection
• Tumor Cells, Cultured
• Viral Regulatory and Accessory Proteins/antagonists & inhibitors
• Viral Regulatory and Accessory Proteins/genetics
• Viral Regulatory and Accessory Proteins/physiology

• Cell Line
• Cell Proliferation
• Hepatocytes/cytology
• Hepatocytes/metabolism
• Humans
• Interleukin-6/metabolism
• Phosphoprotein Phosphatases/metabolism
• Protein Binding
• Protein Interaction Mapping
• Protein Phosphatase 2C
• Signal Transduction/physiology
• Trans-Activators
• Viral Regulatory and Accessory Proteins/metabolism

• Amino Acid Sequence
• Carcinoma, Hepatocellular/virology
• Cell Transformation, Viral
• Hepatitis B virus/genetics
• Hepatitis B virus/physiology
• Humans
• Liver Neoplasms/virology
• Molecular Sequence Data
• Trans-Activators/genetics
• Trans-Activators/metabolism
• Viral Regulatory and Accessory Proteins
• Virus Replication

Silencing gene expression through a process known as RNA interference (RNAi) has been known in the plant world for many years. In recent years, knowledge of the prevalence of RNAi and the mechanism of gene silencing through RNAi has started to unfold. It is now believed that RNAi serves in part as an innate response against invading viral pathogens and, indeed, counter silencing mechanisms aimed at neutralizing RNAi have been found in various viral pathogens. During the past few years, it has been demonstrated that RNAi, induced by specifically designed double‐stranded RNA (dsRNA) molecules, can silence gene expression of human viral pathogens both in acute and chronic viral infections. Furthermore, it is now apparent that in in vitro and in some in vivo models, the prospects for this technology in developing therapeutic applications are robust. However, many key questions and obstacles in the translation of RNAi into a potential therapeutic platform still remain, including the specificity and longevity of the silencing effect, and, most importantly, the delivery of the dsRNA that induces the system. It is expected that for the specific examples in which the delivery issue could be circumvented or resolved, RNAi may hold promise for the development of gene‐specific therapeutics. Copyright © 2006 John Wiley & Sons, Ltd.

• Animals
• Antiviral Agents/therapeutic use
• Gene Silencing
• Genetic Therapy
• Humans
• Models, Biological
• RNA Interference
• RNA, Double-Stranded/physiology
• Virus Diseases/drug therapy

AIM: To investigate the expression of insulin-like growth factor-II (IGF-II) in hepatocellular carcinoma (HCC) as well as its correlations with the pathogenesis, development and prognosis of HCC.

METHODS: IGF-II expression was detected by immunohistochemistry in 30 HCC and their corresponding non-cancerous tissues. Liver HBV DNA was detected by in situ molecular hybridization technique and the relationship was analyzed between IGF-II expression and HBV replication or the clinical pathological characteristics.

RESULTS: The stronger expression of IGF-II was found in liver cancer tissues. The positive rate of IGF-II expression was 83.3% in HCC, and 46.7% in non-cancerous liver tissues (P < 0.01), respectively. The expression of IGF-II was significantly higher in HCC with moderate or low differentiation than that with well differentiation (90.0%, 100% vs 42.9%, P < 0.05 or P < 0.01). IGF-II expression was markedly lower in HCC without serosa invasion than that with serosa invasion (95.0% vs 60.0%, P < 0.05). IGF-II expression was also correlated with tumor size (< 5 cm vs ≥ 5 cm: 58.3% vs 100%, P < 0.01), but with tumor number (P > 0.05). The level of IGF-II expression in HBV DNA-positive HCC was significantly higher than that in HBV DNA-negative ones (94.7% vs 63.6%, P < 0.05).

CONCLUSION: IGF-II is highly expressed in HCC, and the aberrant expression of IGF-II is correlated with the degree of differentiation, invasion and tumor size, and it may be used as a marker for development and prognosis of HCC.

• Hepatocellular carcinoma
• Insulin-like growth factor-II
• Immunohistochemistry
• HBV DNA