Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide, which finally leads to development of hepatocellular carcinoma. Chronic hepatitis C is characterized by several histological features in the liver which discriminate it from other forms of hepatitis: bile duct damage, lymphoid follicles and steatosis (fatty change). Little is known, however, about the role of HCV or its viral proteins in the pathogenesis of hepatitis. Recently, the core protein of HCV has been suggested to have a transcriptional regulatory function, and thereby to be involved in inducing phenotypic changes in hepatocytes. To clarify whether or not the HCV core protein has an effect on pathological phenotypes in the liver, two independent transgenic mouse lines carrying the HCV core gene were established. These mice developed progressive hepatic steatosis, indicating that the HCV core protein plays a direct role in the development of hepatic steatosis, which characterizes hepatitis C. This transgenic mouse system would be a good animal model for the study of pathogenesis in human HCV infection.
J Gen Virol 1997 Jul
PMID:Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. 922 25

Hepatitis C virus (HCV) is a major cause of chronic viral hepatitis. Development of anti-viral strategies has been hampered by the lack of efficient cell systems to propagate HCV in vitro. To establish a long-term culture system, we tested human hepatoma (HuH7, HepG2) and porcine non-hepatoma (PK15, STE) cell lines, as well as several culture and infection conditions. As a marker for virus replication, minus-strand HCV RNA in infected cells was detected by an enhanced detection system using nested RT-PCR followed by hybridization analysis. Short-term efficiency of HCV infection (10 days) was slightly increased by addition of polyethylene glycol (PEG) and/or dimethyl sulfoxide (DMSO) to culture media during inoculation of HuH7, PK15 and STE cells, but no augmentation in long-term culture was achieved, suggesting enhanced attachment of HCV to cells rather than more efficient infection. A stabilizing effect on HCV propagation was observed for 50 days in a serum-free medium with stimulation of the low-density lipoprotein (LDL) receptor expression by lovastatin. Using partially serum-free culture conditions, long-term persistence of HCV in cells and release of virions into supernatant was achieved for up to 130 days. Infectivity of released virions in supernatants after long-term culturing (day 30-80) was shown by successful infection of fresh cells. In conclusion, supplementation with PEG, DMSO and lovastatin during inoculation did not enhance virus replication substantially, but continued stimulation of LDL-receptor expression resulted in infections which persisted for over 4 months. These data support the hypothesis of an LDL-receptor mediated uptake of HCV into cells in vitro.
J Gen Virol 1997 Oct
PMID:Establishment of persistent hepatitis C virus infection and replication in vitro. 934 66

A defective hepatitis C virus (HCV) genome in the ascitic fluid of a patient with hepatocellular carcinoma was cloned and sequenced up to the 3' poly(U) stretch. When compared with the published Taiwanese HCV sequence, this defective genome contained deletions of single nucleotides at eight sites, double nucleotides at two sites, triple nucleotides at four sites, quadruple nucleotides at one site and replacement of a short stretch of sequence at one site. For comparison, the corresponding regions containing these mutations were also cloned from a serum sample from this patient. Except for deletions of two triple nucleotides in the hypervariable region, the reading frames of all serum-derived clones were intact. The defective HCV genome encoded a truncated core protein with 90 amino acid residues (the last 20 amino acid residues came from a different reading frame), whereas the serum-derived genome encoded a full-length core protein. When expressed in Huh-7 cells, these two proteins were localized to the nucleus and cytoplasm, respectively. Using specific primer-sets, ascites- and serum-derived genomes were each detected alone in ascitic fluid and serum samples, respectively, whereas both sequences were present in ascitic mononuclear cells. The defective sequence thus constituted the major virus population in the ascitic fluid whereas a putative helper genome coexisted with it inside the ascitic mononuclear cells. This sequence is possibly a defective and interfering genome.
J Gen Virol 1997 Nov
PMID:Molecular cloning of a defective hepatitis C virus genome from the ascitic fluid of a patient with hepatocellular carcinoma. 936 61

Hepatitis B virus (HBV) isolates with A-1762 to T and G-1764 to A mutations in the core promoter have been associated with active hepatitis, severe liver disease following liver transplantation, hepatocellular carcinoma and acute fulminant courses--in the latter case combined with a C-1653 to T mutation. In this study, a mutant core promoter region containing the T-1653, T-1762 and A-1764 mutations was placed into the context of a wild-type HBV genome and analysed by transfection. The mutations reduced the level of pre-C mRNA (by 55%) and e-antigen secretion. In contrast, no significant effects on the levels of pregenome/C and pre-S/S mRNAs, intracellular core, polymerase, and pre-S /S2 proteins and secreted S-antigen were observed. The amount of progeny virus DNA in the cells and in the culture medium was increased marginally, if at all.
J Gen Virol 1998 Feb
PMID:Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653) --> T, A(1762) --> T and G(1764) --> A mutations in the core promoter. 947 23

Persistent infection by hepatitis B virus (HBV) correlates with the prevalence of hepatocellular carcinoma. It has recently been demonstrated that the complete viral genome very efficiently transforms the immortalized murine hepatocyte line FMH202 in vitro. Here it is shown that the viral transactivating protein X (HBx) is sufficient to transform FMH202 cells, albeit with lower efficiency. Clonal cell lines expressing HBx mRNA in moderate or high amounts grew in soft agar and formed tumours in nude mice. Growth efficiency in soft agar of HBx transformed cell lines was much lower than that of cell lines transformed with the complete genome, and latency of tumour induction in nude mice was significantly longer after inoculation of HBx than of HBV transformed FMH202 cell lines. A marker of complete transformation, p53, was found to be phosphorylated more strongly in HBx transfected cell lines than in controls, and a cellular kinase was found to be associated with p53 complexes from HBx transformed cell lines. p53 was of wild-type conformation and was located in the nucleus of transformed cells.
J Gen Virol 1998 Apr
PMID:Properties of tumour suppressor p53 in murine hepatocyte lines transformed by hepatitis B virus X protein. 956 72

In order to characterize the hepatitis B virus (HBV) hepatocellular receptor, several proteins have previously been identified in HepG2 hepatoma cells and in primary cultured normal human hepatocytes (PCHs) that reacted with an anti-idiotypic antibody against a preS1(21-47)-specific MAb (F35.25). Here, we report the identification of one of these preS1-binding proteins, a 35 kDa protein (preS1-BP35), as glyceraldehyde-3-phosphate dehydrogenase (GAPD). GAPD is well-known as a key enzyme involved in glycolysis and gluconeogenesis. Nevertheless, GAPD has also been shown to have many other functions such as protein kinase activity (GAPD-PK). HBV core particles derived from infected hepatocytes possess an associated kinase activity that phosphorylates HBcAg, and the nucleocapsid may acquire sequential functions through selective phosphorylation. Therefore, we have investigated the potential role of GAPD-PK in HBV replication. In this study, we found that the endogenous PK associated with human liver-derived HBV core particles (hL-HBcAg) and GAPD-PK were sensitive to the same types of inhibitors. Interestingly, capsid protein phosphorylation decreased in a concentration-dependent manner (at concentrations of 5-30 mM) in the presence of specific inhibitors for GAPD-PK (NADH and GAP). Furthermore, we demonstrated in vitro that GAPD-PK could phosphorylate the major core protein P22 in hL-HBcAg particles. The data suggest that GAPD is an additional cellular kinase which might interfere in the life-cycle of HBV.
J Gen Virol 1998 Jul
PMID:Phosphorylation of the hepatitis B virus core protein by glyceraldehyde-3-phosphate dehydrogenase protein kinase activity. 968 Jan 29

The phosphoprotein NS5A of hepatitis C virus has recently been suggested to control PKR protein kinase for resistance to interferon. To investigate other functions of NS5A, studies were initiated on the regulation of transcription of important cellular genes and of cell growth by this protein. The results suggested that NS5A protein represses transcription of the cell cycle regulatory gene p21WAF1, while it activates the human proliferating cell nuclear antigen gene in murine fibroblasts and human hepatoma cells. Furthermore, introduction of NS5A into murine fibroblasts (NIH3T3) promoted anchorage-independent growth and tumour formation in nude mice. Thus, NS5A appears to exhibit a role in cell growth regulation.
J Gen Virol 1999 May
PMID:Hepatitis C virus NS5A protein modulates cell cycle regulatory genes and promotes cell growth. 1035 64

The Cu/Zn superoxide dismutase (SODI) catalyzes the dismutation of superoxide radicals produced in the course of biological oxidations. When placed under the control of the rat SOD1 gene promoter and transfected into human HepG2 hepatoma cells, the activity of a chloramphenicol acetyltransferase reporter gene was found to increase three- to four-fold in the presence of heavy metals (cadmium, zinc and copper). Functional analysis of mutant derivatives of the SOD1 gene promoter and the use of a heterologous promoter system confirmed that the induction of the SOD1 gene by metal ions requires a metal-responsive element (MRE) located between positions -273 and -267 (GCGCGCA). It was also shown by gel mobility shift assays that an MRE binding protein is induced by the exposure of the human liver cell line HepG2 to heavy metals. These results suggest that the MRE participates in the induction of the SOD1 gene by heavy metals.
Mol Gen Genet 1999 Sep
PMID:Heavy metal-mediated activation of the rat Cu/Zn superoxide dismutase gene via a metal-responsive element. 1051 27

The HBx protein of hepatitis B virus is a multifunctional protein that is implicated in the pathogenesis of hepatocellular carcinoma by regulating gene transcription, causing cell proliferation and, as shown recently, inducing cell death. However, analysis of the effects of HBx in stable cultured cell clones has been hampered because only cell lines that adapted to the effects of HBx were selected during the establishment of cell clones. Here, we describe a system in which transcription of the X gene of hepatitis B virus is switched on by the use of the site-specific Cre recombinase. Two human liver cell lines, HLF and HepG2, were used, the former with a mutant p53 allele and the latter with wild-type p53. The stable cell clones isolated, which carried the X gene in a transcriptionally silent state, were infected with recombinant adenovirus carrying Cre recombinase. Ninety-six hours after adenovirus infection, cell clones that expressed HBx had undergone TUNEL-positive cell death with characteristics of apoptosis. Apoptosis was induced despite concomitant inactivation of the p53 protein as a result of its cytoplasmic translocation by HBx. In contrast, neither the X gene-carrying cells infected with wild-type adenovirus nor various control cells infected with Cre-expressing adenovirus exhibited apoptosis. These results indicate that the expression of HBx protein leads to liver cell apoptosis independently of the p53 pathway. The significance of HBx-induced apoptosis in natural infection is unclear, but it may contribute to the development of hepatitis and serve to spread progeny virus to neighbouring cells while evading the host immune responses.
J Gen Virol 1999 Dec
PMID:Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system. 1056 59

The structure of hepatitis B virus (HBV) nucleocapsids has been revealed in great detail by cryoelectron microscopy. How nucleocapsids interact with surface antigens to form enveloped virions remains unknown. In this study, core mutants with N-terminal additions were created to address two questions: (1) can these mutant core proteins still form nucleocapsids and (2) if so, can the mutant nucleocapsids interact with surface antigens to form virion-like particles. One plasmid encoding an extra stretch of 23 aa, including six histidine residues, fused to the N terminus of the core protein (designated HisC183) was expressed in Escherichia coli and detected by Western blot. CsCl gradient and electron microscopy analyses indicated that HisC183 could self-assemble into nucleocapsids. When HisC183 or another similar N-terminal fusion core protein (designated FlagC183) was co-expressed with a core-negative plasmid in human hepatoma cells, both mutant core proteins self-assembled into nucleocapsids. These particles also retained kinase activity. Using an endogenous polymerase assay, a fill-in HBV DNA labelled with isotope was obtained from intracellular nucleocapsids formed by mutant cores. In contrast, no such signal was detected from the transfection medium, which was consistent with PCR and Southern blot analyses. Results indicate that core mutants with N-terminal extensions can form nucleocapsids, but are blocked during the envelopment process and cannot form secreted virions. The mutant nucleocapsids generated from this work should facilitate further study on how nucleocapsids interact with surface antigens.
J Gen Virol 1999 Oct
PMID:Hepatitis B viral core proteins with an N-terminal extension can assemble into core-like particles but cannot be enveloped. 1057 58


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