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

GP73 is a novel type II Golgi transmembrane protein that is expressed at high levels in the hepatocytes of patients with viral hepatitis (R. D. Kladney, G. A. Bulla, L. Guo, A. L. Mason, A. E. Tollefson, D. J. Simon, Z. Koutoubi, and C. J. Fimmel, 2000, Gene 249, 53-65) and is induced in cultured cells by infection with viruses including adenoviruses. Its biological function and the mechanisms by which its expression may be regulated by viral infection are unknown. Here we report that GP73 is induced at the RNA and protein level in human Hep3B hepatoma cells infected by human Ad5 and Ad2. Hep3B cells were infected with wild-type or mutant adenoviruses. GP73 expression was measured by RNase protection assay, immunoblotting, or immunofluorescence microscopy. GP73 RNA and protein levels were strikingly induced following infection. The rise in GP73 expression coincided with the appearance of the adenovirus E1A and DBP proteins and preceded the expression of the fiber protein, a marker of the late phase of infection. Infection did not affect the expression of giantin, GPP130, or golgin-84, three integral Golgi membrane proteins with structural similarities to GP73. Mapping studies using a panel of mutant adenoviruses demonstrated that the E1A C-terminus, specifically its CtBP interaction domain (CID), is required for GP73 expression. Subsequently, Hep3B cells were transiently transfected with plasmids expressing wild-type or mutant E1A proteins. These studies confirmed that E1A induced GP73 expression via the CID. Our studies establish GP73 as a novel adenovirus-induced cellular protein whose expression is regulated through the CID of the E1A protein.
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PMID:Upregulation of the Golgi protein GP73 by adenovirus infection requires the E1A CtBP interaction domain. 1235 26

Various cytokines and chemokines play a role in carcinogenesis. However, no study has previously been undertaken to investigate comprehensively the expressions of cytokines and chemokines in hepatoma cells. In this study, we determined which cytokines and chemokines are expressed in hepatoma cells. Recently, it was reported that the expressions of several chemokines could be increased by Fas stimulus in many normal and cancer cells. Therefore, we also investigated whether chemokines expression is regulated by Fas ligation. To address this issue, we performed RNase protection assays upon 13 cytokines and 8 chemokines genes in 10 human hepatoma cell lines, comprising 8 hepatitis B virus (HBV)-associated hepatoma cell lines. Transforming growth factor-beta2 (TGF-beta2) was found to be expressed in 8 HBV-associated hepatoma cell lines, and to be potently expressed in 5 cell lines; however, the mRNA expressions of interleukin-10 (IL-10), IL-12, interferon-gamma(IFN-gamma) and tumor necrosis factor-alpha(TNF-alpha) were not detected in any cell lines examined. Among the chemokines investigated in this study, IL-8 was expressed by 8 HBV- associated hepatoma cell lines, and monocyte chemoattractant protein-1 (MCP-1) by 7 HBV-associated hepatoma cell lines. However, the mRNA expressions of macrophage inflammatory protein-1alpha(MIP-1alpha), MIP-1beta, interferon-inducible protein-10 (IP-10), RANTES, lymphotactin and I-309 were either very weak or undetectable. Fas ligation did not increase chemokines expression in hepatoma cells. Conclusively, TGF-beta2, IL-8 and MCP-1 were overexpressed in HBV-associated hepatoma cells, and the expressions of chemokines were not increased by Fas ligation in human hepatoma cells.
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PMID:Expression patterns of cytokines and chemokines genes in human hepatoma cells. 1240 81

Rana catesbeiana ribonuclease (RC-RNase) exerted strong anti-tumor activity and its cytotoxicity was shown to correlate with differentiation stages of three different hepatoma cell lines. In this study, we demonstrate different RC-RNase cytotoxicity in undifferentiated HL-60 cells and in those that had been induced to differentiate by retinoic acid or dimethylsulfoxide. RC-RNase showed cytotoxicity in undifferentiated HL-60 cells, but not in HL-60 cells undergoing terminal differentiation. Furthermore, the caspase-9/caspase-3 pathway was activated when RC-RNase induced death in undifferentiated HL-60 cells and induction of differentiation led to a reversal of the caspase activation pathway.
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PMID:Induction of differentiation rescues HL-60 cells from Rana catesbeiana ribonuclease-induced cell death. 1243 86

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.
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PMID:Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. 1252 48

4-phenylbutyrate (triButyrate trade mark, PB) a derivative of the short-chain fatty acid, butyrate, possesses anti-tumor activity in vitro in different tumor cell lines. Unlike most cytostatic compounds, PB possesses low toxicity. In order to evaluate possible clinical use of PB in cancer therapy, hepatocarcinoma (Hep3B) and hepatoblastoma (HepT1) cell lines, as well as xenografts derived from those in nude rats, were treated with PB in different dose (1-100 mM) and time regimens. Treatment with 10 mM of PB for 24 h (or 5 mM for 48 h) was shown to significantly inhibit Hep3B cell growth in vitro. The HepT1 cell line was more sensitive to PB treatment: already 1 mM of PB for 24 h significantly inhibited the growth of the cells. PB also resulted in regression of xenografts derived from these cell lines in vivo, when administrated by mini-pump with an intratumor catheter, yielding 20 micro mol of PB per cm3 of tumor volume per day. TUNEL assay and caspase-3 activity measurements suggested apoptosis to be the cell death mechanism in both cell lines and xenografts. Increased histones H3 and H4 acetylation was shown in both cells and xenografts, and the inhibition of histone deacetylase is proposed as the main trigger for the anti-tumor action of PB. Concomitant induction of p21Waf1/Cip1 expression was detected by RNase protection assay and Western blotting. Reduction in expression of alpha-fetoprotein was found both in Hep3B cells and xenografts, suggesting also a differentiation effect by PB.
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PMID:Apoptosis and tumor remission in liver tumor xenografts by 4-phenylbutyrate. 1257 11

A peptide, with a molecular mass of 9.5kDa and demonstrating an N-terminal sequence similar to ubiquitin, was isolated from fruiting bodies of the mushroom Agrocybe cylindracea. The peptide was isolated with a purification protocol involving ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, FPLC-ion exchange chromatography on Mono S and FPLC-gel filtration on Superdex 75. The peptide was unadsorbed on DEAE-cellulose and adsorbed on Affi-gel blue gel and Mono S. It showed antiproliferative activity on leukemia cell line (M1) and hepatoma cell line (HepG2), and enhanced nitric oxide production in murine peritoneal macrophages with a potency comparable to that of lipopolysaccharide. A pH of 6.0 was required for optimal RNase activity. Its RNase activity was stable over the temperature range of 0-60 degrees C. It exerted ribonucleolytic activity preferentially on polyC, much lower activity on polyU, and negligible activity on polyA and polyG.
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PMID:Purification and characterization of a ubiquitin-like peptide with macrophage stimulating, antiproliferative and ribonuclease activities from the mushroom Agrocybe cylindracea. 1289 48

Biochemical studies revealed that nonstructural proteins of hepatitis C virus (HCV) interacted with each other and were associated with intracellular membranes. The goals of this study were to determine whether nonstructural viral proteins are colocalized at specific intracellular sites where HCV RNA is replicated and to identify the virus components of the HCV replication complex (RC). Immunofluorescence and subcellular fractionation studies were performed to determine the intracellular colocalization of nonstructural HCV proteins and the replicating RNA in a human hepatoma cell line, Huh7, in which a subgenomic HCV RNA was replicated persistently. The replicating HCV RNA was labelled with 5-bromouridine 5'-triphosphate (BrUTP). Results show that each of the nonstructural HCV proteins was colocalized predominantly with the newly synthesized HCV RNA labelled with BrUTP and an endoplasmic reticulum (ER) protein, calnexin. Consistent with these findings, subcellular fractionation and Western blot analyses revealed that the nonstructural HCV proteins were colocalized with HCV RNA mainly in the membrane fractions. Conversely, the viral nonstructural proteins and RNA remained in the soluble fractions upon treatment with detergent, confirming the membrane association of the HCV RC. HCV RNA in the membrane-bound RC was resistant to RNase treatment, whereas it became sensitive to RNases once the membranes were disrupted by treatment with detergent, suggesting that the HCV RC is assembled within membrane structures. Collectively, these findings demonstrate that HCV RNA replication occurs in the perinuclear ER membrane-bound HCV RC, containing nonstructural viral proteins and RNA.
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PMID:Replication of hepatitis C virus RNA occurs in a membrane-bound replication complex containing nonstructural viral proteins and RNA. 1367 11

The majority of persons with chronic hepatitis C virus (HCV) infection develop liver fibrosis. Transforming growth factor (TGF)-beta 1 plays a pivotal role in the pathogenesis of post-inflammatory liver scarring. To clarify the influence of HCV infection on liver fibrosis, a reporter assay was used to investigate the effect of viral proteins on TGF-beta 1 expression in human hepatoma cells. Of all HCV proteins investigated (core, E1/E2/p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only the core protein activated the TGF-beta 1 promoter and upregulated TGF-beta 1 expression measured by an RNase protection assay. Bases -376 to -331 bp in the promoter region of TGF-beta 1 are responsible for upregulation by HCV core protein, and the nuclear protein that binds to this region increased with the stimulation of HCV core protein. Blocking the mitogen-activated protein kinase pathway prevented upregulation of TGF-beta 1 by HCV core protein. The immunological response is supposed to be a major factor to cause the secretion of TGF-beta 1 from non-parenchymal cells, but the results suggest that the HCV core protein expression may upregulate directly TGF-beta 1 transcription in parenchymal cells and suggest a new paradigm for exacerbation of liver fibrosis by HCV infection.
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PMID:Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. 1463 11

Human hepatoma cell lines undergo apoptosis after treatment with cisplatin (CP), by mechanisms that are not fully understood, although our previous study demonstrated that Fas-dependent or -independent pathways are involved. To elucidate the mechanisms of CP-induced apoptosis in Hep3B cells, which are Fas- and p53-negative, we investigated mitochondria associated pathways, the involvement of NF-kappaB, and p73 activation. Results of Western blot and flow cytometry assay revealed that the translocation of Bax, resulted in the loss of mitochondrial membrane potential (Deltaphi(m)) and the efflux of cytochrome c and of second mitochondria-derived activator of caspase/DIABLO from mitochondria into the cytosol. Caspase-3, -8 and -9 were activated by CP treatment, however, CP-induced apoptosis was not completely blocked by pretreating with the pan-caspase inhibitor, benzyloxycarbonyl-valinyl-alaninyl-aspartyl-(O-methyl)-fluoromethylketone, indicating that caspase-independent apoptotic pathways might also be involved. RNase protection assay confirmed that NF-kappaB downregulation leading to the suppression of its target genes, such as XIAP and TRAF2, and p73 accumulation were also observed in Hep3B cells treated with CP. CP-induced apoptosis was inhibited to some extent by transiently overexpressed p73 dominant negative and XIAP, but not by p73DN or XIAP alone. In conclusion, this study demonstrates that CP-induced apoptosis in Hep3B cells is associated with mitochondrial dysregulation, NF-kappaB downregulation and p73 accumulation.
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PMID:Cisplatin-induced apoptosis in Hep3B cells: mitochondria-dependent and -independent pathways. 1504 63

In this report, we examined the role of activin in the regulation of cell growth inhibition of human hepatocarcinoma cells. Using RNase protection assay for various cell cycle regulators and Western blotting experiments, we show that activin treatment of HepG2 cells leads to increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p15INK4B. Furthermore, transient co-transfection studies of the p15INK4B promoter/luciferase construct performed in HepG2 cells demonstrates that activin induction of the p15INK4B promoter is mediated through the Smad pathway. p15INK4B gene promoter mapping analysis revealed a 66-bp region within the proximal domain of the promoter, which contains a consensus site for the transcription factor Sp1, as critical for mediating the activin effect on p15INK4B gene expression. Finally, gel mobility shift experiments, using the Sp1 consensus site, revealed increased DNA binding of Sp1 in response to activin treatment of HepG2 cells, further confirming the involvement of Sp1 in activin-mediated p15INK4B gene promoter activation. Together, our data indicates an important role for the cyclin-dependent kinase inhibitor p15INK4B in activin-induced cell cycle arrest in liver cells.
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PMID:Activin induces hepatocyte cell growth arrest through induction of the cyclin-dependent kinase inhibitor p15INK4B and Sp1. 1509 10


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