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)

Fas antigen (ag) is a cell surface protein known to trigger apoptosis in a variety of cells upon specific antibody binding. On the other hand, Bcl-2 protein, an oncogene product located at the mitochondrial inner surface, prolongs cell survival by blocking apoptosis. In this study we examined the expression of Fas ag and bcl-2 protein in 17 cases of hepatocellular carcinoma (HCC) to determine their role on HCC. By flow cytometric analysis, mean (SD) value of the expression of Fas ag on hepatocytes derived from normal liver, diseased liver (chronic hepatitis or liver cirrhosis) and HCC was 5.8 (4.7)%, 10.3 (6.9)%, and 24.0 (18.2)%, respectively. Fas ag expression on hepatoma cells was significantly greater than normal and diseased liver cells. The expression of Bcl-2 protein in normal liver, diseased liver and HCC was 4.3 (8.5)%, 0.8 (2.5)% and 2.1 (3.4)%, respectively, and the difference was not significant. These results suggest that induction of apoptosis may be a possible therapy against HCC.
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PMID:Expression of Fas antigen and Bcl-2 protein in hepatocellular carcinoma. 750 84

The role of nuclear protein phosphorylation in intracellular signal transduction of tumor-necrosis factor-alpha (TNF-alpha) in the human hepatoma cell line PLC(PRF/5) was investigated. TNF-alpha, which displays cytolytic activity against PLC hepatoma cells, elevated the in vitro phosphorylation of two nuclear proteins (21 kDa and 34 kDa) 16 h after treatment. The cytotoxicity and enhanced nuclear protein phosphorylation by TNF-alpha treatment decreased in the presence of dexamethasone. Both the 21-kDa and 34-kDa proteins were extracted with 2.2 M NaCl from nuclear pellets and phosphorylated in kinase reaction mixtures containing a high concentration of salt. By phosphoamino acid analysis, the specificity of the nuclear kinase was found to be directed toward serine residues. The protein kinase inhibitors H7, staurosporine and herbimycin A, inhibited the phosphorylation of the 21-kDa and 34-kDa proteins in vitro, but calphostin C and heparin did not. The treatment of cells with 4 beta-phorbol 12-myristate 13-acetate or okadaic acid did not affect the in vitro phosphorylation of the two nuclear proteins. An anti-Fas antibody increased the phosphorylation of the 21-kDa and 34-kDa proteins in PLC cells. DNA fragmentation was observed in PLC cells treated with TNF-alpha and anti-Fas antibody after 24 h treatment. These data suggest an involvement of nuclear protein kinase in signal-transduction pathways of apoptotic cell damage triggered by TNF-alpha in PLC hepatoma cells.
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PMID:Enhanced phosphorylation of nuclear 21-kDa and 34-kDa proteins in hepatoma cell death induced by tumor-necrosis factor-alpha. 755 42

A transgenic mouse model for hepatocarcinoma has been previously produced by targeting SV40 T-antigen expression to the liver. To evaluate the perturbation of cell death occurring during hepatocarcinogenesis, we examined the Fas-induced apoptosis on hepatocytes expressing T-antigen. Whereas anti-Fas antibody induced apoptosis in primary cultured normal hepatocytes, they imparted a weak cytotoxicity on primary cultured hepatocytes expressing T-antigen. This resistance of hepatic Fas-mediated apoptosis appears to result in an enhancement of a protective mechanism involving the protein kinase C signaling pathway rather than in a down-regulation of Fas-antigen expression. We further demonstrated that anti-Fas antibody does not have as efficient a lethal effect in T-antigen transgenic mice as in wild-type mice. The livers of transgenic mice injected with anti-Fas mAbs showed large intact regions with a few scattered apoptotic bodies: these regions strictly corresponded with carcinoma nodules, expressing high level of T-antigen. Our results describe a novel function for SV40 T-antigen which could contribute to viral pathogenesis by protecting infected cells against the host apoptotic defense mechanism.
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PMID:Fas-dependent apoptosis is impaired by SV40 T-antigen in transgenic liver. 756 65

CTLs- and lymphokine-induced apoptosis of infected hepatocytes during the course of chronic viral hepatitis is thought to be important for both disease termination and prevention of hepatocellular transformation. We therefore studied apoptosis induced by Fas (APO-1 or CD95)-a widely expressed cell surface receptor whose ligand is involved in lymphocyte cytotoxicity-in a set of human hepatoma cell lines. As normal hepatocytes, all of the human hepatoma cell lines tested do express detectable amounts of Fas on their surface. Nevertheless, only PLC/PRF/5 cells undergo apoptosis following treatment with anti-Fas. Systematic cloning and sequence analysis of the Fas cDNA did not show mutations in the Fas gene in any of the cells lines tested. However, due to alternative splicing, 5 to 10% of the Fas cDNAs are deleted of 63 internal nucleotides corresponding to the transmembrane domain, thus encoding for a soluble and secreted form of Fas (Fas delta TM), potentially able to neutralize anti-Fas or Fas-Ligand. Although we could not demonstrate a direct correlation between resistance of different hepatoma cell lines to Fas mediated death and endogenous expression of this transcript, we show that PLC/PRF 5 stable transfectants overexpressing Fas delta TM are less sensitive to anti-Fas than control cells. In three different cell lines, resistance to anti-Fas was overcome by treatment with the protein synthesis inhibitor cycloheximide. Although this could suggest the existence of short-lived repressors of the Fas-activated apoptotic signalling pathway(s), we show that translational inhibition is not required for the synergistic effect of cycloheximide to take place, and that resistant hepatoma cells can be sensitized to anti-Fas by subinhibitory concentrations of this protein synthesis inhibitor. Since cycloheximide is able to activate intracellular signalling independently on its effects on protein synthesis, we suggest that it might provide a costimulatory signal that cooperates with Fas in the induction of cell death and that, at least in the cells we tested, resistance to Fas is not an active process involving gene transcription and translation but only the consequence of an inadequate apoptotic stimulation.
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PMID:Resistance to Fas-mediated apoptosis in human hepatoma cells. 756 76

The p53 tumor suppressor gene product is a transcriptional transactivator and a potent apoptotic inducer. The fact that many of the DNA tumor virus oncoproteins bind to p53 and affect these p53 functions indicates that this interaction is an important step in oncogenic transformation. We and others have recently demonstrated that the hepatitis B virus oncoprotein, HBx, can form a complex with p53 and inhibit its DNA consensus sequence binding and transcriptional transactivator activity. Using a microinjection technique, we report here that HBx efficiently blocks p53-mediated apoptosis and describe the results of studies exploring two possible mechanisms of HBx action. First, inhibition of apoptosis may be a consequence of the failure of p53, in the presence of HBx, to upregulate genes, such as p21WAF1, Bax, or Fas, that are involved in the apoptotic pathway. Data consistent with this hypothesis include HBx reduction of p53-mediated p21WAF1 expression. Alternatively, HBx could affect p53 binding to the TFIIH transcription-nucleotide excision repair complex as HBx binds to the COOH terminus of p53 and inhibits its binding to XPB or XPD. Binding of p53 to these constituents of the core TFIIH is a process that may be involved in apoptosis. Because the HBx gene is frequently integrated into the genome of hepatocellular carcinoma cells, inhibition of p53-mediated apoptosis by HBx may provide a clonal selective advantage for hepatocytes expressing this integrated viral gene during the early stages of human liver carcinogenesis.
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PMID:Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. 852 83

The primary diseases of 209 explanted livers of the transplantation center of the University of Heidelberg are presented. Liver cirrhosis was found in 48.8% as the primary disease followed by the group of malignancies of the liver (28.2%) with HCC as the predominant tumor. Fulminant liver failure was found in 13.8% as the primary disease. Metabolic disorders comprised a small group of 11 cases (5.3%). 7 cases were transplanted for Budd Chiari syndrome (3.3%) and one case was transplanted for E. alveolaris. The examination of fulminant viral hepatitis revealed evidence of the involvement of the APO-1/Fas (CD95) system in the pathogenesis of this disorder. Prognostic factors for recurrence of hepatocellular carcinoma are size and number of tumor nodules as well as proliferative activity of the tumors determined by Ki67 immunostaining. Diagnosis of HCV infection of the livers is best established by RT-PCR after RNA extraction and is still superior to other immunohistochemical or in-situ methods.
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PMID:[Pathology of the explanted liver in liver transplantation]. 860 Jun 90

We tried to induce tumor cell death in vivo through Fas (CD95)-mediated apoptosis. Murine hepatoma MH 134 (Fas-) was transfected with murine Fas antigen cDNA. Fas+ F6b but not Fas- N1d cells underwent apoptosis after treatment with anti-Fas antibody in vitro. The possibility of eradicating tumor cells in vivo with anti-Fas antibody was investigated using double-mutant gld/gld lpr/lpr mice which lack both Fas ligand (FasL) and Fas to avoid cytotoxic activity of the antibody to the liver and interference from endogenous FasL. A single administration of anti-Fas antibody efficiently suppressed the growth of F6b tumors but not that of N1d tumors in these mice. Thus, the therapy with Fas-FasL system may be a promising approach for cancer treatment, and this model is useful for study on in vivo apoptosis-mediated antitumor activity.
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PMID:A trial to kill tumor cells through Fas (CD95)-mediated apoptosis in vivo. 892 Sep 22

Chemotherapeutic drugs are cytotoxic by induction of apoptosis in drug-sensitive cells. We investigated the mechanism of bleomycin-induced cytotoxicity in hepatoma cells. At concentrations present in the sera of patients during therapy, bleomycin induced transient accumulation of nuclear wild-type (wt) p53 and upregulated expression of cell surface CD95 (APO-1/Fas) receptor in hepatoma cells carrying wt p53 (HepG2). Bleomycin did not increase CD95 in hepatoma cells with mutated p53 (Huh7) or in hepatoma cells which were p53-/- (Hep3B). In addition, sensitivity towards CD95-mediated apoptosis was also increased in wt p53 positive HepG2 cells. Microinjection of wt p53 cDNA into HepG2 cells had the same effect. In contrast, bleomycin did not enhance susceptibility towards CD95-mediated apoptosis in Huh7 and in Hep3B cells. Furthermore, bleomycin treatment of HepG2 cells increased CD95 ligand (CD95L) mRNA expression. Most notably, bleomycin-induced apoptosis in HepG2 cells was almost completely inhibited by antibodies which interfere with CD95 receptor/ligand interaction. These data suggest that apoptosis induced by bleomycin is mediated, at least in part, by p53-dependent stimulation of the CD95 receptor/ligand system. The same applies to other anti-cancer drugs such as cisplatin and methotrexate. These data may have major consequences for drug treatment of cancer and the explanation of drug sensitivity and resistance.
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PMID:Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. 902 73

Previous studies have shown that the administration of concanavalin A (ConA) into mice induces immune-mediated liver injury, which can be largely abrogated by neutralizing tumor necrosis factor(TNF)alpha. Vesnarinone is an experimental drug which is known to inhibit TNF alpha release. Here we demonstrate that vesnarinone inhibits ConA-induced hepatic injury. In a dose-dependent manner, vesnarinone inhibits in several mouse strains the increase of serum aminotransferase concentrations. additional experiments show that vesnarinone inhibits ConA-mediated accumulation of DNA fragmentation in the liver. Furthermore, the drug significantly reduces the levels of circulating TNF alpha and interleukin-6 (IL-6). Vesnarinone does not modulate TNF alpha and IL-6 action on hepatic cells, as shown by its failure to reduce the cytokine specific-stimulation of acute phase plasma proteins in the rat hepatoma H-35 cell line. Neither vesnarinone nor anti-TNF alpha protect against direct liver injury induced by a sublethal dose of agonist anti-Fas (CD95) antibody. Taken together, these results suggest that vesnarinone blocks hepatic injury, in part by inhibiting the release of TNF alpha in vivo.
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PMID:Vesnarinone inhibits immune-mediated but not Fas (CD95) agonist-mediated hepatic injury. 922 79

Cross-linking of Fas (CD95, APO-1) and Fas ligand (FasL; CD95L) induces apoptosis of Fas-bearing cells. Recent evidence suggests that FasL. expression plays an important role in maintenance of immune privilege in murine testis and eye and in tumour escape from immune rejection in colon cancer, melanoma and hepatocellular carcinoma. Bcl-2 is a membrane protein that suppresses apoptosis in response to a variety of stimuli. In this paper we describe abundant expression of FasL protein and mRNA transcripts within the immune privileged environment of the placenta by immunohistochemistry and reverse transcription in-situ polymerase chain reaction methods. The syncytiotrophoblast layer, the main site of feto-maternal interface, and extravillous trophoblasts, demonstrated consistent immunoreactivity for FasL in term placentae. Co-occurrence of Fas and Bcl-2 were detected with a similar pattern of distribution with FasL. The TUNEL method revealed evidence of apoptosis in the placental tissues. We speculate that abundant presence of FasL in the trophoblast contributes to immune privilege in this unique environment, perhaps by fostering apoptosis of activated Fas-expressing lymphocytes of maternal origin. An apoptotic process mediated by FasL may also play a role in placental invasion during implantation and underscores similarities between the trophoblast and neoplastic cells.
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PMID:Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. 929 48


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