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)

The effect of IFN-alpha on the growth of 5 hepatoma cell lines and a normal liver-derived cell line were examined. IFN dose-dependently inhibited the growth of cell lines except for HLE and PLC/PRF/5 in which the inhibition only occurred at a high concentration over 10,000 IU/ml. IFN-alpha induced the G1 arrest of these cells according to upregulation of p21WAF-1 expression, which is induced in PLC/PRF/5 and HLE only at a high IFN concentration. The receptor for IFN-alpha was well expressed in all the cell lines. DNA rearrangement of IRF-1 was detected in HLE and PLC/PRF/5 by Southern blotting, while IRF-2 gene was preserved. IFN-induced gene expressions were compared between HCC-T, HCC-M and PLC/PRF/5. RT-PCR demonstrated that the full-length IRF-1 and -2 mRNA was transcribed in all cell lines, but the mRNA amount of former gene in PLC/PRF/5 was less than that in HCC-T and HCC-M, about 1/10 by competitive RT-PCR. The sequence analysis of IRF-1 cDNA was performed and the full-length mRNA transcription was reconfirmed in PLC/PRF/5, but no significant point mutation was detected. These results suggest that IFN-alpha inhibits hepatoma growth by increasing p21WAF-1 expression only when the IRF-1 gene is preserved normally.
 ...
PMID:Interferon regulatory factor-1 gene abnormality and loss of growth inhibitory effect of interferon-alpha in human hepatoma cell lines. 982 33

To investigate the role of integrins in hepatocellular carcinoma (HCC) invasion, we analyzed the relationship between the expression and activity of beta1 integrins and the invasive ability of multiple HCC cell lines. Human HCC cell lines, PLC/PRF/5, Hep3B, HepG2, HLE, HuH7, and C3A cells, had high expression of beta1 and alpha6 subunits, and various levels of alpha1, alpha2, alpha3, and alpha5 expression as determined by cell surface flow cytometry. Activity of beta1 integrins was evaluated by cell adhesion to collagen, fibronectin, and laminin in the presence or absence of the stimulatory anti-beta1 monoclonal antibody (mAb) TS2/16. Different types of HCC cells showed various levels of constitutive activity of beta1 integrins as assessed by the TS2/16 requirement in cell adhesion. TS2/16 rapidly stimulated constitutively inactive or partially active beta1 integrins to fully active states, and as the result, the levels of cell adhesion to each ligand correlated with the expression levels of corresponding beta1 integrins. Thus, in the presence of TS2/16 stimulation, the levels of cell adhesion to collagen, fibronectin, and laminin correlated predominantly with the expression levels of alpha2, alpha5, and alpha6, respectively. Remarkably, as a result of in vitro chemoinvasion assay, the levels of constitutive activity of beta1 integrins correlated with the invasive ability of HCC cells. The inhibitory anti-beta1 mAb 13 almost completely blocked the invasion of PLC/PRF/5 and Hep3B cells that are the most invasive HCC cell lines. Alternatively, the stimulatory anti-beta1 mAb TS2/16 strongly inhibited the invasion. These results not only show an essential role of beta1 integrins in invasion of HCC cells but also suggest subtle regulatory mechanisms of cell invasion.
 ...
PMID:Role of beta1 integrins in adhesion and invasion of hepatocellular carcinoma cells. 986 52

The cellular metabolism of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic and genotoxic product of oxidative stress-induced lipid peroxidation, was investigated in rat H35 hepatoma cells. Previous studies from our laboratory (1) have characterized the degree to which oxidative, reductive, and conjugative metabolic pathways function simultaneously during hepatocellular metabolism of 4-HNE to rapidly eliminate the compound from suspensions of freshly isolated rat hepatocytes. In the current studies, we have extended the investigation of 4-HNE metabolism to examine the pharmacokinetic parameters of 4-HNE elimination and export in a hepatoma cell line and determined that the ensuing oxidative and conjugative metabolites of 4-HNE are rapidly and efficiently transported out the cell. Low concentrations of 4-HNE (25 microM) were used in an attempt to simulate physiologically relevant conditions. The H35 hepatoma cell line studied was first evaluated for enzymes known to play important roles in the metabolism of 4-HNE and were found to possess activities for glutathione S-transferase, aldehyde dehydrogenase (ALDH), and alcohol dehydrogenase of 24.00 +/- 1.12, 3. 45 +/- 0.17, and 6.44 +/- 0.29 nmol min-1 mg-1 protein, respectively. Hepatoma cells were incubated with 25 microM 4-HNE and metabolites in intra- and extracellular fractions were quantitated by reversed-phase HPLC over the time course of treatment. Reduced glutathione (GSH) and the GSH metabolites of 4-HNE were quantitated by reversed-phase HPLC as the dinitrobenzene derivatives. Uptake of 4-HNE from the extracellular medium occurred with an estimated rate of 0.398 +/- 0.181 min-1 10(6) hepatoma cells-1. The oxidative metabolite of 4-HNE, 4-hydroxy-2-nonenoic acid (HNA), produced by ALDH, appeared rapidly in the intracellular fraction achieving concentrations of 0.28 HNA nmol 10(6) hepatoma cells-1 and was efficiently eliminated with a first-order rate constant of 0.988 min-1. The GST-mediated conjugative metabolite, 3-glutathionyl-4-hydroxy-2-nonanal (4-HNE-SG), rapidly reached maximal intracellular concentrations of 1.88 +/- 0.44 nmol 10(6) hepatoma cells-1 and was eliminated at a rate of 0.101 +/- 0.033 min-1. Extracellular rates of formation, representing export, for HNA and 4-HNE-SG were 0.247 +/- 0.045 and 0.044 +/- 0.009 min-1 10(6) hepatoma cells-1, resulting in maximal extracellular concentrations for HNA and 4-HNE-SG of 0.70 +/- 0.10 and 3.03 +/- 0. 84 nmol 10(6) hepatoma cells-1. Approximately 75% of the administered concentration of 4-HNE was converted to measurable metabolites, with the 4-HNE-GSH conjugate accounting for 61% of total administered 4-HNE and HNA accounting for 14%. Collectively, these results demonstrate that oxidative and conjugative pathways are primarily responsible for elimination of 4-HNE at low concentrations in the hepatoma cell line evaluated and that the 4-HNE metabolites resulting from these pathways are rapidly and efficiently exported out of the cell.
 ...
PMID:Formation and export of the glutathione conjugate of 4-hydroxy-2, 3-E-nonenal (4-HNE) in hepatoma cells. 988 35

Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, inactivates urokinase-type plasminogen activator (uPA) and regulates degradation of the extracellular matrix; whether it functions for or against tumor progression, however, has been the subject of controversy. To assess the role of PAI-1 in invasion and proliferation of hepatocellular carcinoma (HCC) cells, HLE cells were transfected with a vector capable of expressing an antisense PAI-1 transcript. Analysis of seven stably transfected clones (PAI-1-) showed reductions of 81% in PAI-1 mRNA by northern blot analysis and 63% in the cellular PAI-1 antigen level by enzyme-linked immunosorbent assay (ELISA). There was no change in the levels of secreted PAI-1 or PAI-2. The activity of cellular uPA increased by 54%, without change in the protein level or the secreted uPA activity evaluated by ELISA. Morphologically, PAI-1 antisense induced a spindle shape with narrower cytoplasmic processes in HLE cells. The forced inhibition of PAI-1 increased the invasion and the growth of PAI-1- cells by 75% and 82%, respectively. These results suggest that PAI-1 plays a role in inhibiting invasion and proliferation, and the balance between uPA and PAI-1 expression is important to assess the invasiveness of HCC cells.
 ...
PMID:Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. 1047 Feb 87

Prediction of radiosensitivity would be valuable for heavy-ion radiotherapy. Premature chromosome condensation (PCC) technique has been a potential predictive assay in photon radiotherapy, but has not been investigated for hepatomas receiving heavy ions. Two human hepatoma cell lines, i.e., HLE and HLF, were irradiated with either 290 MeV/u carbon ions or 200 kVp X rays. Cell lethality was assayed by colony formation and compared with the unrejoined fraction of chromatin breaks as measured by PCC technique. Carbon ions at linear energy transfer (LET) of 76 keV/micron produced cell death more effectively than those of 13 keV/micron and X rays. For the cell killing, the relative biological effectiveness (RBE) of 13 and 76 keV/micron carbon ions compared with X rays was 1.10-1.24 and 2.57-2.59, respectively. Mean number of chromosomes in HLE and HLF cells was similar to each other, i.e., 60.48 and 60.28. RBEs for chromatin breaks of 13 and 76 keV/micron carbon ions were 1.30-1.31 and 2.64-2.79, respectively. A strong correlation between unrejoined chromatin breaks and cell killing for human hepatoma cells was observed irrespective of radiation quality. We conclude that PCC provides a potential predictor for the radiosensitivity of individual hepatoma that are treated with photon as well as heavy ion irradiation.
 ...
PMID:Chromosome breakage and cell lethality in human hepatoma cells irradiated with X rays and carbon-ion beams. 1049 44

We examined the effects of clofibric acid, a peroxisome proliferator, on the production of superoxide radicals, on the levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and on the expression of superoxide dismutases (SODs) in the human HepG2 hepatoma cell line. To this end, HepG2 cells were treated for 1 or 5 days with 0.25, 0.50, or 0.75 mM clofibric acid. The production of superoxide radicals was only enhanced in HepG2 cells exposed for 5 days to the different clofibric acid concentrations. However, this overproduction of superoxide radicals was not accompanied by increased rates of lipid peroxidation, as the MDA and 4-HNE levels did not change significantly. Manganese (Mn) SOD activity was increased when HepG2 cells were treated for 1 day with 0.50 or 0.75 mM clofibric acid. For this duration of treatment, no change was observed in total SOD and copper/zinc (Cu/Zn) SOD activities. For a 5-day treatment, total SOD and MnSOD activities as well as the enzyme apoprotein and MnSOD mRNA levels increased whatever the clofibric acid concentration used. This transcriptional induction of the MnSOD gene was correlated with an activation of the activator protein-1 transcription factor for 1 and 5 days of treatment, but was independent of nuclear factor-kappa B and of peroxisome proliferator-activated receptor. On the other hand, the PP exerted very little effect if any on Cu,ZnSOD expression. In contrast to rodent data, PP treatment of human hepatoma cells induces MnSOD expression.
 ...
PMID:Effects of the peroxisome proliferator clofibric acid on superoxide dismutase expression in the human HepG2 hepatoma cell line. 1050 55

The present study was aimed at devising an efficient nonviral strategy for suicide gene therapy of hepatocellular carcinoma (HCC). To improve the efficiency of DNA delivery and expression, we applied Epstein-Barr virus (EBV)-based plasmid vectors instead of conventional plasmid vectors and combined them with cationic liposome (EBV/lipoplex) or polyamidoamine dendrimer (PAAD) (EBV/polyplex). When the beta-galactosidase gene was transferred to HuH7, PLC/PRF/5, or HLE cells, < or =50-fold higher beta-galactosidase activities were demonstrated in the cells transfected with EBV vector compared with those transfected with conventional plasmid vectors. PAAD-mediated transfection of HCC with pSES.Tk (an EBV-based vector carrying the herpes simplex virus-1 thymidine kinase gene) resulted in a marked reduction in viable cell number by the addition of ganciclovir (GCV). The HCC cells transfected with pSES.Tk/PAAD showed 100- to 1000-fold higher susceptibilities to GCV than those transfected with pS.Tk (a conventional plasmid vector carrying herpes simplex virus-1 thymidine kinase gene)/PAAD. The pSES.Tk-transfected HCC cells were effectively killed by day 9 in culture with a clinically feasible concentration of GCV (25 microM), whereas the pS.Tk-transfected cells survived the culture. These results demonstrate highly efficient suicide gene transfer into various HCC cells by EBV-based plasmid vectors in vitro, suggesting the possible application of this nonviral vector system to gene therapy of HCC.
 ...
PMID:Highly efficient suicide gene expression in hepatocellular carcinoma cells by epstein-barr virus-based plasmid vectors combined with polyamidoamine dendrimer. 1067 53

The Akt/PI-3 kinase pathway is a system essential for cell survival. In the current study, we showed that hepatocyte growth factor (HGF) activates the Akt/PI-3 kinase pathway to suppress Fas-mediated cell death in human hepatocellular carcinoma (HCC; 3 lines; SK-Hep1, HLE, and Chang Liver cell lines), hepatoblastoma (1 line; HepG2), and embryonic hepatocyte (1 line; WRL). Five tested cell lines showed the resistance to Fas-mediated cell death by the pretreatment of HGF. This HGF-induced cell survival was suppressed by wortmannin (Akt/PI-3 kinase pathway inhibitor), suggesting an involvement of Akt. When cells were pretreated with HGF, Fas-mediated cell death was suppressed, followed by Akt phosphorylation at Ser473. Fas-death-inducing signaling complex (DISC) formation, especially FADD and caspase 8 interaction, was suppressed by HGF and the suppression of the Akt/PI-3 kinase pathway by transient expression of PTEN, resulting in acquisition of Fas-DISC formation and Fas-mediated cell death in HGF-treated cells. We suggest that HGF promotes cell survival in hepatocyte-derived cell lines (HCC, hepatoblastoma, and embryonic hepatocyte) from Fas-mediated cell death via Fas-DISC suppression as a result of Akt activation.
 ...
PMID:Hepatocyte growth factor promotes cell survival from fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fas-death-inducing signaling complex suppression. 1100 25

The 14-3-3 sigma gene has been implicated in G2/M cell cycle arrest by p53. Frequent inactivation of the 14-3-3 sigma gene by hypermethylation of CpG islands has recently been reported in human breast carcinoma. The aim of this study was to examine the methylation status of CpG islands of the 14-3-3 sigma gene in hepatocellular carcinoma (HCC). The methylation status of the 14-3-3 sigma gene was evaluated in four normal liver tissues and 19 paired specimens of carcinoma and adjacent non-tumorous liver tissues using bisulfite-single strand conformation polymorphism (bisulfite-SSCP), a combination of sodium bisulfite modification and fluorescence-based polymerase chain reaction (PCR)-SSCP. The 14-3-3 sigma protein expression was examined by immunohistochemical staining. Hypermethylation of CpG islands of the 14-3-3 sigma gene was detected in 89% (17/19) of the HCC tissues but not in any of the four normal liver tissues. All of the 14 methylation-positive HCC samples analysed by immunohistochemistry showed loss of 14-3-3 sigma expression, while both of the methylation-negative HCC samples retained the expression, and a significant correlation was found between methylation and loss of expression. Lower levels of methylation were detected in adjacent non-tumorous liver tissues (6/16 in cirrhotic tissues and 1/3 in chronic hepatitis tissues), but the 14-3-3 sigma expression was retained in all of these tissues. In a methylation-positive HCC cell line, HLE, 5-aza-2'-deoxycytidine (5-aza-dC)-induced demethylation of CpG islands led to reactivation of gene expression, indicating that hypermethylation plays a causal role in inactivation of the 14-3-3 sigma gene in HCC. Hypermethylation and the resulting loss of expression of the 14-3-3 sigma gene corresponds to one of the most common abnormalities reported to date in HCC, suggesting their crucial role in the development and/or progression of HCC.
 ...
PMID:Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma. 1107 47

Hepatocarcinogenesis is closely related to hepatic fibrosis. In this study, we investigated the relationship of type II transforming growth factor-beta receptor (T beta RII) to hepatic fibrosis and hepatocellular carcinoma (HCC). In vivo: liver tissues were obtained from 30 patients (10 chronic hepatitis, 7 cirrhosis, 13 HCC). Protein expression and immunolocalization of T beta RII were examined by Western blot analysis and immunohistochemistry. In vitro: T beta RII protein expression in hepatoma cell lines (HepG2, Hep3B, HLE, HLF and Huh7) was examined by Western blot analysis. Next, we transfected T beta RII cDNA to Huh7, and compared the change of cell number and observed the induction of apoptosis after TGF-beta1 treatment using a FACScan flow cytometer. In vivo: T beta RII immunolocalization in liver tissues was significantly decreased in patients with HCC compared with that of patients with chronic hepatitis or liver cirrhosis. In Western blot analysis, T beta RII expression in tissues attenuated in comparison with that in non-tumor tissues in some patients with HCC. In vitro: T beta RII protein expression in HLE, HLF and Huh7 cells was weaker than that in HepG2 and Hep3B cells. In Huh7 cells transfected T beta RII cDNA, cell arrest and apoptosis were obviously induced. These results indicated that human HCC has a reduced expression of T beta RII for TGF-beta1. This may provide a selective growth advantage to HCC to escape the inhibitory growth signals of TGF-beta1, and may be linked with critical steps in the growth of hepatoma cells.
 ...
PMID:Relation of type II transforming growth factor-beta receptor to hepatic fibrosis and hepatocellular carcinoma. 1111 38


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>