UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A range of hepatoma cell lines (RH1, HTC, FaO, 7800C1 and MH1C1), has been studied with the aim of establishing an in vitro model to investigate the molecular mechanisms of hepatocarcinogenicity induced by the peroxisome proliferator class of non-genotoxic carcinogens. In view of speculation that peroxisome proliferators suppress hepatocyte apoptosis in vivo, we have placed particular emphasis on evaluating whether hepatoma cell lines retain the ability to undergo apoptotic cell death. Expression of the liver-specific differentiation marker albumin and the peroxisome proliferator-activated receptor (PPAR) was highest in the Reuber hepatoma cell line, FaO. This cell line also demonstrated the most marked response to the peroxisome proliferator nafenopin with a 2.2-fold induction of the microsomal enzyme cytochrome p450IVA1. This response was found to display intercellular heterogeneity by immunocytochemistry. Thus, the FaO cell line maintained characteristics of hepatocytes, both in vivo and in vitro, in terms of expression of constitutive and inducible markers. However, none of the cell lines tested mirrored the hyperplastic response of hepatocytes to nafenopin, since no increase in cell growth kinetics was observed on addition of nafenopin to the growth medium. The mode of cell death in confluent FaO cultures was characterised as apoptosis, by fluorescence microscopy and agarose gel electrophoresis of extracted DNA. Cells detaching from confluent FaO cultures exhibited chromatin condensation and DNA fragmentation patterns characteristic of cels undergoing apoptotic death.Interestingly, no apoptosis was seen in monolayer cells, suggesting that apoptosis in vitro is associated with cell shrinkage and detachment similar to that documented for the liver in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Non-genotoxic hepatocarcinogenesis in vitro: the FaO hepatoma line responds to peroxisome proliferators and retains the ability to undergo apoptosis. 838 74

Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.
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PMID:Fatty-acid metabolism and the pathogenesis of hepatocellular carcinoma: review and hypothesis. 839 60

Peroxisome proliferators cause rapid and coordinated transcriptional activation of genes encoding peroxisomal beta-oxidation system enzymes by activating peroxisome proliferator-activated receptor (PPAR) isoform(s). Since the thyroid hormone (T3; 3,3',5-triiodothyronine) receptor (TR), another member of the nuclear hormone receptor superfamily, regulates a subset of fatty acid metabolism genes shared with PPAR, we examined the possibility of interplay between peroxisome proliferator and T3 signaling pathways. T3 inhibited ciprofibrate-induced luciferase activity as well as the endogenous peroxisomal beta-oxidation enzymes in transgenic mice carrying a 3.2-kb 5'-flanking region of the rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase gene fused to the coding region of luciferase. Transfection assays in hepatoma H4-II-E-C3 and CV-1 cells indicated that this inhibition is mediated by TR in a ligand-dependent fashion. Gel shift assays revealed that modulation of PPAR action by TR occurs through titration of limiting amounts of retinoid X receptor (RXR) required for PPAR activation. Increasing amounts of RXR partially reversed the inhibition in a reciprocal manner; PPAR also inhibited TR activation. Results with heterodimerization-deficient TR and PPAR mutants further confirmed that interaction between PPAR and TR signaling systems is indirect. These results suggest that a convergence of the peroxisome proliferator and T3 signaling pathways occurs through their common interaction with the heterodimeric partner RXR.
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PMID:Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferator and T3 signaling pathways. 852 10

Activation of gene expression by hypolipidemic peroxisome proliferators (e.g. native and substituted long chain fatty acids, aryloxyalkanoic fibrate drugs) is accompanied by transcriptional suppression of liver transferrin gene in treated animals or human hepatoma cell line. Transcriptional suppression of liver transferrin by hypolipidemic peroxisome proliferators results from (a) displacement of hepatic nuclear factor (HNF)-4 from the transferrin promoter by nonproductive binding of the peroxisome proliferator-activated receptor-retinoic acid X receptor heterodimer to the (-76/-52) PRI promoter element of the human transferrin gene and (b) suppression of liver HNF-4 gene expression by hypolipidemic peroxisome proliferators with a concomitant decrease in its availability for binding to the transferrin PRI promoter element. HNF-4 gene suppression and its displacement from the transferrin promoter result in eliminating HNF-4-enhanced transcription of transferrin. Liver transferrin suppression by hypolipidemic peroxisome proliferators may result in reduced iron availability as well as modulation of transferrin-induced differentiation processes. Transcriptional suppression of HNF-4-enhanced liver genes (e.g. apolipoprotein C-III, transferrin) may complement the pleiotropic biological effect exerted by hypolipidemic peroxisome proliferators.
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PMID:Transcriptional suppression of the transferrin gene by hypolipidemic peroxisome proliferators. 855 May 63

The adrenal steroid dehydroepiandrosterone (DHEA) stimulates a dramatic increase in both the size and the number of peroxisomes present in liver when given at pharmacological doses to rodents. Structurally diverse chemicals including many fatty acids, hypolipidemic drugs and other foreign chemicals, can also induce such a peroxisome proliferative response. This response is associated with a dramatic induction of perosisomal fatty acid beta-oxidation enzymes and microsomal cytochrome P450 4A fatty acid hydroxylases and, long-term, can lead to induction of hepatocellular carcinoma. This review examines the underlying mechanisms by which DHEA induces peroxisome proliferation and evaluates the possible role of peroxisome proliferator-activated receptor (PPAR) in this process. Like DHEA, the 17 beta-reduced metabolite 5-androstene-3 beta. 17 beta-diol (ADIOL) is an active peroxisome proliferator when administered in vivo, whereas androgenic and estrogenic metabolites of DHEA are inactive. In primary rat hepatocytes, however, DHEA and ADIOI are inactive as inducers of P450 4A and peroxisomal enzymes unless first metabolized by steroid sulfotransferase to the 3 beta-sulfates, DHEA-S and ADIOL-S. Investigations as to whether DHEA utilizes the same induction mechanism employed by classic, foreign chemical peroxisome proliferators, namely, activation of the intracellular receptor molecule PPAR, have shown that DHEA-S and ADIOL-S are ineffective with respect to PPAR activation in transient transfection/trans-activation assays. This inactivity of DHEA-S in vitro suggests a requirement for specific cellular transport or for further metabolism of the steroid which is only met in liver cells. Alternatively, the action of DHEA-S may require accessory proteins or other nuclear factors that modulate the activity of PPAR, such as retinoid X receptor (RXR), hepatocyte nuclear factor-4 (HNF-4) or chick ovalbumin upstream promoter transcription factor (COUP-TF). Investigations using Ca(2+)-channel blockers such as nicardipine suggest that there are important mechanistic similarities between the foreign chemical- and DHEA-S-stimulated induction responses, and support the hypothesis that these two classes of peroxisome proliferators both activate Ca(2+)-dependent signaling pathways. Further studies are required to ascertain whether this potential of DHEA and its sulfated metabolites to serve as physiological modulators of fatty acid metabolism and peroxisome enzyme expression contributes to the striking anti-carcinogenic and other useful chemoprotective properties that DHEA is known to possess.
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PMID:Role of metabolism in the activation of dehydroepiandrosterone as a peroxisome proliferator. 894 97

The role of members of the nuclear receptor superfamily of transcription factors in regulating hepatitis B virus (HBV) transcription was investigated. Hepatocyte nuclear factor 4 (HNF4), the retinoid X receptor (RXR), and the peroxisome proliferator-activated receptor (PPAR) were examined for their capacity to modulate the level of transcriptional activity from the four HBV promoters by transient-transfection analysis in the dedifferentiated hepatoma cell line, HepG2.1. It was found that the nucleocapsid and large surface antigen promoters were transactivated in the presence of HNF4 whereas the enhancer I/X gene, nucleocapsid, and large surface antigen promoters were transactivated in the presence of RXR and PPAR. Characterization of the nuclear receptors interacting with the nucleocapsid promoter region demonstrated that HNF4 is the primary transcription factor binding to the regulatory region spanning nucleotides -127 to -102 whereas HNF4, RXR-PPAR heterodimers, COUPTF1, and ARP1 bind the regulatory region spanning nucleotides -34 to -7. Transcriptional transactivation from the nucleocapsid promoter by HNF4 appears to be mediated through the two HNF4 binding sites in the promoter, whereas modulation of the level of transcription from the nucleocapsid promoter by RXR-PPAR appears to be regulated by the regulatory sequence element spanning nucleotides -34 to -7 and the HBV enhancer 1 region. These observations indicate that HBV transcription, and pregenomic RNA synthesis in particular, is regulated by ligand-dependent nuclear receptors. Agonists and antagonists capable of regulating the activity of these nuclear receptors may permit the modulation of HBV transcription and consequently replication during viral infection.
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PMID:Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter. 899 26

The role of retinoic acids (RA) on liver fatty acid-binding protein (L-FABP) expression was investigated in the well differentiated FAO rat hepatoma cell line. 9-cis-Retinoic acid (9-cis-RA) specifically enhanced L-FABP mRNA levels in a time- and dose-dependent manner. The higher induction was found 6 h after addition of 10(-6) M 9-cis-RA in the medium. RA also enhanced further both L-FABP mRNA levels and cytosolic L-FABP protein content induced by oleic acid. The retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR), which are known to be activated, respectively, by 9-cis-RA and long chain fatty acid (LCFA), co-operated to bind specifically the peroxisome proliferator-responsive element (PPRE) found upstream of the L-FABP gene. Our result suggest that the PPAR-RXR complex is the molecular target by which 9-cis-RA and LCFA regulate the L-FABP gene.
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PMID:9-cis-retinoic acid enhances fatty acid-induced expression of the liver fatty acid-binding protein gene. 927 50

Genes containing peroxisome proliferator-activated receptor (PPAR) binding sites are both inducible by peroxisome proliferators and expressed in a tissue-specific fashion. A PPAR-responsive reporter gene cotransfected with a PPARalpha expression vector was highly expressed in H4IIEC3 hepatoma cells. Addition of clofibrate resulted in a modest further induction of the reporter gene. In CV-1 cells, high expression of the reporter required the addition of clofibrate. H4IIEC3 cells had higher levels of retinoid X receptor (RXRalpha) than CV-1 cells; cotransfection of CV-1 cells with PPARalpha plus RXRalpha expression plasmids abolished the cell line difference in basal and clofibrate-stimulated expression of the reporter. Lipid extracts of hepatoma cells or of liver or kidney stimulated expression of the reporter; extracts of CV-1 cells were far less effective. Chromatographic analysis of these extracts revealed high levels of three fractions of lipid in liver and H4IIEC3 cells that were lower in CV-1 cells. We conclude that (1) in cells expressing high levels of both RXRs and PPARalpha, such as hepatocytes and kidney cells, these factors are constitutively active; (2) activators of PPARalpha may increase its ability to form heterodimers with RXRs when the latter are limiting; and (3) hepatoma cells, liver, and kidney contain lipid-extractable compounds capable of activating PPARalpha.
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PMID:High-level expression of RXRalpha and the presence of endogenous ligands contribute to expression of a peroxisome proliferator-activated receptor-responsive gene in hepatoma cells. 963 38

Regulation of gene expression of three putative long-chain fatty acid transport proteins, fatty acid translocase (FAT), mitochondrial aspartate aminotransferase (mAspAT), and fatty acid transport protein (FATP), by drugs that activate peroxisome proliferator-activated receptor (PPAR) alpha and gamma were studied using normal and obese mice and rat hepatoma cells. FAT mRNA was induced in liver and intestine of normal mice and in hepatoma cells to various extents only by PPARalpha-activating drugs. FATP mRNA was similarly induced in liver, but to a lesser extent in intestine. The induction time course in the liver was slower for FAT and FATP mRNA than that of an mRNA encoding a peroxisomal enzyme. An obligatory role of PPARalpha in hepatic FAT and FATP induction was demonstrated, since an increase in these mRNAs was not observed in PPARalpha-null mice. Levels of mAspAT mRNA were higher in liver and intestine of mice treated with peroxisome proliferators, while levels in hepatoma cells were similar regardless of treatment. In white adipose tissue of KKAy obese mice, thiazolidinedione PPARgamma activators (pioglitazone and troglitazone) induced FAT and FATP more efficiently than the PPARalpha activator, clofibrate. This effect was absent in brown adipose tissue. Under the same conditions, levels of mAspAT mRNA did not change significantly in these tissues. In conclusion, tissue-specific expression of FAT and FATP genes involves both PPARalpha and -gamma. Our data suggest that among the three putative long-chain fatty acid transporters, FAT and FATP appear to have physiological roles. Thus, peroxisome proliferators not only influence the metabolism of intracellular fatty acids but also cellular uptake, which is likely to be an important regulatory step in lipid homeostasis.
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PMID:Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. 964 25

In the AH-130 hepatoma, a poorly differentiated tumor, maintained by weekly transplantations in rats, a low percentage of cells spontaneously underwent apoptosis, mainly during the transition from logarithmic- to stationary-growth phase. It was possible to induce massive apoptosis of cells by treating them with clofibrate, a peroxisome proliferator and hypolipidemic drug. Similar results were obtained with HepG2 cells. With 1 mM clofibrate, apoptosis began to manifest itself after 1 h of treatment in vitro, and was assessed by morphological analysis, by DNA fragmentation carried out with agarose gel electrophoresis, and with flow cytometric determination of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling. The mechanisms whereby clofibrate induces apoptosis are still unclear. Since the peroxisome proliferator-activated receptor was expressed at a very low level and was not stimulated by clofibrate in the AH-130 hepatoma cells, its involvement seems unlikely. Moreover, lipid peroxidation was not increased after clofibrate treatment. Phospholipids and cholesterol were significantly decreased. The decreased cholesterol content might suggest an inhibition of the mevalonate pathway and, therefore, of isoprenylation of proteins involved in cell proliferation.
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PMID:Peroxisome proliferators induce apoptosis in hepatoma cells. 967 79

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