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)

Retinoic acid stimulates the expression of tissue-type plasminogen activator (t-PA) in vascular endothelial cells in vitro and enhances t-PA levels in plasma and tissues in vivo. Compared with the in vivo situation, high retinoic acid concentrations are required to induce optimally t-PA expression in vitro. These findings led us to study retinoic acid metabolism in cultured human endothelial cells. For comparison, these studies were also performed in the human hepatoma cell line, HepG2, and key experiments were repeated with human primary hepatocytes. Both hepatocyte cultures gave very similar results. Human endothelial cells were shown to possess an active retinoic acid metabolizing capacity, which is quantitatively comparable to that of hepatocytes, but different from that of hepatocytes in several qualitative aspects. Our results demonstrate that all-trans-retinoic acid is quickly metabolized by both endothelial cells and hepatocytes. All-trans-retinoic acid induces its own metabolism in endothelial cells but not in hepatocytes. 9-cis-Retinoic acid is degraded slowly by endothelial cells, whereas hepatocytes metabolize 9-cis-retinoic acid very quickly. Furthermore, our data show that hepatocytes, but not endothelial cells, detectably isomerise all-trans-retinoic acid to 9-cis-retinoic acid and vice versa. In both endothelial cells and hepatocytes all-trans-retinoic acid metabolism was inhibitable by the cytochrome P-450 inhibitors liarozole (10 microM) and ketoconazole (10 microM), albeit to different extents and with different specificities. In the presence of the most potent retinoic acid metabolism inhibitor in endothelial cells, liarozole, at least 10-fold lower all-trans-retinoic acid concentrations were required than in the absence of the inhibitor to obtain the same induction of t-PA. In conclusion, our results clearly demonstrate that all-trans-retinoic acid and 9-cis retinoic acid are actively but differently metabolized and isomerised by human endothelial cells and hepatocytes. The rapid metabolism of retinoic acid explains the relatively high concentrations of retinoic acid required to induce t-PA in cultured endothelial cells.
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PMID:Differences in metabolism and isomerization of all-trans-retinoic acid and 9-cis-retinoic acid between human endothelial cells and hepatocytes. 926 2

Retinoic acid, the active metabolite of vitamin A, plays a role in the growth and differentiation of a variety of normal and malignant cells. In response to 5 microM retinoic acid the human hepatoma-derived cell line HepG2 underwent significant growth inhibition (not associated with cell death), which reached a level of 80% in comparison with controls, after 12 days of continuous treatment. Retinoic acid also induced morphological changes in these cells, in particular the development of canalicular-like structures, indicating progression to a more differentiated phenotype. In addition, a reduced expression of alpha-fetoprotein was found. We suggest that our results may be important for the design of novel therapeutic approaches using RA for the treatment of liver tumors.
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PMID:Growth inhibition and induction of specific hepatic phenotype expression by retinoic acid in HEPG2 cells. 1065 25

Retinoic acid (RA) induces apoptosis in Hep3B human hepatoma cells. 9-Cis-RA (c-RA) had a similar effect as all-trans-RA (t-RA) in inducing cell death in Hep3B cells. RA-induced Hep3B-cell death was associated with inhibited expression of the hepatocyte nuclear factor 4 (HNF-4) gene. Palmitoyl-CoA ((C16:0)-CoA), the reported HNF-4 ligand, prevented RA-induced apoptosis. The effect of (C16:0)-CoA was specific, since palmitic acid and co-enzyme A had no effect in preventing RA-induced apoptosis. Bovine serum albumin (BSA) also prevented RA-induced apoptosis. However, in contrast to BSA, which induced cell growth, (C16:0)-CoA alone had no effect on cell growth. Investigating the possible role of HNF-4 in apoptosis, the reported HNF-4 antagonist (C18:0)-CoA was employed, and it also prevented RA-induced apoptosis. By transient transfection, overexpression of HNF-4 did not prevent RA-induced apoptosis. The induction and prevention of apoptosis caused by RA and (C16:0)-CoA were associated, respectively with the induction and inhibition of the expression of transforming growth factor beta (TGFbeta), which is known to play a role in apoptosis. Furthermore, RA and (C16:0)-CoA can regulate AP-1, which is a key regulator of the TGFbeta gene. Our data indicate that fatty acyl-CoAs can prevent RA-induced apoptosis and that TGFbeta, rather than HNF-4, may play a role in these regulatory processes. Our data also suggest that (C16:0)-CoA and (C18:0)-CoA are not the agonist and antagonist for HNF4, respectively in the Hep3B cell system.
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PMID:Fatty acyl-CoAs inhibit retinoic acid-induced apoptosis in Hep3B cells. 1079 35

Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-beta (TGF-beta), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-beta activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally. HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-alpha (RXRalpha) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of "clonal deletion" therapy for cancer chemoprevention, a new category of cancer chemotherapy.
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PMID:Retinoids in liver fibrosis and cancer. 1177 8

Reln mRNA and protein levels are reduced by approximately 50% in various cortical structures of post-mortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. We show that the reelin promoter directs expression of a reporter construct in multiple human cell types: neuroblastoma cells (SHSY5Y), neuronal precursor cells (NT2), differentiated neurons (hNT) and hepatoma cells (HepG2). Deletion constructs confirmed the presence of multiple elements regulating Reln expression, although the promoter activity is promiscuous, i.e. activity did not correlate with expression of the endogenous gene as reflected in terms of reelin mRNA levels. Co-transfection of the -514 bp human reelin promoter with either Sp1 or Tbr1 demonstrated that these transcription factors activate reporter expression by 6- and 8.5-fold, respectively. Within 400 bp of the RNA start site there are 100 potential CpG targets for DNA methylation. Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site. RA-induced differentiation was also associated with demethylation of the reelin promoter. To test if methylation silenced reelin expression, we methylated the promoter in vitro prior to transfection. In addition, we treated NT2 cells with the methylation inhibitor aza-2'-deoxycytidine and observed a 60-fold increase in reelin mRNA levels. The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent. These findings indicate that one determinant responsible for regulating reelin expression is the methylation status of the promoter. Our data also raise the interesting possibility that the down-regulation of reelin expression documented in psychiatric patients might be the consequence of inappropriate promoter hypermethylation.
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PMID:On the epigenetic regulation of the human reelin promoter. 1208 79

Natural killer (NK) cells are important effector cells for the first line of defense against tumor, but the mechanisms by which they recognize and kill human hepatocellular carcinoma (HCC) remains to be elucidated. Distant MHC class I homologs MICA and MICB are recently identified human ligands for NK cell activating receptor NKG2D. In our present study, MICA or MICB transcript was detected in 6 of 10 human hepatocellular carcinoma tissues, but not in the surrounding non-cancerous tissues. Immunohistochemical analysis showed that MICA/B were expressed in the tumor cells of the cancerous tissues. Huh7 and HepG2 hepatoma cells, but not Hep3B cells, substantially expressed MICA/B on their cell surface. MICA/B expressed on hepatoma cells contributed to their NK sensitivity, because Huh7 and HepG2 were less susceptible to NK cytolysis when MAb against MICA/B was added during the cytolysis assay. Of interest is the finding that retinoic acid upregulated expression of MICA/B in Huh7 and HepG2 cells. Retinoic acid-treated hepatoma cells induced IFN gamma production from cocultured NK cells and rendered themselves more susceptible to NK cells. This was clearly dependent on upregulation of MICA/B, because both the enhanced IFN gamma production and NK cytolysis were completely abolished by MAb-mediated masking of MICA/B. These results suggest that MICA/B, expressed on a subset of human HCCs, may play an important role in their susceptibility to NK cells. Furthermore, retinoic acid can function as a modulator of MICA/B expression and thereby further activate NK cells.
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PMID:Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. 1256 59

Retinoic acid-receptor-related orphan receptor (ROR) alpha is a nuclear receptor involved in many pathophysiological processes such as cerebellar ataxia, inflammation, atherosclerosis and angiogenesis. In the present study we first demonstrate that hypoxia increases the amount of Rora transcripts in a wide panel of cell lines derived from diverse tissues. In addition, we identified a functional promoter sequence upstream of the first exon of the human Rora gene, spanning -487 and -45 from the translation initiation site of RORalpha1. When cloned in a luciferase reporter vector, this sequence allowed the efficient transcription of the luciferase gene in several cell lines. Interestingly, the activity of the Rora promoter was enhanced by hypoxia in HepG2 human hepatoma cells, and this effect was dependent on an HRE (hypoxia response element) spanning from -229 to -225. Using electrophoretic-mobility-shift assays, we showed that HIF-1 (hypoxia-inducible factor 1), which plays a key role in the transcriptional response to hypoxia, bound to this HRE. Overexpression of HIF-1alpha increased the activity of the Rora promoter through the HRE. Overexpression of a dominant-negative form of HIF-1alpha producing transcriptionally inactive HIF-1alpha/HIF-1beta dimers abolished hypoxic activation of the Rora promoter. This indicated that HIF-1 is involved in the response of RORalpha to hypoxia. Taken together, our data reveal Rora as a new HIF-1 target gene. This illustrates, at the molecular level, the existence of cross-talk between signalling pathways mediated by HIF-1 and those mediated by nuclear receptors.
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PMID:The gene encoding human retinoic acid-receptor-related orphan receptor alpha is a target for hypoxia-inducible factor 1. 1527 Jul 19

Retinoic acid exerts antiproliferative and differentiative effects in normal and transformed in vitro hepatocytes. In order to verify whether these effects are related to a modulation of adhesion molecules, we used Western blot analysis and immunofluorescence microscopy to investigate the E-cadherinl/beta-catenin complex, the main system of adherens junctions, and the occludin/ZO-1 complex present in the tight junctions in HepG2 cells cultured in the presence or absence of retinoic acid. Results showed that retinoic acid treatment increases the amount of beta-catenin bound to E-cadherin by decreasing its tyrosine-phosphorylation level. Similar results were obtained with the tight junction system, in which the amount of occludin/ZO-1 complex is increased by a similar mechanism that reduced the level of ZO-1 phosphorylation on tyrosine. Immunofluorescence images also confirm these results, showing the localization on the cell surface of both adhesion complexes. Their insertion into the plasma membrane could be suggestive of an optimal reassembly and function of adherens and tight junctions in hepatoma cells, indicating that retinoic acid, besides inhibiting cell proliferation, improves cell-cell adhesion, sustaining or inducing the expression of a more differentiated phenotype.
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PMID:Influence of retinoic acid on adhesion complexes in human hepatoma cells: a clue to its antiproliferative effects. 1550 Feb 94

Retinoic acid (RA) is an important regulator of normal cellular proliferation and differentiation and suppressor of tumor growth by cell cycle arrest and apoptosis. Furthermore, RA showed a chemo-preventive activity in preclinical and/or clinical models of lung, head and neck, breast, and hepatocellular carcinoma (HCC). In this study, we examined the effect of RA on the proliferation of human HCC cells, in order to analyze its mode of action and, finally, we attempted to find a surrogate biomarker of RA for HCC chemopreventive treatment. Our findings suggested that the growth inhibition of RA in HCC cells differed according to G(1) phase delay by CDK2 or 4, finally induction of apoptosis. No correlation was found between RA sensitivity and the expression of nuclear retinoid receptors, such as RARs or RXRs in HCC cells. RA treatment caused cell cycle arrest at G(1) and decreased the expressions and activities of CDK2 or CDK4 in RA-sensitive HepG2 and SNU354 cells. On the other hand, RA-resistant Hep3B and SNU449 cells progressed into the S/G(2)+M phase and showed increased CDK2 and CDK4 expression and activity. Since the inhibition of CDK2 or 4 activities resulted in sensitization of HCC cells to RA, the combination of RA and compounds of inhibiting CDKs such as UCN01 and flavopiridol might be a useful targeted therapy strategy for HCC.
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PMID:CDK2/4 regulate retinoic acid-induced G1 arrest in hepatocellular carcinoma cells. 1571 61

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (alpha, beta, gamma). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)alpha is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORalpha as a regulator of fibrinogen-beta gene expression in human hepatoma cells and in mouse liver. A putative RORalpha response element (RORE) was identified in the human fibrinogen-beta promoter. EMSA showed that RORalpha binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORalpha-dependent transcriptional activation to both the human fibrinogen-beta and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORalpha specifically increases endogenous fibrinogen-beta mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-beta RORE is occupied by RORalpha in HepG2 cells. Thus, the human fibrinogen-beta gene is a direct target for RORalpha. Furthermore, fibrinogen-beta mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORalpha in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.
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PMID:The gene encoding fibrinogen-beta is a target for retinoic acid receptor-related orphan receptor alpha. 1594 50


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