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)

Cytochrome P450 (CYP) is known to turn over rapidly both in vivo in the liver, and in vitro in cultured hepatoma cells expressing CYP. We examined changes in heme metabolism by analyzing gene expression of the non-specific delta-aminolevulinate synthase (ALAS-N), and heme oxygenase-1 (HO-1), the rate limiting enzyme in heme synthesis and catabolism, respectively, in the human hepatoma cell line HLE/2E1, in which CYP2E1 was overexpressed by transfection of its expression vector. Both ALAS-N mRNA and HO-1 mRNA levels were found to be markedly up-regulated in HLE/2E1 cells as compared with those in non-transfected cells (HLE), or in mock-transfected cells (HLE/MOCK). Treatment of HLE/2E1 cells with succinylacetone (SA), a potent inhibitor of delta-aminolevulinate dehydratase and thereby heme synthesis, resulted in a further increase in ALAS-N mRNA but a decrease in HO-1 mRNA levels. In contrast, treatment of cells with heme, as heme arginate, to SA-pretreated HLE/2E1 cells restored both mRNA levels to the untreated control level. These findings suggest that the overexpression of CYP2E1 results in the up-regulation of ALAS-N in order to meet with an increased demand for heme synthesis for CYP2E1 formation, while it also results in the up-regulation of HO-1 presumably by enzyme induction by free heme released from CYP2E1, which then results in the elimination of toxic excess free heme and ultimately restores the physiologic milieu.
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PMID:CYP2E1 overexpression up-regulates both non-specific delta-aminolevulinate synthase and heme oxygenase-1 in the human hepatoma cell line HLE/2E1. 1246 18

Generally, hepatoma is not a chemosensitive tumor, and the mechanism of resistance to anticancer drugs is not fully elucidated. We aimed to comprehensively evaluate the relationship between chemosensitivity and gene expression profile in human hepatoma cells, by using microarray analysis, and analyze the data by constructing relevance networks. In eight hepatoma cell lines (HLE, HLF, Huh7, Hep3B, PLC/PRF/5, SK-Hep1, Huh6, and HepG2), the baseline expression levels of 2300 genes were measured by cDNA microarray. The concentrations of eight anticancer drugs (nimustine, mitomycin C, cisplatin, carboplatin, doxorubicin, epirubicin, mitoxantrone, and 5-fluorouracil) needed for 50% growth inhibition were examined and used as a measure of chemosensitivity. These data were combined and comprehensive pair-wise correlations between gene expression levels and the 50% growth inhibition values were calculated. Significant correlations with significance were used to construct networks of similarity. Fifty-two relations, including 42 genes, were selected. Among them, nearly 20% were various types of transporters, and most of them negatively correlated with chemosensitivity. Transporter associated with antigen processing 1 was associated with resistance to mitoxantrone, consistent with previous reports. Other transporters were not reported previously to associate with chemosensitivity. Resistance to doxorubicin and its analogue, epirubicin, were positively correlated with topoisomerase II beta expression, whereas it negatively correlated with expression of carboxypeptidases A3 and Z. Response to nimustine was associated with expression of superoxide dismutase 2. Relevance networks identified several negative correlations between gene expression and resistance, which were missed by hierarchical clustering. Our results suggested the necessity of systematically evaluating the transporting systems that may play a major role in resistance in hepatoma. This may provide useful information to modify anticancer drug action in hepatoma.
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PMID:Relevance network between chemosensitivity and transcriptome in human hepatoma cells. 1258 37

Daphnane-type diterpene gnidimacrin (NSC 252940) shows significant antitumor activity against murine tumors and human tumor cell lines. This compound binds to and directly activates protein kinase C (PKC), arresting the cell cycle at the G(1) phase through inhibition of cdk2 activity in human K562 leukemia cells. In our study, we examined whether cellular PKC is involved in the antiproliferating effect of gnidimacrin. In a 24-hr exposure of K562 cells to high concentrations of bryostatin 1 (0.11-3.3 microM), both expression of PKC alpha and PKC betaII was downregulated, and thereafter these cells became resistant to gnidimacrin in response to the degree of PKC downregulation. In addition, PKC alpha and PKC betaII genes were transfected to gnidimacrin-resistant human hepatoma HLE cells that demonstrated positive expression of PKC alpha and negative expression of PKC betaII. PKC betaII gene-transfected cells became sensitive to gnidimacrin in relation to the degree of PKC betaII expression. The most sensitive clone to show 0.001 microg/mL (1.2 nM) as IC(50) in a continuous 4-day exposure was obtained. While PKC alpha gene-transfected cells exhibited an increase in PKC alpha expression and became sensitive to gnidimacrin, sensitivity was one-hundredth of that in PKC betaIotaIota gene-transfected cells. These results suggest that PKC, in particular PKC betaIotaIota, is necessary in the antitumor effect of gnidimacrin.
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PMID:Involvement of PKC betaII in anti-proliferating action of a new antitumor compound gnidimacrin. 1274 Sep 6

trans-4-Hydroxy-2-nonenal (4-HNE), a major product of lipid peroxidation, is able to interact with DNA to form 6-(1-hydroxyhexanyl)-8-hydroxy-1,N(2)-propano-2'-deoxyguanosine (4-HNE-dG) adducts, but its genotoxicity and mutagenicity remain elusive. It has been reported that 4-HNE treatment in human cells induces a high frequency of G.C to T.A mutations at the third base of codon 249 (AGG*) of the p53 gene, a mutational hot spot in human cancers, particularly in hepatocellular carcinoma. This G.C to T.A transversion at codon 249, however, has been thought to be caused by etheno-DNA adducts induced by the endogenous metabolite of 4-HNE, 2,3-epoxy-4-hydroxynonanal. We have recently found that 4-HNE preferentially forms 4-HNE-dG adducts at the GAGG*C/A sequence in the p53 gene including codon 249 (GAGG*C). Our finding supports the possibility that G.C to T.A mutations at codon 249 may be induced by 4-HNE-dG adducts. To investigate this possibility, we determined the mutational spectrum induced by 4-HNE-dG adducts in the supF gene of shuttle vector pSP189 replicated in human cells. We have found that 4-HNE-dG adducts are mutagenic and genotoxic in human cells, and that G.C to T.A transversions are the most prevalent mutations induced by 4-HNE-dG adducts. Furthermore, 4-HNE-dG adducts induce a significantly higher level of genotoxicity and mutagenicity in nucleotide excision repair (NER)-deficient human and Escherichia coli cells than in NER-proficient cells, indicating that NER is a major pathway for repairing 4-HNE-dG adducts in both human and E. coli cells. Together, these results suggest that 4-HNE-dG adducts may contribute greatly to the G.C to T.A mutation at codon 249 of the p53 gene, and may play an important role in carcinogenesis.
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PMID:Mutational spectrum and genotoxicity of the major lipid peroxidation product, trans-4-hydroxy-2-nonenal, induced DNA adducts in nucleotide excision repair-proficient and -deficient human cells. 1282 Aug 94

Human hepatocellular carcinomas (HCCs) show resistance to apoptosis mediated by several death receptors. Because cellular FLICE/caspase-8-inhibitory protein (cFLIP) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits death signaling mediated by all known death receptors, including Fas, TNF-receptor (TNF-R), and TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs), we investigated the expression and function of cFLIP in human HCCs. We found that cFLIP is constitutively expressed in all human HCC cell lines and is expressed more in human HCC tissues than in nontumor liver tissues. Metabolic inhibitors, actinomycin D (ActD) or cycloheximide (CHX), dramatically rendered HCC cells sensitive to Fas-mediated apoptosis. Neither caspase-8 nor caspase-3 was activated by agonistic anti-Fas antibody alone, but both caspases were activated by Fas stimulation in the presence of ActD or CHX, indicating the importance of caspase-8 inhibitors that are sensitive to metabolic inhibitors. Actually, cFLIP expression was decreased in ActD or CHX treatment. cFLIP down-regulation induced by cFLIP antisense oligodeoxynucleotides sensitized HLE cells to Fas, TNF-R, and TRAIL-R-mediated apoptosis. Furthermore, cFLIP over-expression activated nuclear factor (NF)-kappaB and cFLIP down-regulation attenuated NF-kappaB activation induced by TNF-alpha or TRAIL. Pretreatment with pan-caspase-inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD-fmk), restored NF-kappaB activity attenuated by cFLIP down-regulation. cFLIP expression was increased by TNF-alpha, TRAIL, or vascular endothelial growth factor but decreased by wortmannin, indicating that cFLIP expression is regulated by both the NF-kappaB and phosphatidylinostiol-3 kinase (PI-3)/Akt pathways. These results suggest that cFLIP plays an important role in cell survival not simply by inhibiting death-receptor-mediated apoptosis but also by regulating NF-kappaB activation in human HCCs.
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PMID:Cellular FLICE/caspase-8-inhibitory protein as a principal regulator of cell death and survival in human hepatocellular carcinoma. 1286 Oct 43

The TNF-receptor family has a dual signaling pathway, including induction of apoptosis and NF-kappaB activation associated with cell survival. Hepatocellular carcinoma (HCC) cells express TNF-receptor family members and the signaling from these receptors induces NF-kappaB activation. However, the role of Fas in induction of NF-kappaB activation in HCC cells is not well understood. In this study, SK-Hep1, HepG2 or HLE cells were stimulated by anti-Fas agonistic antibody. Fas stimulation induced NF-kappaB activation in a dose-dependent manner in SK-Hep1 and HepG2 cell lines, but not in HLE cells. Anti-Fas agonistic antibody or the metabolic inhibitor, cyclo-heximide (CHX), failed to kill SK-Hep1 cells, but co-incubation with anti-Fas agonistic antibody and CHX was effective for induction of apoptosis. SK-Hep1 cell lines receiving Fas stimulation had increased viability, but the extent of cell proliferation was not dose-dependent. The observation suggests that Fas stimulation may contribute to HCC cell survival or proliferation.
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PMID:Fas stimulation activates NF-kappaB in SK-Hep1 hepatocellular carcinoma cells. 1288 71

Lysosomal-associated protein transmembrane-4 beta (LAPTM4B), a novel gene upregulated in hepatocellular carcinoma (HCC), was cloned using fluorescence differential display, RACE, and RT-PCR. It contains seven exons and encodes a 35-kDa protein with four putative transmembrane regions. Both the N- and C-termini of the protein are proline-rich, and may serve as potential ligands for the SH3 domain. Immunohistochemical analysis localized the protein predominantly to intracellular membranes. Northern blot showed that the LAPTM4B mRNAs were remarkably upregulated in HCC (87.3%) and correlated inversely with differentiation status. LAPTM4B was also overexpressed in many HCC-derived cell lines. It was also highly expressed in fetal livers and certain adult normal tissues including the heart, skeletal muscle, testis, and ovary. Promoter function assays showed a distinct difference in the gene's activities between BEL7402 and HLE cell lines, suggesting that the transcription factors responsible for regulation of the gene in the two cell lines are different, and that possible negative regulatory cis-elements may exist upstream of the promoter region. It was demonstrated that the N-terminus of LAPTM4B was essential for survival of the cells. Cells harboring the full-length LAPTM4B cDNA expression clone displayed a slightly increased efficiency in colony formation. These results suggest that LAPTM4B is a potential protooncogene, whose overexpression is involved in carcinogenesis and progression of HCC. In normal cells, it may also play important roles such as regulation of cell proliferation and survival.
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PMID:Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma. 1290 89

The levels of fucosylated glycoproteins in various cancers and inflammatory processes have been a subject of intense study. The level of fucosyltransferases and intracellular GDP-L-fucose, a sugar nucleotide and a common donor substrate for all fucosyltransferases, may regulate the level of fucosylated glycoproteins. This study reports on the determination of GDP-L-fucose levels in human hepatocellular carcinoma (HCC) and surrounding tissues, using a recently established high-throughput assay system. Levels of GDP-L-fucose in HCC tissues were significantly increased compared with adjacent nontumor tissues or normal livers. The mean +/- SD for GDP-L-fucose level was 3.6 +/- 0.2 micro mol/mg in control liver, 4.6 +/- 0.9 micro mol/mg in adjacent noninvolved liver tissues (chronic hepatitis, 4.4 +/- 0.7 micro mol/mg; liver cirrhosis, 4.8 +/- 0.9 micro mol/mg), and 7.1 +/- 2.5 micro mol/mg in HCC tissues. The level of GDP-L-fucose in HCC decreased in proportion with tumor size (r = -0.675, P = 0.0002). When expression of the series of genes responsible for GDP-L-fucose synthesis was investigated, the gene expression of FX was found to be increased in 70% (7 of 10) of the HCC tissues examined compared with that in their surrounding tissues. The levels of GDP-L-fucose were positively correlated with the expression of FX mRNA (r = 0.599, P = 0.0074). The levels of FX gene expression in some human hepatoma and hepatocyte cell lines were determined. FX mRNA production was strongly increased in HepG2 and Chang liver, moderately increased in Hep3B and HLF, and, in HLE, was similar to that of a normal human liver tissue. To investigate the effect of GDP-L-fucose on core fucosylation, FX cDNA was transfected into Hep3B cells, which express a relatively low level of GDP-L-fucose:N-acetyl-beta-D-glucosaminide alpha1-6 fucosyltransferase (alpha1-6 FucT) and FX mRNA. Transfection of this gene caused an increase in GDP-L-fucose levels as well as the extent of fucosylation on glycoproteins, including alpha-fetoprotein, as judged by reactivity to lectins. Collectively, the results herein suggest that the high level of fucosylation in HCC is dependent on a high expression of FX followed by increases in GDP-L-fucose, as well as an enhancement in alpha1-6 FucT expression. Thus, an elevation in GDP-L-fucose levels and the up-regulation of FX expression represent potential markers for HCC.
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PMID:Relationship between elevated FX expression and increased production of GDP-L-fucose, a common donor substrate for fucosylation in human hepatocellular carcinoma and hepatoma cell lines. 1455 15

To identify methylation-mediated silencing of genes in hepatocellular carcinoma (HCC), we surveyed genes induced by treatment with 5-aza-2'-deoxycytidine (5-Aza-CdR) in six human hepatoma cell lines using cDNA microarray analysis and determined the methylation status of 5' CpG islands by bisulfite DNA sequencing or methylation-specific PCR. Fifty genes exhibited a >5-fold induction in response to treatment with 5-Aza-CdR in at least one of the hepatoma cell lines examined. Among these genes, the hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene was maximally induced by 5-Aza-CdR in three of six cell lines studied (HLE, HuH7, and Hep3B). Bisulfite sequencing revealed that the 5' CpG island of this gene was densely methylated in HLE, HuH7, and Hep3B cells. After treatment with 5-Aza-CdR, re-expression and demethylation of HAI-2/PB gene were detected in these cells. These findings suggest that HAI-2/PB expression may be inappropriately repressed by promoter hypermethylation in HCC. Methylation-specific PCR analysis demonstrated that HAI-2/PB hypermethylation occurred in 21 of 26 HCC tumors (80.8%), whereas in the corresponding nontumorous liver tissues, it was found in 7 of 26 samples (26.9%). In addition, HAI-2/PB hypermethylation was not detected in any of the seven normal liver samples from individuals without HCC. Reverse transcription-PCR analysis demonstrated that promoter hypermethylation was associated with the reduced expression of the HAI-2/PB gene in HCC tumors. In conclusion, we have found that the HAI-2/PB gene is silenced by promoter hypermethylation in human hepatoma cells by means of cDNA microarray analysis after 5-Aza-CdR treatment, and that HAI-2/PB hypermethylation occurs frequently in primary HCC tumors.
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PMID:Hepatocyte growth factor activator inhibitor 2/placental bikunin (HAI-2/PB) gene is frequently hypermethylated in human hepatocellular carcinoma. 1469 80

The fibroblast growth factor (FGF) function has been considered to contribute to various human tumors and malignant growth of neoplasm. Hepatocellular carcinoma (HCC) is a typical hypervascular tumor, and it is suggested that FGF may be involved in hepatocarcinogenesis. Therefore, the relationship between the progression of HCC and expression of FGFs and FGF receptors (FGFRs) was evaluated in this study. We investigated the expression of messenger ribonucleic acids (mRNAs) of FGFs and FGFRs by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in eight human hepatoma-derived cell lines (Hep3B, HLE, HLF, HUH6, HUH7, KIM1, Li7, and PLC/PRF/5), one hepatoblastoma-derived cell line (HepG2), and human primary hepatocytes. In addition, effects of FGF-1, FGF-2, and FGF-7 on the growth of hepatoma-derived cell lines were studied in serum-free defined culture conditions. An RT-PCR analysis revealed that all cell lines except PLC/PRF/5 expressed all FGFR mRNAs: FGF-R1 (IIIc), -R2 (IIIb), -R2 (IIIc), -R3 (IIIb), -R3 (IIIc), and -R4 mRNAs. In contrast, human primary hepatocytes expressed FGF-R1 (IIIc), -R3 (IIIc), and -R4 mRNAs but not mRNAs of FGF-R2 (IIIb), -R2 (IIIc), and -R3 (IIIb). All cell lines except HUH6 and HUH7 expressed FGF-1 and FGF-2 mRNAs. Addition of exogenous FGF-1 or FGF-2 (or both) to culture stimulated cell proliferation in several cell lines, but FGF-7 exhibited no growth stimulation in all cells. Hepatoma cells may possess a proliferation mechanism regulated by an autocrine mechanism, a paracrine mechanism, or both, which are mediated by FGF-1/FGFR or FGF-2/FGFR (or both). In addition, a gain of FGF-R2 (IIIb), -R2 (IIIc), and -R3 (IIIb) may be associated with malignant transformation of liver tumor and may eventually serve as useful diagnostic and prognostic indicators.
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PMID:Expression of fibroblast growth factor receptor genes in human hepatoma-derived cell lines. 1475 49


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