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 G:C-->T:A mutational hotspot at codon 249 of the p53 tumor suppressor gene has previously been identified in hepatocellular carcinoma (HCC) of patients from Qidong, China and southern Africa in which aflatoxin B1 (AFB1) and hepatitis B virus (HBV) are known synergistic risk factors. We have examined p53 mutation patterns of HCC from geographic areas in which the risk factors vary. Nine HCC lines and four hepatoblastoma lines (HB) were examined for p53 gene mutations and the relationship with HBV infection. Five of the nine HCC lines had homozygous mutation or deletion randomly distributed in exons 6-8, whereas none of the four HB cell lines had p53 mutations. One of the four HB lines (HepG2) had an N-ras mutation at codon 61 position 2. The p53 point mutations in the three HCC cell lines from Japan resulted in the amino acid changes of cysteine for tyrosine in cell line HuH 7 at codon 220 (A:T-->G:C), alanine for glycine in cell line HLF at codon 244 (G:C-->C:G), and serine for arginine in cell line HLE at codon 249 (G:C-->C:G). In addition, the deletion of 18 base pairs from codon 264 position 3 to codon 270 position 1 has resulted in the deletion of Leu-Gly-Arg-Asn-Ser-Phe from the amino acids sequences 256-270 in the Japanese cell line HuH 4. The cell line PLC/PRF/5 that showed p53 mutation at codon 249 (G:C-->T:A) with substitution of serine for arginine was derived from a South African patient. Our results indicate that whereas the p53 gene is not mutated in the HB cell lines, the HCC cell lines frequently contain an abnormal p53 gene. In addition, p53 point mutations were not detected in the four Japanese HCC cell lines that were positive for genomic integration of HBV X-gene and surface antigen gene. The three Japanese HCC cell lines with p53 mutations did not contain HBV sequences, indicating that hepatocarcinogenesis associated with p53 mutation does not require the genomic integration of HBV sequences.
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PMID:p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. 838 56

The daphnane-type diterpene gnidimacrin, isolated from the root of the Chinese plant, Stellera chamaejasme L., was found to strongly inhibit cell growth of human leukemias, stomach cancers and non-small cell lung cancers in vitro at concentrations of 10(-9) to 10(-10) M. On the other hand, even at 10(-6) to 10(-5) M, the small cell lung cancer cell line H69 and the hepatoma cell line HLE were refractory to gnidimacrin. The agent showed significant antitumor activity against murine leukemias and solid tumors in an in vivo system. In K562, a sensitive human leukemia cell line, gnidimacrin induced blebbing of the cell surface, which was completely inhibited by staurosporine at concentrations above 10(-8) M, and arrested the cell cycle transiently to G2 and finally the G1 phase at growth-inhibitory concentrations. It inhibited phorbol-12,13-dibutyrate(PDBu) binding to K562 cells and directly stimulated protein kinase C (PKC) activity in the cells in a dose-dependent manner (3-100 nM). Although activation of PKC isolated from refractory H69 cells was observed only with 100 nM gnidimacrin, the degree of activation was lower than that produced by 3 nM in K562 cells. Our results suggest that gnidimacrin acts as a PKC activator for tumor cells and that this mechanism may be responsible for its antitumor activity.
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PMID:Antitumor activity of daphnane-type diterpene gnidimacrin isolated from Stellera chamaejasme L. 860 23

We have developed a recombinant replication-defective adenovirus containing human alpha-fetoprotein (AFP) promoter/enhancer to direct cell type-specific expression of the herpes simplex virus thymidine kinase (HSVtk) gene to AFP-producing hepatocellular carcinoma (HCC) cells. After an in vitro infection by a recombinant adenovirus carrying the lacZ gene under the control of human AFP promoter/enhancer (AdAFPlacZ), an expression of the lacZ gene was demonstrated efficiently in AFP-producing HuH-7 and HepG2 cell lines, but not in AFP-nonproducing HLE and HLF cell lines, although lacZ gene expression was demonstrated in all these cell lines when infected with adenovirus vector carrying lacZ gene driven by the beta-actin-based promoter. Expression of the HSVtk gene by adenovirus, from AFP promoter/enhancer (AdAFPtk) induced the cells sensitive to ganciclovir (GCV) in the AFP-producing cell line efficiently, but not in AFP-nonproducing HLF hepatoma cells. An in vitro bystander effect was observed when only 10% of the cells were infected with AdAFPtk. These findings suggest that the AFP promoter/enhancer sequence can provide the tumor-specific activity for the therapeutic gene expression, and that the AdAFPtk vector induces the selective growth inhibition by GCV in the adenovirus-infected human hepatoma cells in vitro. Recombinant adenovirus transfer of the HSVtk gene under the control of tumor-specific promoter followed by GCV may have promise as a targeted in situ treatment for solid neoplasms.
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PMID:Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. 867 52

To analyze gene expression of alpha-fetoprotein (AFP) and albumin in hepatocellular carcinoma (HCC), messenger RNAs (mRNAs) of these proteins in six human hepatoma cell lines and in 30 cases of HCC were quantitatively analyzed by competitive reverse transcription (RT) followed by polymerase chain reaction (PCR). The transcriptional levels of both AFP and albumin genes in HepG2 and Huh 7 cell lines were 10(10) copies/microgram RNA, in contrast to approximately 10(5) copies/microgram RNA in HLE and HLF cell lines. AFP and albumin mRNA levels in three normal livers were 10(5) and 10(10) transcripts/microgram RNA, respectively. In 30 cases with HCC AFP mRNA level in neoplasm was 10 to 10(5)-fold enhanced as compared with that of nonneoplastic portion, and correlated with serum AFP level and tumor size (P < .01). In contrast, albumin mRNA level was not reduced in the neoplasms presenting enhanced AFP mRNA levels, indicating that AFP and albumin gene expression in situ is not necessarily mutually exclusive. Prospective analysis revealed that an increased serum AFP was shown at the time of recurrence among patients with enhanced AFP mRNA levels in neoplasm only, indicating that AFP mRNA levels in neoplasm could be a clinically predictable tool.
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PMID:Quantitation of alpha-fetoprotein and albumin messenger RNA in human hepatocellular carcinoma. 867 55

The incidence of hepatocellular carcinoma (HCC) is particularly high in regions of Asia and sub-Saharan Africa where rates of infection with human hepatitis-B virus (HBV) and aflatoxin-B1 contamination of food are high. In HCC tumors occurring in inhabitants of these regions, a G-to-T mutation frequently occurs at position 249 of the tumor-suppressor gene p53. This suggests that HBV and p53 mutation may collaborate in the carcinogenic process in liver. We have examined the effect of the HBV protein HBX in HCC lines with exogenous wild-type p53 or mutated p53 on transactivation of 2 different reporter genes. Transfection of HCC lines with wild-type p53 and a reporter with the promoter from the p53-responsive gene WAF1/p21 resulted in a high level of expression, as expected. When cells were co-transfected with a reporter gene driven by the HBV core promoter and with the HBX gene, expression was enhanced in the Hep 3B, HLE, PLC/PRF/5 and HuH 7 lines, but not in the HuH 1 line. Co-transfection of the reporter with a plasmid containing wild-type p53 resulted in significant inhibition of the HBV core promoter in all of the lines, whereas the mutated p53 gene had no effect. Our results indicate that wild-type p53 can inhibit transcription from the HBV core promoter. In similar experiments, both HBX and p53 were co-transfected into HCC lines with the WAF1/p2l reporter gene. HBX inhibited p53-induced expression in 4 of the 6 lines (Hep 3B, HuH 1, HuH 7 and HLE), there was no effect in one line (HLF), and enhancement was evident in PLC/PRF/5. Our results indicate that inhibition of p53 transcriptional activity by HBX does occur in HCC, but is highly cell-context-dependent. Inhibition of transcription from the HBV core promoter by wild-type p53 appears to be more universal, and may represent a mechanism by which wild-type p53 can protect against the carcinogenic process in liver.
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PMID:Inhibition of hepatitis-B-virus core promoter by p53: implications for carcinogenesis in hepatocytes. 882 64

Syndecans comprise a gene family of transmembrane proteoglycans that regulate cellular behavior through interactions with various effectors, including heparin-binding growth factors and insoluble matrix components. Syndecan-1, the most extensively studied, localizes in epithelial cells and has been shown to present in normal hepatocytes. However, little is known about the change of syndecan-1 expression in human hepatocellular carcinoma (HCC). We investigated syndecan-1-protein expression by immunohistochemistry in 57 HCC tissue samples. Syndecan-1 gene expression was also determined. Syndecan-1 protein was expressed in cytoplasm and cell membrane of the hepatocytes and in the bile duct epithelial cells of liver with underlying hepatitis and cirrhosis. Conversely, among 57 HCC tissues, 39 HCC (68.4%) showed negative staining; 50% of well-differentiated HCC showed positive staining, whereas 82.4% of poorly differentiated HCC were negative. Loss of syndecan-1-protein expression was more prevalent in HCC with intra-hepatic metastasis (85.2%) than those without metastasis (48.0%). Similarly, syndecan-1 expression was significantly reduced in HCC with extra-hepatic metastasis (91.7%) as compared with the HCC without extra-hepatic metastasis (62.2%). The gene expression of syndecan-1 was significantly lower in HCC tissue than that in non-tumoral liver tissue. In 2 human HCC cell lines with poorly differentiated phenotype, HLE and HLF, syndecan-1 expression was markedly decreased both at the mRNA and the protein levels. These results suggest that the loss of syndecan-1 expression is a characteristic feature of HCC with high metastatic potential.
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PMID:Reduced expression of syndecan-1 in human hepatocellular carcinoma with high metastatic potential. 935 69

Gemfibrozil reduces the plasmal levels of cholesterol and triglyceride in patients with hyperlipidemia by a mechanism that is not well understood. The present study evaluated the effect of gemfibrozil on the LDL receptor in human hepatoma cells compared with that of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Exposure to gemfibrozil, 40 mumol/L, for 3 days increased the binding of 125I-LDL to the surface of three lines of human hepatoma cell, HepG2, HuH7, and HLE by 1.5- to 2.0-fold. Similar findings were observed with pravastatin. Scatchard analysis with 125I-LDL indicated an increased number of LDL receptors on the cell surface of HepG2 cells when treated with gemfibrozil and pravastatin. However, the gemfibrozil-treated cells exhibited no increase in the binding of 125I-epidermal growth factor (EGF). Gemfibrozil increased the levels of LDL receptor mRNA and protein in HepG2 cells. The increase in LDL receptor activity induced by pravastatin was abolished by concomitant administration of mevalonic acid, 770 mumol/L. This effect was not seen with gemfibrozil, suggesting the mechanism differs for the two lipid-lowering drugs. To determine whether this increase in mRNA was due to transcriptional activation, we prepared HepG2 cells transfected with an LDL receptor promoter-reporter construct that contained a sterol regulatory element. The expression of LDL receptor regulated by the sterol regulatory element was increased by pravastatin, but not by gemfibrozil. We evaluated the stability of the mRNA in the presence of actinomycin D to explain the increase in the LDL receptor mRNA. Gemfibrozil prolonged the half-life of the mRNA for LDL receptor but not that for the EGF receptor. Stabilization of the LDL receptor mRNA is suggested to be the novel mode of action of gemfibrozil.
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PMID:Upregulation of low density lipoprotein receptor by gemfibrozil, a hypolipidemic agent, in human hepatoma cells through stabilization of mRNA transcripts. 940 46

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

We investigated whether hepatocyte growth factor (HGF) enhances the invasion activity of three human HCC cell lines, HLF, HLE, and HC-4, in vitro. The analysis of the invasiveness consisted of the production of u-PA and the chemotaxis for fibronectin. Invasion activity of all cell lines was enhanced by the addition of recombinant human hepatocyte growth factor (rhHGF) to the medium. HGF stimulated the production of u-PA in HLF cells. HGF accelerated the chemotaxis of HC-4 and HLE. These data suggest that HGF increase the invasion activity of human HCC cell lines by affecting the production of u-PA or the chemotaxis for fibronectin.
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PMID:Hepatocyte growth factor enhances the invasion activity of human hepatocellular carcinoma cell lines. 947 7

A series of alpha,beta-unsaturated aldehydes was evaluated to determine if these compounds could mediate inducible expression of glutathione S-transferase (GST) through the 5'-flanking antioxidant response element (ARE). The ARE from rGST A1 was subcloned into a luciferase reporter construct and used to transiently transfect rat Clone 9 hepatoma cells. Transfected cells were treated with 4-hydroxy-trans-2-nonenal (4-HNE), trans-2-hexenal (t-2-HE), 2-propenal (acrolein, 2-PE), and ethacrynic acid (EA), a control compound also containing an alpha,beta-unsaturated carbonyl moiety. Each compound was evaluated for cytotoxicity to construct dosing regimens in transfection studies. IC50 values for growth inhibition were measured using 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide. IC50 values in Clone 9 cells were: 4-HNE, 6.3 +/- 0.7 microM; t-2-HE, 16.0 +/- 0.7 microM; 2-PE, 2.2 +/- 0.4 microM; and EA, 38.0 +/- 1.6 microM. A dose-dependent increase in luciferase activity was observed in transfected cells with all four compounds tested, indicating that alpha, beta-unsaturated aldehydes function as direct activators of the ARE. To determine whether or not the observed promoter activation led to increased transcriptional and translational induction of GST, cells were treated with the various compounds and assayed for increases in GST mRNA, protein, and enzyme activity. Studies in Clone 9 cells revealed increased steady-state message for GST A1 and A4, increased GST A4-4 protein by Western blotting, and increased GST activity toward 1-chloro-2,4-dinitrobenzene in response to treatment with all four compounds evaluated. Collectively, these studies demonstrate that EA and certain alpha,beta-unsaturated aldehydes produced as a result of cellular membrane lipid peroxidation are activators of the ARE and efficient inducers of GST A1-1 and A4-4.
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PMID:Alpha,beta-unsaturated aldehydes increase glutathione S-transferase mRNA and protein: correlation with activation of the antioxidant response element. 979 58

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