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)

Eight LF x ICIG cell hybrid clones, isolated upon fusion of normal ICIG-7 human fibroblasts with tumorigenic, non-metastatic LF Cl.2A cells derived from a DAB-induced rat hepatocarcinoma, were studied. They were all highly tumorigenic and were capable of developing spontaneous lung metastases in syngeneic animals. All the hybrids were characterized by a rapid loss of human chromosomes. However, in long-term culture, they all revealed a persistence of human genetic information as assessed by Southern blotting. In hybrid lines in which human chromosomes were still visible, the most recurrent were numbers 7 and 9. Neither chromosome 7, previously reported to bear some of the genes controlling metastasis in human X mouse T-cell hybrids, nor chromosome 9 appeared to be correlated with the metastatic potential of LF X ICIG hybrids. The same conclusion applied (1) to a human 3.3-kb EcoRI DNA fragment which was amplified (approx. 10-fold) only in metastases induced by one out of 3 metastatic hybrids tested; (2) to the transcription level of c-Ha-ras and c-Ki-ras genes which was enhanced (approx. 4-fold) in metastatic and non-metastatic lines as well. Co-transfection of LF Cl.2A cells with pHSG 272 selectable marker DNA and genomic DNA from normal ICIG-7 human cells or from a hybrid-induced metastasis, reproducibly gave rise to geneticin-resistant transfectants capable of producing spontaneous lung metastases. Neither transfectants nor transfectant-induced metastases harbored detectable human DNA sequences but all harbored pHSG 272 DNA. These results again call for caution in gene transfer studies of the metastatic process.
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PMID:Spontaneous metastatic potential of rat hepatocarcinoma cells after cell fusion or DNA transfection. 130 25

Mutations in the p53 gene are frequent genetic alterations in human hepatocellular carcinomas. We have examined, by single-strand conformation polymorphism analysis of polymerase chain reaction products, a total of 93 carcinogen-induced liver tumors from mice of three different strains (C3H/He, C57BL/6J, and B6C3F1) for the presence of p53 aberrations. Hepatoma lines, established from 12 liver tumors, were also included in the analysis. While structural aberrations of the p53 gene were not detected in any of the primary mouse liver tumors analyzed, single-base substitutions occurred at different locations within the p53 gene in three of the cell lines during in vitro propagation. One hepatoma line carried two point mutations on separate alleles. All four mutations were either G:C----C:G or C:G----G:C transversions. Mutations at codon 61 of the c-Ha-ras gene, which were frequent in primary liver tumors from C3H/He and B6C3F1 mice, were not detected in the hepatoma lines. Our data indicate (i) that c-Ha-ras but not p53 mutations play an important role during the early stages of mouse hepatocarcinogenesis and (ii) that p53 mutations confer a selective growth advantage to the mutated hepatoma cells in vitro.
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PMID:p53 mutations are absent from carcinogen-induced mouse liver tumors but occur in cell lines established from these tumors. 138 43

We studied the effects of transfection of the normal c-Ha-ras gene, rasGly-12, and its oncogenic mutant, rasVal-12, on expression of the alpha-fetoprotein (AFP) and albumin genes in a human hepatoma cell line, HuH-7. The mutant and, to a lesser extent, the normal ras gene caused reduction of the AFP mRNA but not the albumin mRNA level in transfected HuH-7 cells. Cotransfection experiments with a rasVal-12 expression plasmid and a chloramphenicol acetyltransferase reporter gene fused to AFP regulatory sequences showed that rasVal-12 suppressed the activity of enhancer and promoter regions containing A + T-rich sequences (AT motif). In contrast, rasVal-12 did not affect the promoter activity of the albumin and human hepatitis B virus pre-S1 genes even though these promoters contain homologous A + T-rich elements. ras transfection appeared to induce phosphorylation of nuclear proteins that interact with the AFP AT motif, since gel mobility analysis revealed the formation of slow-moving complexes which was reversed by phosphatase treatment. However, similar changes in complex formation were observed with the albumin and hepatitis B surface antigen pre-S1 promoters. Therefore, this effect alone cannot explain the specific down regulation of the AFP promoter and enhancer activity. ras-mediated suppression of the AFP gene may reflect the process of developmental gene regulation in which AFP gene transcription is controlled by a G-protein-linked signal transduction cascade triggered by external growth stimuli.
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PMID:c-Ha-ras down regulates the alpha-fetoprotein gene but not the albumin gene in human hepatoma cells. 169 Aug 41

Somatic alterations of the c-Ha-ras gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with MspI and HpaII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid coding sequence of the c-Ha-ras gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Ha-ras-related BamHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Ha-ras locus with HpaII and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-ras gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis.
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PMID:Point mutation, allelic loss and increased methylation of c-Ha-ras gene in human hepatocellular carcinoma. 184 46

With dot blot and cytoplasmic hybridization techniques we found that the c-Ha-ras, c-Ki-ras, c-N-ras, c-myc and c-fos oncogenes were over-expressed in human hepatocellular carcinoma cell line BEL 7402 cells. The mRNA expression of c-Ha-ras, c-Ki-ras, c-N-ras and c-myc oncogenes could be inhibited by 2 mmol/L sodium butyrate treatment, but this had no effect on the expression of c-fos. However, the mRNA expression of c-Ha-ras, c-N-Ras and c-myc oncogenes was enhanced by 4 mmol/L sodium butyrate treatment, while the expression of c-Ki-ras and c-fos remained unchanged. No significant effect on the expression of carbamyl phosphate synthetase I, a tissue-specific enzyme associated with the differentiation of liver cells, was observed by 2 mmol/L or 4 mmol/L sodium butyrate treatment of the hepatoma cells.
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PMID:[Expression of cellular oncogenes in human hepatocellular carcinoma cell line BEL 7402 and the effect of sodium butyrate on the expression of cellular oncogenes]. 196 12

There was an overexpression of the c-myc gene (11-fold) and of the c-Ha-ras gene (2-fold) in rat hepatoma 3924A cells compared to normal rat liver as measured by dot-blot analysis of total cytoplasmic RNA. The overexpression of c-myc was attributed to a 10- to 14-fold amplification and rearrangement of the c-myc sequences as determined by Southern blot analysis. The expression of the c-myc also was dependent upon the proliferative state of the hepatoma cells. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide; NSC 286193), an inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of GTP biosynthesis, resulted in a rapid drop (less than 1 h) to 50% of control in the target enzyme activity in the hepatoma cells and in a subsequent marked decrease to 55% in GTP concentration. These events were followed at 12 h of tiazofurin treatment by a 3-fold reduction in the expression of the c-myc gene and a 9-fold decline in that of the c-Ha-ras gene. These results in the hepatoma cells provide evidence in support of the earlier demonstrated correlation in K562 cells between GTP concentration and expression of c-myc and c-ras genes (Olah et al., 1989). These genes might depend on GTP for their expression in hepatoma cells and they might cooperate in a signal pathway that controls cell proliferation.
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PMID:Down-regulation of c-myc and c-Ha-ras gene expression by tiazofurin in rat hepatoma cells. 197 79

Methionine-dependent (Met-Hcy+) revertant sublines were isolated from a methionine-independent (Met+Hcy-) rat hepatocarcinoma cell line (LF). Characterization of these sublines has shown that long-term culture in methionine-deprived medium significantly decreases their ability to grow in vitro, their tumorigenicity in new-born syngeneic animals and their level of transcription of 3 oncogenes (c-Ki-ras, c-Ha-ras, c-myc) involved in hepatic growth. These data strongly support a relationship between methionine-dependence and ability to grow in vivo as tumors. A shift in methionine-supplemented medium for several cell generations of the various sublines grown in methionine deprived medium, has revealed that under these conditions, the cells maintain a diminished in vitro growth and tumorigenic capacity, despite an increased transcription of c-Ki-ras, c-Ha-ras and c-myc. This points out the complexity of the relationship between the level of activity of some oncogenes and the expression of the malignant phenotypes.
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PMID:Methionine-independence, tumorigenicity and oncogene expression of rat hepatocarcinoma cells. 212 16

With RNA-DNA hybridization techniques, the mRNA expression of c-Ha-ras, c-Ki-ras, N-ras, and c-fos oncogenes in rat liver with neoplastic nodules or hepatocellular carcinoma induced by DENA was found to be higher than that in normal liver. No significant difference of c-myc expression was observed between normal liver and liver with neoplastic nodules or hepatocellular carcinoma. In the initiation stage of hepatocarcinogenesis in DENA+AAF+PH+PB and AAF+PH+PB model systems, the expression of c-myc increased markedly, and that of N-ras was remarkably stimulated under the action of AAF. It appears that a cooperative action between the c-myc and N-ras oncogenes was involved in the initiation of hepatocarcinogenesis. In the promotion stage, the expression of c-myc and N-ras returned to a normal level. The expression of c-fos decreased progressively in both the initiation and promotion stages, while that of c-Ha-ras and c-Ki-ras was not much changed. The significance of these results is briefly discussed.
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PMID:[Expression of cellular oncogenes during hepatocarcinogenesis in rats]. 214 11

The expression of the c-myc gene has previously been shown to be elevated and deregulated in the human hepatoma cell line Hep G2 (B. E. Huber and S. S. Thorgeirsson, Cancer Res., 47: 3414-3420, 1987). We now report that the Hep G2 N-ras gene is activated to a dominant-acting, transforming gene by a missense mutation in codon 61. Hep G2 DNA produced transformed foci when transfected into NIH 3T3 cells. Subsequent to a secondary round of transfection, Southern blot analysis of tumorigenic NIH 3T3 foci demonstrated the presence of human N-ras sequences. Nucleotide sequence analysis of one Hep G2 N-ras allele demonstrated that codons 12, 13, and 59 were normal and that codon 61 had a missense mutation (CAA to CTA). This mutation results in the incorporation of leucine instead of glutamine at residue 61 of the N-ras gene product, p21. N-ras sequences were amplified by the polymerase chain reaction from both Hep G2 genomic DNA and Hep G2 complementary DNA. Analysis of the amplified sequences demonstrated that only one Hep G2 N-ras allele exhibited the codon 61 mutation and that both the mutant and normal alleles were transcribed. Northern blot analysis demonstrated equivalent steady-state levels of N-ras transcripts in Hep G2 cells and normal human liver. The steady-state levels of N-ras and ornithine decarboxylase transcripts were positively correlated suggesting a positive relationship between N-ras expression and the replication rate of Hep G2 cells. c-Ki-ras and c-Ha-ras transcripts were not detected in either Hep G2 cells or normal human liver. Immunoprecipitation experiments using the monoclonal antibody Y13-259 demonstrated the presence of p21 in Hep G2 cells. Expression of a dominant-acting, transforming N-ras gene, in conjunction with the altered regulation of the c-myc gene, documents two important genetic lesions that could be responsible for the transformed phenotype of Hep G2 cells.
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PMID:Characterization of a transforming N-ras gene in the human hepatoma cell line Hep G2: additional evidence for the importance of c-myc and ras cooperation in hepatocarcinogenesis. 215 25

In order to characterize the genes overexpressed in an hepatoma cell line, the HTC cells, and in diethylnitrosamine induced solid hepatomas, we constructed a complementary DNA library from HTC cells and performed differential screening with probes from HTC cells, from malignant nodules obtained 70 weeks after the carcinogen treatment, and from hepatocytes from normal rat liver. Eight clones corresponding to messenger RNAs (mRNAs) much more expressed in hepatomas than in hepatocytes from normal liver were isolated. Three, clones pHT 71, pHT 13, and pHT 26, were further analyzed by the study of their corresponding transcripts in hepatocytes from regenerating liver and in the hepatocytes from the nontumorous parts of the liver. Clone pHT 71 corresponds to a single 2.3-kilobase mRNA which is present in high levels in carcinoma nodules in hepatoma cell lines, in the nontumorous parts of the liver, and in hepatocytes isolated from regenerating liver 30 h after partial hepatectomy. Clone pHT 13 hybridizes with three distinct transcripts 3.8, 2.6, and 1.6 kilobases long. High levels of the 3.8- and 1.6-kilobase mRNAs are present in carcinoma nodules, in hepatoma cell lines, and in the nontumorous parts of the liver. However, the levels of these RNAs are similar in hepatocytes from regenerating liver and in hepatocytes obtained from normal rat liver. Clone pHT 26 corresponds to a 0.6-kilobase mRNA which exists at a high level only in cancer nodules and in hepatoma cell lines. We were unable to observe any cross-hybridization between these clones and the oncogenes which have been found to be expressed in hepatomas (c-fos, c-Ha-ras, c-Ki-ras, N-ras, and c-myc). The mRNAs corresponding to the three clones have not been detected in various tissues from normal adult rats. Our study shows that a high level of these mRNAs might be associated with rat liver carcinogenesis.
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PMID:Isolation and characterization of complementary DNA clones for genes overexpressed in chemically induced rat hepatomas. 242 72


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