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)

To study the possible role of proto-oncogenes in the multistep process of human liver hepatocarcinogenesis, we have examined the expression of c-N-ras and c-myc in human hepatocellular carcinomas and liver tissue surrounding the tumors as well as cirrhotic livers which are generally considered to precede the formation of human hepatocellular carcinoma. One to four-fold higher expression of the c-N-ras proto-oncogene was observed in twelve hepatoma patients as compared to normal liver. Increased expression of c-N-ras was also observed in liver tissue surrounding these tumors. Eight patients exhibited an apparent higher expression of the c-N-ras oncogene in adjacent liver tissue than in their corresponding tumor tissues. Six human liver cirrhosis patients also exhibited a slight increase in c-N-ras expression. Southern blot analysis demonstrated an amplified c-N-ras sequence in these tissues surrounding the tumors. In the study of the c-myc gene, variable degrees of highly enhanced expression were found in all twelve hepatoma patients as compared to normal liver. The c-myc gene was also expressed in the adjacent liver tissue and in some of the human cirrhotic livers. Our studies give further evidence that the expression of c-N-ras and c-myc proto-oncogenes are involved in the process of human hepatocarcinogenesis.
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PMID:The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. 216 54

Several growth factors and mitogens have been shown to activate the proto-oncogene product Raf-1 protein kinase in murine fibroblasts, apparently through a direct agonist-stimulated tyrosine phosphorylation of the Raf-1 protein. We investigated the possibility that insulin could also activate the Raf-1 kinase, since its receptor also contains an intrinsic insulin-activated protein tyrosine kinase activity. In several cell lines expressing relatively large numbers of insulin receptors, insulin rapidly stimulated the phosphorylation of immunoreactive Raf-1 protein. In H35 cells, a line of well differentiated rat hepatoma cells, the effect of insulin was maximal by 6 min and at 7 nM insulin and occurred normally in cells virtually completely depleted of protein kinase C activity. The insulin-stimulated increase in Raf-1 protein phosphorylation occurred concurrently with a 3-fold increase in Raf-1 protein kinase activity. However, phosphoamino acid analysis showed that only phosphoserine and a trace of phosphothreonine were present in the Raf-1 protein after insulin stimulation of the cells. This was true even when investigated at shorter times (4 min) after insulin stimulation and despite the use of phosphotyrosine phosphatase inhibitors. We conclude that insulin can rapidly activate the Raf-1 kinase in some insulin-sensitive cell types but that this activation probably occurs through a mechanism distinct from direct phosphorylation of the Raf-1 protein by the insulin receptor protein tyrosine kinase.
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PMID:Insulin activates the Raf-1 protein kinase. 219 71

The expression of a number of proto-oncogenes (myc, erb B, Ha-ras, bas, rel, mos, sis, myb, ki-ras, fms, src and fos) was studied in developing rat liver. Northern blot hybridization shows that cellular counterpart of erb B, Ha-ras, and fos oncogenes were in an early stage of liver development, and the expressions of these proto-oncogenes gradually decreased as the liver developed, while c-myc transcript was found only in the rat fetal liver. The transcripts of these oncogenes were found in high level in Morris hepatoma 7777. Bas proto-oncogene was found in high expression at early stages of rat liver development but was not in hepatoma 7777. The expression of other proto-oncogenes studied (src, fm, rel, mos, sis, myb and ki-ras) did not change significantly during liver development and was almost the same in hepatoma and normal adult liver. Southern blot analysis demonstrates that gene amplification and apparent gene rearrangement were not responsible for the change in expression of erb B, Ha-ras, myc and fos proto-oncogenes. Our study gives further evidence that erb B, myc, Ha-ras and fos proto-oncogenes are involved in the control of cell growth and in the process of rat hepatocarcinogenesis.
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PMID:Differential expression of cellular oncogenes during rat liver development. 245 53

Aberrant proto-oncogene expression has been implicated in hepatic cell proliferation, transformation and carcinogenesis using a rat model. To investigate the role of ras p21 product expression in human hepatocellular carcinoma (HCC), we have localized ras p21 in formalin fixed, paraffin-embedded normal and abnormal livers utilizing the avidin-biotin peroxidase method and a monoclonal antibody to ras-gene product p21. A semi-quantitative estimate of p21 expression was performed by serial dilutions of primary antibody. While low dilutions of anti-p21 stained normal hepatocytes, higher dilutions failed to react with normal hepatocytes and these dilutions were used for assessment of p21 enhancement. Increased p21 expression of ras oncogene in HCC occurs in fibrolamellar carcinomas and other better differentiated HCC. Tumor dedifferentiation is associated with an attenuation of p21 expression. Liver adjacent to HCC exhibits p21 enhancement, in contrast to liver surrounding metastatic carcinoma, suggesting increased p21 expression in HCC induction.
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PMID:ras oncogene p21 expression in hepatocellular carcinoma. 255 Jun

Maturation-promoting factor (MPF) is a cell cycle control element able to cause metaphase when injected into amphibian oocytes or when incubated with nuclei in a cell-free system. Highly purified MPF consists of a complex between a 34K (K = 10(3) Mr) serine/threonine protein kinase, identified as a Xenopus homolog of the cdc2+ gene product, p34cdc2, and a 45K substrate, identified as a Xenopus B-type cyclin. p34cdc2 is also present in purified preparations of chromatin-derived growth-associated histone H1 kinase from Novikoff hepatoma cells. p34cdc2 is active when dephosphorylated and inactive when phosphorylated during oocyte meiotic cell cycles and in mitotic cell cycles following egg activation. Analysis of the substrate specificity of p34cdc2 indicates a consensus sequence for phosphorylation of (K/R)S/TP(X)K/R. Among substrates identified with this consensus are histone H1 and the pp60c-src proto-oncogene, which is known to be activated and phophorylated in mitosis. MPF injection into oocytes activates ribosomal protein S6 kinase II, which is also a lamin kinase. The mechanism of activation is indirect, possibly involving the c-src proto-oncogene. Continued analysis of regulation of MPF activation/inactivation and characterization of substrates for phosphorylation will have important implications for cell cycle and cell growth control.
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PMID:Maturation-promoting factor and the regulation of the cell cycle. 269 38

Hepatitis B virus (HBV) is clearly a factor in the development of hepatocellular carcinoma, but its mechanism of action remains obscure. One possibility is that the HBV integration event alters the expression of a nearby growth-regulatory cellular gene. A 9-kilobase (kb) DNA fragment containing an HBV insert plus flanking cellular sequences was cloned from a hepatoma specimen from Shanghai, People's Republic of China. Restriction mapping of the insert revealed a large inverted repeat structure consisting of both viral sequences (encompassing all of the core and pre-S regions and portions of the X and S genes) and at least 3 kb of unique cellular sequences. The virus-cell junction mapped 11 nucleotides from the DR1 region, in a position within the HBV X gene and included in the cohesive overlap region. A probe generated from 1.0 kb of the flanking cellular DNA mapped the viral insert to chromosome 17 in the region designated 17p11.2-17p12, which is near the human proto-oncogene p53. Sequence data from a portion of the flanking cellular DNA revealed a stretch of approximately 70 base pairs that showed highly significant homology with a conserved region of a number of functional mammalian DNAs, including the human autonomously replicating sequence 1 (ARS1).
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PMID:Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma. 284 34

Glucocorticoid hormones induced a stringent dependence on serum for the in vitro proliferation of Fu5 rat hepatoma cells by suppressing the growth rate and final quiescent cell density. Treatment of dexamethasone-suppressed quiescent Fu5 with serum plus insulin caused a rapid reinitiation of cellular proliferation and DNA synthesis that peaked at 16 h. RNA dot blot analysis of this time course showed that the transcript levels for the proto-oncogenes c-fos, c-myc, and c-rasKi peaked at 0.5, 2, and 4 h, respectively, while expression of c-rasHa and ornithine decarboxylase transcripts rose steadily during 16 h. Microspectrofluorimetric measurements of cytosolic calcium (Ca2+i) with fura-2 showed that insulin and serum, alone or in combination, elicited no changes in Ca2+i over a 50-min time course, although ATP, which is not a mitogen, induced large increases in Ca2+i. Cytosolic pH, pHi, was also measured using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Insulin and serum, alone or in combination, did not cause pHi to increase in either 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (pHi 7.17)- or HCO3/CO2 (pHi 7.19)- buffered media. Acid-loading of cells with NH4Cl indicated that both quiescent and proliferating Fu5 cells have equally active, amiloride-sensitive Na/H exchangers. Therefore, induction of DNA synthesis and proto-oncogene expression occurs in Fu5 epithelial tumor cells in the absence of any short term increases of pHi or Ca2+i.
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PMID:Glucocorticoids confer normal serum/growth factor-dependent growth regulation to Fu5 rat hepatoma cells in vitro. Sequential expression of cell cycle-regulated genes without changes in intracellular calcium or pH. 305 98

To examine the transcriptional regulation of the human cytochrome P450IA1 gene, a 3574 bp fragment containing 1140 bp of 5' flanking sequences, exon 1 (leader information only), intron 1, and the leader sequences from exon 2, was cloned upstream of the reporter gene, chloramphenicol acetyltransferase, and used to transfect the human hepatoma cell line, HepG2. In transient expression assays, treatment of the transfected cells with 3-methylcholanthrene, benzo[a]pyrene or 2,3,7,8-tetrachlorodibenzofuran was shown to induce the expression of chloramphenicol acetyltransferase 10-fold. Previous studies by other investigators have identified a xenobiotic responsive element at greater than 800 bp 5' to the cap site in the mouse and rat cytochrome P450IA1 gene. In the current report, deletion of sequences from the 5' side of the P450IA1 fragment, as well as internal deletions, were used to identify at least three additional regulatory elements. A second positive, 3-methylcholanthrene responsive element was localized to sequences between -49 and -560 in addition to confirming the location of a similar element between -831 and -1140. These elements flank a potent negative regulatory element that has been conserved between the rat, mouse and human P450IA1 genes and also exhibits significant sequence identity with one of the negative control elements of the human c-Ha-ras1 proto-oncogene. Deletion of the negative control element clearly demonstrated that the fragments containing xenobiotic responsive elements also possess positive, constitutive control activity. A fourth element located within intron 1 was shown to potentiate the activity of 3-methylcholanthrene when the cells were treated simultaneously with the glucocorticoid agonist, dexamethasone.
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PMID:Identification of multiple regulatory elements on the human cytochrome P450IA1 gene. 340 63

Dichloroacetic (DCA) and trichloroacetic (TCA) acids, two major by-products formed during chlorine disinfection of drinking water, increase the incidence of tumors in B6C3F1 mice by 6- and 3-fold respectively. In order to understand better the mechanism by which these two compounds induce liver tumors, the incidence and spectrum of mutations in the K- and H-ras proto-oncogenes in these tumors were analyzed. DNA from spontaneous, DCA- and TCA-induced liver tumor from B6C3F1 male mice was evaluated for point mutations in exons 1, 2 and 3 of the two genes by single-stranded conformation polymorphism. Results demonstrated a similar incidence of mutations for exon 2 of H-ras in spontaneous carcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%), 1.0 g/l (48%) and TCA 4.5 g/l (45%). Only four showed mutations in the other exons of Hras or in K-ras. Sequence analysis of spontaneous tumor samples with second exon H-ras mutations revealed a change in codon 61 from CAA to AAA in 80% and CAA to CGA in 20% of tumors. In contrast, tumors with H-ras mutations from DCA-treated mice revealed a H-61 change from CAA to AAA in 21% at 3.5 g/l and 16% at 1.0 g/l. CAA to CGA was observed in 50% of tumors from mice given DCA 3.5 or 1.0 g/l, and CAA to CTA was present in 29% and 34% of the two dosage groups respectively. Interestingly, TCA showed the same mutational spectrum as the spontaneous liver tumors. The data indicates that induction of liver carcinoma by DCA and TCA involves activation of the H-ras proto-oncogene at a frequency similar to that observed in spontaneous tumors. However, the mechanism(s) for including hepatocellular carcinoma does not appear to be identical for DCA and TCA.
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PMID:Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids. 769 4

We have shown previously that insulin at the physiological concentration suppresses hepatitis B surface antigen (HBsAg) gene expression in cultured human hepatoma Hep3B cells, and this suppression phenomenon is concomitant with the stimulation of cell proliferation. We have now examined whether these two distinct insulin actions on the Hep3B cells are mediated through the same or different signaling pathways. After prolonged treatment with high concentration of tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA), the protein kinase C-alpha (PKC-alpha) level in the Hep3B cells was diminished and could not be detected by Western blot analysis. Under this condition, TPA treatment has no effect on the number or affinity of the insulin receptor on Hep3B cells. However, insulin-stimulated cell proliferation was completely abolished in the PKC-alpha depleted cells. In contrast, insulin still suppressed HBsAg gene expression with the same ED50 (approximately 0.5 nM) as the control cell. The induction of proto-oncogene egr-1 (early-growth-regulatory-1) by insulin and TPA under similar conditions were also examined. Both insulin and TPA stimulated egr-1 gene expression up to 10-fold in the control cell, but neither of these two agents showed any effect on egr-1 gene expression in the PKC-alpha down-regulated Hep3B cells. These observations indicate that the PKC-alpha may be involved in the insulin induced egr-1 expression and cell proliferation but not in the insulin suppressed HBsAg gene expression in human hepatoma cells.
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PMID:Differential pathways of insulin action upon the hepatitis B surface antigen gene expression and cell proliferation in human hepatoma cells. 778 17


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