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)

A comparative study of glucose-6-phosphatase, alcaline RNase, ATPase, inosine diphosphatase and 5'-nucleotidase activities in isolated rat liver and hepatoma-27 nuclei and nuclear envelopes was performed. The tumor nuclear membranes were shown to be free from G-6-Pase activity in contrast to the liver nuclear membranes. The nuclear RNase activity was strongly inhibited in the hepatoma and could be unmasked in the presence of 3-10(-4) M pCMB. Hepatoma nuclear and nuclear envelopes ATP-ase activity was found to be moderately decreased as compared to those of the normal tissue. The values of inosine diphosphatase activity in hepatoma were similar to those in liver. The role of the nuclear envelope in nuclear-cytoplasmic interactions as well as nuclear location of G-6-Pase are discussed.
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PMID:[Various enzymes of isolated nuclear membranes and cell nuclei of the liver and hepatoma 27 of rats]. 19 29

Hypocrellin A (HA), a perylene quinone derivative, is a new photosensitizer extracted from Hypocrella bambusae (B et Br) Sace. A high voltage sodium lamp was used as the light source; the illumination intensity was 105 mW/cm2. After HA 25 micrograms/ml and illumination for 10 min, mitochondrial ATPase and microsomal G-6-Pase of hepatoma cells were intensively inhibited, but mitochondrial MAO was not affected. Sulfhydryl contents of the mitochondrial and microsomal membrane proteins were significantly reduced. Lipid peroxidation of mitochondrial and microsomal membrane lipids were greatly enhanced. It is concluded that mitochondria and microsomes are the sensitive targets in cells with respect to HA photosensitization.
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PMID:[Photodynamic action of hypocrellin A on hepatoma cell mitochondria and microsomes]. 256 Mar 14

In the present work the activities of GGT and G-6-Pase and the content of Cyt P-450 were determined in surgically removed liver specimens (16 hepatocellular carcinomas, 8 focal nodular hyperplasias and 4 adenomas). The activities were compared to the surrounding seemingly normal liver tissue. In the adenomas neither of the enzymes studied showed alterations, characteristic for hepatocarcinogenesis. Four out of 8 FNHs had the enzyme pattern that was found in experimental liver carcinogenesis. Liver carcinoma specimens proved to be heterogenous. Neither elevated GGT nor reduced G-6-Pase activity was consistent in these samples although the average of G-6-Pase activity decreased to 50 percent. Cytochrome P-450 was significantly reduced in the majority of cases, showing the best agreement with the tendency observed in experimental models. As an other approach, the qualitative and quantitative alterations of proteoglycans (PG) were analized in the same tumor samples. The amount of sugar components of PGs the glycosaminoglycans (GAG) increased by many times in liver tumors. Carcinoma samples were characterized by about twentyfold increase in chondroitin sulfate content, compared to normal liver. The enhancement of GAGs is partly the consequence of a selective alteration in PG expression. The amount of perlecan and decorin was found to be increased, while syndecan disappeared from liver carcinomas. These data suggest that malignant transformation in liver is accompanied by specific alteration in the content, composition and structure of PGs. Presumably, these changes have significance in tumor progression and have also the potential to be used as markers for liver tumors.
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PMID:Potential markers (enzymes, proteoglycans) for human liver tumors. 799 53

From 50 published cases of hepatocellular adenoma (HCA) in glycogen storage disease, type I (GSD I) some characteristic features may be deduced: 1. The male:female ratio was 2:1. This sharply contrasts to HCA of other origin which shows a strong female preponderance. 2. The histology of adenomas largely corresponded to other adenomas, except for the appearance of Mallory bodies, accompanied by neutrophilic inflammation and a peculiar lamellar fibrosis. This observation is of particular interest because Mallory bodies have so far not been described in adenomas but are a well established feature in hepatocellular carcinoma of any aetiology. 3. Adenomas had a tendency to regress after continuous nocturnal intragastric feeding, although not all cases responded favourably. 4. Ten cases of hepatocellular carcinoma (HCC) are recorded in GSD I in literature, whereby in half of them transition from HCA into HCC seems likely. 5. The similarity in clinical presentation and evolution with oestrogen-induced tumours is striking. Pathogenesis of adenoma formation in GSD I is not understood. Experimental evidence and the clinical observation of regression after correction of the metabolic imbalance suggest three possible candidate mechanisms: (1) a glucagon/insulin imbalance; (2) cellular glycogen overload; and (3) proto-oncogene activation. Evidence in favour of these three mechanisms from experimental studies and observations in humans are briefly reviewed.
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PMID:Glycogen storage disease I and hepatocellular tumours. 839 47

The glucocorticoid receptor (GR) and the tumor suppressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia. Dex inhibits the functions of p53 (apoptosis, Bax, and p21(WAF1/CIP1) expression) and GR (PEPCK and G-6-Pase expression). Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubiquitylation of GR and p53. The ubiquitylation of GR requires p53, the interaction of p53 with Hdm2, and E3 ligase activity of Hdm2. These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival.
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PMID:Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2. 1156 47

Summary. Insulin is known to inhibit glucose-6-phosphatase gene expression through PI 3-kinase/PKB mediated phosphorylation and inactivation of the forkhead transcription factor FKHR, which is a potent transactivator of the glucose-6-phosphatase gene. To study the function and regulation of the transcription factor FKHR in hepatic cells, we constructed a hydroxytamoxifen-inducible version of FKHR by fusing a part of the hormone binding domain of the estrogen receptor (ER) to the C-terminus of FKHR (FKHR-ER). In HepG2-cells transiently transfected with plasmids encoding the FKHR-ER fusion protein and a glucose-6-phosphatase reporter construct, hydroxytamoxifen induced a marked induction of glucose-6-phosphatase promoter activity, whereas no effect was observed in control cells. We next generated a H4IIEC3 rat hepatoma cell line stably expressing both FKHR-ER and a glucose-6-phosphatase promoter-based reporter construct. After 2h stimulation with hydroxytamoxifen, the promoter activity was stimulated 3-5 fold, and continued to increase up to 100-fold after 15 h. The response was half maximal at 0.5 microM hydroxytamoxifen. Insulin (1 nM) decreased the hydroxytamoxifen induced promoter activity by about 70% of the maximal response. This cell system can be used for (1) the identification of FKHR dependent genes and for (2) high throughput screening (HTS) of agents affecting the activity of FKHR and its regulation by insulin. Abbreviations used: FKHR, forkhead in rhabdomyosarcoma; G6Pase, glucose-6-phosphatase; PKB, protein kinase B; PI 3-kinase, phosphatidyl-inositol 3-kinase; IRU, insulin-responsive unit; Tx, 4-hydroxytamoxifen, ER, estrogen receptor; HBD, hormone binding domain
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PMID:Construction and characterization of a conditionally active construct of the insulin-regulated forkhead transcription factor FKHR. 1237 35

The key insulin-regulated gluconeogenic enzyme G6Pase (glucose-6-phosphatase) has an important function in the control of hepatic glucose production. Here we examined the inhibition of G6Pase gene transcription by TNF (tumour necrosis factor) in H4IIE hepatoma cells. TNF decreased dexamethasone/dibtuyryl cAMP-induced G6Pase mRNA levels. TNFalpha, but not insulin, led to rapid activation of NFkappaB (nuclear factor kappaB). The adenoviral overexpression of a dominant negative mutant of IkappaBalpha (inhibitor of NFkappaB alpha) prevented the suppression of G6Pase expression by TNFalpha, but did not affect that by insulin. The regulation of G6Pase by TNF was not mediated by activation of the phosphoinositide 3-kinase/protein kinase B pathway, extracellular-signal-regulated protein kinase or p38 mitogen-activated protein kinase. Reporter gene assays demonstrated a concentration-dependent down-regulation of G6Pase promoter activity by the transient overexpression of NFkappaB. Although two binding sites for NFkappaB were identified within the G6Pase promoter, neither of these sites, nor the insulin response unit or binding sites for Sp proteins, was necessary for the regulation of G6Pase promoter activity by TNFalpha. In conclusion, the data indicate that the activation of NFkappaB is sufficient to suppress G6Pase gene expression, and is required for the regulation by TNFalpha, but not by insulin. We propose that NFkappaB does not act by binding directly to the G6Pase promoter.
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PMID:Tumour necrosis factor alpha decreases glucose-6-phosphatase gene expression by activation of nuclear factor kappaB. 1516 11

The first steps of glucose metabolism are carried out by members of the families of GLUTs (glucose transporters) and HKs (hexokinases). Previous experiments using the inhibitor of glucose transport, CB (cytochalasin B), revealed that compartmentalization of GLUTs and HKs is a major factor in the control of glucose uptake in L6 myotubes [Whitesell, Ardehali, Printz, Beechem, Knobel, Piston, Granner, Van Der Meer, Perriott and May (2003) Biochem. J. 370, 47-56]. In the present paper, we evaluate compartmentalization of GLUTs and HKs in a hepatoma cell line, H4IIE, which is characterized by excess GLUT activity, HKI in a particulate and a cytosolic fraction, and insignificant G6Pase (glucose-6-phosphatase) activity. The measured activity of glucose transport exceeded the rate of phosphorylation approx. 30-fold. Treatment with 25 microM CB (K(i) approximately 3 microM in H4IIE cells) paradoxically increased the excess of GLUTs over phosphorylation (GLUTs are inhibited 80%, while phosphorylation is inhibited 98%). The global relationships of the data could be reconciled most simply by a two-compartment model. In this model, phosphorylation of glucose is carried out by a subset of HK molecules supplied by a subset of GLUTs that are more sensitive to CB than the other GLUTs. The agent, DCC (dicyclohexylcarbodi-imide) caused HKI to translocate from the particulate compartment to the cytosolic compartment and potently inhibited glucose phosphorylation. The particulate compartment may represent the mitochondria, to which the more CB-sensitive GLUTs may control the transport of glucose.
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PMID:Compartmentalization of transport and phosphorylation of glucose in a hepatoma cell line. 1547 66

The G6Pase (glucose-6-phosphatase catalytic subunit) catalyses the final step in the gluconeogenic and glycogenolytic pathways, the hydrolysis of glucose-6-phosphate to glucose. We show here that, in HepG2 hepatoma cells, EGF (epidermal growth factor) inhibits basal mouse G6Pase fusion gene transcription. Several studies have shown that insulin represses basal mouse G6Pase fusion gene transcription through FOXO1 (forkhead box O1), but Stoffel and colleagues have recently suggested that insulin can also regulate gene transcription through FOXA2 (forkhead box A2) [Wolfrum, Asilmaz, Luca, Friedman and Stoffel (2003) Proc. Natl. Acad. Sci. 100, 11624-11629]. A combined GR (glucocorticoid receptor)-FOXA2 binding site is located between -185 and -174 in the mouse G6Pase promoter overlapping two FOXO1 binding sites located between (-188 and -182) and (-174 and -168). Selective mutation of the FOXO1 binding sites reduced the effect of insulin, whereas mutation of the GR/FOXA2 binding site had no effect on the insulin response. In contrast, selective mutation of the FOXO1 and GR/FOXA2 binding sites both reduced the effect of EGF. The effect of these mutations was additive, since the combined mutation of both FOXO1 and GR/FOXA2 binding sites reduced the effect of EGF to a greater extent than the individual mutations. These results suggest that, in HepG2 cells, GR and/or FOXA2 are required for the inhibition of basal G6Pase gene transcription by EGF but not insulin. EGF also inhibits hepatic G6Pase gene expression in vivo, but in cultured hepatocytes EGF has the opposite effect of stimulating expression, an observation that may be explained by a switch in ErbB receptor sub-type expression following hepatocyte isolation.
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PMID:Insulin and epidermal growth factor suppress basal glucose-6-phosphatase catalytic subunit gene transcription through overlapping but distinct mechanisms. 1884 35

Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.
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PMID:Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease. 1976 33


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