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)

Long-term studies of the carcinogenicity of N-methyl-N-nitrosourea (MNU) in inbred guinea pigs were undertaken to develop an animal model of pancreatic adenocarcinoma. MNU, freshly, dissolved in 0.015 M sodium citrate buffer, pH 6.0, was administered by gavage once weekly at a dose of 10 mg/kg body weight to inbred strain 13 guinea pigs. By 27 weeks, 54% of guinea pigs given MNU weekly died, mostly due to severe atrophy and fatty metamorphosis of the exocrine acinar cells of the pancreas. Of 34 guinea pigs that survived more than 27 weeks of MNU administration, 10 (29%) developed pancreatic adenocarcinoma between 28 and 44 weeks. Other tumors included adenocarcinoma of the stomach (two animals) and of colon (one animal), lymphoma of mesenteric nodes (three animals), and a hepatoma (one animal). Atypical changes involving acinar cells were observed in certain pancreatic lobules and included ductular or pseudoductular transformation, acinar ectasia, increased mitotic activity, and periacinar fibrosis. These changes are suggestive of acinar cell dedifferentiation, and their role, if any, in the histogenesis of pancreatic adenocarcinoma remains to be elucidated. These studies suggest the feasibility of using inbred guinea pigs for developing a satisfactory model of pancreatic adenocarcinoma. Additional studies are necessary to minimize the high mortality rate during the first 6 months and to enhance the incidence of pancreatic adenocarcinoma.
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PMID:Pancreatic adenocarcinoma in inbred guinea pigs induced by n-methyl-N-nitrosourea. 114 36

The effects of agents which are known to be differentiation inducers on a human hepatoma cell line PLC/PRF/5 were investigated. Dexamethasone (DEX), sodium butyrate (SB) or dimethylsulfoxide (DMSO) were examined. They all reduced cell proliferation but differ from each other in effect on the secretion of alphafetoprotein (AFP) and hepatitis B surface antigen (HBsAg), changes in morphology and RNA transcription. SB changed the cell from polygonal into a fibroblast-like type and decreased AFP secretion. DMSO decreased the cell size and changed AFP secretion in the same manner as SB. DEX changed the cell into a larger size, as well as increased AFP secretion. HBsAg secretion and also HB virus DNA transcription was enhanced by 3 agents. AFP and myc gene transcriptions were reduced by SB but DMSO reduced only AFP. Albumin gene transcription was enhanced by SB and DEX. These results indicate that the decrease of PLC/PRF/5 proliferation is induced through different mechanisms by these 3 agents.
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PMID:Effect of dexamethasone, dimethylsulfoxide and sodium butyrate on a human hepatoma cell line PLC/PRF/5. 128 20

We previously studied fibrinolysis and fibrinogenolysis by analyzing fragments of fibrin/fibrinogen degradation products (FDP) employing sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. In this report, we characterized the fragments of FDP in four patients with disseminated intravascular coagulation (DIC), that were caused by various diseases. In the patients suffering from acute lymphoblastic leukemia (case 1) and acute suppurative cholangitis (case 3), DD and DY/X fragments resulting from fibrinolysis accounted for the most part of the FDP fragments. In case 3, D fragments resulting from fibrinogenolysis were also observed to much less extent. In a DIC associated with acute myeloblastic leukemia (case 2), both fibrinolysis and fibrinogenolysis were increased and resulted in high levels of D, Y and DY/X fragments, concomitant with moderate levels of DD and high molecular weight (HMW) fragments in the patient's sera. The increased fibrinogenolysis in this case was attributed to accelerated activation of plasmin. In a DIC patient of case 4, who underwent an operation due to hepatocellular carcinoma, marked increase in DY/X and HMW fragments and slight increase in DD fragment were observed on the day of operation. Hyperfibrinolysis documented in case 4 was explained by both increased production of thrombin and moderately accelerated activation of plasmin. Both qualitative and quantitative changes in the fragments of FDP during the courses of treatment in two cases of DIC were also noted. In summary, each underlying disease expresses characteristic pattern of FDP fragments in DIC.
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PMID:[Studies on the fragments of FDP in 4 patients with DIC]. 130 14

Plasma tissue-type plasminogen activator (t-PA) is cleared rapidly in vivo by the liver. Previous studies with the human hepatoma cell line HepG2 have identified a clearance system for t-PA modulated by plasminogen activator inhibitor type 1 (PAI-1). In the present study, a rat hepatoma cell line MH1C1 is shown to contain a PAI-1-independent t-PA clearance system. At 4 degrees C, binding of 125I-t-PA to MH1C1 cells was rapid, specific, and saturable. Scatchard analysis of the binding data yielded a mean estimate of 105,000 high affinity binding sites per cell (Kd = 4.1 nM). When the bound ligand was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the majority (about 90%) of the specific binding was in the form of uncomplexed 125I-t-PA. This is in contrast to HepG2 cells in which specific binding was mainly in the form of a sodium dodecyl sulfate-stable 125I-t-PA.PAI-1 complex. When availability of matrix-associated PAI-1 was blocked by preincubation with anti-PAI-1 antibody or removed by elastase treatment, specific 125I-t-PA binding to MH1C1 cells was unaffected, whereas most of the specific 125I-t-PA binding to HepG2 cells was abolished. Furthermore, when the active site of t-PA was inactivated with diisopropyl fluorophosphate, the diisopropyl fluorophosphate-t-PA specifically competed for binding of 125I-t-PA to MH1C1 cells, but failed to block specific 125I-t-PA binding to HepG2 cells. At 37 degrees C, PAI-1-independent t-PA binding to MH1C1 cells was followed by ligand uptake and degradation with kinetics similar to that seen in HepG2 cells. Chemical cross-linking of t-PA to MH1C1 cells revealed a specific t-PA binding protein with a molecular mass of about 500,000 daltons. Ligand-receptor complexes generated by chemical cross-linking were immunoprecipitable by anti-t-PA antibody but not by anti-PAI-1 antibody, further supporting the finding that binding of t-PA to MH1C1 cells is PAI-1-independent.
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PMID:Identification and partial characterization by chemical cross-linking of a binding protein for tissue-type plasminogen activator (t-PA) on rat hepatoma cells. A plasminogen activator inhibitor type 1-independent t-PA receptor. 132 1

Recombinant tissue factor pathway inhibitor (rTFPI) has been expressed in four mammalian expression systems using human SK hepatoma, mouse C127, baby hamster kidney (BHK), and Chinese hamster ovary (CHO) cells as hosts. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, the immunoaffinity purified rTFPIs all show broad bands and the mean molecular weight of SK hepatoma and C127 rTFPIs (M(r) approximately 38,000) appear larger than those of BHK and CHO rTFPIs (M(r) approximately 35,000). All these proteins inhibit factor Xa and appear to bind factor Xa with 1:1 stoichiometry. The ability of these proteins to inhibit tissue factor-induced coagulation in plasma was examined using a prothrombin time assay. The relative activities of SK rTFPI:C127 rTFPI:BHK rTFPI:CHO rTFPI were found to be 28:15:2.1:1. By Western blot using specific antisera against the amino- and carboxy-termini of TFPI as probes, it is found that all the immunoaffinity purified rTFPIs possess approximately equal amounts of the amino terminus, but the C127 and BHK rTFPIs are deficient in carboxy terminus and the CHO rTFPI is essentially devoid of this region of the protein. Mono S chromatography allowed separation of the full-length and the truncated molecules with high and low anticoagulant activities, respectively. The above results suggest that proteolysis of the carboxy terminus of TFPI occurs to different extent when TFPI is expressed in different cells and that the carboxy terminal region of the TFPI molecule is important for the inhibition of tissue factor-induced coagulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of recombinant tissue factor pathway inhibitors expressed in human SK hepatoma, mouse C127, baby hamster kidney, and Chinese hamster ovary cells. 132 78

The uptake of tritiated cysteinyl leukotrienes (LTC4, LTD4, LTE4) and LTB4 was investigated in freshly isolated rat hepatocytes and different hepatoma cell lines under initial-rate conditions. Leukotriene uptake by hepatocytes was independent of an Na+ gradient and a K+ diffusion potential across the hepatocyte membranes as established in experiments with isolated hepatocytes and plasma membrane vesicles. Kinetic experiments with isolated hepatocytes indicated a low-Km system and a non-saturable system for the uptake of cysteinyl leukotrienes as well as LTB4 under the conditions used. AS-30D hepatoma cells and human Hep G2 hepatoma cells were deficient in the uptake of cysteinyl leukotrienes, but showed significant accumulation of LTB4. Moreover, only LTB4 was metabolized in Hep G2 hepatoma cells. Competition studies on the uptake of LTE4 and LTB4 (10 nM each) indicated inhibition by the organic anions bromosulfophthalein, S-decyl glutathione, 4,4'-diisothiocyanato-stilbene-2,2'-disulfonate, probenecid, docosanedioate, and hexadecanedioate (100 microM each), but not by taurocholate, the amphiphilic cations verapamil and N-propyl ajmaline, and the neutral glycoside ouabain. Cholate and the glycoside digitoxin were inhibitors of LTB4 uptake only. Bromosulfophthalein, the strongest inhibitor of leukotriene uptake by hepatocytes, did not inhibit LTB4 uptake by Hep G2 hepatoma cells under the same experimental conditions. Leukotriene-binding proteins were analyzed by comparative photoaffinity labeling of human hepatocytes and Hep G2 hepatoma cells using [3H]LTE4 and [3H]LTB4 as the photolabile ligands. Predominant leukotriene-binding proteins with apparent molecular masses in the ranges of 48-58 kDa and 38-40 kDa were labeled by both leukotrienes in the particulate and in the cytosolic fraction of hepatocytes, respectively. In contrast, no labeling was obtained with [3H]LTE4 in Hep G2 cells. With [3H]LTB4 a protein with a molecular mass of about 48 kDa was predominantly labeled in the particulate fraction of the hepatoma cells, whereas in the cytosolic fraction a labeled protein in the range of 40 kDa was detected. Our results provide evidence for the existence of distinct uptake systems for cysteinyl leukotrienes and LTB4 at the sinusoidal membrane of hepatocytes; however, some of the inhibitors tested interfere with both transport systems. Only LTB4, but not cysteinyl leukotrienes, is taken up and metabolized by the transformed hepatoma cells.
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PMID:Leukotriene uptake by hepatocytes and hepatoma cells. 132 71

Patients with liver disease have a variety of coagulation abnormalities. These derangements are of uncertain origin and do not always correlate with disease severity or activity. We have measured the levels and proportions of the total fibrin-related and fibrinogen-related antigens, the principal fibrin (D-dimer) and fibrinogen (D-monomer) degradation fragments and intermediates of fibrin formation (fibrin monomers) in patients with a variety of acute and chronic liver diseases in whom all known other precipitating causes of disseminated intravascular coagulation had been excluded. Fibrin-related and fibrinogen-related antigens were extracted from serum using antihuman fibrinogen-IgG covalently bound to activated amino-phenylthioether paper disks and were subjected to 4% to 11% sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions. Fibrin-related and fibrinogen-related antigen proportions were determined by densitometry, and their levels were measured by radioimmunoassay. Levels of total fibrin-related and fibrinogen-related antigens (and D-dimer) were significantly elevated (p less than 0.01) in patients with cirrhosis (121 to 641 ng/ml) and hepatocellular carcinoma (416 to 8,786 ng/ml) when compared with patients with acute viral hepatitis (84 to 322 ng/ml) and control subjects (38 to 186 ng/ml). In addition, D-monomer levels were elevated. These findings strongly suggest that disseminated intravascular coagulation is a component of the coagulopathy of certain liver diseases. Because fibrin-related and fibrinogen-related antigens have anticoagulant, vasoactive and immunosuppressive properties, their elevated presence may be biologically significant in these patients.
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PMID:Elevated fibrin-related and fibrinogen-related antigens in patients with liver disease. 132 11

The regulation of acetyl-CoA carboxylase (ACC) by glucose and other fuel molecules has been examined in Fao Reuber hepatoma cells and Syrian hamster insulin tumor (HIT) cells in order to determine whether lipogenic substrates acutely alter ACC activity and to examine the mechanism of such regulation. In Fao cells, preincubated in simple medium without substrates, glucose addition results in a rapid activation of ACC. This effect, mimicked by other fuels such as lactate, is characterized by an increase in enzyme Vmax and a decrease in the activation constant for citrate. Several lines of evidence indicate that this activation of ACC is due to enzyme dephosphorylation, including the kinetic changes observed, the persistence of enzyme activation through ACC isolation, the necessity of inclusion of sodium fluoride/EDTA in the cell lysis buffer for preservation of the glucose-induced change, and the direct demonstration of diminished 32P-labeling of ACC after glucose exposure. Identical effects of glucose are also observed in HIT cells, although the ACC activation is smaller in magnitude and less sensitive than that observed in Fao cells. Other insulin secretagogues such as glutamine, lactate, and isobutylmethylxanthine are also found to activate HIT ACC. Others have suggested that glucose-induced changes in malonyl-CoA in beta-cells may be linked to glucose-induced insulin secretion. However, studies conducted in late passage HIT cells, which fail to secrete insulin in response to glucose stimulation, reveal the same glucose-induced activation seen in early passages, secretion-competent HIT cells, suggesting that glucose-induced ACC activation is not by itself sufficient to provoke insulin secretion. Taken together, these findings indicate that glucose and other fuel molecules can play a major role in the rapid regulation of the fatty acid synthesis pathway. The activation of fatty acid synthesis by substrate-induced ACC dephosphorylation insures ultimate fuel storage of glucose-derived carbon as fatty acid, while substrate-induced increases in the ACC product, malonyl CoA, would serve to simultaneously limit the rate of fatty acid oxidation through its allosteric regulation of carnitine palmitoyltransferase I.
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PMID:Glucose regulation of acetyl-CoA carboxylase in hepatoma and islet cells. 134 95

The MDR1 gene, considered to be involved in multidrug resistance of cancer cells, is expressed in liver, kidney, small intestine and the blood-brain barrier. We investigated MDR1 gene expression in the well-differentiated hepatoma cell line HepG2 after exposure to several stresses and found that sodium arsenite treatment increased MDR1 gene expression 2.6-fold. Deletion analysis of the MDR1 promoter indicated that the transcriptional activation after exposure to arsenite depends on a 60-bp region containing two heat-shock responsive elements.
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PMID:Heat-shock responsive elements in the induction of the multidrug resistance gene (MDR1). 136 Apr 9

The regulation of the synthesis by the cytokines interleukin-1 (IL-1) and IL-6 of the positive acute-phase protein alpha 1-acid glycoprotein (AGP) and of the negative acute-phase protein alpha 2-HS glycoprotein (AHSG) has been studied in a long-term culture system of the human hepatoma cell line Hep3B. The culture system contained 30 nM-sodium selenite as the only supplement. This allowed maintenance of the synthesis of the proteins under study at a near steady state for over 3 months. An increase in AGP mRNA and a decrease in AHSG mRNA were observed when cells were treated for two successive 48 h-periods with monocyte-conditioned medium. A return to basal levels was obtained after cessation of the cytokine addition. Two further additions of cytokines led to alterations in mRNA levels similar to those observed following the first cytokine treatment. The amounts of AGP and AHSG secreted were altered in accordance with the mRNA modifications. These results suggest that new cytokine receptors were being constantly synthesized during cell culture. When cytokines were present in the culture medium for 10 days, maximum alterations in AGP and AHSG synthesis were obtained following 2 and 4 days of treatment respectively, but further alterations in protein levels could not be observed afterwards. Expression of IL-6 receptor mRNA was not up-regulated by cytokines, but only by 1 microM-dexamethasone. Our results show that, in this long-term culture system, cytokines induce a response in hepatoma cells similar to that observed in vivo during human inflammatory states. This model could be used to evaluate the effects of agonists or antagonists of cytokines responsible for the hepatic acute-phase protein response.
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PMID:The human hepatoma Hep3B cell line as an experimental model in the study of the long-term regulation of acute-phase proteins by cytokines. 138 66


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