Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During inflammatory states, hepatocytes are induced to synthesize and secrete a group of proteins called acute-phase proteins. It has recently been shown that besides interleukin-6 (IL-6), related cytokines such as leukemia inhibitory factor, oncostation M and interleukin-11 are also mediators of the hepatic acute-phase response. All these mediators belong to the hematopoietic family of alpha-helical cytokines. Here we show that an additional member of this cytokine family, ciliary neurotrophic factor (CNTF), induces the hepatic acute-phase protein genes haptoglobin, alpha 1-antichymotrypsin, alpha 2-macroglobulin and beta-fibrinogen in human hepatoma cells (HepG2) and in primary rat hepatocytes with a time course and dose-response comparable with that of IL-6. Our next aim was to define the receptor components used by CNTF on hepatic cells. Using a cell-free binding assay we exclude that CNTF binds to the 80 kDa IL-6 receptor, a protein with significant homology to the CNTF receptor which has recently been cloned from neuroblastoma cells. In human hepatoma cells (Hep3B) which lack the leukemia inhibitory factor receptor, CNTF was not able to induce acute-phase protein synthesis, indicating that this receptor protein may be part of the functional CNTF receptor on hepatic cells.
 ...
PMID:Ciliary neurotrophic factor induces acute-phase protein expression in hepatocytes. 128 89

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Genetic factors determining thrombosis and fibrinolysis. 134 88

Rat hepatic cells respond to interleukin (IL) -1, IL-6, and dexamethasone treatment by increasing the transcription rate of acute-phase plasma protein genes. The same conditions lead to changes in the expression of CAAT-enhancer binding protein (C/EBP) isoforms which are specific to the hepatic cell line. To identify the relationship between C/EBP isoforms and acute-phase protein gene activation, the hormone-specific expression of C/EBP alpha, beta, and delta was determined in H-35 and HTC cells and was compared to acute-phase liver. C/EBP beta was found to be the principal isoform in hepatoma cells and to be strongly stimulated by cytokines and dexamethasone in H-35 cells. Transactivating functions were observed for all three C/EBP isoforms by cotransfection of CAT gene reporter constructs containing cytokine and glucocorticoid response elements of acute-phase protein genes and expression plasmids for mouse C/EBP alpha, beta, and delta into rat and human hepatoma cells. The degree of C/EBP-mediated transactivation was, however, extremely variable among the different regulatory elements. Transcription run-on reactions with nuclei from transiently transfected H-35 cells indicated that cotransfected C/EBP beta increases basal expression of reporter gene constructs as well as the dexamethasone-mediated stimulation of constructs containing the glucocorticoid response elements of the rat alpha 1-acid glycoprotein gene, but did not accelerate or enhance hormone-dependent transcription activation of reporter gene plasmids containing the IL-6 regulatory element of the beta-fibrinogen gene. Activation of the reporter gene constructs appeared to be temporally and quantitatively correlated with the amount of nuclear C/EBP as determined by two-dimensional Western and Southwestern blot analyses.
 ...
PMID:Role of CAAT-enhancer binding protein isoforms in the cytokine regulation of acute-phase plasma protein genes. 138 74

Independent of de novo protein synthesis, interleukin-1, interleukin-6, and dexamethasone caused immediate stimulation of transcriptional activity of most major acute phase plasma protein genes in the rat hepatoma H-35 cells. However, activation of alpha 2-macroglobulin and alpha 1-acid glycoprotein genes were delayed by 2-4 h and required ongoing protein synthesis. The hormones also increased transiently the transcription of the junB gene and the amounts of JunB, C/EBP, and C/EBP-like mRNA. To identify whether JunB and C/EBP have the ability to control both the early and late acute phase reactants, expression vectors for mouse C/EBP and JunB together with reporter gene constructs containing recognized hormone-specific regulatory elements were introduced into hepatoma cells. C/EBP displayed prominent transactivation activity with the interleukin-1 and glucocorticoid regulatory elements of alpha 1-acid glycoprotein, the interleukin-1 regulatory element of haptoglobin gene, and the interleukin-6 regulatory element of beta-fibrinogen. The interleukin-6 regulatory elements of the first two genes and the glucocorticoid response element of the third gene were not affected by C/EBP. These data suggest that normal hormone activation of these three acute phase reactant genes might involve, in part, C/EBP-related factors which have a broad range of specificity. H-35 cells stably transformed with a mouse C/EBP expression vector showed an elevated basal level as well as cytokine inducible expression of some but not all acute phase reactants. Cotransfected JunB resulted in reduced activity of cytokine-responsive constructs and in lower transactivation by C/EBP. JunB appears to function as a modulator of plasma protein expression during the course of acute phase response.
 ...
PMID:Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. 171 61

Treatment of rat hepatoma H-35 cells with purified human recombinant interleukin-11 (IL-11) resulted in the stimulated production of several major acute phase plasma proteins. The qualitative and quantitative changes were comparable to those mediated by IL-6 or leukemia inhibitor factor (LIF). Like IL-6, IL-11 acted synergistically with IL-1 on type 1 acute phase proteins. The combination of IL-11 and dexamethasone yielded a magnitude of stimulation which was more similar to the combination of LIF and dexamethasone than IL-6 and dexamethasone. IL-11 elicited in treatment of primary cultures of rat hepatocytes a qualitative change of plasma protein production which was similar to that in H-35 cells. Comparison of rat and human hepatoma cells indicated that the IL-11 response did not correlate with that of IL-6 or LIF, suggesting that the action of IL-11 was mediated by an IL-11-specific receptor system. However, the intracellular transduction of the IL-11, IL-6, and LIF signals to the acute phase protein genes seems to rely, in part, on common elements as judged from their stimulatory effects on the transfected expression vector containing the IL-6 response element of the rat beta-fibrinogen gene. The finding that IL-11 shares liver-regulating properties with IL-6 and LIF suggests that IL-11 has the potential of contributing to the control of systemic homeostasis and hepatic acute phase response.
 ...
PMID:Interleukin-11 regulates the hepatic expression of the same plasma protein genes as interleukin-6. 171 62

To clarify the meaning of increased serum fibrin/fibrinogen degradation products (FDP) in the postoperative period of hepatectomy, blood coagulation and fibrinolysis were studied using recently devised laboratory assays of a group of 30 patients with hepatocellular carcinoma. Twenty of these cases were associated with liver cirrhosis. As a control group, 15 patients with colorectal carcinoma without liver diseases were also selected. In the early postoperative period following hepatectomy, a hypercoagulable state designated as intravascular thrombin generation was confirmed from the finding of increased plasma levels of fibrinopeptide A (FPA). Fibrinopeptide B beta 15-42 (B beta 15-42) in the plasma also increased immediately after the peak of FPA, followed by a gradual decline in B beta 15-42 levels. On the other hand, FDP in the serum increased significantly rather late in the postoperative period following hepatectomy without increased levels of plasmin-alpha 2-plasmin inhibitor complex. However, postoperative increase of fibrin/fibrinogen degradation products-D (FDP-D) was modest and not different from the colectomy group. Therefore, the relevance of intravascular coagulation in the hepatectomy for the patients with liver cirrhosis seems not to be significant, and then such an increase of FDP in the serum seems to be related to other mechanisms.
 ...
PMID:Increased fibrin/fibrinogen degradation products without increase of plasmin-alpha 2-plasmin inhibitor complex after hepatectomy for hepatocellular carcinoma. 215 47

The synthesis of fibrinogen in the liver is drastically enhanced during the inflammatory process. Two factors are involved: glucocorticoids and the hepatocyte stimulating factor which is identical with interleukin 6 (Il6), also called interferon beta 2. The function of the 5'-flanking region of the human beta-fibrinogen (beta-Fg) gene has been studied by deletion analysis with the chloramphenicol acetyltransferase (CAT) gene as a transient expression vector. In this analysis, a fragment containing 150 base pairs (bp) upstream from the cap site is sufficient to drive expression of the CAT gene in the hepatoma cells HepG2, but not in HeLa cells. The beta-Fg gene is induced by dexamethasone and Il6 in HepG2. We identify a domain located between -2900 and -1500 bp upstream from the transcription start point involved in dexamethasone sensibility. This distal regulatory region can confer hormone inductibility to a heterologous promoter and exert its effect in either orientation. The sequence located between -150 and -82 bp upstream from the transcription start point is responsive for the Il6-stimulated expression. This 68-bp sequence contains probably all the cis-acting Il6-responsive element of the human beta-Fg gene.
 ...
PMID:Human beta-fibrinogen gene expression. Upstream sequences involved in its tissue specific expression and its dexamethasone and interleukin 6 stimulation. 231 33

The rat hepatoma cell line Fao was used to study the role of three inflammatory mediators on the mRNA regulation of several acute-phase proteins. In the presence of 10(-6) M dexamethasone beta-fibrinogen mRNA levels increased 6-fold after addition of recombinant human IL 6 (rhIL 6). rhIL 1 beta or recombinant human tumor necrosis factor alpha (rhTNF alpha) had essentially no effect on beta-fibrinogen mRNA induction but led to a 20-fold increase in alpha 1-acid glycoprotein mRNA in the presence of dexamethasone. On the other hand, rhIL 6 was a much weaker stimulator of alpha 1-acid glycoprotein mRNA synthesis. All three mediators reduced albumin mRNA concentrations to about 30% of controls. Whereas the induction of beta-fibrinogen mRNA was potentiated by dexamethasone, the synthetic glucocorticoid analog was an absolute requirement for the stimulation of alpha 1-acid glycoprotein mRNA. The mRNA levels of the negative acute-phase protein albumin were induced 5-fold by dexamethasone alone. The beta-fibrinogen mRNA induction started immediately after addition of rhIL 6 and reached a maximum between 12 and 18 h. In contrast, the time-course for alpha 1-acid glycoprotein mRNA synthesis showed a lag phase of 8 h followed by an increase up to 20 h after rhIL 1 beta. rhTNF alpha led to an even more delayed increase in alpha 1-acid glycoprotein mRNA. Whereas in the case of beta-fibrinogen mRNA induction no synergistic effect was observed between various concentrations of the three mediators, the combination of rhIL 6/rhIL 1 beta as well as rhIL 6/rhTNF alpha or rhIL 1 beta/rhTNF alpha regulated synergistically alpha 1-acid glycoprotein and albumin mRNA. It is concluded that discrete acute-phase proteins are regulated differently by the inflammatory mediators IL 6, IL 1 beta and TNF alpha, indicating that the acute-phase response is more complex than previously assumed. The Fao cell line used in this study turned out to be an ideal model for acute-phase protein regulation, suitable for the discrimination between the inflammatory mediators IL 6 and IL 1/TNF alpha.
 ...
PMID:Action of recombinant human interleukin 6, interleukin 1 beta and tumor necrosis factor alpha on the mRNA induction of acute-phase proteins. 245 92

Secretory products of cultured human blood monocytes contain a hepatocyte-stimulating factor which is able to induce the acute-phase proteins alpha 2-macroglobulin and fibrinogen in rat liver cells. Total RNA was isolated from unstimulated and lipopolysaccharide-stimulated human monocytes and translated in a reticulocyte lysate. The capability of the cell-free synthesized proteins to induce the acute-phase proteins alpha 2-macroglobulin and fibrinogen was assayed in rat hepatocyte primary cultures and in the rat hepatoma cell line Fao. The products translated from the mRNA of lipopolysaccharide-stimulated human monocytes induced mRNAs for alpha 2-macroglobulin and fibrinogen and therefore contain hepatocyte-stimulating factor. The translation products of unstimulated monocytes had no effect. A cDNA containing the coding sequence for interleukin-6 (B-cell stimulatory factor 2, interferon-beta 2/26-kDa protein, interleukin HP1) derived from human T-cells cloned into the transcription vector pGEM4 was transcribed in vitro. Translation of the isolated RNA in a reticulocyte lysate led to the synthesis of a protein of about 25 kDa. This cell-free synthesized interleukin-6 exhibited hepatocyte-stimulating activity measured by the induction of beta-fibrinogen mRNA in Fao cells. Using an antibody against interleukin-6, two proteins of 22 kDa and 23 kDa were immunoprecipitated from the culture medium of lipopolysaccharide-stimulated human monocytes. These two proteins were not synthesized by unstimulated monocytes. When total RNA from unstimulated human monocytes and lipopolysaccharide-stimulated human monocytes and lymphocytes was subjected to Northern analysis and hybridized with the interleukin-6 cDNA, a strong hybridization signal corresponding to an RNA of about 1300 bases was detected only in the RNA from lipopolysaccharide-stimulated human monocytes, indicating that human monocytes express the interleukin-6 gene after stimulation. The data presented in this paper strongly suggest that hepatocyte-stimulating factor from human monocytes and interleukin-6 from T-cells are identical.
 ...
PMID:Cell-free-synthesized interleukin-6 (BSF-2/IFN-beta 2) exhibits hepatocyte-stimulating activity. 245 23

Conditioned medium from human monocytes contains a partially characterized hepatocyte-stimulating factor that simultaneously elevates the mRNA levels of the acute-phase protein beta-fibrinogen and decreases albumin mRNA in rat hepatoma cells. We demonstrate that recombinant human B-cell stimulatory factor 2, which is identical to interferon-beta 2/26 kDa protein and interleukin-HP1, exhibits the same activity as hepatocyte-stimulating factor. Furthermore, a specific antibody against B-cell stimulatory factor 2 was able to inhibit hepatocyte-stimulating factor in conditioned medium from human monocytes. Our data show that hepatocyte-stimulating factor and B-cell stimulatory factor 2 are functionally and immunologically related proteins.
 ...
PMID:Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. 330 75


1 2 Next >>