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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) induces changes in gene expression and the N-glycosylation pattern of acute-phase proteins in hepatocytes. IL-6 exerts its action via a cell surface receptor complex consisting of an 80 kDa IL-6 binding protein (gp80) and a 130 kDa glycoprotein (gp130) involved in signal transduction. A genetically engineered gp80-derived soluble human IL-6-receptor (shIL-6-R) significantly enhanced the IL-6 effect on N-glycosylation changes (revealed by reactivity with the lectin-concanavalin A) of a1-protease inhibitor (PI) secreted by human hepatoma cells (HepG2). Stable transfection of IL-6-cDNA into HepG2 cells (HepG2-IL-6) resulting in constitutive secretion of 2 micrograms of IL-6 per 10(6) cells in 24 h led to a down-regulation of surface-bound gp80 and subsequent homologous desensitization of HepG2-IL-6 cells towards IL-6. Soluble human IL-6-R functionally substituted membrane-bound gp80 resulting in a reconstitution of responsiveness of HepG2-IL-6 cells.
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PMID:Soluble human interleukin-6-receptor modulates interleukin-6-dependent N-glycosylation of alpha 1-protease inhibitor secreted by HepG2 cells. 132 38

Human hepatitis B virus (HBV) carriers run an increased risk of hepatocellular carcinoma (HCC), where the expression of HBV genes play the most important role in the initial stage of hepatocarcinogenesis. As the integration of HBV DNA into the cellular DNA of HCC as well as chronic hepatitis was demonstrated very frequently, the virus-cell fusion gene was considered to be most essential for hepatocarcinogenesis. Among the virus-cell fusion genes, the X gene is known to function as a transactivator for viral and cellular genes at the time of chronic infection. One mechanism for hepatocarcinogenesis that appears particularly reasonable is transactivation of cellular oncogenes by the X-cell fusion protein. In 1990, we found a part of the amino acid sequences in the X protein to be highly homologous to functionally essential sequences in the Kunitz domain, characteristic of Kunitz-type serine protease inhibitors. It has been recently demonstrated that X protein expressed in E. coli or from the in vitro translation system binds to a specific serine protease from the liver cells. These results indicate that transactivation function of X protein may be exerted by acting as a protease inhibitor analogue to control the proteolytic pathway of cellular transcription factor(s). On the other hand, viral hepatitis resulting from viruses other than hepatitis A virus and HBV has been referred to as non-A, non-B hepatitis. In 1989, the viral genome was molecularly cloned as a positive-strand RNA having about 10 kb in size and named as hepatitis C virus (HCV). Details of genetic structure and mechanism of expression are currently under investigation at molecular level.
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PMID:[Gene expression of hepatitis viruses in the liver and hepatocarcinogenesis]. 132 91

To explore the process of lipoprotein assembly, plasmids encoding truncated forms of apolipoprotein B (apoB) were transfected into Chinese hamster ovary (CHO) fibroblasts. (One, encoding apoB53, the N-terminal 53% of apoB100, can direct the assembly and secretion of lipoproteins when expressed in hepatoma cells, while the other, encoding the shorter apoB15, does not direct lipoprotein assembly.) Expression of apoB15 in CHO cells resulted in the accumulation of apoB15 protein in both medium and cells. In contrast, apoB was not detectable in medium or within CHO cells transfected with the plasmid encoding apoB53, despite the expression of apoB53 mRNA. ApoB53 did accumulate within transfected cells incubated with the thiol protease inhibitor N-acetylleucylleucylnorleucinal (ALLN), suggesting that it is synthesized but completely degraded in the absence of the inhibitor. ApoB53 was not secreted despite its presence within ALLN-treated cells. Essentially all the apoB53 that accumulated in microsomes from ALLN-treated cells was associated with the membrane and was susceptible to degradation by exogenous trypsin, indicating exposure on the cytoplasmic face of the membrane. Thus, translocation of apoB53 across the endoplasmic reticulum membrane is blocked. However, the apoB53 bound to concanavalin A, suggesting that it is glycosylated and therefore partly exposed to the lumen as well. ApoB requires a unique process, not expressed in CHO fibroblasts, for its complete translocation and entrance into the secretory pathway. This process might account for the inability of abetalipoproteinemic patients to secrete apoB.
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PMID:Translocation of apolipoprotein B across the endoplasmic reticulum is blocked in a nonhepatic cell line. 140 18

Ethanol alters many metabolic processes within the liver. Both ethanol abuse and the inability to mount an acute phase response (APR) have been associated with an increased morbidity and mortality in critically ill patients. To determine if ethanol influences the hepatic APR, relative amounts of two different human acute phase protein mRNA's were examined in the human hepatoma cell line Hep 3B before and after exposure to ethanol. Hep 3B cells were treated with one or more of the following: ethanol ((E) 150 mM); interleukin-1 beta ((IL-1) 200 units/ml); or interleukin-6 ((IL-6) 50 units/ml). After a 12-20 hr incubation relative amounts of mRNA for a1-protease inhibitor (PI) or beta fibrinogen were determined by Northern blot hybridization. Both ethanol and IL-6 were found to induce a1-PI mRNA. Fibrinogen mRNA was induced by IL-6 but not by ethanol, and no induction of PI or fibrinogen mRNA was found with IL-1. This suggests that under certain conditions, ethanol may influence acute phase protein metabolism. To our knowledge, this is the first description of an ethanol induced alteration of acute phase protein mRNA.
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PMID:Ethanol induces a1-protease inhibitor mRNA in Hep 3B cells. 165 92

The alpha 1-protease inhibitor (alpha 1-PI) proteins of mice are encoded by a group of genes whose members are expressed coordinately in a liver-abundant pattern and are regulated primarily at the transcriptional level. To better understand the developmental and tissue-specific regulation of this gene family, one member that is analogous to the human alpha 1-antitrypsin gene was chosen for study. Deletional analysis of the upstream regulatory region of this gene was performed, spanning from -10 kilobases to -80 base pairs relative to the transcriptional start site. Two functional positive cis-acting elements within the 522 bases immediately upstream of the start site for transcription were shown to modulate the level of expression from this promoter when introduced into human or mouse hepatoma cells, and a third region acted as a negative regulatory element in that its deletion resulted in a two- to sixfold increase of expression of a transfected minigene construct. Sequence comparison between the regulatory domains of two mouse alpha 1-PI genes and the human alpha 1-antitrypsin gene showed that the mouse gene contains a novel positive cis-acting element which is absent in human gene and that a specific eight-base-pair difference between species results in a strong positive cis-acting element in the human gene acting as a negative element in the mouse gene. An enhancer located approximately 3,000 base pairs upstream of the major start site for transcription was also identified. This element is position and orientation independent. Several different DNA-protein binding assays were used to demonstrate that each DNA segment with functional significance in transfection assays interacts specifically with proteins found in adult mouse liver nuclei. The major positive-acting element appeared to be specifically recognized by nuclear proteins found only in tissues that express alpha 1-PI, while the negative element binding proteins were ubiquitous. Thus, the distal regulatory domain including bases -3500 to -133 of this murine alpha 1-PI gene family member is more complex than was previously demonstrated. It is composed of a set of at least three additional functional cis-acting regulatory elements besides those which have been mapped by others and has a far upstream enhancer.
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PMID:Negative and positive cis-acting elements control the expression of murine alpha 1-protease inhibitor genes. 169 57

Alpha-2-macroglobulin (alpha 2-M), a serum protease inhibitor that also binds cytokines, neutralized the inhibitory effect exerted by transforming growth factor-beta (TGF-beta) on IL-6-induced C-reactive protein (CRP) production by the human hepatoma cell line PLC/PRF/5. alpha 2-M was found to bind noncovalently with TGF-beta to form a complex that, upon acidification, released TGF-beta inhibitory activity as detected by IL-6-induced CRP production. Although alpha 2-M also binds IL-6, it did not alter IL-6-induced CRP production by the hepatoma cells. The interaction between alpha 2-M and TGF-beta may influence the production of acute-phase proteins by liver hepatocytes.
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PMID:Effect of alpha-2-macroglobulin on cytokine-mediated human C-reactive protein production. 171 12

The alpha 1-antitrypsin deficient subject (protease inhibitor (PI) phenotype ZZ) has an increased susceptibility to liver disease. The condition is most commonly identified in early infancy as a conjugated hyperbilirubinaemia with hepatitis (11%) or a bleeding state due to vitamin K malabsorption (2%). 50% of cases have cirrhosis and 25% die in the first decade of life. A further 2% present with cirrhosis in later childhood. Adult males are at risk of hepatoma development with or without cirrhosis. Diagnosis is by isoelectric focussing or allele-specific oligonucleotide hybridization. The treatment is that of cholestasis and cirrhosis including transplantation. The pathobiology of the deficiency state, the mechanism of liver damage and the vulnerability of the newborn liver are discussed in this review. A plea is made for a trial of infusions of alpha 1-antitrypsin in early infancy, as is used safely but without proven efficacy in the emphysematous PIZZ subject. Prospects of therapy by gene modification are also reviewed.
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PMID:Alpha 1-antitrypsin deficiency and liver disease: clinical presentation, diagnosis and treatment. 174 15

We have previously shown that changes in acute-phase protein glycosylation result from alterations occurring within hepatocytes as a result of regulation by cytokines, that the glycosylation patterns of proteins secreted by Hep 3B and Hep G2 cells respond differently to the crude mixtures of cytokines found in conditioned medium from LPS-stimulated monocytes, and that interleukin-6 (IL-6) causes increased concanavalin A (Con A) binding of alpha 1 protease inhibitor in Hep 3B cells and decreased Con A binding of this protein in Hep G2 cells. In the present study we found that transforming growth factor beta 1 (TGF-beta), like IL-6, led to secretion of forms of alpha 1-protease inhibitor with increased Con A binding in Hep 3B cells, and that IL-6 and TGF-beta in combination were additive. In contrast, in Hep G2 cells, TGF-beta had an effect opposite to that produced by IL-6, leading to secretion of forms of alpha 1-protease inhibitor with increased Con A binding. When employed in combination with IL-6. TGF-beta abolished the effect of that cytokine. These studies indicate that TGF-beta influences glycosylation of alpha 1-protease inhibitor in two human hepatoma cell lines in a manner that can be differentiated from that of IL-6. The identification of TGF-beta as a second defined cytokine capable of influencing glycoprotein glycosylation and the demonstration that the effect of one cytokine can be modulated by another cytokine support the view that changes in glycosylation of plasma proteins are mediated by combinations of cytokines.
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PMID:Transforming growth factor beta 1 influences glycosylation of alpha 1-protease inhibitor in human hepatoma cell lines. 217 6

To investigate our earlier hypothesis that carbohydrates play a regulatory role in the intracellular transport of secretory glycoproteins, we used 1-deoxynojirimycin (DNJ), and inhibitor of glucosidase I and II of the rough endoplasmic reticulum (RER), to modify the structure of N-linked glycan moieties of secretory glycoproteins of human hepatoma (Hep G2) cells in culture. Using a pulse-chase protocol, we found that treatment of Hep G2 cultures with 1.25 mM DNJ markedly reduced the rate of secretion of alpha 1-protease inhibitor, ceruloplasmin, and alpha 2-macroglobulin, but had no effect on the export of fibronectin, alpha-fetoprotein and transferrin, nor on albumin which lacks carbohydrate. For example, 50% of newly synthesized alpha 1-protease inhibitor, the glycoprotein most dramatically affected, was secreted by 27 min in control cultures versus 110 min in DNJ-treated cultures. Percoll gradient cell fractionation analyses revealed that DNJ inhibited transport of the affected secretory glycoproteins in the RER segment of the ER/Golgi pathway. For example, 50% of newly synthesized alpha 1-protease inhibitor was lost from the RER fraction by 10 min in untreated cells, but 70 min was required for the transport of a similar amount of protein in DNJ-treated cells. DNJ treatment also inhibited the rate at which the N-linked glycan moieties of the affected glycoproteins became resistant to endo H in the Golgi. Since the glycan moiety of secreted forms of the affected glycoproteins were fully processed to the complex structure, suggesting escape from DNJ inhibition, we concluded that removal of terminal glucose residues from the glycan chain of secretory glycoproteins is required for their transport from the RER to the Golgi. We suggest that the oligosaccharide moieties on alpha 1-protease inhibitor, ceruloplasmin and alpha 2-macroglobulin form part of the binding site for a receptor which regulates transport of these glycoproteins.
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PMID:Differential effects of 1-deoxynojirimycin on the intracellular transport of secretory glycoproteins of human hepatoma cells in culture. 243 31

Undefined monocyte-derived cytokines have previously been shown to affect glycan processing in glycoproteins secreted by human hepatoma cell lines. Hep 3B cells, when incubated with the cytokine interferon beta 2/B-cell stimulating factor 2/interleukin 6, secreted forms of alpha 1-protease inhibitor, ceruloplasmin, and alpha-fetoprotein with increased reactivity with concanavalin A (Con A) while incubation of Hep G2 cells with this cytokine led to secretion of forms of these proteins with decreased reactivity with Con A, reflecting changes in their oligosaccharide chains. The difference in response of these two transformed cell lines to this cytokine undoubtedly reflects differences in their intracellular glycan processing mechanisms. Changes in glycosylation patterns were dissociated from changes in rate of synthesis: this cytokine caused increased synthesis of alpha 1-protease inhibitor and ceruloplasmin, and decreased synthesis of alpha-fetoprotein in both cell lines.
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PMID:Interferon beta 2/B-cell stimulating factor 2/interleukin 6 affects glycosylation of acute phase proteins in human hepatoma cell lines. 247 Jan 33


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