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)

The pattern of gene expression in fetal hepatocytes transformed in culture with a hepatocarcinogen (FRL cells) is studied with respect to a range of markers which are either developmentally regulated and/or shown to be expressed at high levels in hepatoma cells. The relative abundance of the respective mRNAs is determined and immunocytochemistry is used to detect the respective proteins in cultured cells. When compared with its normal counterpart, FRL cells retain the expression of transferrin, alpha 1-acid glycoprotein, gamma-glutamyltranspeptidase, and tyrosine aminotransferase at near normal levels, while expression of the liver-specific isoenzymes of pyruvate kinase (L form) and aldolase (B form) is reduced. The cell lines are different in that they fail to express albumin, alpha-fetoprotein, thiostatin and alpha 2-macroglobulin, and they express high levels of M2-pyruvate kinase and aldolase A, markers often found in abundance in hepatoma cells. Therefore transformation has resulted in different effects on different genes. Furthermore, it is of interest to find that the cells coexpress both forms of the pyruvate kinase isoenzymes which does not occur in the normal developing hepatocyte. These results indicate that it is possible to use this model to study changes which accompany transformation of fetal rat hepatocytes. The resulting cell lines have a stable phenotype and retain the changes which result from transformation even after extended passaging. This facilitates comparisons between the precursor cell and the tumor cell, both of which can be maintained under controlled conditions which exist in culture.
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PMID:Gene expression in clonally derived cell lines produced by in vitro transformation of rat fetal hepatocytes: isolation of cell lines which retain liver-specific markers. 170 49

As resolved by electrophoresis in non-reducing SDS gels, transferrin newly made in Hep G2 cells migrates as a very diffuse set of species. During a subsequent 1-h chase all transferrin polypeptides are converted to a single, rapidly migrating species. These changes in gel mobility are due to alterations in the pattern of disulfide bonding, are not caused by carbohydrate processing, and occur while the protein is in the rough endoplasmic reticulum. Cyclosporin A causes an approximately 10-min lag in transferrin folding, after which folding resumes at the normal rate. Cyclosporin A also retards transferrin maturation from the endoplasmic reticulum and its secretion, at concentrations that do not affect secretion of other hepatoma proteins. Neither FK506 nor rapamycin affect transferrin folding. We conclude that an initial stage in transferrin folding is accelerated by an endoplasmic reticulum peptidyl-proline isomerase that is inhibited by cyclosporin A.
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PMID:Cyclosporin A inhibits an initial step in folding of transferrin within the endoplasmic reticulum. 171 45

Genetic haemochromatosis is characterised by an inappropriately high rate of iron absorption by the small intestine. The disease is transmitted as an autosomal recessive condition. The gene frequency in the Caucasian population is approximately 1 in 20 and the disease frequency is 1 in 400. Excessive iron deposition occurs in the liver, pancreas, heart, pituitary and joints and hepatic iron concentrations above approximately 400 mumol/g dry weight are always associated with fibrosis and usually with cirrhosis and progressive liver failure. Accurate diagnosis depends upon the demonstration of elevated hepatic iron stores. An hepatic iron index [hepatic iron concentration (in mumol/g dry weight) divided by patient age] of greater than 2.0 distinguishes homozygous subjects from the other conditions in which slight increases in hepatic iron concentration may occur, e.g. in a subject heterozygous for haemochromatosis or alcoholic liver disease. If cirrhosis is present, patients are at a high risk of developing hepatocellular carcinoma. Therefore, they should undergo regular abdominal ultrasound and alpha-fetoprotein estimation. In the absence of cirrhosis, phlebotomy restores life expectancy to normal. Venesection should be continued until all excess iron stores are removed as judged by failure of a rise in haemoglobin concentration on cessation of phlebotomy. Screening of first degree relatives should commence from a young age (e.g. 10 years). If serum ferritin or transferrin saturation are abnormal, liver biopsy should be undertaken. HLA typing of the family allows for the identification of those siblings who are most likely to develop the disease. Secondary iron overload is often multifactorial in origin. Iron chelation therapy with subcutaneous deferoxamine (desferrioxamine) should only commence after careful consideration of the potential benefits in each individual patient.
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PMID:Current concepts in rational therapy for haemochromatosis. 171 64

Insulin is widely used as a growth factor in hepatocyte culture but its effect on the production of acute-phase proteins has not been studied. By measuring four positive (fibrinogen, alpha 1-antitrypsin, alpha 1-acid glycoprotein, and alpha 1-antichymotrypsin) and four negative (albumin, prealbumin, transferrin, and retinol binding protein) acute-phase proteins produced by the Hep G2 hepatoma cell line, we have shown that insulin is an important modulator of acute-phase protein production. Our data show that insulin is able to inhibit the synthesis of prealbumin, transferrin, and fibrinogen. The results also show a complex interaction between insulin, interleukin 6, and glucocorticoids because insulin is able to inhibit the dexamethasone induction of alpha 1-antichymotrypsin, and in the presence of interleukin 6, dexamethasone is able to regulate the production of fibrinogen and prealbumin. The regulatory role of insulin in fibrinogen production was confirmed by pulse chase labeling followed by immunoprecipitation and fluorography.
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PMID:Insulin modulation of acute-phase protein production in a human hepatoma cell line. 172 87

Transferrin receptors take up transferrin-iron complexes into hepatic cells. Although the receptor is not highly expressed in normal liver cells, malignant transformation of the cells increases its expression. As part of the expressed receptors are released into blood, a significant increase of serum receptors are observed in cases of hepatoma. Therefore, measurement of transferrin receptors in blood from patients with hepatoma may be useful for estimating the tumor burden and determinating therapeutic effects. Asialoglycoprotein receptors are expressed strongly in normal liver cells, whereas the expression is decreased in various chronic liver diseases and hepatoma. Although the active shedding of the receptors clearly occurs in vitro, as does that of the transferrin receptor, determination of the significance of these shed receptors in blood will require further studies.
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PMID:Mechanism and clinical significance of soluble hepatic cell-surface receptors. 179 62

A rat hepatoma cell line 3'-mRLh-2 was established from 3'-methyl-4-dimethylaminoazobenzene-induced hepatoma. Cells proliferated well in 5Fs-DM-160, a chemically-defined serum-free medium; population doubling time was 68.5 h, and modal chromosome number was 81 (21%). The cells were transplantable, and the transplanted tumors were histologically diagnosed as hepatocellular carcinoma. They were cytochemically positive for gamma-glutamyl transpeptidase. The cells possessed about 30% of tyrosine aminotransferase activity level in the rat liver, and showed 5.5 to 7.4-fold induction of this enzyme activity in response to dexamethasone. Also, the cells secreted alpha-fetoprotein, albumin, transferrin, alpha 1-acid glycoprotein, C-reactive protein, fibrinogen, complement component C3, and other five-serum proteins. Furthermore, the conditioned medium stimulated DNA synthesis in primary cultures of adult rat hepatocytes in a dose-dependent, saturable manner and in the absence of epidermal growth factor. These properties of the cell line 3'-mRLh-2 were compared with those of the popular rat hepatoma cell lines, such as H4-II-E-C3 from Reuber hepatoma H35 and HTC from Morris hepatoma 7288C.
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PMID:Expression of liver-specific functions and secretion of a hepatocyte growth factor by a newly established rat hepatoma cell line growing in a chemically-defined serum-free medium. 183 93

Iron is essential for life, but iron overload is toxic and potentially fatal. The liver is a major site of iron storage and is particularly susceptible to injury from iron overload, especially when (as in primary hemochromatosis) the iron accumulates in hepatocytes. Iron can be taken up by the liver in several forms and by several pathways including: (1) receptor-mediated endocytosis of diferric or monoferric transferrin or ferritin, (2) reduction and carrier-facilitated internalization of iron from transferrin without internalization of the protein moiety of transferrin, (3) electrogenic uptake of low molecular weight, non-protein bound forms of iron, and (4) uptake of heme from heme-albumin, heme-hemopexin, or hemoglobin-haptoglobin complexes. Normally, pathway 2 is probably the major one for uptake of iron by hepatocytes. Iron is stored in the liver in the cores of ferritin shells and as hemosiderin, an insoluble product derived from iron-rich ferritin. Iron in hepatocytes stimulates translation of ferritin mRNA and represses transcription of DNA for transferrin and transferrin receptors. The major pathologic effects of chronic hepatic iron overload are: (1) fibrosis and cirrhosis, (2) porphyria cutanea tarda, and (3) hepatocellular carcinoma. Although precise pathogenetic mechanisms remain unknown, iron probably produces these and other toxic effects by increasing oxidative stress and lysosomal lability. Vigorous efforts at diagnosis and treatment of iron overload are essential since the pathologic effects of iron are totally preventable by early vigorous iron removal and prevention of iron re-accumulation.
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PMID:Iron and the liver. 184 76

Suramin, a polyanionic compound used clinically for the treatment of African trypanosomiosis and onchocerciasis, has been shown to inhibit the action of various growth factors such as platelet-derived growth factor, epidermal growth factor, fibroblast growth factor and transforming growth factor-beta to stimulate DNA synthesis of cells. Therefore, we investigated effects of suramin on cell proliferation of various types of human malignant cells in culture. Cell lines used were as follows: cervical cancer (HeLa), mammary cancer (MCF-7), bladder cancer (EJ), hepatoma (HuH-7, PLC/PRF/5), embryonal carcinoma (PA-1), and three in vitro transformed human fibroblast lines (KMST-6, SUSM-1, and VA-13). A serum-free defined medium, ASF103, was used when the effect of suramin on proliferation of cells was investigated. This culture medium contains only bovine serum albumin (0.1%), transferrin (5 micrograms/ml) and insulin (5 micrograms/ml) as peptide factors. On day 1, the drug was added to culture medium at the concentration of 25-100 micrograms/ml and 72-96 hr later, the number of cells was counted. The growth inhibition was expressed as the percentage of cells surviving after treatment of cells with suramin, with survival in the control condition representing 100 percent. Proliferation of HuH-7 cells was prominently inhibited and those of PA-1, PLC/PRF/5 and KMST-6 were moderately inhibited under the same conditions of treatment. On the other hand, other five cell lines were not responsive to up to 100 micrograms/ml suramin.
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PMID:[Effects of suramin on cell proliferation of various types of human malignant cells]. 184 19

We have used successive density gradient centrifugation with vesicles prepared from a human hepatoma Hep G2 post nuclear supernatant to obtain a highly enriched preparation of early endosomes. A monoclonal antibody (8E4) raised against this early endosome preparation recognizes a single polypeptide highly enriched in light vesicle membranes. The antigen has a molecular weight of 195 kDa by SDS-PAGE in the presence or absence of a reducing agent. Western blot analysis shows that the 8E4 antigen is detectable only in light vesicle membranes and not among heavy membranes, whole cytosol, or nuclear pellet proteins. The 8E4 antigen appears to be an integral membrane protein as it is precipitated by Triton X-114. The distribution of the 8E4 antigen in a Nycodenz density gradient fractionation of light vesicle membranes is identical to the distribution of 125I-ASOR-labeled early endosomes but distinct from the distribution of the plasma membrane enzyme, alkaline phosphodiesterase. In addition, incubation of cells with a horseradish peroxidase-transferrin conjugate followed by 3,3'-diaminobenzidine cytochemistry specifically quenches 8E4 antigen detection by protein dot blot analysis. These data strongly suggest that the 8E4 antigen is an integral membrane protein primarily located in endocytic vesicles.
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PMID:Identification of an endosome-specific antigen. 184 26

Endocytosed proteins destined for degradation in lysosomes are targeted mainly to early endosomes following uptake. Late endosomes are the major site for entry of newly synthesized lysosomal hydrolases via the cation-independent mannose 6-phosphate receptor into the degradative pathway. No consensus exists as to the mechanism of transport from early to late endosomes. We used asialoorosomucoid and transferrin to label selected parts of the degradative and receptor-recycling pathways, respectively, in the human hepatoma cell line HepG2. Intracellular mixing of sequentially endocytosed 125I- and HRP-labeled ligands was monitored by using 3,3'-diaminobenzidine-mediated density perturbation. The entire endocytic pathway of asialoorosomucoid, except for the lysosomes, remained fully accessible to subsequently endocytosed transferrin conjugated to HRP with unchanged kinetics. These results together with immunoelectron microscopic data support a model in which early endosomes gradually mature into late endosomes.
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PMID:Late endosomes derive from early endosomes by maturation. 185 Mar 21


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