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)

[35S]Sulfate labeling of the human hepatoma cell line HepG2 showed it to contain many sulfated proteins of diverse molecular weight range. The isolation of tyrosine O-sulfate indicated the supernatant fraction to contain a 5- to 7-fold higher level than the cellular fraction at the end of a 24-hr incubation. The proteins in the supernatant fraction were immunoprecipitated and examined for sulfation. Of 15 proteins tested, 7 were found to be sulfated as indicated by [35S]sulfate incorporation into proteins separated by NaDodSO4/PAGE and detected by autoradiography. The 35S-labeled bands were excised from the dried gel and subjected to extensive Pronase hydrolysis and the hydrolysates were analyzed for tyrosine [35S]sulfate by a two-dimensional procedure combining high-voltage electrophoresis and thin-layer chromatography [Liu, M. C. & Lipmann, F. (1984) Proc. Natl. Acad. Sci. USA 81, 3695-3698]. Of the sulfated proteins, three--fibrinogen, alpha-fetoprotein, and fibronectin--were found to contain tyrosine O-sulfate. The simultaneous presence of carbohydrate-bound sulfate, however, could not be exactly determined, but the other four [35S]sulfate-containing proteins--alpha 1-antitrypsin, alpha 1-antichymotrypsin, alpha 2-macroglobulin, and transferrin--did not reveal any tyrosine O-sulfate and might be sulfated on their carbohydrate moieties.
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PMID:Tyrosine sulfation of proteins from the human hepatoma cell line HepG2. 241 72

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

We have immunohistochemically localized fibronectin, lysozyme and alpha-fetoprotein (AFP) in 21 human hepatocellular carcinoma (HCC) tissues obtained by surgical resection at both light and electron microscopic levels. Three distinct distribution patterns of fibronectin (sinusoidal, periacinar, and pericellular patterns) were observed. The sinusoidal and periacinar patterns were mainly observed in HCC of pseudoglandular or trabecular patterns and of Edmondson's grade I or II, whereas the pericellular pattern was observed in HCC of compact or trabecular patterns and of Edmondson's III grade, suggesting that the pericellular fibronectin was rather associated with undifferentiated HCC. Electron microscopic observation of the pericellular fibronectin showed fibronectin to be present in the dilated intercellular spaces where microvilli were moderately developed. We observed intracytoplasmic staining of fibronectin in 2 of the 21 HCC cases. By immunoelectron microscopy, fibronectin was observed in the endoplasmic reticulum (ER) of some HCC cells. In the 21 HCC cases, lysozyme-positive cancer cells were observed in 10 cases, and AFP in 6 cases. At the ultrastructural level, lysozyme was identified in the ER and the perinuclear spaces of HCC cells, suggesting that lysozyme was synthesized by these cells. Lysozyme-positive cases tended to be more frequently observed in cases with the pericellular pattern of fibronectin rather than those with sinusoidal or periacinar patterns.
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PMID:Immunohistochemical study of fibronectin, lysozyme, and alpha-fetoprotein (AFP) in human hepatocellular carcinoma. 243 68

Studies were carried out to analyze the mechanism by which extracellular matrix (ECM) molecules and soluble growth factors interplay to control capillary endothelial cell growth. Bovine adrenal capillary endothelial cells attached to purified matrix components but spread poorly and exhibited low levels of DNA synthesis in the absence of exogenous growth factors or serum. Addition of cationic, heparin-binding growth factor purified from either human hepatoma cells or normal bovine pituitary (fibroblast growth factor) induced extensive cell spreading and up to eight fold increases in DNA synthetic rates relative to levels observed in cells on similar substrata in the absence of mitogen. However, the extent of this response differed depending upon the type of ECM molecule used for cell attachment (fold increase on type III collagen greater than gelatin greater than type IV collagen greater than fibronectin greater than type V collagen much greater than laminin). Computerized morphometry demonstrated that endothelial cell DNA synthetic rates increased in an exponential fashion in direct relation to linear increases in cell and nuclear size (projected areas). Similarly sized cells always displayed the same level of DNA synthesis independent of the type of ECM molecule used for cell attachment or the presence of saturating amounts of growth factor. In all cases, DNA metabolism appeared to be coupled to physical expansion of the cell and nucleus rather than to a specific cell morphology (e.g. polygonal versus bipolar). These findings suggest that ECM may act locally as a "solid state" regulator of angiogenesis through its ability to selectively support or prohibit cell and nuclear extension in response to stimulation by soluble mitogens.
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PMID:Endothelial growth factors and extracellular matrix regulate DNA synthesis through modulation of cell and nuclear expansion. 243 64

Previously, monoclonal antibody FDC-6 was established, which defines a structure specific for fibronectins isolated from fetal and malignant cells and tissues. The presence of the FDC-6-defined structure at type III connecting segment (III CS) is characteristic of oncofetal fibronectin (onf-FN), and its absence is characteristic of normal fibronectin (nor-FN) (Matsuura, H., and Hakomori, S. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 6517-6521). Hepatoma fibronectin was sequentially digested by various proteases, followed by subsequent chromatography on an FDC-6 affinity column and reverse-phase columns at each step of digestion. A single strongly active glycosylhexapeptide (glycopeptide 1) and an inactive glycosylpentapeptide (glycopeptide 3) were isolated from glycopeptide A containing 35 amino acid residues. The minimum essential structure required for the FDC-6 activity was found to be a hexapeptide sequence Val-Thr-His-Pro-Gly-Tyr having NeuAc alpha 2----3Gal beta 1----3GalNAc or its core (Gal beta 1----3GalNAc or GalNAc) linked at threonine. Various synthetic peptides including the Val-Thr-His-Pro-Gly-Tyr sequence and a glycopeptide having the Val-Thr-His-Pro-Gly pentapeptide with the same glycosylation at threonine were all inactive. Elimination of sialic acid slightly increased the activity, and subsequent elimination of galactose did not alter the activity; however, removal of the Gal beta 1----3GalNAc residue by endo-alpha-N-acetylgalactosaminidase from desialylated glycopeptide A resulted in total inactivation of the reactivity with FDC-6 antibody. Thus, a single glycosylation at a defined threonine residue of the III CS region may induce conformational changes in the peptide to form the specific oncofetal epitope recognized by FDC-6 antibody. This finding opens the possibility that a number of other oncofetal epitopes consist of a peptide and a common O-linked carbohydrate and that the combination produces a conformation specific to cancer or to a stage of development.
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PMID:The oncofetal structure of human fibronectin defined by monoclonal antibody FDC-6. Unique structural requirement for the antigenic specificity provided by a glycosylhexapeptide. 244 38

We succeeded in the separation of AFP-producing cell lines (HH2-1 and HH2-6) and a non-AFP-producing cell line (HH2-4) from cultures of human hepatocellular carcinoma and also succeeded in culturing the AFP-producing cell lines in a serum-independent medium (HHSF). The cells cultured in this medium showed no morphological difference from those cultured in the medium containing serum, and retained growth ability well. Although the protein synthesis of the cells was reduced in the serum-independent medium, they were still able to produce a variety of proteins such as transferrin (TF) and fibronectin (FN) in addition to alpha-fetoprotein (AFP) and albumin (ALB).
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PMID:Establishment of an AFP-producing serum-independent culture cell line of human liver cancer and changes in protein synthesis associated with the absence of serum (First Part). 245 Aug 3

In this study, we investigated protein (total protein) synthesis and production of such as alpha-fetoprotein (AFP) and albumin (ALB) in the media for cultured human hepatocellular carcinoma cells. Consequently, it was found that total protein (TP) in the medium was consumed rapidly in the first day, thereafter TP consumption was not quantitatively significant. Since this cell line was also found to produce transferrin (TF) and fibronectin (FN), we investigated the AFP, ALB and TF production of this cell line by adding dexamethasone, a glucocorticoid involved in protein metabolism. As a result of adding dexamethasone, it was found that AFP and ALB (or TF) production increased simultaneously.
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PMID:Establishment of an AFP-producing serum-independent culture cell line of human liver cancer and changes in protein synthesis associated with the absence of serum (second part). 245 Aug 4

A Morris hepatoma 7777-derived cell line, DTH-3, was used to study the control of fibronectin gene expression. In cultures of DTH-3 cells in conventional medium supplemented with serum or in chemically defined MX-83 medium supplemented with insulin no cell surface fibronectin was detectable by indirect immunofluorescence techniques using specific polyclonal antibodies. By Northern blot hybridization analysis a dose- and time-dependent accumulation of 8 kb fibronectin mRNA in response to hydrocortisone treatment was demonstrated. Furthermore, 24 h after addition of hydrocortisone an extensive fibrillar fibronectin network was established. The results suggest that the hydrocortisone-dependent induction of fibronectin production might, at least in part, be controlled at the transcriptional level.
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PMID:Hydrocortisone-induced accumulation of fibronectin mRNA and cell surface-associated fibronectin. 246 Apr 64

The monoclonal antibody FDC-6 defines a structure specific to oncofetal fibronectins (onf-FN) isolated from fetal and malignant cells and tissues. The absence of this structure is characteristic of normal fibronectin (nor-FN) isolated from plasma and adult normal tissue (Matsuura, H., and Hakomori, S. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 6517-6521). The minimum structure required for FDC-6 reactivity was determined to be Val-Thr-His-Pro-Gly-Tyr (VTHPGY) with alpha-N-acetylgalactosamine (alpha-GalNAc) at Thr, although alpha-GalNAc per se is not involved in the FDC-6 epitope (Matsuura, H., Takio, K., Titani, K., Greene, T., Levery, S. B., Salyan, M. E. K., and Hakomori, S. (1988) J. Biol. Chem. 263, 3314-3322). Thus, a single glycosylation on the normally occurring peptide of FN may induce conformational changes in the peptide to form the specific oncofetal epitope recognized by FDC-6 antibody. The FDC-6-nonreactive synthetic peptide containing the VTHPGY sequence was converted into FDC-6-reactive form on incubation with alpha-N-acetylgalactosaminyltransferase and UDP-[3H]GalNAc in the homogenate of hepatoma cell HUH-7, human fetal fibroblast cell line WI-38, or human epidermoid carcinoma cell line A431. Such a conversion did not take place when the same enzyme fraction of normal adult tissue was incubated with the VTHPGY peptide under the same conditions. Thus, the occurrence of alpha-GalNAc transferase recognizing the VTHPGY peptide sequence (UDP-GalNAc:VTHPGY alpha-GalNAc transferase) is specific for fetal and cancer tissues, and absent in normal adult tissues. However, a similar alpha-GalNAc transferase activity capable of transferring the GalNAc residue to other Ser or Thr hydroxyl groups of nor-FN, and presumably located at the type III connecting segment region, was detectable in homogenate of various normal tissues. Such enzyme activity was determined with the use of enzymatically de-O-glycosylated nor-FN. Thus, the enzymatic basis of FDC-6 epitope formation is a subtle change in the substrate specificity of alpha-GalNAc transferase. The normal enzyme is incapable of transferring alpha-GalNAc from UDP-GalNAc to the Thr residue of the VTHPGY sequence, but is capable of transferring alpha-GalNAc to other Ser or Thr residues of FN. In contrast, alpha-GalNAc transferase of fetal and cancer tissues may have broader specificity and the capability to transfer GalNAc to Thr or Ser residues, including those of the VTHPGY sequence.
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PMID:An alpha-N-acetylgalactosaminylation at the threonine residue of a defined peptide sequence creates the oncofetal peptide epitope in human fibronectin. 247 5

A hybrid clone was developed by the fusion of a pluripotent mouse teratocarcinoma cell line PCC-4 AzaR to the Zajdela ascitic hepatoma (ZAH) of rat origin. This hybrid cell line, F2231A, possessed a predominantly teratocarcinoma morphology with a large nucleus and prominent nucleoli, and grew in nests. F2231A cells formed undifferentiated tumours in irradiated Sv/129 mice. It formed aggregates when subcultured at high densities in bacteriological Petri dishes. The hybrid cell line differentiated in response to retinoic acid and also underwent spontaneous differentiation upon overgrowth. Karyological analysis showed the presence of several rat chromosomes in the hybrid and upon isozyme analysis it was found that only the rat variant of the X-linked enzyme HGPRT was expressed. Analysis of the genomic DNA with a cloned probe, specific for rat repetitive sequences, gave strong positive signals in the hepatoma parent and F2231A cells while the parental embryonal carcinoma (EC) cells were negative. The hybrid cell line, like the PCC-4 cells, expressed the SSEA-1 surface marker but not SSEA-3, intercellular fibronectin and EGF receptors. Upon differentiation of F2231A cells there was a loss of expression of SSEA-1. The mRNA for alpha-fetoprotein was expressed by the hybrid cell line and in this respect it resembled the hepatoma parent. Albumin mRNA was not detectable in the hybrid cell line. The mRNA for the transformation-related protein, p53, was expressed at a high level in F2231A cells. The hybrid cell line F2231A retained several of the biochemical and immunological properties of the teratocarcinoma cells.
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PMID:A malignant, stem cell-like somatic hybrid between a mouse teratocarcinoma and a rat ascitic hepatoma is differentiation competent. 247 69


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