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)

We have isolated a population of post-TGN secretory vesicles from hepatocytes. These vesicles of 100-150 nm diameter carry heparan sulfate proteoglycans. Secretory proteins (albumin, apo-lipoprotein E, fibrinogen) are sorted into different post-TGN secretory vesicles. A member of the ARF family of small GTP-binding proteins is associated with these vesicles. A unique peripheral membrane protein of these vesicles (VAPP14) was shown to exist also on the TGN. Brefeldin A leads to a dissociation of VAPP14 from the TGN. Antibodies against VAPP14 inhibit budding of proteoglycan containing vesicles from the TGN in a cell-free system. Inhibition occurred also in the presence of GTP-gamma-S. The same type of vesicles exists in H35 Reuber hepatoma cells.
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PMID:Sorting and budding of constitutive secretory vesicles in hepatocytes and hepatoma cells. 757 49

Rats fed a choline-deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipoproteins. We have previously reported that 1,2-sn-diradylglycerol accumulates in the livers of rats fed a choline-deficient diet for 1-27 weeks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 2100-2105, 1993). In the present study, we examined the changes that occur in rat liver at 52 weeks of choline deficiency and determined whether these changes were reversible when choline was returned to the diet of the deficient animals for 1 or 16 weeks. At 52 weeks, non-tumor liver samples from the experimental animals had increased 1,2-sn-diradylglycerol concentrations in the lipid droplets compared with control animals. Plasma membrane 1,2-sn-diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in membrane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated free fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the plasma membrane remained significantly elevated at 52 weeks in deficient livers. Hepatic foci expressing gamma-glutamyltranspeptidase were detected only in the deficient rats (0.83% of liver volume) and 15% of these rats had hepatocellular carcinoma at 1 year on the diet. At 53 weeks (1 week after choline was returned to the deficient group), 1,2-sn-diradylglycerol concentrations in the lipid droplets and hepatic free fatty acids had dropped to control levels. By 68 weeks (16 weeks of re-feeding choline), the membrane protein kinase C activity had returned to normal. At this time, 14% of the experimental animals had hepatocellular carcinoma. We suggest that choline deficiency altered the protein kinase C-mediated signal transduction within liver and this contributed to hepatic carcinogenesis in these animals.
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PMID:Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver. 785 65

Plasma membrane purified from Buffalo rat liver tissue not only had the ability to bind 125I-EGF (2.77 pg of EGF/mg of membrane protein), but also exhibited both high (Kd = 0.08 nM) and low (Kd = 5.67 nM) affinity receptors. However, the binding of EGF to hepatoma plasma membrane was insignificant. EGF receptor in plasma membrane from normal liver tissue was identified by ECL Western blotting using monoclonal anti-EGF receptor antibody and phosphorylated via the stimulation of EGF. This phosphorylation was inhibited by genistein, a tyrosine kinase inhibitor. However, these effects were not observed in hepatoma cell membrane. These results suggest that plasma membrane purified from normal rat liver tissue has a high level of functional EGF receptor, whereas, hepatoma plasma membrane lacks the receptor.
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PMID:Studies of epidermal growth factor (EGF) receptor in plasma membrane from rat liver and hepatoma tissues. 795 Oct 42

Choline deficiency, via deprivation of labile methyl groups, is associated with a greatly increased incidence of hepatocarcinoma in experimental animals. This dietary deficiency also causes fatty liver, because choline is needed for hepatic secretion of lipoproteins. We hypothesized that fatty liver might be associated with the accumulation of 1,2-sn-diradylglycerol and subsequent activation of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction. We observed that rats fed a choline-deficient diet for 1, 6, or 27 weeks had increased hepatic concentrations of 1,2-diradylglycerol. At 1 and 6 weeks, hepatic plasma membrane from choline-deficient rats had increased concentrations of 1,2-sn-diacylglycerol and 1-alkyl, 2-acylglycerol, with the latter accounting for 20-26% of membrane 1,2-sn-diradylglycerol (as compared with only 2-5% in controls). Protein kinase C activity was increased in hepatic plasma membrane at 1 week of choline deficiency. By Western blotting there was an increase in the amount of protein kinase C zeta and a decrease in the amount of protein kinase C delta in liver at 1 week. By 6 weeks of choline deficiency, hepatic plasma membrane and cytosolic protein kinase C (PKC) activities were increased significantly, with increased amounts of hepatic plasma membrane protein kinase C alpha, and delta detected by Western blotting. Glycogen synthase activity in liver was diminished after 1 week of choline deficiency; this enzyme is inhibited by PKC-mediated phosphorylation. We suggest that choline deficiency perturbed PKC-mediated transmembrane signaling within liver and that this contributed to the development of hepatic cancer in these animals.
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PMID:Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline-deficient rats. 842 Sep 80

The ligand-binding subunit (gp80) of the human interleukin-6 receptor (IL-6R) was transiently expressed in COS-7 cells. The metabolically labeled protein was shown to be quantitatively released from the membrane within 20 h. We identified the protein released from the transfected COS-7 cells after purification to homogeneity and N-terminal sequencing as a soluble form of the gp80/IL-6R. Shedding of the gp80 protein was strongly induced by 4 beta-phorbol-12-myristate-13-acetate, indicating that the process was regulated by protein kinase C (PKC). This was further corroborated by the finding that co-transfection of a PKC expression plasmid led to enhanced shedding of the gp80 protein. Since shedding of gp80 could not be prevented by treatment of the cells with inhibitors of all known classes of proteases, a novel protease seems to be involved. As a control, an unrelated membrane protein (vesicular stomatitis virus glycoprotein) was transfected into COS-7 cells and analyzed for shedding. Since the turnover of this protein was not mediated by shedding, we conclude that the release of gp80 from COS-7 cells is a specific process. The shed gp80 protein specifically binds IL-6, and this complex shows biological activity on human hepatoma cells. Human peripheral blood monocytes released a soluble form of the gp80 protein into the culture medium upon PMA treatment indicating that PKC-regulated shedding is the physiological mechanism of generation of the soluble IL-6R.
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PMID:The soluble interleukin-6 receptor is generated by shedding. 843 81

The membrane-association of early biosynthetic form of cathepsin D has been demonstrated in hepatoma cells, and this membrane-association is not mediated by mannose 6-phosphate residues, implying that a mannose 6-phosphate receptor-independent mechanism operates in the sorting of cathepsin D. In this paper, to demonstrate whether cathepsin D is associated with the lysosomal membranes, an in vitro binding experiment was carried out employing lysosomal cathepsin D or microsomal procathepsin D isolated from rat liver. Immunoblotting analysis revealed that an intermediate form of cathepsin D was associated with the lysosomal membranes; this lysosomal membrane-associated cathepsin D was released from the membranes by washing with Na2CO3 (pH 10.6) but not with solutions containing mannose 6-phosphate. This suggested that cathepsin D associates with the membranes by ionic-interaction, and that the membrane-associated cathepsin D resides as a peripheral membrane protein in the lysosomal membrane fraction. To confirm that the intermediate form of cathepsin D specifically interacts with the lysosomal integral membrane proteins, the lysosomal membrane fraction was treated with trypsin and the binding experiment was conducted. The result showed that the binding capacity of cathepsin D to the lysosomal membranes was apparently abolished and cathepsin D did not rebind to the membranes. These data suggest that the intermediate form of cathepsin D is preferentially recognized by the lysosomal membranous protein which complements the mannose 6-phosphate receptor-dependent intracellular sorting mechanism.
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PMID:Cathepsin D associates with lysosomal membranous protein. 859 33

By immunofluorescence and freeze fracture methods, we have studied the establishment of hepatic cell polarity in WIF-B9 cells, a subclone of the WIF-B rat hepatoma-derived hybrid cell line. As previously shown (Ihrke et al. (1993) J. Cell Biol. 123, 1761-1775; Shanks et al. (1994) J. Cell Sci. 107, 813-825), these cells are a suitable model for in vitro studies of various hepatic functions, particularly polarity: in confluent cultures, the majority of cells form bile canaliculus-like structures; membrane domains are settled, according to plasma membrane protein localization similar to rat hepatocytes in situ. We here report that the establishment of WIF-B9 cell polarity is a slow progressive biphasic phenomenon. During the first days of culture, the majority of cells do not make bile canaliculus-like structures. However, they display a polarity similar to that of simple epithelial cells: apical membrane proteins and villin are found at the cell apex; basolateral ones, excluded from this area, are expressed in the remaining membrane area; the tight junction-associated protein ZO-1 and actin are concentrated at the boundary of these two poles, whereas E-cadherin is present at the lateral pole just under the apex. With time in culture, the number of cells expressing this simple epithelial polarized phenotype decreases progressively and, after 10-15 days, depending on the plating density, nearly all the cells express the typical hepatic polarized phenotype. The expression of these two phenotypes is mutually exclusive. Freeze-fracture replicas of both types of polarized cells show either macula occludens, fascia occludens (simple epithelial polarity) or zonula occludens (hepatic polarity), associated with gap junctions. In this last case, two or three continuous strands are generally present all around the bile canaliculus-like structures.
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PMID:Establishment of hepatic cell polarity in the rat hepatoma-human fibroblast hybrid WIF-B9. A biphasic phenomenon going from a simple epithelial polarized phenotype to an hepatic polarized one. 879 49

Expression of P-glycoprotein, a phylogenetically conserved integral plasma membrane protein, is implicated as one of the most important factors contributing to tumor cell multidrug resistance. Formalin-fixed, paraffin-embedded normal and neoplastic canine tissues were studied using an avidin-biotin complex technique employing three murine monoclonal antibodies (C494, C219, JSB-1) to different epitopes of the P-glycoprotein molecule. Evaluation of immunostaining of normal canine tissues revealed positive labeling detected by each antibody in the liver, proximal renal tubular epithelium, adrenal cortex, colonic epithelium, and capillary endothelial cells of the brain. A total of 166 tumors of epithelial or mesenchymal origin were evaluated for P-glycoprotein immunoreactivity. Hepatomas (4/4), colorectal adenomas (7/7), colorectal carcinomas (4/4), adrenal cortical adenomas (3/3), hemangiopericytomas (15/15), apocrine gland adenocarcinomas (4/5, 80%), and transitional cell carcinomas (2/2) consistently labeled with at least one of the antibodies. Histiocytomas (0/10), cutaneous plasma cell tumors (0/10), fibromas (0/3), fibrosarcomas (0/4), and leiomyomas (0/4) were uniformly negative with all antibodies. Malignant lymphomas (6/22, 27.3%), malignant melanomas (4/13, 30.8%), leiomyosarcomas (3/6, 50%), mammary gland carcinomas (12/19, 63.2%), mammary gland adenomas (3/9, 33.3%), squamous cell carcinomas (8/10, 80%), basal cell tumors (5/7, 71.4%), apocrine gland adenomas (1/2, 50%), cholangiocarcinomas (2/3, 66.7%), and thyroid gland carcinomas (2/4, 50%) gave variable results. The antibodies C494, JSB-1, and C219 labeled 66/166 (39.8%), 53/166 (31.9%), and 38/166 (22.9%) of all tumors studied, respectively. A total of 26/166 (15.7%), 22/166 (13.3%), and 37/166 (22.6%) of tumors were labeled by all three, just two, or one antibody alone, respectively. The antibody C494 was the only antibody labeling 28/166 (16.9%) of the cases. JSB-1 alone labeled 9/166 (5.4%) of the tumors. C219 failed to label any tumors not also labeled by either C494 or JSB-1. Labeling by C494 was more intense and specific than labeling by the other two antibodies. Results indicate that P-glycoprotein can be detected in routinely processed canine tissues. The detection of P-glycoprotein within canine liver, kidney, adrenal gland, and colon and within tumors arising from these tissues is consistent with that reported in the literature for human tissues. Variable labeling results of other tumors such as malignant lymphoma and mammary gland carcinomas also is consistent with reports of human studies. Detection of multidrug resistance markers such as P-glycoprotein in canine tissues may provide additional information upon which to base a prognosis or to design treatment regimens for canine tumors.
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PMID:Immunohistochemical detection of P-glycoprotein in formalin-fixed and paraffin-embedded normal and neoplastic canine tissues. 888 80

Cross-linking of Fas (CD95, APO-1) and Fas ligand (FasL; CD95L) induces apoptosis of Fas-bearing cells. Recent evidence suggests that FasL. expression plays an important role in maintenance of immune privilege in murine testis and eye and in tumour escape from immune rejection in colon cancer, melanoma and hepatocellular carcinoma. Bcl-2 is a membrane protein that suppresses apoptosis in response to a variety of stimuli. In this paper we describe abundant expression of FasL protein and mRNA transcripts within the immune privileged environment of the placenta by immunohistochemistry and reverse transcription in-situ polymerase chain reaction methods. The syncytiotrophoblast layer, the main site of feto-maternal interface, and extravillous trophoblasts, demonstrated consistent immunoreactivity for FasL in term placentae. Co-occurrence of Fas and Bcl-2 were detected with a similar pattern of distribution with FasL. The TUNEL method revealed evidence of apoptosis in the placental tissues. We speculate that abundant presence of FasL in the trophoblast contributes to immune privilege in this unique environment, perhaps by fostering apoptosis of activated Fas-expressing lymphocytes of maternal origin. An apoptotic process mediated by FasL may also play a role in placental invasion during implantation and underscores similarities between the trophoblast and neoplastic cells.
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PMID:Trophoblasts express Fas ligand: a proposed mechanism for immune privilege in placenta and maternal invasion. 929 48

The sister gene of P-glycoprotein (Spgp) is a liver-specific ATP-binding cassette protein highly related to the P-glycoprotein (Pgp) family (S. Childs et al, Cancer Res., 55: 2029-2034, 1995). Spgp appears to be related to the Pgp family by an ancient duplication occurring before the division of fish and mammals. P-Glycoproteins have diverse functions including broad specificity multidrug resistance in cell lines and tumors, detoxification of tissues such as the intestine and blood-brain barrier, and phosphatidylcholine transport in liver. Spgp is a Mr approximately 170,000 glycosylated plasma membrane protein localized to the canalicular surface of hepatocytes in the rat liver. The full-length cDNA of Spgp was isolated from rat, and its expression was characterized in situ and in transfected cells. The expression of Spgp correlates with the differentiation of hepatocytes and is seen only in late liver development. It is not observed in hepatoma cell lines. The physiological function of Spgp in liver is unknown, but it maps to 2q31 in humans, in the vicinity of liver transport disorders for bile acids and cholesterol. Spgp may therefore be involved in some aspect of bile acid or cholesterol metabolism. Spgp transfectants have a low level resistance to Taxol but not to other drugs that form part of the multidrug resistance phenotype. This resistance is reversible by the Pgp-reversing agents cyclosporin A, PSC833, and verapamil, suggesting a conservation in some functions of Pgps across large evolutionary distance.
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PMID:Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein. 975 29


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