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)

Hypoxia-induced erythropoietin (Epo) production in vitro is suppressed by interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF) and phorbol esters. Herein, the Epo-synthesizing human hepatoma cell line HepG2 was used to investigate whether protein kinase C (PKC) is involved in the inhibitory action of the cytokines. Within 1 h after the onset of hypoxia, Epo mRNA levels were markedly increased in untreated HepG2 cells as quantitated by competitive reverse transcription PCR. The cytokines IL-1 beta and TNF prevented this hypoxia-induced increase in Epo mRNA levels. In phorbol-ester-treated cells first inhibitory effects on Epo mRNA levels were observed only after 3 h. Western blot analyses revealed the presence of four isoenzymes of PKC in HepG2 cells. None of these isoenzymes was translocated in response to TNF or IL-1 beta, suggesting that the cytokines do not activate PKC in HepG2 cells. In contrast, phorbol esters translocated and, upon prolonged exposure, down-regulated PKC isoenzymes alpha and epsilon. Activation of protein kinase A by dibutyryl-cAMP partially antagonized the cytokine-dependent inhibition of Epo production but did not influence the inhibitory effect of phorbol esters. Endogenous cAMP levels in HepG2 cells were unchanged by cytokine treatment. Obviously, at least two signaling pathways exist that can confer inhibition of Epo production in HepG2 cells. One of these may be mediated by down-regulation of the PKC alpha or epsilon isoenzyme. The other pathway, however, which is triggered by IL-1 beta and TNF, is independent of PKC.
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PMID:Distinct signaling pathways mediate phorbol-ester-induced and cytokine-induced inhibition of erythropoietin gene expression. 752 38

Insulin treatment of the rat hepatoma H-35 cells results in a reduced stimulation of acute phase plasma protein gene expression by IL-1- and IL-6-type cytokines. The cell response to insulin appears to involve both stimulatory and inhibitory regulatory mechanisms because a clonal variant line of the H-35 cells has been identified in which insulin increases specifically the IL-1 stimulation of alpha 1-acid glycoprotein (AGP) gene, while still reducing the expression of the other acute phase protein genes. The magnitude of insulin and cytokine effect is dependent upon the proliferation state of the cell culture. One of the genetic targets of the insulin stimulation has been located to the cytokine-response element of the AGP gene and involves a cooperativity with the 5' adjacent IL-1-responsive element. The molecular mechanism of insulin inhibition, however, remains to be identified.
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PMID:Insulin cooperates with IL-1 in regulating expression of alpha 1-acid glycoprotein gene in rat hepatoma cells. 753 58

Changes in cytokines, intercellular cell-matrix adhesion molecules and integrins may influenced tumor cell invasion and metastases. This study described the distribution, pattern and intensity of cytokine TGFa, adhesion molecules CD 34 and CD 44 and integrins a2, a3, CD 29 (beta 1 chain) and CD 61 (beta 3 chain) in hepatocellular carcinoma (HCC), metastatic liver tumors and hepatic cirrhosis. Fresh snap-frozen tissue from 20 cases of HCC, 5 metastatic adenocarcinomas and 10 cirrhotic livers was studied immunohistochemically using available antibodies. The most intense staining of TGFa was found in metastatic adenocarcinoma, following by regenerating hepatocytes in cirrhotic liver and well differentiated HCC. Insignificant differences in activity of CD 34 in various pathologies, up-regulation of CD 44 in poorly differentiated HCC and down-regulation in metastatic tumors were found. All integrins studied showed down-regulation in poorly differentiated HCC, relatively high activity of a2, a3 and beta 1 in metastatic tumors and the presence of all integrins in cirrhotic liver.
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PMID:Differential expression of transforming growth factor alpha, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis. 753 39

The role of an androgen, dehydroepiandrosterone (DHEA) has been studied on the constitutive and IL-6 induced fibrinogen production of HepG-2 cells. DHEA markedly augments the constitutive fibrinogen production of the hepatoma cells in a dose dependent fashion. Oppositely, for IL-6 induced fibrinogen production, DHEA is strongly inhibitory. The effectiveness of DHEA on the constitutive fibrinogen production is further potentiated if the hepatoma cells are preincubated with a glucocorticosteroid, dexamethasone. These findings demonstrate that the complex interaction between the steroid- and cytokine-directed regulation of the production of acute phase proteins is further coloured by the action of androgens on immune and hormonal systems.
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PMID:Dehydroepiandrosterone modulates the spontaneous and IL-6 stimulated fibrinogen production of human hepatoma cells. 755 18

Recently, a novel cytokine, cardiotrophin-1 (CT-1), was cloned and found to induce cardiac myocyte hypertrophy in vitro. Amino acid sequence similarity showed CT-1 to be a member of the IL-6/LIF/CNTF/OSM/IL-11 cytokine family. Since all known members of the IL-6 cytokine family induce an hepatic acute phase protein (APP) gene expression, we investigated the ability of CT-1 to induce a liver acute phase response. Upon stimulation of rat hepatoma cells, CT-1 and LIF induced the strongest rat fibrinogen mRNA expression, OSM and IL-6 induced a less pronounced response. When human hepatoma cells and primary rat hepatocytes were stimulated with CT-1, the expression of human haptoglobin and rat alpha 2-macroglobulin mRNA was induced. The induction of the acute phase response was dose- and time-dependent. In this study we demonstrate that CT-1, a novel cytokine belonging to the IL-6 cytokine family, is a hepatocyte stimulating factor.
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PMID:A new hepatocyte stimulating factor: cardiotrophin-1 (CT-1). 755 64

In the search for cytokines whose antiproliferative action could be enhanced by combination with dipyridamole, 2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido[5,4-d]pyrim idine, the combination of tumor necrosis factor-alpha (TNF-alpha) with this agent was evaluated in various human tumor cell lines. Inhibition of the proliferation of human melanoma cell lines MM-1CB and HMV-1 by TNF-alpha (1-10(2) U/ml) was enhanced in culture dishes by combination treatment with dipyridamole (0.1-10 microM). The enhancement effect was also detected in other tumor cell lines: T98 (glioma), SCC-1CB (squamous cell carcinoma), HAC-2 (ovarian clear-cell carcinoma), HLE (hepatoma), HEC-1 (endometrial adenocarcinoma) and HOC-21 (ovarian serous cystadenocarcinoma). The incorporation of [14C]amino acids and [3H]uridine into acid-insoluble cell materials in the combination-treated cells was not significantly different from that in cells treated with TNF-alpha or dipyridamole. However, the incorporation of [3H]thymidine was specifically inhibited in all cell lines examined after more than 12 h of the TNF-alpha and dipyridamole combination treatment, although neither agent alone inhibited this incorporation. On the other hand, the growth of tumors induced by the injection of MM-1CB and HMV-1 cells into nude mice was more markedly inhibited by the subcutaneous administration of TNF-alpha in combination with orally administered dipyridamole than by either agent alone. The results presented suggested that dipyridamole is beneficial in assuring the effectiveness of anti-cancer cytokine therapy.
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PMID:Dipyridamole combined with tumor necrosis factor-alpha enhances inhibition of proliferation in human tumor cell lines. 755

The precise cause of the anaemia that is commonly associated with severe pulmonary tuberculosis (PTB) has not been elucidated. The role of erythropoietin (Epo), the central hormone regulating red cell formation, still awaits clarification. We therefore determined serum Epo levels in patients with PTB; group 1, haemoglobin less than 110 g/L, group 2, haemoglobin greater than 110 g/L; group 3, controls, consisted of matched individuals with uncomplicated iron deficiency; group 4, healthy volunteers. Peripheral blood monocytes were obtained from patients with PTB and the controls, cultured, and the supernatant fluid (SNF) harvested. Tumour necrosis factor alpha (TNF alpha) levels were determined in the SNF, which were then added in various dilutions to a hepatocellular carcinoma cell line (HepG2) capable of regulated EPO synthesis in vitro. The influence of this cytokine was defined by the addition of specific neutralising anti-TNF alpha antibodies in this assay system. Patients in group 1 had significantly lower Epo levels (54 + 11 mU/mL) compared with those in group 3 (142 +/- 41 mU/mL) (p < 0.01). Monocyte supernatants from patients in the anaemic PTB group had markedly elevated TNF alpha levels and significantly suppressed Epo output by HepG2 cells in vitro (p < 0.01). This inhibition was consistently abrogated by anti-TNF alpha antibodies. Serum Epo levels were inappropriately low in untreated PTB patients when compared with corresponding haemoglobin levels in iron deficient controls. This blunted response could be ascribed to release of TNF alpha or other cytokines by activated monocytes.
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PMID:Blunted erythropoietin response to anaemia in tuberculosis. 758 43

The activation of proliferation of rat liver hepatic stellate cells (HSC) in cooperation with hepatocytes (PC) was studied using a coculture system and cell-conditioned media, respectively. The proliferation of HSC was followed by incorporation of [3H] thymidine and BrdU into DNA and by DNA content per culture. Strong stimulation of HSC proliferation was noticed under reduced fetal calf serum (FCS) conditions (0.2%) during a 48-hour coculture with PC, rat hepatoma, human hepatoma, and transforming growth factor (TGF)-alpha-transgenic mouse PC, respectively. The extent of stimulation was frequently higher than that observed by the addition of 10% FCS. Transformed HSC (myofibroblasts) could also be stimulated by cocultured PC, but the magnitude of activation was lower than that of (untransformed) HSC. Using radioreceptor assays, we could demonstrate significant concentrations of insulinlike growth factor (IGF)-1 (300 ng/10(6) cells x 48 hours) and quite lower concentrations of bFGF and TGF-alpha in the hepatocyte-conditioned media (PCcM), whereas IGF-2 was not detectable. With anti-IGF-1 neutralizing antibody, the stimulatory activity of PCcM could be reduced by approximately 50%. PCcM, which mimics the effects of cocultures and supports strongly the action of exogenous IGF-1 on HSC proliferation, leaving that of other cytokines (TGF-alpha, IL-1 alpha, bFGF, aFGF, TNF-alpha), added either separately or in various combinations, uninfluenced. The latter cytokines were without significant effects on HSC proliferation. The mitogenic activity of cytokine combinations containing IGF-1 could be enhanced severalfold by limiting amounts of PCcM. Maximum stimulation of cell proliferation of 40-fold above control cultures was reached by IGF-1 in combination with TGF-alpha and bFGF in presence of diluted PCcM, which is approximately 6-fold higher than in the absence of PCcM. [125I] IGF-1 added to PCcM was bound by more than 90% to carrier proteins. The results confirm in cocultures strong mitogenic activation of HSC by PC. It is suggested that IGF-1 and respective IGF-binding proteins are of great importance in the mitogenic signal transfer between hepatocytes and hepatic stellate cells.
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PMID:Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. 759 Jun 70

Antisense oligonucleotide to the translation initiation sequence of human c-mpI reduced the proliferation of human CD34+ bone marrow cells in response to interleukin-3 (IL-3) alone or to the combination of IL-3 and thrombopoietin (TPO). To investigate the molecular basis for these cytokine interactions, we analyzed the relationship between the receptor subunits for IL-3 and TPO and determined whether both receptors activate identical signal transduction pathways. The function of the receptor subunits was characterized in transiently transfected hepatoma cells and fibroblasts by the activation of gene expression via specific regulatory elements and by the stimulation of DNA-binding activity of STAT proteins. Although c-mpl and IL-3 receptor (IL-3R) reconstituted a qualitatively comparable gene regulatory response, there was no detectable functional interaction between their respective receptor subunits. By comparing the receptor action in different cell lines, we observed that in human hepatoma cells the signaling of c-mpI was 100-fold less sensitive to TPO than in rat hepatoma cells. However, IL-3R signaling was comparable between the two cell types, suggesting that c-mpI and IL-3R do not use identical signal transducing mechanisms. The cytoplasmic domains necessary for c-mpI signaling were determined by testing deletion mutants. The membrane-proximal box 1 sequence motif was critical for gene regulation and for STAT protein activation that seemed to involve the Janus kinase 2 (JAK2). Because IL-3R was less dependent on JAK2 than c-mpI, different levels of JAK2 expression may account, in part, for the quantitative difference in IL-3 and TPO response among various cell lines.
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PMID:Signal transduction by the receptors for thrombopoietin (c-mpL) and interleukin-3 in hematopoietic and nonhematopoietic cells. 760 89

PSK, a protein-bound polysaccharide obtained from cultured mycelia of Coriolus versicolor in basidiomycetes, is a biological response modifier, diverse operations of which include an antitumor action. We have previously reviewed recent research which had demonstrated that in animals, PSK has a preventive effect on chemical carcinogen-induced, radiation-induced, and spontaneously developed carcinogenesis (Kobayashi et al., Cancer Epidemiol., Biomarkers & Prev., 2: 271-276, 1993). We now focus on the effects of PSK once the progression of carcinogenesis has begun, and review what is now known of the preventive action of PSK on cancer metastasis. Recent research reports that PSK suppresses pulmonary metastasis of methylcholanthrene-induced sarcomas, human prostate cancer DU145M, and lymphatic metastasis of mouse leukemia P388, and that it has prolonged the survival period in spontaneous metastasis models. PSK also suppresses the metastasis of rat hepatoma AH60C, mouse colon cancer colon 26, and mouse leukemia RL male 1 in artificial metastasis models. PSK influences the steps of cancer metastasis in a number of ways: (a) by suppression of intravasation through the inhibition of tumor invasion, adhesion and production of cell matrix-degrading enzymes; (b) by suppression of tumor cell attachment to endothelial cells through the inhibition of tumor cell-induced platelet aggregation; (c) by suppression of tumor cell migration after extravasation through the inhibition of tumor cell motility; and (d) by suppression of tumor growth after extravasation through the inhibition of angiogenesis, the modulation of cytokine production, and the augmentation of effector cell functions. In addition, PSK has suppressed the malignant progression of mouse tumor cells through superoxide trapping.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antimetastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. 760 3


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