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)

Normal rat liver cells (BRL-1) that respond to isoproterenol (beta+2), prostaglandin E1 (PGE+1) and adenosine (Ado+) with a rise in adenosine 3':5'-monophosphate (cAMP) content have been hybridized with rat hepatoma cells (H35) which do not respond to any of these agonists (beta-2, PGE-1 and Ado-). Both the initial hybrid line (BF5) and a subclone (BF5-1-1) expressed a beta+2, PGE+1, Ado- phenotype. However, full expression of the responsive phenotype in the BF5 line was apparent only if phosphodiesterase activity was blocked, for example, by methylisobutylxanthine (MIX). Direct measurements showed the rate of degradation of cAMP to be 7 times greater in intact BF5 cells than in the BRL-1 parent. In contrast to BF5 cells, the BF5-1-1 cells did not express maximal responsiveness to any of the agonists even in the presence of MIX. The differential accumulation of intracellular cAMP observed with BRL-1, BF5 and BF5-1-1 cells in response to isoproterenol was shown not to be as a result of differential rates of excretion of cAMP. Furthermore, no differences in the apparent affinities of the beta 2-catecholamine receptors for isoproterenol were observed. It is suggested that the increased degradative capacity of BF5 cells accounts for the difference in cAMP accumulation in these cells compared with the BRL-1 parent. The reduced responsiveness of BF5-1-1 cells, however, does not appear to be solely due to increased phosphodiesterase activity. It appears that the beta 2- phenotype may not always be dominant in hybrid crosses of this type as has been reported previously.
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PMID:Expression of the regulation of cAMP metabolism in somatic cell hybrids. 9 76

Overexpression of mdr1-type P-glycoproteins (P-gps) is thought to contribute to primary chemotherapy resistance of untreated hepatocellular carcinoma. However, mechanisms of endogenous multidrug resistance 1 (mdr1) gene activation still remain unclear. Because recent studies have demonstrated overexpression of cyclooxygenase-2 (COX-2) in hepatocytes during early stages of hepatocarcinogenesis, we investigated whether the COX system, which catalyzes the rate-limiting step in prostaglandin synthesis, participates in mdr1 gene regulation. In the present study, primary rat hepatocyte cultures, exhibiting time-dependent mdr1b overexpression, demonstrated basal COX-2 and COX-1 mRNA expression and liberation of prostaglandin E(2) (PGE(2)), indicative of an active COX-dependent arachidonic acid metabolism. PGE(2) accumulation in culture supernatants was further enhanced by arachidonic acid (1mumol/L) and epidermal growth factor (EGF) (16 nmol/L). PGE(2) and prostaglandin F(2alpha) (PGF(2)alpha) (3-6mug/mL), added directly to the culture medium, significantly up-regulated intrinsic mdr1b mRNA overexpression and mdr1-dependent transport activity. Up-regulation was maximal after 3 days of culture. Like prostaglandins, the COX substrate, arachidonic acid, also induced mdr1b gene expression. Apart from this, structurally different COX inhibitors (indomethacin, meloxicam, NS-398) mediated significant inhibition of time-dependent and EGF-induced mdr1b mRNA overexpression, resulting in enhanced intracellular accumulation of the mdr1 substrate, rhodamine 123 (Rho123). Thus, the present data support the conclusion that the release of prostaglandins through activation of the COX system participates in endogenous mdr1b gene regulation. COX-2 inhibition might constitute a new strategy to counteract primary mdr1-dependent chemotherapy resistance.
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PMID:The cyclooxygenase system participates in functional mdr1b overexpression in primary rat hepatocyte cultures. 1214 66

Cyclooxygenase-2 (COX-2)-controlled prostaglandin (PG) metabolism recently has been implicated in the pathogenesis of hepatocellular carcinoma (HCC). However, the biologic role and molecular mechanism of COX-2-mediated PGs in the control of liver cancer growth have not been established. This study was designed to examine the direct effect of COX-2 and its inhibitor celecoxib on the growth control of liver cancer cells. Human HCC cell lines Hep3B and HepG2 transfected with COX-2 expression vector showed increased cell growth and enhanced phosphorylation of serine/threonine protein kinase B (Akt). The level of COX-2 expression and Akt phosphorylation is correlated positively in cultured HCC cells and human liver cancer tissues. Inhibition of Akt activation by phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 significantly decreased the viability of Hep3B and HepG2 cells (P <.01). These results reveal a novel role of Akt activation in COX-2-induced HCC cell survival. Furthermore, HCC cells treated with the COX-2 inhibitor celecoxib showed significant reduction of Akt phosphorylation and marked morphologic and biochemical characteristics of apoptosis. Overexpression of COX-2 or addition of exogenous PGE(2) partially prevented celecoxib-induced apoptosis (P <.01). In conclusion, our results suggest the involvement of COX-2-dependent and -independent mechanisms in celecoxib-mediated HCC cell apoptosis.
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PMID:Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. 1293 2

The relation between transforming growth factor-beta (TGF-beta) and cyclooxygenase (COX) in hepatoma malignancy is not understood yet. To investigate regulation mechanism of endogenous TGF-beta on hepatoma, we established MH129F mouse hepatoma cell overexpressing the cytoplasmic domain of type II TGF-beta receptor (TRII). MH129F cell apoptosis was elevated almost 20% after 5 ng/ml TGF-beta1 treatment. However, soluble TRII-overexpressing cells (MH129F/TRIIs) did not show any change of growth pattern after TGF-beta1 treatment because MH129F/TRIIs cells blocked the growth inhibitory effect of TGF-beta1. In MH129F/TRIIs cells, expression of cycooxygenase-2 (COX-2) and bcl-2 was remarkably elevated, and then enhancement of COX-2 mediated induction of prostaglandin E(2) (PGE(2)) production up to 7-fold. Especially, vascular endothelial growth factor (VEGF) expression was regulated by COX-2 in MH129F/TRIIs cells, which were inhibited endogenous TGF-beta response. Implantation of 5x10(6) MH129F/TRIIs cells into nude mice showed the significantly enhanced tumor formation, and intensity of COX-2 expression was slightly higher in MH129F/TRIIs tumor section than control. Moreover, a strong antitumor response was observed in MH129F/TRIIs-bearing mice that were treated with a specific COX-2 inhibitor, celecoxib. Therefore, we suggest that COX-2 mediate the tumorigenicity of hepatoma cells blocking endogenous TGF-beta effect via VEGF regulation.
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PMID:Loss of endogenous TGF-beta effect induces mouse hepatoma malignancy by correlation with cyclooxygenase-2 and VEGF. 1296 30

Exposure of endothelial cells to hypoxia-induced angiopoietin-2 (Ang2) expression. The increase in Ang2 mRNA levels occurred by transcriptional regulation and by post-transcriptional increase in mRNA stability. Induction of Ang2 mRNA resulted in an increase of intracellular and secreted Ang2 protein levels. Since the transcriptional regulation of several genes involved in angiogenesis during hypoxia is mediated by hypoxia-inducible factor-1 (HIF-1), it was conceivable that Ang2 expression might be regulated by the same oxygen-dependent mechanism. However, our data showed that pharmacological HIF inducers, CoCl(2) and DFO, did not affect Ang2 expression. Moreover, HIF-1-deficient hepatoma cell (Hepa1 c4) and its wild-type counterpart (Hepa1 c1c4) up-regulates Ang2 during hypoxia. These results indicated that hypoxia-driven Ang2 expression may be independent of the HIF pathway. Using neutralizing VEGF antibody or pharmacological inhibitors of VEGF receptors, we showed that hypoxia-induced VEGF participates but could not account completely for Ang2 expression during hypoxia. In addition, hypoxia elicited an increase of cyclooxygenase-2 (COX-2) expression and a parallel increase in prostanglandin E(2) (PGE(2)) and prostacyclin (PGI(2)) production. COX-2 inhibitors decreased the hypoxic induction of Ang2 and the hypoxic induction of PGE(2) and PGI(2) in a dose-dependent manner. Similarly, COX-2 but not COX-1 antisense treatment decreased hypoxic induction of Ang2 expression, and this effect was reversed by exogenous PGE(2). Finally, exogenous PGE(2) and PGI(2) were able to stimulate Ang2 under normoxic conditions. These findings suggest that COX-2-dependent prostanoids may play an important role in the regulation of hypoxia-induced Ang2 expression.
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PMID:Hypoxic regulation of angiopoietin-2 expression in endothelial cells. 1470 52

Activity-guided fractionation of the leaves of Macaranga triloba, using an in vitro bioassay based on the inhibition of cyclooxygenase-2, resulted in the isolation of a rotenoid, 4,5-dihydro-5'alpha-hydroxy-4'alpha-methoxy-6a,12a-dehydro-alpha-toxicarol (1), as well as 12 known compounds, (+)-clovan-2beta,9alpha-diol, ferulic acid, 3,7,3',4'-tetramethylquercetin, 3,7,3'-trimethylquercetin, 3,7-dimethylquercetin, abscisic acid, 1beta,6alpha-dihydroxy-4(15)-eudesmene, 3beta-hydroxy-24-ethylcholest-5-en-7-one, loliolide, scopoletin, taraxerol, and 3-epi-taraxerol. The structure of compound 1 was determined using spectroscopic methods. All isolates were evaluated for their potential to inhibit cyclooxygenases-1 and -2 by measuring PGE(2) production, and to induce quinone reductase in cultured Hepa 1c1c7 mouse hepatoma cells.
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PMID:Potential cancer chemopreventive constituents of the leaves of Macaranga triloba. 1475 6

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, which can lead to the development of liver cirrhosis and hepatocellular carcinoma. Recently, the activation of cyclooxygenase-2 (Cox-2) has been implicated in the HCV-associated hepatocellular carcinoma. In this study, we focus on the signaling pathway leading to Cox-2 activation induced by HCV gene expression. Here, we demonstrate that the HCV-induced reactive oxygen species and subsequent activation of NF-kappaB mediate the activation of Cox-2. The HCV-induced Cox-2 was sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca(2+) chelator (BAPTA-AM), and calpain inhibitor (N-acetyl-Leu-Leu-Met-H). The levels of prostaglandin E(2) (PGE(2)), the product of Cox-2 activity, are increased in HCV-expressing cells. Furthermore, HCV-expressing cells treated with the inhibitors of Cox-2 (celecoxib and NS-398) showed significant reduction in PGE(2) levels. We also observed the enhanced phosphorylation of Akt and its downstream substrates glycogen synthase kinase-3beta and proapoptotic Bad in the HCV replicon-expressing cells. These phosphorylation events were sensitive to inhibitors of Cox-2 (celecoxib and NS-398) and phosphatidylinositol 3-kinase (LY294002). Our results also suggest a potential role of Cox-2 and PGE(2) in HCV RNA replication. These studies provide insight into the mechanisms by which HCV induces intracellular events relevant to liver pathogenesis associated with viral infection.
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PMID:Hepatitis C virus stimulates the expression of cyclooxygenase-2 via oxidative stress: role of prostaglandin E2 in RNA replication. 3293 70

Recent evidence indicates that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are involved in hepatocarcinogenesis. This study was designed to evaluate the possible interaction between the COX-2 and EGFR signaling pathways in human hepatocellular carcinoma (HCC) cells. Immunohistochemical analysis using serial sections of human HCC tissues revealed positive correlation between COX-2 and EGFR in HCC cells (P < 0.01). Overexpression of COX-2 in cultured HCC cells (Hep3B) or treatment with PGE(2) or the selective EP(1) receptor agonist, ONO-DI-004, increased EGFR phosphorylation and tumor cell invasion. The PGE(2)-induced EGFR phosphorylation and cell invasiveness were blocked by the EP(1) receptor siRNA or antagonist ONO-8711 and by two EGFR tyrosine kinase inhibitors, AG1478 and PD153035. The EP(1)-induced EGFR transactivation and cell invasion involves c-Src, in light of the presence of native binding complex of EP(1)/Src/EGFR and the inhibition of PGE(2)-induced EGFR phosphorylation and cell invasion by the Src siRNA and the Src inhibitor, PP2. Further, overexpression of COX-2 or treatment with PGE(2) also induced phosphorylation of c-Met, another receptor tyrosine kinase critical for HCC cell invasion. Moreover, activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells, whereas blocking PGE(2) synthesis or EP(1) attenuated EGFR phosphorylation induced by EGF, suggesting that the COX-2/PGE(2)/EP(1) pathway also modulate the activation of EGFR by its cognate ligand. These findings disclose a cross-talk between the COX-2/PGE(2)/EP(1) and EGFR/c-Met signaling pathways that coordinately regulate human HCC cell invasion.
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PMID:Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. 2617 17

It was previously reported that a methanol extract of Gloiopeltis furcata (MEGF), a kind of edible seaweed, inhibited the growth of several human cancer cell lines. In the present study, the effect of MEGF on the growth of human hepatocarcinoma HepG2 cells and its effect on the cyclooxygenases (COXs) expression were investigated. MEGF markedly reduced the viability of HepG2 cells and induced the G2/M arrest of the cell cycle in a concentration dependent manner. These effects were associated with the down-regulation of cyclin A, up-regulation of cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) and dephosphorylation of Cdc25C. Furthermore, it was found that MEGF decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E(2) (PGE(2)) synthesis. These findings indicate that MEGF may have a possible therapeutic potential in hepatoma cancer patients.
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PMID:Methanol extract of the seaweed Gloiopeltis furcata induces G2/M arrest and inhibits cyclooxygenase-2 activity in human hepatocarcinoma HepG2 cells. 1707 9

Peroxisome proliferator-activated receptor delta (PPARdelta) is a nuclear transcription factor that is recently implicated in tumorigenesis besides lipid metabolism. This study describes the cross-talk between the PPARdelta and prostaglandin (PG) signaling pathways that coordinately regulate human hepatocellular carcinoma (HCC) cell growth. Activation of PPARdelta by its pharmacologic ligand, GW501516, enhanced the growth of three human HCC cell lines (HuH7, HepG2, and Hep3B), whereas inhibition of PPARdelta by small interfering RNA prevented growth. PPARdelta activation up-regulates the expression of cyclooxygenase (COX)-2, a rate-limiting enzyme for PG synthesis, and tumor growth. PPARdelta activation or PGE(2) treatment also induced the phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a key enzyme that releases arachidonic acid substrate for PG production via COX. Activation of cPLA(2)alpha by the calcium ionophore A23187 enhanced PPARdelta binding to PPARdelta response element (DRE) and increased PPARdelta reporter activity, which was blocked by the selective cPLA(2)alpha inhibitors. Consistent with this, addition of arachidonic acid to isolated nuclear extracts enhanced the binding of PPARdelta to DRE in vitro, suggesting a direct role of arachidonic acid for PPARdelta activation in the nucleus. Thus, PPARdelta induces COX-2 expression and the COX-2-derived PGE(2) further activates PPARdelta via cPLA(2)alpha. Such an interaction forms a novel feed-forward growth-promoting signaling that may play a role in hepatocarcinogenesis.
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PMID:Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells. 1717 83


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