Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor gamma (PPARgamma) has been implicated in the differentiation and growth inhibition of cancer cells. We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma (HCC) cell growth, proliferation, and apoptosis in vitro and in vivo. We also studied relationships between PPARgamma activation and cyclooxygenase-2 (COX-2) expression. Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone. Cell growth was determined via WST-1 assay, proliferation by cell cycle analysis and proliferating cell nuclear antigen (PCNA) Western blotting, and apoptosis by flow cytometry and TUNEL. Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored, and the effects of treatment with troglitazone were determined. In resected HCCs, PPARgamma expression was less compared with the histologically normal surrounding liver. In cultures of Hep3B and Huh7 cells, basal expression of PPARgamma was relatively low, but troglitazone caused dose-dependent induction of PPARgamma expression. Cell cycle analysis revealed a decreased proportion of cells in S phase, with arrest at G0/G1. Concomitant downregulation of PCNA and an increase in TUNEL staining, cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone. Troglitazone-mediated PPARgamma activation also suppressed COX-2 expression and induced p27 in HCC cells. Administration of troglitazone to Huh7 tumor-bearing mice significantly reduced tumor growth and caused tumor regression. In conclusion, collectively, these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC. PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth.
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PMID:Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo. 1637 40

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are expressed in smooth muscle cells (SMCs). This study was designed to compare the effects of PPARalpha and PPARgamma on SMC proliferation and migration and to determine how they operate. Treatment of SMCs from porcine coronary artery revealed that mitogen-stimulated DNA synthesis was blocked by the PPARalpha ligand 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643) and 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)) (a putative PPARgamma agonist) but not by the PPARgamma agonist rosiglitazone or the PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy acetic acid (GW501516). Inhibition of DNA synthesis by clofibrate and 2-(4-(2-(1-cyclohexanebutyl-3-cyclohexylureido)ethyl)phenylthio)-2-methylproprionic acid (GW7647) confirmed that SMC proliferation is affected by PPARalpha. This conclusion was supported by the fact that WY14,643 also inhibited the proliferation of H4IIE hepatoma cells (expressing only PPARalpha) but not A10 SMCs (expressing only PPARgamma1). In contrast, the effective inhibition of all cell types with 15d-PGJ(2) indicated that this compound probably operates via a PPARgamma-independent mechanism. Interestingly, rosiglitazone did not inhibit DNA synthesis of either H4IIE or A10 cells, suggesting that the activation of PPARgamma does not influence cell proliferation. Phosphorylation of cyclin-dependent kinase 2 and expression of proliferating cell nuclear antigen were inhibited by WY14,643 but not by rosiglitazone or 15d-PGJ(2), indicating that PPARalpha prevents progression into S phase. Although rosiglitazone did not block SMC proliferation, it (like WY14,643) reduced neointimal hyperplasia in vitro. This observation can be rationalized by the fact that both WY14,643 and rosiglitazone inhibit SMC migration, probably through matrix metalloproteinase 9. Our study therefore shows that selective interference with mediators of cell cycle progression and cell migration via activation of PPARs may prevent growth-related vascular diseases such as restenosis and atherosclerosis.
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PMID:Peroxisome proliferator-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration. 1640 62

The acyl-CoA binding protein (ACBP) is a 10 kD intracellular lipid binding protein that binds and transports acyl-CoA esters. The protein is expressed in most cell types at low levels; however, expression differs markedly between different cell types with expression being particularly high in e.g. cells with a high turnover of fatty acids. We show here that the relatively high basal promoter activity of the rat ACBP gene in fibroblasts and hepatoma cells relies on sequences between -331 to -182 and on the Sp1 and NF-Y sites at -172 and -143, respectively. The basal transcription is modulated by members of the PPAR and SREBP families. In adipocytes, PPARgamma is in part responsible for the induction during adipocyte differentiation, but other transcription factors appear to play a role as well. In hepatocytes, SREBP-1c is the main regulator of ACBP in response to changes in insulin levels during fasting/refeeding. PPARalpha counteracts this effect by stimulating ACBP expression during fasting. In addition, PPARalpha mediates the induction of ACBP expression in response to peroxisome proliferators. PPARalpha and PPARgamma do not require sequences upstream of -182 for transactivation; however, SREBP-1c requires the synergistic action of sequences in intron 1 for transactivation of the ACBP promoter.
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PMID:ACBP--a PPAR and SREBP modulated housekeeping gene. 1641 Oct 19

Apolipoprotein M (apoM) is a novel apolipoprotein present mostly in high-density lipoprotein (HDL) in human plasma. In the present study, we demonstrate that insulin, insulin-like growth factor I (IGF-I), and IGF-I potential peptide (IGF-IPP) significantly inhibits apoM expression, in a dose- and a time-dependent manner, in the human hepatoma cell line, HepG2 cells. Insulin-induced down-regulation of apoM was blocked by AG1024 (a specific insulin receptor inhibitor) and LY294002 (a phosphatidylinositol 3-kinase (PI3K) inhibitor), which indicates that it is mediated via the activation of PI3K pathway. In contrast, PD98059 (a MAP kinase inhibitor) did not influence insulin-induced down-regulation of apoM expression, and activation of neither PPAR-alpha agonist (GW7647) nor PPAR-gamma agonist (GW1929) influences apoM expression in HepG2 cells, which indicates that regulation of apoM expression is not related to the activation of PPAR-alpha and PPAR-gamma in hepatic cells, whereas, both PPAR-alpha and PPAR-gamma agonists could inhibit apoB expression. Moreover, in the present study, we demonstrated that PPAR beta/delta agonist (GW501516) could inhibit both apoM and apoB expression in the HepG2 cells. In conclusion, this study shows that apoM expression is regulated by PI3-kinase in HepG2-cells.
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PMID:Down-regulation of apolipoprotein M expression is mediated by phosphatidylinositol 3-kinase in HepG2 cells. 1654 71

Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a transcriptional coactivator involved in several aspects of energy metabolism. It is induced or activated under different stimuli in a highly tissue-specific manner and subsequently partners with certain transcription factors in those tissues to execute various biological programs. In the fasted liver, PGC-1alpha is induced and interacts with hepatocyte nuclear factor 4alpha (HNF4alpha) and other transcription factors to activate gluconeogenesis and increase hepatic glucose output. Given the broad spectrum of liver genes responsive to HNF4alpha, we sought to determine those that were specifically targeted by the combination of PGC-1alpha and HNF4alpha. Coexpression of these two molecules in murine stem cells reveals a high induction of mRNA for apolipoproteins A-IV and C-II. Forced expression of PGC-1alpha in mouse and human hepatoma cells increases the mRNA of a subset of apolipoproteins implicated in very low density lipoprotein and triglyceride metabolism, including apolipoproteins A-IV, C-II, and C-III. Coactivation of the apoC-III/A-IV promoter region by PGC-1alpha occurs through a highly conserved HNF4alpha response element, the loss of which completely abolishes activation by PGC-1alpha and HNF4alpha. Adenoviral infusion of PGC-1alpha into live mice increases hepatic expression of apolipoproteins A-IV, C-II, and C-III and increases serum and very low density lipoprotein triglyceride levels. Conversely, knock down of PGC-1alpha in vivo causes a decrease in both apolipoprotein expression and serum triglyceride levels. These data point to a crucial role for the PGC-1alpha/HNF4alpha partnership in hepatic lipoprotein metabolism.
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PMID:Partnership of PGC-1alpha and HNF4alpha in the regulation of lipoprotein metabolism. 1657 44

Expression of aldehyde dehydrogenase 3A1 (ALDH3A1) in certain normal and tumor cells is associated with protection against the growth inhibitory effect of reactive aldehydes generated during membrane lipid peroxidation. We found that human lung tumor (A549) cells, which express high levels of ALDH3A1 protein, were significantly less susceptible to the antiproliferative effects of 4-hydroxynonenal compared to human hepatoma HepG2 or SK-HEP-1 cells that lack ALDH3A1 expression. However, A549 cells became susceptible to lipid peroxidation products when they were treated with arachidonic acid. The growth suppression of A549 cells induced by arachidonic acid was associated with increased levels of lipid peroxidation and with reduced ALDH3A1 enzymatic activity, protein, and mRNA levels. Furthermore, arachidonic acid treatment of the A549 cells resulted in an increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), whereas NF-kappaB binding activity was inhibited. Blocking PPARgamma using a selective antagonist, GW9662, prevented the arachidonic acid-mediated reduction of ALDH3A1 expression as well as the growth inhibition of A549 cells, suggesting the central role of PPARgamma in these phenomena. The increase in PPARgamma and the reduction in ALDH3A1 were also prevented by exposing cells to vitamin E concomitant with arachidonic acid treatment. In conclusion, our data show that the arachidonic acid-induced suppression of A549 cell growth is associated with increased lipid peroxidation and decreased ALDH3A1 expression, which may be due to activation of PPARgamma.
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PMID:Arachidonic acid suppresses growth of human lung tumor A549 cells through down-regulation of ALDH3A1 expression. 1671 94

PPARgamma agonists were reported to be implicated in many biological functions in certain kinds of cells, however, little is known about the effects of PPARgamma on hepatocarcinoma cell. We explored the effects of rosiglitazone, a PPARgamma activator, on human hepatocarcinoma cell line BEL-7404 and its mechanism. After BEL-7404 was exposed to rosiglitazone, its migration was significantly inhibited, which associated with downregulation of the phosphorylation of Akt and FAK, while no significant change was detected in the phosphorylation of ERK after rosiglitazone treatment. It is now known that phosphorylated FAK is a substrate of PTEN and Akt phosphorylation can be regulated by PTEN via the PIP(3) level. We found rosiglitazone upregulated PTEN expression in a dose- and time-dependent manner, which was mediated by PPARgamma. Furthermore, PTEN overexpression resulted in inhibition of cell migration and PTEN knock-down blocked the effect of rosiglitazone on cell migration. It suggested that PTEN was required for rosiglitazone-induced inhibition of BEL-7404 cells migration. In conclusion, our results demonstrated that PTEN played a critical role in rosiglitazone inhibiting cell migration in BEL-7404.
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PMID:PPARgamma activator rosiglitazone inhibits cell migration via upregulation of PTEN in human hepatocarcinoma cell line BEL-7404. 1677 33

The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the oxidation of glucose to acetyl-CoA. Phosphorylation of PDC by the pyruvate dehydrogenase kinases (PDK2 and PDK4) inhibits PDC activity. Expression of the PDK genes is elevated in diabetes, leading to the decreased oxidation of pyruvate to acetyl-CoA. In these studies we have investigated the transcriptional regulation of the PDK4 gene by the estrogen-related receptors (ERRalpha and ERRgamma). The ERRs are orphan nuclear receptors whose physiological roles include the induction of fatty acid oxidation in heart and muscle. Previously, we found that the peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) stimulates the expression of PDK4. Here we report that ERRalpha and ERRgamma stimulate the PDK4 gene in hepatoma cells, suggesting a novel role for ERRs in controlling pyruvate metabolism. In addition, both ERR isoforms recruit PGC-1alpha to the PDK4 promoter. Insulin, which decreases the expression of the PDK4 gene, inhibits the induction of PDK4 by ERRalpha and ERRgamma. The forkhead transcription factor (FoxO1) binds the PDK4 gene and contributes to the induction of PDK4 by ERRs and PGC-1alpha. Insulin suppresses PDK4 expression in part through the dissociation of FoxO1 and PGC-1alpha from the PDK4 promoter. Our data demonstrate a key role for the ERRs in the induction of hepatic PDK4 gene expression.
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PMID:Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression. 1707 27

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, liver X receptor alpha (LXRalpha), and coactivators PPARgamma coactivator 1alpha (PGC-1alpha), PGC-1beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXRalpha, PPARalpha, PPARgamma, LXRalpha, and PGC-1alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARalpha (carnitine palmitoyltransferase 1alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXRalpha promoter or the PGC-1alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRalpha, PPARalpha, PPARgamma, and LXRalpha, as well as coactivators PGC-1alpha, PGC-1beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.
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PMID:Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells. 1722 43

Previously we have demonstrated that glucagon receptor mRNA expression in cultured rat hepatocytes and pancreatic islets can be regulated by various factors, including cAMP; however, the regulation of the human glucagon receptor gene has not been well-defined. Here we have characterized the promoter regions of the human glucagon receptor gene. Primer extension studies yielded multiple products in both liver and pancreas, corresponding to transcription start sites situated at -166 and -477 relative to the start of translation, indicating two putative promoters. Both transcription start sites were found to be active, when sequence immediately upstream of the start sites were cloned into luciferase reporter constructs. The transcriptional activity of the proximal promoter, but not the distal promoter, could be inhibited approximately 50% by cAMP, indicating that the previously observed inhibitory effects of cAMP on glucagon receptor mRNA expression is mediated at the level of gene transcription. The cAMP-mediated downregulation of the proximal promoter was examined by deletion analysis in the human hepatoma cell line HepG2 and the cAMP responsiveness was found to be located in a region between 1051 and 1016 base pairs upstream of the transcription start site, which contains several putative cAMP responsive elements. Expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), known to be upregulated in the liver by fasting, was found to abolish the cAMP-dependent downregulation of glucagon receptor mRNA expression in vitro, whereas overexpression of PGC-1beta had no effect.
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PMID:Identification of a novel human glucagon receptor promoter: regulation by cAMP and PGC-1alpha. 1737 60


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