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)

We have reported previously that acyclic retinoid, a synthetic retinoid X receptor alpha (RXRalpha)-ligand, suppresses the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. On the other hand, HCCs become refractory to physiological concentrations of the natural RXRalpha-ligand, 9-cis retinoic acid (9cRA), due to extracellular signal-regulated kinase (Erk) 1/2-mediated phosphorylation and inactivation of RXRalpha. Here, we show that acyclic retinoid restores the function of RXRalpha in human HCC-derived HuH7 cells by inactivating the Ras-Erk 1/2 signaling system, thereby dephosphorylating RXRalpha. In contrast, 9cRA failed to suppress phosphoErk 1/2 levels and subsequent RXRalpha phosphorylation. Although 9cRA also suppressed Ras activity, it simultaneously down-regulated mitogen-activated protein kinase phosphatase-1, an enzyme that inactivates Erk, thereby leaving the phosphorylation status of Erk unchanged. A combination of 9cRA (a potent ligand) and acyclic retinoid (a weak ligand preventing phosphorylation) resulted in a marked cooperation in transactivation via the RXR-response element and in inhibiting the proliferation of HuH7 cells. These events provide a novel molecular basis for the antitumor activity of acyclic retinoid against HCC.
 ...
PMID:Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. 1280 34

MCD (malonyl-CoA decarboxylase), which catalyses decarboxylation of malonyl-CoA, is known to play an important role in the regulation of malonyl-CoA concentration. Recently, it has been observed that the expression of MCD is significantly decreased in the hearts of the PPARalpha (peroxisome-proliferator-activated receptor alpha) (-/-) mice, where the rate of fatty-acid oxidation is decreased by the increased malonyl-CoA level [Campbell, Kozak, Wagner, Altarejos, Dyck, Belke, Severson, Kelly and Lopaschuk (2002) J. Biol. Chem. 277, 4098-4103]. This suggests that MCD may be transcriptionally regulated by PPARalpha. To investigate whether PPARalpha is truly responsible for transcriptional regulation of the rat MCD gene, transient reporter assay was performed in CV-1 cells. The promoter activity was increased by 17-fold in CV-1 cells co-transfected with PPARalpha/retinoid X receptor alpha expression plasmid. In sequence analysis of the promoter region, three putative PPREs (PPAR response elements) were identified, and promoter deletion analysis showed that PPRE2 and PPRE3 were functional. Electrophoretic mobility-shift assays revealed that PPARalpha/retinoid X receptor alpha heterodimer indeed bound to the two PPREs, and the binding specificity of PPARalpha on PPRE was also confirmed by experiments with mutated oligonucleotides. These results indicate that the elements behaved as a responsive site to PPARalpha activation. MCD mRNA levels in WY14643-treated rat hepatoma cells as well as in the liver of fenofibrate-fed Otsuka Long-Evans Tokushima fatty rats were also found to be increased, suggesting that PPARalpha can activate the rat hepatic MCD transcription by binding to the PPREs in the promoter. We propose that MCD performs an important role in understanding the regulatory mechanism between activated PPARalpha and fatty-acid oxidation by altering the malonyl-CoA concentration.
 ...
PMID:Peroxisomal-proliferator-activated receptor alpha activates transcription of the rat hepatic malonyl-CoA decarboxylase gene: a key regulation of malonyl-CoA level. 1464 Nov 10

We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC.
 ...
PMID:Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review). 1501 Aug 15

Cyclooxygenase 2 (COX-2) and retinoid X receptor alpha (RXRalpha) are suggested to have roles in carcinogenesis. COX-2 inhibitors have been reported to suppress growth of hepatocellular carcinoma (HCC) cell lines in vitro. However, little is known about the preventive effect of these drugs on spontaneous hepatocarcinogenesis in vivo. Etodolac exists in a racemic mixture containing S- and R-etodolac. S-etodolac is responsible for COX-2 inhibitory activity and R-etodolac is related to the downregulation of RXRalpha. Here, the effect of etodolac on spontaneous development of HCC in fatty liver Shionogi mice is evaluated. Etodolac was administered at a low (2 mg/kg) or high (10 mg/kg) dose three times a week for 16 months starting at the age of 3 months. The development of HCC was suppressed slightly in the high-dose group, and suppressed markedly in the low-dose group, although the development of fatty liver was not inhibited in either group. Plasma prostaglandin E2 levels were also decreased significantly in the low-dose group, consistent with the suppression of HCC. The expression of RXRalpha and proliferating cell nuclear antigen in non-tumorous liver tissues was decreased significantly in both the low-dose and high-dose groups. These findings show that etodolac treatment at an optimum dose suppresses hepatocarcinogenesis in vivo, and may be useful for preventing the development of HCC in humans.
 ...
PMID:Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase-2 inhibitor. 1686 10

Unlike the livers of humans and mice, and most hepatoma cells, which accumulate triglycerides when treated with microsomal triglyceride transfer protein (MTP) inhibitors, L35 rat hepatoma cells do not express MTP and cannot secrete very low density lipoprotein (VLDL), yet they do not accumulate triglyceride. In these studies we show that transcriptional co-repression of the two lipid transfer proteins, liver fatty acid-binding protein (L-FABP) and MTP, which cooperatively shunt fatty acids into de novo synthesized glycerolipids and the transfer of lipids into VLDL, respectively, act together to maintain hepatic lipid homeostasis. FAO rat hepatoma cells express L-FABP and MTP and demonstrate the ability to assemble and secrete VLDL. In contrast, L35 cells, derived as a single cell clone from FAO cells, do not express L-FABP or MTP nor do they assemble and secrete VLDL. We used these hepatoma cells to elucidate how a conserved DR1 promoter element present in the promoters of L-FABP and MTP affects transcription, expression, and VLDL production. In FAO cells, the DR1 elements of both L-FABP and MTP promoters are occupied by peroxisome proliferator-activated receptor alpha-retinoid X receptor alpha (RXRalpha), with which PGC-1beta activates transcription. In contrast, in L35 cells the DR1 elements of both L-FABP and MTP promoters are occupied by chicken ovalbumin upstream promoter transcription factor II, and transcription is diminished. The combined findings indicate that peroxisome proliferator-activated receptor alpha-RXRalpha and PGC-1beta coordinately up-regulate L-FABP and MTP expression, by competing with chicken ovalbumin upstream promoter transcription factor II for the DR1 sites in the proximal promoters of each gene. Additional studies show that ablation of L-FABP prevents hepatic steatosis caused by treating mice with an MTP inhibitor. Our findings show that reducing both L-FABP and MTP is an effective means to reduce VLDL secretion without causing hepatic steatosis.
 ...
PMID:Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. 1695 Jul 64

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.
 ...
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

Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28gamma/REGgamma regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28gamma gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28gamma-dependent manner. Heterodimer composed of liver X receptor alpha (LXRalpha) and retinoid X receptor alpha (RXRalpha) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXRalpha/RXRalpha to LXR-response element in the presence but not the absence of PA28gamma. These findings suggest that PA28gamma plays a crucial role in the development of liver pathology induced by HCV infection.
 ...
PMID:Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. 1723 12

Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4alpha (HNF4alpha). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4alpha and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4alpha (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4alpha as well as decreased endogenous HNF4alpha protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor alpha, retinoid X receptor alpha, and thyroid hormone receptor beta) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor alpha and peroxisome proliferator-activated receptor alpha. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.
 ...
PMID:Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. 1738 49

The nuclear hormone receptors hepatocyte nuclear factor 4 (HNF4) and retinoid X receptor alpha (RXRalpha) plus peroxisome proliferator-activated receptor alpha (PPARalpha) heterodimer support hepatitis B virus (HBV) pregenomic RNA synthesis and viral replication in nonhepatoma cells. Small heterodimer partner (SHP), an orphan nuclear hormone receptor lacking a DNA binding domain, inhibits nuclear hormone receptor-mediated viral transcription and replication. The inhibition of HBV replication by SHP is dependent on the presence of nuclear hormone receptors. HBV replication that is dependent on HNF4 is considerably more sensitive to SHP-mediated inhibition than RXRalpha/PPARalpha-directed viral biosynthesis. SHP inhibition of HBV biosynthesis in HepG2 cells suggests that multiple nuclear hormone receptors mediate viral replication in this human hepatoma cell line. These observations suggest that the physiological regulation of HBV biosynthesis by SHP in the liver will depend on both the level of SHP expression and the relative contribution of HNF4 and RXRalpha/PPARalpha, plus potentially additional nuclear hormone receptors, to HBV RNA synthesis and replication.
 ...
PMID:Differential inhibition of nuclear hormone receptor-dependent hepatitis B virus replication by the small heterodimer partner. 1823 86

Thyroid hormones are important regulators of differentiation, growth, metabolism, and physiological function of virtually all tissues. Active thyroid hormone T(3) affects expression of genes that encode for angiogenic proteins like adrenomedullin or vascular endothelial growth factor and erythropoietin, as well as for glucose transporters and phospho fructokinase that determine glucose use. Interestingly, those target genes are also hypoxia inducible and under the control of the oxygen-dependent transcription factor hypoxia-inducible factor (HIF)-1). We and others have reported that T(3) stimulates HIF-1 activation, which intimately links T(3) and HIF-1 induced gene expression. Here, we studied intracellular pathways that mediate HIF-1alpha regulation by T(3). We found that T(3)-dependent HIF-1 activation is not limited to hepatoma cells but is also observed in primary human hepatocytes, kidney and lung carcinoma cells. T(3) increased the HIF-1alpha subunit mRNA and protein within a few hours through activation of the thyroid hormone receptor beta retinoid X receptor alpha heterodimer because knockdown of each of the partners abrogated the stimulation by T(3). However, T(3) had no direct effect on transcription of HIF-1alpha, but activation of the thyroid hormone receptor beta/retinoid X receptor alpha heterodimer by T(3) stimulated expression of the hepatic leukemia factor, which increases HIF-1alpha gene expression.
 ...
PMID:Thyroid hormone induces hypoxia-inducible factor 1alpha gene expression through thyroid hormone receptor beta/retinoid x receptor alpha-dependent activation of hepatic leukemia factor. 1823 67


<< Previous 1 2 3 Next >>