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)

Hepadnavirus replication occurs in hepatocytes in vivo and in hepatoma cell lines in cell culture. Hepatitis B virus (HBV) replication can occur in nonhepatoma cells when pregenomic RNA synthesis from viral DNA is activated by the expression of the nuclear hormone receptors hepatocyte nuclear factor 4 (HNF4) and the retinoid X receptor alpha (RXR alpha) plus peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer. Nuclear hormone receptor-dependent HBV replication is inhibited by hepatocyte nuclear factor 3 (HNF3). In contrast, HNF3 and HNF4 support duck hepatitis B virus (DHBV) replication in nonhepatoma cells, whereas the RXR alpha-PPAR alpha heterodimer inhibits HNF4-dependent DHBV replication. HNF3 and HNF4 synergistically activate DHBV pregenomic RNA synthesis and viral replication. The conditions that support HBV or DHBV replication in nonhepatoma cells are not able to support woodchuck hepatitis virus replication. These observations indicate that avian and mammalian hepadnaviruses have distinct transcription factor requirements for viral replication.
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PMID:Avian and Mammalian hepadnaviruses have distinct transcription factor requirements for viral replication. 1209 59

Mutations in the HNF4alpha gene have been correlated with maturity-onset diabetes of the young, which is characterized mainly by pancreatic beta-cell dysfunction and is also associated with mild liver abnormalities. HNF4alpha D126Y and D126H mutations were found in a patient with early-onset type 2 diabetes, and the R324H mutation was found in a common type 2 diabetic nephropathic patient. We investigated whether these mutations, which have not yet been functionally characterized, impair HNF4alpha function in three cell models: HEK 293 embryonal kidney cells, HepG2 hepatoma cells, and betaTC3 pancreatic beta-cells. The R324H mutation had no effect on HNF4alpha function with either the HNF1alpha and L-type pyruvate kinase (LPK) promoters, but the D126Y and D126H mutations impaired HNF4alpha transcriptional activities in all tested cell lines. These impairments by D126Y and D126H mutations, which are located in the T box, are not due to a loss of dimerization but to a loss of DNA binding. Interestingly, the strongest functional consequences of these mutations were observed on the HNF1alpha promoter in betaTC3 cells. Given the key role of the transcription factor HNF1alpha in pancreatic beta-cell function, it can be inferred that impairment of HNF4alpha function by these mutations affects metabolic pathways in pancreatic beta-cells and contributes to development of diabetes. Moreover, the HNF4alpha-mediated activation of the apolipoprotein CIII promoter in HepG2 cells was significantly impaired by D126Y and D126H mutations. These results support clinical findings that liver function can also be impaired in diabetic patients having HNF4alpha mutations.
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PMID:Mutations in hepatocyte nuclear factor 4alpha (HNF4alpha) gene associated with diabetes result in greater loss of HNF4alpha function in pancreatic beta-cells than in nonpancreatic beta-cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. 1211 Sep 48

Fetal rat hepatocytes treated with transforming growth factor beta (TGF-beta) die by apoptosis. However, a subpopulation of them survives and undergoes an epithelial mesenchymal transition (EMT). This transition also occurs upon incubation with fetal bovine serum. We have isolated the subpopulations that undergo EMT (TGF-beta-treated-fetal hepatocytes: TbetaT-FH; serum-treated-fetal hepatocytes: ST-FH) and show that they present high levels of vimentin and Snail expression and lack cytokeratin 18 and E-cadherin. Both TbetaT-FH and ST-FH cells require mitogens to grow and maintain the response to TGF-beta in terms of growth inhibition. However, they lack differentiation markers such as the liver-enriched transcription factors hepatocyte nuclear factor 4 (HNF-4) or HNF-1alpha and express the progenitor marker OV-6. Interestingly, the EMT process confers them resistance to the apoptotic effect of TGF-beta, with cells showing higher levels of active AKT and Bcl-x(L) than fetal hepatocytes. In summary, these cells are refractory to the apoptotic effects of TGF-beta, showing characteristics of liver progenitors and of some hepatocellular carcinoma cells.
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PMID:The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor Beta in fetal rat hepatocytes. 1249 70

To study the effects of the nuclear receptors (NRs) HNF4alpha and COUP-TF1 on the life cycle of hepatitis B virus (HBV), the human hepatoma cell line Huh7 was transiently cotransfected with plasmids containing the HBV genome and encoding these two NRs. Overexpression of HNF4alpha and COUP-TF1 led to a 9-fold increase and a 7- to 10-fold decrease, respectively, in viral DNA synthesis. These two NRs also exhibited distinct modes of regulation of viral transcription. Overexpression of HNF4alpha led to a more-than-10-fold increase in synthesis of the pregenomic RNA but to only a 2- to 3-fold increase in synthesis of the pre-C and S RNAs. Moreover, the NR response element within the pre-C promoter, NRRE(preC,) played the major role in activation of pregenomic RNA synthesis by HNF4alpha. On the other hand, overexpression of COUP-TF1 led to an over-10-fold repression of synthesis of both pre-C and pregenomic RNAs mediated through either NRRE(preC) or NRRE(enhI). HNF4alpha and COUP-TF1 antagonized each other's effects on synthesis of pregenomic RNA and viral DNA when they were co-overexpressed. A naturally occurring HBV variant which allows for binding by HNF4alpha but not COUP-TF1 in its NRRE(preC) exhibited significantly higher levels of synthesis of pregenomic RNA and viral DNA than wild-type HBV in coexpression experiments. Last, deletion analysis revealed that non-NRRE sequences located within both the C and pre-S1 regions are also essential for maximum activation of the pregenomic promoter by HNF4alpha but not for repression by COUP-TF1. Thus, HNF4alpha and COUP-TF1 function through different mechanisms to regulate expression of the HBV genes.
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PMID:Distinct modes of regulation of transcription of hepatitis B virus by the nuclear receptors HNF4alpha and COUP-TF1. 1255 87

Constitutive androstane receptor (CAR; NR1I3) controls the metabolism and elimination of endogenous and exogenous toxic compounds by up-regulating a battery of genes. In this work, we analyzed the expression of human CAR (hCAR) in normal liver during development and in hepatocellular carcinoma (HCC) and investigated the effect of hepatocyte nuclear factor 4alpha isoforms (HNF4alpha1 and HNF4alpha7) on the hCAR gene promoter. By performing functional analysis of hCAR 5'-deletions including mutants, chromatin immunoprecipitation in human hepatocytes, electromobility shift and cotransfection assays, we identified a functional and species-conserved HNF4alpha response element (DR1: ccAGGCCTtTGCCCTga) at nucleotide -144. Both HNF4alpha isoforms bind to this element with similar affinity. However, HNF4alpha1 strongly enhanced hCAR promoter activity whereas HNF4alpha7 was a poor activator and acted as a repressor of HNF4alpha1-mediated transactivation of the hCAR promoter. PGC1alpha stimulated both HNF4alpha1-mediated and HNF4alpha7-mediated hCAR transactivation to the same extent, whereas SRC1 exhibited a marked specificity for HNF4alpha1. Transduction of human hepatocytes by HNF4alpha7-expressing lentivirus confirmed this finding. In addition, we observed a positive correlation between CAR and HNF4alpha1 mRNA levels in human liver samples during development, and an inverse correlation between CAR and HNF4alpha7 mRNA levels in HCC. These observations suggest that HNF4alpha1 positively regulates hCAR expression in normal developing and adult livers, whereas HNF4alpha7 represses hCAR gene expression in HCC.
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PMID:Differential regulation of constitutive androstane receptor expression by hepatocyte nuclear factor4alpha isoforms. 1746 91

Frequently, primary hepatocytes are used as an in vitro model for the liver in vivo. However, the culture conditions reported vary considerably, with associated variability in performance. In this study, we characterized the differentiation character of primary human hepatocytes cultured using a highly defined, serum-free two-dimensional sandwich system, one that configures hepatocytes with collagen I as the substratum together with a dilute extracellular matrix (Matrigeltrade mark) overlay combined with a defined serum-free medium containing nanomolar levels of dexamethasone. Gap junctional communication, indicated by immunochemical detection of connexin 32 protein, was markedly enhanced in hepatocytes cultured in the Matrigel sandwich configuration. Whole genome expression profiling enabled direct comparison of liver tissues to hepatocytes and to the hepatoma-derived cell lines, HepG2 and Huh7. PANTHER database analyses were used to identify biological processes that were comparatively over-represented among probe sets expressed in the in vitro systems. The robustness of the primary hepatocyte cultures was reflected by the extent of unchanged expression character when compared directly to liver, with more than 77% of the probe sets unchanged in each of the over-represented categories, representing such genes as C/EBPalpha, HNF4alpha, CYP2D6, and ABCB1. In contrast, HepG2 and Huh7 cells were unchanged from the liver tissues for fewer than 48% and 55% of these probe sets, respectively. Further, hierarchical clustering of the hepatocytes, but not the cell lines, shifted from donor-specific to treatment-specific when the probe sets were filtered to focus on phenobarbital-inducible genes, indicative of the highly differentiated nature of the hepatocytes when cultured in a highly defined two-dimensional sandwich system.
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PMID:Gene expression profiling and differentiation assessment in primary human hepatocyte cultures, established hepatoma cell lines, and human liver tissues. 1751 62

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.
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PMID:Differential inhibition of nuclear hormone receptor-dependent hepatitis B virus replication by the small heterodimer partner. 1823 86

The rat hepatic gene CYP4F1 encodes a fatty acid omega hydroxylase P450 that metabolizes proinflammatory eicosanoids and long-chain fatty acids. We have completely sequenced the CYP4F1 gene (Accession Nos. AF200361 and AF181083), identified multiple transcription start sites, and characterized a strong core promoter region, -760/116, induced by retinoic acids and peroxisome proliferators in rat hepatoma McA-RH7777 cells. Three peroxisome proliferator responsive elements (PPRE) bind both PPARalpha/RXRalpha and HNF4alpha. Co-transfection of McA-RH7777 cells with the -760/116 reporter construct and PPARalpha/RXRalpha or HNF4alpha showed that HNF4alpha activated while PPARalpha/RXRalpha inhibited CYP4F1 promoter activity. Treating cells with Wy14,643 reversed all initial effects, indicating co-regulation of CYP4F1 gene transcription by PPARalpha/RXRalpha and HNF4alpha. Chromatin immunoprecipitation analysis of cells treated with Wy14,643 showed association of PPARalpha/RXRalpha with the active transcription of the CYP4F1 gene while in clofibrate treated rats HNF4alpha binds during gene repression, suggesting differential regulation of the CYP4F1 gene in vivo and in cell lines.
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PMID:Genomic structure and regulation of the rat hepatic CYP4F1 gene by peroxisome proliferators. 1826 87

Pregnane X receptor (PXR; NR1I2), a key transcriptional factor that regulates genes encoding drug-metabolizing enzymes and drug transporters, is abundantly expressed in the human liver. However, studies on the molecular mechanism of human PXR gene regulation are limited. In this study, we examined the involvement of hepatocyte nuclear factor 4alpha (HNF4alpha; NR2A1) in the transcriptional regulation of the human PXR gene in the human liver. The activities of the human PXR promoter containing the direct repeat 1 (DR1) element located at -88/-76 of the promoter were significantly increased by co-expression of HNF4alpha in the human hepatocellular carcinoma cell line. In addition, introduction of mutation into the DR1 element abolished the transcriptional activation of the human PXR promoter by exogenous HNF4alpha. The results of gel mobility shift assays and chromatin immunoprecipitation assays showed that HNF4alpha was bound to the promoter region containing the DR1 element. A knock-down of HNF4alpha by siRNA significantly decreased expression levels of endogenous PXR mRNA in HepG2 cells. Furthermore, expression levels of PXR mRNA positively correlated with those of HNF4alpha mRNA in 18 human liver samples. These results suggested that HNF4alpha transactivated the human PXR gene by binding to the DR1 element located at -88/-76 of the promoter and was involved in the expression of PXR in the human liver.
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PMID:Involvement of hepatocyte nuclear factor 4 alpha in transcriptional regulation of the human pregnane X receptor gene in the human liver. 1830 75

Dedifferentiation and epithelial-mesenchymal transition are important steps in epithelial tumor progression. A central role in the control of functional and morphological properties of different cell types is attributed to tissue-specific transcription factors which form regulatory cascades that define specification and differentiation of epithelial cells during embryonic development. The main principles of the action of such regulatory systems are reviewed on an example of a network of hepatocyte nuclear factors (HNFs) which play a key role in establishment and maintenance of hepatocytes--the major functional type of liver cells. HNFs, described as proteins binding to promoters of most hepatospecific genes, not only control expression of functional liver genes, but are also involved in regulation of proliferation, morphogenesis, and detoxification processes. One of the central components of the hepatospecific regulatory network is nuclear receptor HNF4alpha. Derangement of the expression of this gene is associated with progression of rodent and human hepatocellular carcinomas (HCCs) and contributes to increase of proliferation, loss of epithelial morphology, and dedifferentiation. Dysfunction of HNF4alpha during HCC progression can be either caused by structural changes of this gene or occurs due to modification of up-stream regulatory signaling pathways. Investigations preformed on a model system of the mouse one-step HCC progression have shown that the restoration of HNF4alpha function in dedifferentiated cells causes partial reversion of malignant phenotype both in vitro and in vivo. Derangement of HNFs function was also described in other tumors of epithelial origin. We suppose that tissue-specific factors that underlie the key steps in differentiation programs of certain tissues and are able to receive or modulate signals from the cell environment might be considered as promising candidates for the role of tumor suppressors in the tissue types where they normally play the most significant role.
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PMID:Tissue-specific transcription factors in progression of epithelial tumors. 1860 82


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