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)

Dedifferentiated rat hepatoma cells contain defects that result in the loss of hepatic gene expression, including the liver-enriched HNF4/HNF1alpha pathway. We examined induction of NF-kappaB, a key mediator of the inflammatory response, in hepatoma and dedifferentiated hepatoma cells. We show that exposure of dedifferentiated hepatoma cells, but not rat and human hepatoma cell lines, to proinflammatory cytokines or lipopolysaccharide resulted in rapid and sustained NF-kappaB induction. IkappaB-beta levels, but not NF-kappaB subunit p65 or IkappaB-alpha levels, were elevated compared with those for parental hepatoma cells. Interestingly, LPS-mediated activation of NF-kappaB was found to be independent of degradation of IkappaB-alpha or IkappaB-beta. Thus, these results suggest that loci responsible for maintaining hepatic gene expression also influence cellular responses to inflammatory agents.
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PMID:Defective NF-kappaB signaling in dedifferentiated hepatoma cells. 1532 7

ACAT catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acids. There are two known genes encoding the two ACAT enzymes, ACAT1 and ACAT2 (also known as Soat1 and Soat2). In adult humans, ACAT1 is present in most tissues, whereas ACAT2 is localized to enterocytes and hepatocytes. In this report, we elucidate the mechanisms that control the liver-specific expression of the human ACAT2 gene. We identified hepatic nuclear factor 1 (HNF1) as an important liver-specific trans-acting element for the human ACAT2 gene using the human hepatocellular carcinoma cell lines HuH7 and HepG2. Targeted deletion of the HNF1 binding site in the DNA sequence abolished not only the basal promoter function in HepG2 and HuH7 cells but also the induction of the ACAT2 promoter by HNF1. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that the transcription factors HNF1alpha and HNF1beta interact with this region in the human ACAT2 gene in vitro and in vivo. These data indicate that a) the identified HNF1 binding site serves as a positive regulator sequence, b) the binding site is functionally active both in vivo and in vitro, and c) the transcription factors HNF1alpha and HNF1beta, which bind to this site, play an important part in the regulation of the human ACAT2 promoter.
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PMID:Control of ACAT2 liver expression by HNF1. 1596 90

Humans express two ACAT (acyl-CoA:cholesterol acyltransferase) genes, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption. To investigate the molecular mechanism(s) responsible for the tissue-specific expression of ACAT2, we identified five cis-elements within the human ACAT2 promoter, four for the intestinal-specific transcription factor CDX2 (caudal type homeobox transcription factor 2), and one for the transcription factor HNF1alpha (hepatocyte nuclear factor 1alpha). Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1alpha exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements. In undifferentiated Caco-2 cells, the ACAT2 expression is increased when exogenous CDX2 and/or HNF1alpha are expressed by co-transfection. In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1alpha expression is suppressed by using RNAi (RNA interference) technology. The expression levels of CDX2, HNF1alpha, and ACAT2 are all greatly increased when the Caco-2 cells differentiate to become intestinal-like cells. These results provide a molecular mechanism for the tissue-specific expression of ACAT2 in intestine. In normal adult human liver, CDX2 expression is not detectable and the ACAT2 expression is very low. In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression. A high percentage (seven of fourteen) of liver samples from patients affected with hepatocellular carcinoma exhibited elevated ACAT2 expression. Thus, the elevated ACAT2 expression may serve as a new biomarker for certain form(s) of hepatocellular carcinoma.
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PMID:Human acyl-CoA:cholesterol acyltransferase 2 gene expression in intestinal Caco-2 cells and in hepatocellular carcinoma. 1627 62

We used several of the genetic lesions commonly associated with human liver tumors to reconstruct genetic progression to hepatocellular carcinoma and adenoma in mouse models. We initiated tumorigenesis with a transgene of the protooncogene MET or by hydrodynamic transfection of MET in combination with other genes into the livers of adult animals. Hepatocellular carcinoma in both instances arose from cooperation between MET and constitutively active versions of beta-catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1alpha. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of beta-catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated beta-catenin. The tumors eventually recurred in the absence of MET expression, however, presumably after the occurrence of one or more events that cooperated with activated beta-catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.
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PMID:Distinct pathways of genomic progression to benign and malignant tumors of the liver. 1831 18

Hepassocin (HPS), is a liver-specific gene with mitogenic activity on isolated hepatocytes. It is up-regulated following partial hepatectomy and down-regulated frequently in heptocellular carcinoma (HCC). However, very little is known about the HPS transcription regulation mechanism. In this study, we identified HNF1alpha (hepatocyte nuclear factor-1alpha) as an important liver-specific cis-acting element for HPS using in vivo luciferase assays. Deletion of the HNF1 binding site not only led to a complete loss of HPS promoter activity in vivo but also abolished the induction of the HPS promoter by HNF1alpha. An electrophoretic mobility shift assay demonstrated that HNF1alpha interacted with the HPS gene promoter in vitro. Chromatin immunoprecipitation showed that HNF1alpha interacted with HMGB1 and CREB-binding protein, and all of them were recruited to the HPS promoter in vivo. Moreover, HNF1alpha expression was lower in HCC cell lines and tissues and correlated significantly with the down-regulation of HPS expression. Re-expression of HNF1alpha in human hepatoma HepG2 cells reinduced HPS expression. In contrast, knockdown of endogenous HNF1alpha expression by small interfering RNA resulted in a significant reduction of HPS expression. Furthermore, we found that partial hepatectomy and IL-6 significantly induced promoter activity of HPS, depending on STAT3 and HNF1 binding sites in the HPS promoter. These results demonstrate that the HNF1 binding site and HNF1alpha are critical to liver-specific expression of HPS, and down-regulation or loss of HNF1alpha causes, at least in part, the transcriptional down-regulation of HPS in HCC.
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PMID:Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma. 1930 66

Hepatocellular adenomas (HCA) are rare benign tumours occurring mainly in women under oral contraceptives. HCA bleed frequently and transform rarely into hepatocellular carcinoma. Identification of genes recurrently mutated in HCA and good genotype/phenotype correlations provided the basis of a pathomolecular classification of different HCA subgroups, characterized using immunohistochemical markers. HNF1A-mutated HCA: Biallelic-inactivating mutations of HNF1A gene are identified in 35-40% of HCA. HNF1alpha-inactivated HCA display characteristic pathological features, including marked steatosis. The expression of FABP1 (which is a HNF1A target gene) is downregulated and the absence of L-FABP expression diagnosed this subgroup. beta-Catenin-mutated HCA: beta-catenin mutations leading to activation of the Wnt/beta-catenin pathway represented 10-15% of HCA. They are characterized by overexpression of glutamine synthetase and aberrant nuclear beta-catenin staining. These beta-catenin-activated HCA are at greater risk of malignant transformation; they are difficult to differentiate from well-differentiated HCC. Inflammatory HCA (50%): These are defined by the presence of inflammatory infiltrates, sinusoidal dilatation and thick-walled arteries. Small in-frame deletions that target the binding site of gp130 for IL-6 have been reported in 60% of inflammatory HCA. There is an overexpression of the inflammatory proteins serum amyloid A and C-reactive protein in tumour hepatocytes both at mRNA and protein levels. Inflammatory HCA occurred more frequently in patients with high body mass index; they can be also mutated for beta-catenin and therefore are probably at risk of HCC. Unclassified HCA: Less than 10% of HCA do not express any of the above-mentioned phenotypic markers. Taking into account noticeable differences between the HCA subgroups, in terms of clinical and prognostic features, phenotyping may become an important tool for HCA management strategy.
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PMID:Subtype classification of hepatocellular adenoma. 2035 50


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