UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of p53 has been found in many types of human malignancy. The present study aimed to detect preoperative serum p53 among 158 patients with different gastrointestinal cancers using ELISA technique based on mouse anti-p53 DO-7 monoclonal antibody and anti-p53 rabbit polyclonal antibody. A single band of 53kDa was detected in nuclear protein tissue extracts of selected cancer patients and in 96% of the corresponding sera using Western blot assay. The ELISA technique revealed that the serum p53 was detected in 100% of patients with cholangiocarcinoma, 76% of pancreatic carcinoma, 75% of hepatocellular carcinoma, 70% of colon cancer, 60% of esophagus carcinoma, and 35% of gastric carcinoma. The serum p53 concentrations of the positive patients were highly elevated (P<0.001) compared with healthy individuals. These results suggest that immunodetection of serum p53 could be valuable for post-operative monitoring during follow up in preoperatively positive patients with gastrointestinal cancers.
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PMID:Detection of serum p53 protein in patients with different gastrointestinal cancers. 1267 May 24

The expression of the vitamin K-dependent gamma-glutamyl carboxylase gene in liver is developmentally regulated. Since the gene product catalyzes an essential post-translational modification of the vitamin K-dependent blood coagulation proteins, the regulation of carboxylase expression is critical for hemostasis. We analyzed the activity of the rat carboxylase gene 5'-regulatory DNA sequences in rat hepatoma cell lines at different states of differentiation. These studies demonstrated that the 2.6-kb 5'-flanking sequence has differentiation-dependent transcriptional activity. Transient gene expression assays, examining the effects of nested deletions and site-directed mutagenesis of putative regulatory sequences, together with electrophoretic mobility shift assays (EMSAs) were used to identify sequences critical for the developmentally regulated transcription of the rat carboxylase gene. We identified a DNA sequence (-76 to -65; GTTCCGGCCTTC) not known to bind to transcription factors, yet which functions as an upstream promoter element. In vivo genomic DNA footprinting confirms the presence of nuclear protein-DNA interactions at this site in the endogenous carboxylase gene in differentiated hepatoma cells. Therefore, this DNA sequence has specific nuclear protein-binding activity and functional properties consistent with a regulatory element that plays a critical role in the developmental expression of the carboxylase gene, and hence the regulation of vitamin K-dependent blood coagulation protein synthesis.
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PMID:The vitamin K-dependent gamma-glutamyl carboxylase gene contains a TATA-less promoter with a novel upstream regulatory element. 1271 91

Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapy. A few clinical trials have shown that the cytidine analogue gemcitabine appears to have antitumor activity for HCC, but the overall survival times remain to be improved. In this study, we examined the synergistic effect of adenovirus type 5 E1A (E1A) and gemcitabine on HCC and found that E1A sensitized J5, J7, Huh7, and HepG2 HCC cells to gemcitabine. To further study the E1A-mediated chemosensitization, we established stable cell lines that expressed the E1A gene and then examined whether E1A could have proapoptotic activity while expressed in HCC cells. Our results clearly showed that E1A sensitized HCC cells to gemcitabine through induction of apoptosis. To study the underlying mechanism, we tested nuclear factor (NF)-kappaB activity and found that NF-kappaB was activated in HCC cells treated with gemcitabine but not in HCC cells that expressed E1A. Occurrence of apoptosis entails cleavage of poly (ADP-ribose) polymerase (PARP), a nuclear protein involved in DNA repair, genome stability, and maintenance of telomere length. Our study showed that gemcitabine enhanced PARP expression. However, E1A did not induce PARP cleavage but rather suppressed PARP expression at the transcriptional level. Further study showed that both NF-kappaB and PARP played protective roles in the prevention of E1A+gemcitabine-induced apoptosis.
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PMID:Adenovirus type 5 E1A sensitizes hepatocellular carcinoma cells to gemcitabine. 1455 8

The majority of persons with chronic hepatitis C virus (HCV) infection develop liver fibrosis. Transforming growth factor (TGF)-beta 1 plays a pivotal role in the pathogenesis of post-inflammatory liver scarring. To clarify the influence of HCV infection on liver fibrosis, a reporter assay was used to investigate the effect of viral proteins on TGF-beta 1 expression in human hepatoma cells. Of all HCV proteins investigated (core, E1/E2/p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), only the core protein activated the TGF-beta 1 promoter and upregulated TGF-beta 1 expression measured by an RNase protection assay. Bases -376 to -331 bp in the promoter region of TGF-beta 1 are responsible for upregulation by HCV core protein, and the nuclear protein that binds to this region increased with the stimulation of HCV core protein. Blocking the mitogen-activated protein kinase pathway prevented upregulation of TGF-beta 1 by HCV core protein. The immunological response is supposed to be a major factor to cause the secretion of TGF-beta 1 from non-parenchymal cells, but the results suggest that the HCV core protein expression may upregulate directly TGF-beta 1 transcription in parenchymal cells and suggest a new paradigm for exacerbation of liver fibrosis by HCV infection.
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PMID:Hepatitis C virus core protein upregulates transforming growth factor-beta 1 transcription. 1463 11

Plasminogen activator inhibitor type 1 (PAI-1) has been shown to be an independent risk factor for coronary artery disease, myocardial infarction, and cerebrovascular events. Previous studies on variations in plasma PAI-1 levels and associations between PAI-1 levels and PAI-1 genotypes have suggested that PAI-1 expression maybe regulated in a genotype-specific manner by insulin, hypertriglyceridemic very low-density lipoprotein, and lipoprotein. We investigated whether basal transcription of the PAI-1 gene also is regulated in a genotype-specific manner. Allele-specific polymerase chain reaction-amplified fragments containing a 4G/5G polymorphism of the PAI-1 gene promoter were ligated into the chloramphenicol acetyltransferase (CAT) reporter gene. The constructs of p4G-CAT or pSG-CAT and pSV-beta-galactosidase as an internal control were transiently cotransfected into human HepG2 hepatoma cells. Electrophoresis mobility shift assays (EMSA) employed a fragment from positions -687 to -664 (4G allele) or from -688 to -664 (5G allele) labeled with adenosine triphosphate tagged with phosphorous 32 in the gamma position and used nuclear extracts of HepG2 cells. Analysis of CAT produced by constructs containing the PAI-1 4G or 5G allele showed similar 3-fold increases in CAT activity in the PAI-1 4G/4G and PAI-1 5G/5G constructs, compared with the CAT activity in the pCAT3-Basic construct. Analyses using the probes containing the 4G or 5G allele site in the EMSA assay revealed no difference in the binding of nuclear protein. Our in vitro assay of basal transcription suggests no difference in the transcriptional activities of the alleles of the PAI-1 4G/5G polymorphism.
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PMID:No association of the plasminogen activator inhibitor-1 promoter 4G/5G polymorphism with inhibitor level during basal transcription in vitro. 1521 74

Regucalcin was discovered in 1978 as a Ca(2+)-binding protein that does not contain EF-hand motif of Ca(2+)-binding domain. The name regucalcin was proposed for this Ca2(2+)binding protein, which can regulate liver cell functions related to Ca(2+). The regucalcin gene is localized on chromosome X, and the organization of the regucalcin gene consists of seven exons and six introns. AP-1 and NFI-A1 can bind to the promoter region of the rat regucalcin gene to mediate the Ca(2+) response for transcriptional activation. Regucalcin plays a pivotal role in maintaining intracellular Ca(2+) homeostasis due to activating Ca(2+) pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum) and mitochondria of many cell types. Regucalcin has a suppressive effect on Ca(2+) signaling from the cytoplasm to the nucleus in the proliferative cells. Also, regucalcin has been demonstrated to transport to nucleus, and it can inhibit nuclear protein kinase, protein phosphatase, and deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. Regucalcin can control enhancement of cell proliferation due to hormonal stimulation. Moreover, overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells induced by various signaling factors. Regucalcin plays a multifunctional role in the regulation of cellular function in liver, kidney cortex, heart and brain. Moreover, regucalcin-overexpressing rat has been shown to induce bone loss and hyperlipidemia with increasing age, indicating a pathophysiologic role. Regucalcin transgenic rat may be useful as an animal model in osteoporosis and hyperlipidemia. Thus, regucalcin plays a pivotal role in maintaining cell homeostasis and function. Regucalcin gene expression-related diseases may be found in human.
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PMID:Role of regucalcin in maintaining cell homeostasis and function (review). 1570 26

Growth arrest and DNA damage 45-alpha (GADD45-alpha) is a nuclear protein involved in maintenance of genomic stability, DNA repair, and suppression of cell growth through interaction with nuclear elements, including cyclin-dependent kinase inhibitor 1A (CDKN1A) and PCNA. In this study, GADD45-alpha expression was assessed in 28 cases of hepatocellular carcinoma (HCC) and matched cirrhosis tissues, and correlated with the presence of DNA-bound PCNA and CDKN1A as markers of DNA repair, as well as with clinicopathologic variables including histopathologic grade, tumor size, nodularity, viral status, alpha-fetoprotein serum levels, and p53 and Ki67 immunostaining. GADD45-alpha and CDKN1A messenger RNA (mRNA) were analyzed by reverse transcriptase-polymerase chain reaction. GADD45-alpha protein expression was evaluated by Western blot (WB) and enzyme-linked immunosorbent assays (ELISAs). PCNA and CDKN1A DNA-bound fractions were determined by WB. GADD45-alpha mRNA was down-regulated in 20 of 26 HCCs with respect to matched cirrhosis, but no correlation was found with the corresponding protein levels assessed by both WB and ELISA. GADD45-alpha and CDKN1A protein levels were related to each other both in cirrhotic and in neoplastic tissues, and a concordant up- or down-regulation was observed in HCCs with respect to cirrhosis. DNA-bound PCNA and CDKN1A were present in 5 HCCs and were associated with higher GADD45-alpha protein levels assessed by ELISA. No significant association was found in HCCs between GADD45-alpha protein expression and histopathologic grading, nodule size, focality, and proliferation, whereas a positive correlation was found with alpha-fetoprotein serum levels. In conclusion, GADD45-alpha mRNA was down-regulated with respect to matched cirrhosis in most HCCs; however, no correlation was found between mRNA and protein levels. GADD45-alpha protein levels were higher in HCCs with DNA-bound CDKN1A and PCNA, suggesting a possible role in DNA repair.
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PMID:GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. 1626 Feb 67

The transcription rate and protein expression from both GSTA2 (glutathione S-transferase A2) and albumin genes decrease in rat liver after IL-6 (interleukin 6) plus DEX (dexamethasone) treatment of primary hepatocytes or after LPS (lipopolysaccharide)-induced acute-phase response in animals. The down-regulation is associated with the induced expression of a nuclear protein (termed IL6DEX-NP for IL-6/DEX-induced nuclear protein) that binds to a specific site on the promoter of GSTA2, leading to a decrease in transcriptional activity. IL6DEX-NP is not similar to other transcription factors, and, for identification, we functionally cloned it from a rat liver library using a yeast one-hybrid screen based on DNA-binding activity. The cloned sequence was a truncated form of USP3 (ubiquitin-specific protease 3) and the truncated USP3 protein in a yeast extract bound to DNA containing the IL6DEX-NP recognition sequence. Using 5'- and 3'-RACE (rapid amplification of cDNA ends), the complete sequence of USP3 was found in liver from LPS-treated rats. However, using Western blot analysis, only truncated forms of USP3 could be identified in nuclear extracts from LPS-treated rat livers. A GSTA2 promoter-reporter gene plasmid and USP3-expressing plasmids were transfected into rat hepatoma cells. Expression of the short form of USP3, but not the full-length protein, abolished expression from the reporter gene. Chromatin immunoprecipitation localized USP3 to the GSTA2 promoter in rat hepatocytes in vivo. We believe that the short form of USP3 is IL6DEX-NP and that it may play an important role in the negative regulation of proteins during the acute-phase response.
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PMID:Identification of a short form of ubiquitin-specific protease 3 that is a repressor of rat glutathione S-transferase gene expression. 1627 67

The invasive and metastatic potentials of hepatocellular carcinoma (HCC) are positively correlated with the expression level of alpha3beta1 integrin, a high-affinity adhesion receptor for laminin isoforms. Transforming growth factor (TGF)-beta1 stimulates non-invasive HCC cells to acquire invasive phenotypes in association with the enhanced expression of alpha3 integrin. In this study, we investigated the molecular mechanism underlying the upregulation of alpha3beta1 integrin by TGF-beta1 in non-invasive HepG2 HCC cells. The treatment of HepG2 cells with TGF-beta1 induced the expression of alpha3 integrin and potentiated these cells to adhere to laminin-5 and to migrate through laminin-5-coated membranes. The promoter activity was measured by luciferase assay with a series of deletion constructs of the 5'-flanking region of the mouse alpha3 integrin gene, and the results showed that the -260/-119 region (relative to the major transcription start site) contained elements responsive to TGF-beta1 stimulation. The introduction of mutations into the putative consensus binding sequence for the Ets-family of transcription factors located at -133 greatly decreased the promoter activity responding to TGF-beta1 stimulation. The nuclear proteins extracted from TGF-beta1-stimulated HepG2 cells yielded a larger amount of DNA-nuclear protein complexes than did those extracted from unstimulated cells, as determined by an electrophoretic mobility shift assay using an oligonucleotide containing the Ets-site as a probe. These results suggest that TGF-beta1 stimulates HepG2 cells to express a higher level of alpha3 integrin by transcriptional upregulation via Ets transcription factors and to exhibit a more invasive phenotype.
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PMID:Transforming growth factor-beta1 upregulates transcription of alpha3 integrin gene in hepatocellular carcinoma cells via Ets-transcription factor-binding motif in the promoter region. 1647 24

Alpha-fetoprotein (AFP) is one of the major serum proteins in the early life of mammals. We have previously identified a novel cis-acting element designated as DAS at the 5'-flanking region of the AFP gene and demonstrated that the DAS sequence can be specifically recognized by nuclear protein DAP-II in AFP-producing hepatoma cells and retinoic acid (RA)-induced AFP-producing F9 cells. In this study, we used DNA affinity chromatography to purify the DAP-II proteins from the nuclear extracts (NE) of RA-treated F9 cells. The purified DAP-II complex mainly contained five proteins, with molecular weights of 45, 42, 32, 30, and 20 kDa, respectively. The identification of these proteins was determined by MALDI-TOF mass spectrometric analysis and a database search. These proteins were found to belong to the AUF1 RNA-binding protein family. Protein (30 kDa), one of five proteins in an isolated DAP-II complex, was matched with amino acid sequence highly similar to muAUF1-3. The expression of this protein is inducible by RA, and the pattern of the protein expression is the same as DAP-II proteins in F9 cells after treatment with RA during differentiation. Our results suggest that the 30-kDa protein is a novel isoform of AUF1 family and is the main component of the DAP-II complex that binds to the DAS sequence.
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PMID:AUF1-like protein binds specifically to DAS cis-acting element that regulates mouse alpha-fetoprotein gene expression. 1651 30

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