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)

Thrombospondin-1 (TSP-1) level is tightly regulated at the transcriptional level. To determine the detailed molecular mechanisms of TSP-1 expression, nine serial 5'-deletion constructs of the human genomic tsp-1 promoter (nucleotides -2,220 to +756) were prepared, inserted into luciferase reporter plasmids, and transiently transfected into the Hep3B human hepatocarcinoma cell. Among the nine 5'-deletion constructs, pTSP-Luc-4 (-767 approximately +756) had consistently decreased luciferase activity with or without PMA stimulation, whereas a further truncated construct [pTSP-Luc-4' (-407 approximately +756)] had increased levels of expression. By searching the nucleotides from -767 to -407, a consensus binding sequence (5'-CCATTTT-3') for the repressor Yin Yang-1 (YY-1) at nucleotide -440 was identified. The suppression induced by this site was weakened in the presence of the region upstream of nucleotide -767 (pTSP-Luc-1 and -2). Nuclear protein directly bound to an oligonucleotide containing the repressive YY-1 sequence but the binding capacity of the sequence was decreased by the increased c-Jun levels. Moreover, proteins immunoprecipitated with anti-YY-1 revealed an interaction between c-Jun and YY-1 factor. These data suggest that the repressive YY-1 site of the tsp-1 promoter could not be functional via activating positive cis-elements on the upstream from this site and weakened via c-Jun/YY-1 interactions.
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PMID:Weakening of the repressive YY-1 site on the thrombospondin-1 promoter via c-Jun/YY-1 interaction. 1536 49

The proximal region -234 to (+58 bp) of low-density lipoprotein receptor (LDLR) is responsible for its up-regulation by sterol regulatory element binding protein (SREBP). However, the mechanism of sterol-independent repression of LDLR has not been determined yet. In this study, we observed that there was an early induction and a later repression of LDLR by phorbol ester (PMA) in SK-Hep1 hepatocarcinoma cells and investigated the mechanisms through which PMA repressed LDLR transcription. SK-Hep1 cells were exposed to PMA and LDLR mRNA was evaluated by RT-PCR and Northern blot analysis. The effect of phorbol ester on LDLR transcriptional activity was studied using transient transfection of LDLR promoter-luciferase constructs. Overexpression of N-SREBP-2, a dominant positive SREBP2, did not reverse the PMA-repressed LDLR promoter activity. Serial deletion of LDLR promoter revealed that the region between -1,563 and -1,326 was responsible for the repression. The pretreatment with SB202190, an inhibitor for p38 mitogen-activated protein kinase pathway (p38-MAPK), but not other signaling inhibitors, reversed the PMA-induced repression. The 24 h-treatment with PMA efficiently arrested the SK-Hep1 cell cycle at G0/G1 as demonstrated by FACS analysis and decreased the 3H-thymidine incorporation. The PMA-induced repression of LDLR transcription may be exerted by the factor(s), not SREBP2, induced or modified by p38-MAPK-mediated signaling pathway and associated with cell cycle blockage.
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PMID:Inhibition of low density lipoprotein receptor expression by long-term exposure to phorbol ester via p38 mitogen-activated protein kinase pathway. 1614 74

The role of Ca(2+) ions in PMA-induced generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNL) was studied during Zajdela hepatoma growth in the peritoneal cavity of rats. In PMNL from control healthy animals, a manifold Ca(2+)-induced enhancement of ROS generation and its significant reduction in the presence of Ca(2+) binding agent (BAPTA-AM) were observed. In contrast, ROS generation by PMNL from tumour-carrying animals dramatically increased in Ca(2+)-free medium, being practically insensitive to the agents, which can increase or decrease intracellular Ca(2+) levels. Free cytosolic Ca(2+) ([Ca(2+)](i)) in control PMNL was found to be relatively low ( approximately 250 nmol/L), rising slowly after Ca(2+) addition and further to two-fold in the presence of Ca(2+) and ionomycin in the incubating medium. Tumour growth in animals was accompanied with a significant [Ca(2+)](i) elevation. In Ca(2+)-free medium, [Ca(2+)](i) elevation was up to 480 nmol/L in tPMNL with the additions of Ca(+) and ionomycin as well as EGTA and ionomycin being able to increase [Ca(2+)](i) to 700-900 nmol/L onward. It was concluded that a higher Ca(2+) permeability of the plasma membrane and higher Ca(2+) accumulation in intracellular pools of PMNL was developed at the advanced stages of malignant disease. These results indicate the primed state of circulating PMNL and the independence of PMA-induced ROS generation at intra- and extracellular Ca(2+) levels at the advanced stages of tumour growth in animals.
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PMID:Role of Ca2+ in activation of reactive oxygen species production in polymorphonuclear leukocytes during tumour growth in rats. 1726 35

Aqueous extracts or juice from unripened fruit of Momordica charantia (bitter melon) has traditionally been used in the treatment of diabetes and its complications. Insulin resistance is characterized by significant down-regulation of hepatic insulin signalling as documented by attenuated phosphorylation of insulin receptor (IR), IR substrates 1 and 2, phosphoinositide-3 kinase, protein kinase B, and over-expression of phosphotyrosine phosphatase 1B. We recently demonstrated that bitter melon juice (BMJ) is a potent inhibitor of apoB secretion and TAG synthesis and secretion in human hepatoma cells, HepG2, that may be involved in plasma lipid- and VLDL-lowering effects observed in animal studies. The aim of this study was to evaluate the effects of BMJ on plasma apoB levels and hepatic insulin signalling cascade in mice fed high-fat diet (HFD). Female C57BL/6 mice (4-6 weeks old) were randomized into three groups receiving regular rodent chow, HFD and HFD+BMJ. The data indicate that BMJ not only improves glucose and insulin tolerance but also lowers plasma apoB-100 and apoB-48 in HFD-fed mice as well as modulates the phosphorylation status of IR and its downstream signalling molecules. Investigating the biochemical and molecular mechanisms involved in amelioration of diabetic dyslipidaemia by BMJ may lead to identification of new molecular targets for dietary/alternative therapies.
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PMID:Momordica charantia (bitter melon) reduces plasma apolipoprotein B-100 and increases hepatic insulin receptor substrate and phosphoinositide-3 kinase interactions. 1832 95

Considerable interests have recently been focused on mechanism of human hepatocellular carcinoma (HCC) metastasis-the most fundamental characteristics of HCC and the ultimate cause of most HCC mortality, so screening more potential early prognostic marker and therapeutic target is urgent. In this study, we screened genome of three HCC cell lines with consistently increased metastatic potentials and sharing same genetic background, through DNA microarray and found consecutively up-regulated expression of PKCbeta in these cell lines compared to others PKCs, which was reconfirmed by real time RT-PCR and western blot analysis. Moreover, it was found, after efficient silence of PKCbeta by RNAi assay or inhibition of PKCbeta activity by a specific inhibitor LY317615, migration and invasion of HCC cells significantly decreased. In addition, depletion of PKCbeta protein significantly reversed the enhancement of PMA-stimulated HCC migration and invasion ability in vitro. All the data suggest a key role of PKCbeta in HCC motility and PKCbeta may be a potential therapeutic target.
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PMID:Role of PKCbeta in hepatocellular carcinoma cells migration and invasion in vitro: a potential therapeutic target. 1911 1

Binding of hepatitis C virus (HCV) RNA to core, the capsid protein, results in the formation of the nucleocapsid, the first step in the assembly of the viral particle. A novel assay was developed to discover small molecule inhibitors of core dimerization. This assay is based on time-resolved fluorescence resonance energy transfer (TR-FRET) between anti-tag antibodies labeled with either europium cryptate (Eu) or allophycocyanin (XL-665). The N-terminal 106-residue portion of core protein (core106) was tagged with either glutathione-S-transferase (GST) or a Flag peptide. Tag-free core106 was selected as the reference inhibitor. The assay was used to screen the library of pharmacologically active compounds (LOPAC) consisting of 1,280 compounds and a 2,240-compound library from the Center for Chemical Methodology and Library Development at Boston University (CMLD-BU). Ten of the 28 hits from the primary TR-FRET run were confirmed in a secondary amplified luminescent proximity homogeneous assay (ALPHA screen). One hit was further characterized by dose-response analysis yielding an IC(50) of 9.3 microM. This 513 Da compound was shown to inhibit HCV production in cultured hepatoma cells.
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PMID:A time-resolved fluorescence-resonance energy transfer assay for identifying inhibitors of hepatitis C virus core dimerization. 2003 14

Visualizing oncogene/tumor Ag expression by noninvasive imaging is of great interest for understanding processes of tumor development and therapy. We established transgenic (Tg) mice conditionally expressing a fusion protein of the SV40 large T Ag and luciferase (TagLuc) that allows monitoring of oncogene/tumor Ag expression by bioluminescent imaging upon Cre recombinase-mediated activation. Independent of Cre-mediated recombination, the TagLuc gene was expressed at low levels in different tissues, probably due to the leakiness of the stop cassette. The level of spontaneous TagLuc expression, detected by bioluminescent imaging, varied between the different Tg lines, depended on the nature of the Tg expression cassette, and correlated with Tag-specific CTL tolerance. Following liver-specific Cre-loxP site-mediated excision of the stop cassette that separated the promoter from the TagLuc fusion gene, hepatocellular carcinoma development was visualized. The ubiquitous low level TagLuc expression caused the failure of transferred effector T cells to reject Tag-expressing tumors rather than causing graft-versus-host disease. This model may be useful to study different levels of tolerance, monitor tumor development at an early stage, and rapidly visualize the efficacy of therapeutic intervention versus potential side effects of low-level Ag expression in normal tissues.
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PMID:In vivo imaging of an inducible oncogenic tumor antigen visualizes tumor progression and predicts CTL tolerance. 2014 65

Type IV collagenase matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, have been found to promote invasion and metastasis of malignant tumors. Extracellular matrix (ECM) degradation by MMPs and increased expression of MMPs in cancer cells and tumor microvascular endothelial cells make MMPs an attractive target for cancer. Focused on a common pathomechanism of cancer growth and invasion, the disintegration of connective tissue, we used natural approaches to increase the integrity and strength of connective tissues. Utilizing the principle of nutrition synergy, we developed a novel micronutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract. This study evaluates the potency of the components EGCG and green tea extract independently compared to that of NM on modulation of patterns of MMP-2 and MMP-9 expression in four cancer cell lines expressing MMP-2, MMP-9 or both. Human fibrosarcoma (HT-1080), hepatocellular carcinoma (SK-Hep-1), glioblastoma (T-98G), uterine leiomyosarcoma (SK-UT-1) cell lines were obtained from ATCC and grown in minimum essential medium (MEM) supplemented with 10% FBS, penicillin (100 U/ml) and streptomycin (100 mg/ml) in 24-well tissue culture plates. At near confluence, the cells were treated with agents dissolved in media and tested at concentrations indicated in triplicate at each dose. Cells were also treated with PMA 100 ng/ml to study enhanced expression of MMP-9. MMP expression was assessed by gelatinase zymography. Fibrosarcoma and hepatocellular carcinoma cells expressed both MMP-2 and MMP-9. Glioblastoma cells expressed MMP-2 and PMA treatment induced MMP-9 expression. Uterine leimyosarcoma cells expressed no MMPs but PMA induced MMP-9. NM was the most potent dose-dependent inhibitor of MMPs, followed by green tea extract and EGCG. In conclusion, these results suggest the enhanced efficacy of nutrients working in synergy to modulate complex pathways such as MMP expression.
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PMID:Comparative effects of EGCG, green tea and a nutrient mixture on the patterns of MMP-2 and MMP-9 expression in cancer cell lines. 2066 83

To investigate the relationship of tumor associated glycoprotein-72 (TAG-72) expression with clinicopathological features in hepatocellular carcinoma (HCC) patients. Sixty pairs of HCC and paracarcinomatous (PCLT) tissues, and 10 normal liver (NL) tissues were collected for Western blot analysis, and 244 pairs of HCC and PCLT tissues were collected for immunohistochemistry analysis. TAG-72 protein expression was elevated significantly in HCC tissues compared with PCLT and NL tissues. Its increased expression was correlated with TNM stage, Edmondson-Steiner grade, vein invasion and multiple tumor nodes. It is noteworthy that the HCC patients with high TAG-72 expression had shorter overall survival and disease-free survival than the patients with low expression. Multivariate Cox regression analysis revealed that TAG-72 expression was an independent prognostic factor for HCC patients. The current study demonstrated for the first time that the increased expression of TAG-72 was correlated with poor survival in patients with HCC, indicating that TAG-72 is a novel prognostic marker for HCC.
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PMID:Tumor associated glycoprotein-72 is a novel marker for poor survival in hepatocellular carcinoma. 2243 16

Tamoxifen is a triphenylethylene non-steroidal antiestrogen anticancer agent. It also shows inhibitory effects on metastasis of estrogen receptor (EsR)-independent tumors, but the underlying mechanism is unclear. It was demonstrated in this study that, in EsR-negative and highly metastatic human hepatocellular carcinoma MHCC97H cells, tamoxifen-inhibited cell migration, volume-activated Cl(-) currents (I(Cl,vol)) and regulatory volume decrease (RVD) in a concentration-dependent manner with a similar IC(50). Analysis of the relationships between migration, I(Cl,vol) and RVD showed that cell migration was positively correlated with I(Cl,vol) and RVD. Knockdown of the expression of ClC-3 Cl(-) channel proteins by ClC-3 shRNA or siRNA inhibited I(Cl,vol), and cell migration, and these inhibitory effects could not be increased further by addition of tamoxifen in the medium. The results suggest that knockdown of ClC-3 expression may deplete the effects of tamoxifen; tamoxifen may inhibit cell migration by modulating I(Cl,vol) and cell volume. Moreover, tamoxifen decreased the activity of protein kinase C (PKC) and the effects were reversed by the PKC activator PMA. Activation of PKC by PMA could competitively downregulate the inhibitory effects of tamoxifen on I(Cl,vol). PMA promoted cell migration, and knockdown of ClC-3 expression by ClC-3 siRNA abolished the PMA effect on cell migration. The results suggest that tamoxifen may inhibit I(Cl,vol) by suppressing PKC activation; I(Cl,vol) may be an EsR-independent target for tamoxifen in the anti-metastatic action on cancers, especially on EsR-negative cancers. The finding may have an implication in the clinical use of tamoxifen in the treatments of both EsR-positive and EsR-negative cancers.
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PMID:Tamoxifen inhibits migration of estrogen receptor-negative hepatocellular carcinoma cells by blocking the swelling-activated chloride current. 2304 59

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