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)

Hepatitis B virus (HBV) infection is still a major public health problem worldwide. Although much information about the molecular biology of HBV has been gained in the last decades, little is known about the mechanism of attachment and penetration of the HBV particle into human hepatocytes. The HBV envelope proteins are important for the interaction between the HBV particle and the hepatocyte plasma membrane. Although initially it was suggested that the preS2 domain could act, via polymerized human serum albumin, as an attachment site to human hepatocytes, in recent years other observations showed that the preS1 domain is probably the most important attachment site to human hepatocytes. However, controversial findings on cellular proteins for binding to the preS1 domain has been described, namely the IgA-, the IL6-, the asialoglycoprotein receptor and GAPD. Although the preS1 attachment site may be important, apo H has been shown to bind specifically to small HBsAg. Recently, we have identified human liver Annexin V as a specific small HBsAg-binding protein. In a preliminary report, the direct involvement of human Annexin V in the initial step of HBV infection has been demonstrated. A rat hepatoma cell line, which does not express human Annexin V and which is not infectable by HBV, gained the ability to become infected by HBV after transfection with human Annexin V. This result may facilitate the progress of HBV receptor research and elucidate the molecular mechanism of the initial step of HBV infection.
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PMID:Organ and species specificity of hepatitis B virus (HBV) infection: a review of literature with a special reference to preferential attachment of HBV to human hepatocytes. 918 23

Previously, we have found that human liver annexin V (hA-V; in earlier reports referred as Endonexin II) is a specific hepatitis B surface antigen (HBsAg) binding protein. In this study, we demonstrate that transfection of rat hepatoma FTO 2B cells, a cell line that is not infectable by hepatitis B virus (HBV) and does not express hA-V, with a construct containing the hA-V gene, resulted in hA-V expressing cells susceptible to HBV infection. After in vitro infection, transfected FTO cells (assigned as FTO 9.1 cells) expressing hA-V in cultures were shown to contain HBV-precore/core, X mRNAs, and covalently closed circular (ccc) DNA as detected by polymerase chain reaction (PCR). The presence of HBV ccc and replicative intermediate DNA was also demonstrated by Southern blot hybridization assay. HBV DNA secreted in the culture medium was also evident as determined by quantitative branched DNA (bDNA) assay. HBsAg and hepatitis B core antigen (HBcAg) could also be detected by an immunocytochemical method in 10% to 15% of the cells at day 3 and day 5 after infection. Infectivity of in vitro-propagated HBV was demonstrated by infection of the naive FTO 9.1 cells with the culture supernatant from HBV-carrier cultures. In contrast to primary cultures of human hepatocytes and FTO 9.1 cells, primary rat and mouse hepatocytes, as well as rat hepatoma cell lines that do not express hA-V, are not susceptible to HBV infection. These findings suggest that hA-V plays a key role in the initial step of HBV infection and that the species-specific susceptibility to HBV infection and replication in hepatocytes is associated with the expression of hA-V.
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PMID:Transfection of a rat hepatoma cell line with a construct expressing human liver annexin V confers susceptibility to hepatitis B virus infection. 991 38

Primary hepatocellular carcinoma (HCC) is probably one of the most common fatal forms of liver cancer. We have established permanent cell lines from diethylnitrosamine/phenobarbital induced primary rat liver carcinomas to study new anticancer therapies. The rat hepatocellular carcinoma cell lines (HR-2, HR-3, and HR-4) have been maintained in culture for over 3 years. They form tumors when transplanted sc or im into young syngeneic rats. Immunocytology (alpha-fetoprotein, albumin), biochemical (gamma-glutamyl transferase), and histochemical (glycogen) marker studies and electron microscopy (biliary canaliculi) showed unique, stable differentiation patterns in these tumor lines. They overproduced the c-met protooncogene product and formed colonies spontaneously in semisolid culture with high cloning efficiency (HR-2: 50%-80%, HR-3: 35%-50% and HR-4: 50%-65%). The sensitivity of these cell lines to inhibitors of protein ser/thr phosphatase-2A (PP2A), a key enzyme in the control of G1/S and G2/M cell cycle phase transitions in eukaryotes, was studied in vitro. The specific, weak inhibitor of PP2A, endothall, caused dose- and time-dependent cytostasis specifically in G2/M. The cells died later by apoptosis, which was confirmed by cytology (annexin V-FITC labeling, propidium iodide painting of apoptotic bodies) and by fluorescent activated cell sorter (FACS) DNA measurements. The HR-2, HR-3, HR-4, and Zajdela hepatocellular carcinomas were most sensitive to endothall (IC50 of 1.7, 1.2, 0.9, and 1.7 microg/mL), whereas newborn rat hepatocytes growing exponentially in primary culture (IC50 = 6.2 microg/mL), rat DHD/K12 colon carcinoma cells (IC50 = 3.6 microg/mL), or human HT-29 colon carcinoma cells (IC50 = 4.9 microg/mL) were less sensitive. Thus, endothall inhibits preferentially HCC growth and these new rat hepatocellular carcinoma lines may be useful for further biochemical and pharmacological studies on PP2A inhibitors, and for testing new forms of treatment of hepatic cell carcinomas.
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PMID:Hepatocellular carcinoma cell lines from diethylnitrosamine phenobarbital-treated rats. Characterization and sensitivity to endothall, a protein serine/threonine phosphatase-2A inhibitor. 1021 23

Propolis has been reported to exhibit a wide spectrum of activities including antibiotic, antiviral, anti-inflammatory, immunostimulatory and tumor carcinostatic properties. We showed propolis induced apoptosis in a human hepatoma cell line (SNU449) by FITC-Annexin V/PI staining. We also compared the apoptosis inducing effect between Korean and Commercial (Sigma # p-1010) propolis. There was no difference on apoptosis between them.
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PMID:Apoptosis induced by propolis in human hepatocellular carcinoma cell line. 1037 33

Previously, we have determined that human annexin V (hAV), a Ca2+-dependent phospholipid-binding protein, and not rat AV, binds specifically to small hepatitis B surface antigen (SHBsAg), and that transfection of a rat hepatoma cell line with a construct containing the hAV gene led to hAV expression and conferred susceptibility to hepatitis B virus (HBV) infection. In this work, we have examined the effect of administration of hAV on in vitro binding of SHBsAg to human and to rat hepatocytes and on in vitro HBV infection. The results showed that hAV could bind to human as well as to rat hepatocytes. Because of this property, excess hAV was unable to prevent HBV infection in primary cultures of human hepatocytes. On the other hand, it enabled rat hepatocytes to specifically bind SHBsAg and conferred susceptibility to HBV infection. After infection of primary cultures of rat hepatocytes in the presence of hAV, HBV mRNA, covalently closed circular (ccc) DNA, replicative intermediates, hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg) and secreted HBV DNA were detected. After infection in the absence of hAV, no markers of HBV replication were detected. Hence, from the present study we conclude that hAV is involved in facilitating HBV entry, leading to successful HBV infection in primary cultures of rat hepatocytes, while it is not effective in preventing HBV infection in primary cultures of human hepatocytes.
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PMID:Influence of the administration of human annexin V on in vitro binding of small hepatitis B surface antigen to human and to rat hepatocytes and on in vitro hepatitis B virus infection. 1076 40

Cyclosporin (CsA) inhibits mitochondrial death signaling and opposes tumor necrosis factor (TNF)-induced apoptosis in vitro. However, CsA is also a potent inhibitor of calcineurin, a phosphatase that may participate in cell death. Therefore, we tested the hypothesis that calcineurin regulates TNF cytotoxicity in rat hepatoma cells (FTO2B). TNF-treated FTO2B cells appeared apoptotic by DNA fragmentation, nuclear condensation, annexin V binding, and caspase activation. We studied two calcineurin inhibitors, CsA and FK506, and found that each potently inhibited TNF cytotoxicity. Western blot demonstrated calcineurin in FTO2B homogenates. In a model of mitochondrial permeability transition (MPT), we found that CsA prevented MPT and cytochrome c release, while FK506 inhibited neither. In summary, we present evidence that calcineurin participates in an apoptotic death pathway activated by TNF. CsA may oppose programmed cell death by inhibiting calcineurin activity and/or inhibiting mitochondrial signaling.
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PMID:Regulation of tumor necrosis factor cytotoxicity by calcineurin. 1104 65

Bullatacin, isolated from the fruit of Annona atemoya, is one of the most potentially effective antitumor annonaceous acetogenins. Bullatacin was studied here for its ability to inhibit the proliferation of 2.2.15 cells, hepatitis B virus (HBV) DNA transfected human hepatocarcinoma cell line. It was found that bullatacin induced cytotoxicity of 2.2.15 cells in a time- and dose-dependent manner. Fifty percent effective dose (ED50) on day 1 of exposure to bullatacin were 7.8 +/- 2.5 nM for 2.2.15 cells. [3H]-Thymidine incorporation assays showed almost the same results. Bullatacin-treatment also reduced concentrations of hepatitis B surface antigen (HBsAg) in the cultured medium released from 2.2.15 cells, coincident with the decrease in the cell proliferation. Analysis of mophological changes of bullatacin-treated 2.2.15 by inverted phase-contrast microscope and eletron microscopy revealed a possible model of action for bullatacin to inhibit proliferation of 2.2.15 cells by inducing apoptosis. Most of the bullatacin-induced cell death was found to be due to apoptosis, as determined by double staining with fluorescein-isothiocyanate (FITC)-labeled annexin V and propidium iodide (PI).
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PMID:Bullatacin, a potent antitumor annonaceous acetogenin, inhibits proliferation of human hepatocarcinoma cell line 2.2.15 by apoptosis induction. 1152 56

Upstream binding factor (UBF) is an RNA polymerase I-specific transcription factor. By representational difference analysis, Northern blot, and cDNA array analysis, up-regulation of UBF was detected in 12 of 17 clinical hepatocellular carcinoma samples comparing to the paired normal liver tissues. Introduction of UBF in human lung fibroblast cells that do not express UBF resulted in an accelerated rate of cell growth; on the other hand, antisense oligodeoxynucleotides (ODNs) treatment of UBF-expressing hepatoma cell lines reduced the level of UBF protein, suppressed the colony formation capacity of these cells on soft agarose, and finally caused cell death. Annexin V binding analysis suggested that anti-UBF ODN-caused cell death might involve weak apoptosis, however, DNA laddering and cleavage of poly (ADP-ribose) polymerase were not observed in these ODN-treated cells. Expression profiling of the anti-UBF ODN-treated cells using a human cDNA array revealed that the expression of 30 genes was altered in response to the inhibition of UBF expression. Notably, UBF expression could increase the cell sensitivity to the chemotherapeutic reagent cis-diaminedichloroplatinum (II). We proposed that UBF is fundamental to the survival of cells expressing the gene, and is potential as a target for screening anti-cancer drugs and an indicator in selecting chemotherapeutic reagents.
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PMID:Upstream binding factor up-regulated in hepatocellular carcinoma is related to the survival and cisplatin-sensitivity of cancer cells. 1187 79

We previously reported the isolation of the novel human DENN gene, which is differentially expressed in normal and neoplastic cells. DENN is identical to MADD (mitogen-activated protein kinase-activating death domain), which interacts with tumor necrosis factor receptor 1 through their death domains. DENN is also homologous to Rab3 GEP, a rat Rab3 GDP/GTP exchange protein. Real-time reverse transcription-polymerase chain reaction analysis showed that DENN expression in cancer cell lines was 26-50 times that in normal cells. The Jurkat human leukemia, PLC/PRF/5 human hepatoma, and NS-1 mouse myeloma cell lines as well as the MRC-5 human fetal lung and Vero monkey kidney cell lines were treated successfully with four separate DENN-targeted antisense oligodeoxynucleotides (ODNs) to abrogate DENN expression. Quantitative assessment of cell viability and apoptosis by flow cytometry via fluorescein diacetate and propidium iodide membrane-integrity tests, terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate-biotin nick end-labeling, and annexin V assays showed that antisense silencing of DENN resulted in markedly more pronounced cell death in cancer cells compared with nonmalignant cells. Antisense-treated cell lines exhibited extensive loss of DNA content, forming distinct sub-G(1) peaks, while cell proliferation diminished significantly. Ultrastructural features of programmed cell death in cells subjected to antisense ODNs were authenticated by electron microscopy. In contrast, transfection of cell lines with a plasmid construct to achieve DENN overexpression augmented cellular proliferation and could reverse the apoptotic effect of antisense and staurosporine treatment. Our findings suggest that DENN is intimately involved in anti-apoptotic and cell-survival processes.
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PMID:Induction of marked apoptosis in mammalian cancer cell lines by antisense DNA treatment to abolish expression of DENN (differentially expressed in normal and neoplastic cells). 1241 May 63

2,4-Dichlorophenoxyacetic acid (2,4-D) and its derivatives are herbicides widely used to control the growth of broadleaf and woody plants. Although 2,4-D is well known to be moderately toxic, little information is available on the mechanisms of its toxicity. Results on carcinogenicity, genotoxicity and mutagenicity are contradictory, but neurotoxic, immunosuppressive and hepatotoxic effects have been defined. The aim of the present study was to investigate the cytotoxic effects of 2,4-D on a human hepatoma cell line. HepG2 cells were treated with different concentrations of 2,4-D, and cell viability, induction of apoptosis/necrosis and cell cycle phases were determined. Apoptosis was detected in flow cytometric light scatter histograms, the annexin V assay, the determination of DNA strand breaks with the TUNEL assay and the occurrence of a sub G(0) peak after propidium iodide (PI) staining. The induction of apoptosis by 2,4-D was accompanied by a disruption of the mitochondrial membrane potential as verified by staining with the cationic JC-1 probe. In addition, 2,4-D affected the cell cycle in a concentration-dependent manner. Our investigation suggested that 2,4-D exerts its cytotoxic effects by the induction of apoptosis via a direct effect on the mitochondrial membrane potential.
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PMID:Cytotoxic effects of the herbicide 2,4-dichlorophenoxyacetic acid in HepG2 cells. 1250 71


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