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)

Type-1 plasminogen activator-inhibitor (PAI-1) is a major physiologic inhibitor of plasminogen activation. Incubation of HTC rat hepatoma cells with the cyclic nucleotide analogue, 8-bromo-cAMP, causes a dramatic increase in tissue-type plasminogen activator activity secondary to a 90% decrease in PAI-1 mRNA. Although 8-bromo-cAMP causes a modest decrease in PAI-1 transcription, regulation is primarily the result of a 3-fold increase in the rate of PAI-1 mRNA degradation. To determine the cis-acting sequences required for cyclic nucleotide regulation, we have stably transfected HTC cells with chimeric genes containing sequences from the rat PAI-1 cDNA and the mouse beta-globin gene and examined the effect of cyclic nucleotides on the decay rate of these transcripts. The mRNA transcribed from the beta-globin gene is stable and not cyclic nucleotide-regulated, whereas the transcript from a construct containing the beta-globin coding region and the PAI-1 3'-untranslated region (UTR) is destabilized in the presence of 8-bromo-cAMP, suggesting that this response is mediated by sequences in the PAI-1 3'-UTR. Analyses by deletion of sequences from this chimeric construct indicate that, whereas more than one region of the PAI-1 3'-UTR can confer cyclic nucleotide responsiveness, the 3'-most 134-nucleotide sequence alone is sufficient to do so. Insertion of PAI-1 sequences within the beta-globin 3'-UTR confirms that the 3'-most 134 nucleotides of PAI-1 mRNA can confer cyclic nucleotide regulation of stability on a heterologous transcript, suggesting that this sequence may play a major role in hormonal regulation of PAI-1 mRNA stability.
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PMID:Cyclic nucleotide regulation of type-1 plasminogen activator-inhibitor mRNA stability in rat hepatoma cells. Identification of cis-acting sequences. 960 32

Transforming growth factor-beta (TGF-beta) has been shown to induce apoptosis in normal hepatocytes and hepatoma cells both in vivo and in vitro. However, the mechanism by which TGF-beta induces apoptosis is not clear. The antiapoptotic activity of antioxidants including N-acetyl-L-cysteine (Ac-Cys), ascorbic acid and a novel free radical scavenger, carboxyfullerene (C60) on TGF-beta-treated human hepatoma Hep3B cells was examined. Only the water-soluble hexacarboxylic acid derivative of C60 was found to prevent TGF-beta-induced apoptosis. Antiapoptotic activity of C60 correlated its ability to eliminate TGF-beta-generated reactive oxygen species (ROSs). However, C60 did not interfere with TGF-beta-activated PAI-1 promoter activity in the Hep3B cells. These results indicate that the signaling pathway of TGF-beta-induced apoptosis may be related to the generation of ROSs and may be uncoupled from the TGF-beta-activated gene promoter activity. Furthermore, the regioisomer of C60 with a C3 symmetry was more potent in protecting cells from apoptosis than that with a D3 symmetry, and the C3 isomer had stronger interactions with lipid bilayers than the D3 isomer. The spectroscopic analysis revealed that the C3 isomer had stronger interactions with artificial lipid bilayers than the D3 isomer. Therefore, our study indicates that C60 may interact with membrane to eliminate TGF-beta-induced ROSs and to prevent apoptosis occur in human hepatoma cells.
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PMID:Blockage of apoptotic signaling of transforming growth factor-beta in human hepatoma cells by carboxyfullerene. 965 91

Whether the phenotypes of drug resistance and metastatic activity in cancer are dependent on each other or not is controversial. We compared in vitro invasive properties of human hepatoma cells resistant to epirubicin and rich in P-glycoprotein (Pgp) (HB8065/R) with the parental epirubicin-sensitive, Pgp-poor cells (HB8065/S). The HB8065/R cells displayed elevated capacity to migrate in a transwell chamber assay (three- to fourfold compared to the HB8065/S cells), both in the absence and presence of a reconstituted basement membrane extract (Matrigel). In the presence of the P-gp inhibitor PSC 833 (1.5 micrograms/ml) the capacity of the HB8065/R cells to cross Matrigel-coated filters was attenuated by approximately 25%. Compared to the HB8065/S cells, the resistant cell line expressed higher level of plasminogen activator inhibitor (PAI)-1 mRNA (approximately threefold), which was reflected by a approximately fivefold increase in secreted PAI-1 immunoactivity (approximately 50 ng/10(6) HB8065/R cells). Furthermore, treatment with PSC 833 was associated with upregulation of PAI-1 mRNA (approximately 3.5-fold) and immunoactivity (approximately twofold) in the HB8065/R cells. Level of tissue inhibitor of metalloproteinases (TIMP)-1 was also significantly increased in the HB8065/R cells compared to the HB8065/S cells, whereas both cell lines showed low constitutive expression of TIMP-2. Levels of TIMPs were not altered by PSC 833. These data suggest that overexpression of Pgp in these hepatoma cells may covariate with the phenotypes of both enhanced in vitro invasiveness and high PAI-1 expression, whether randomly acquired or not.
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PMID:Human hepatoma cells rich in P-glycoprotein display enhanced in vitro invasive properties compared to P-glycoprotein-poor hepatoma cells. 980 60

Incubation of HTC rat hepatoma cells with the cyclic nucleotide analogue 8-bromo-cAMP results in a 3-fold increase in the rate of degradation of type-1 plasminogen activator-inhibitor (PAI-1) mRNA. Previous studies utilizing HTC cells stably transfected with beta-globin:PAI-1 chimeric constructs demonstrated that at least two regions within the PAI-1 3'-untranslated region mediate the cyclic nucleotide-induced destabilization of PAI-1 mRNA; one of these regions is the 3'-most 134 nucleotides (nt) of the PAI-1 mRNA (Heaton, J. H., Tillmann-Bogush, M., Leff, N. S., and Gelehrter, T. D. (1998) J. Biol. Chem. 273, 14261-14268). In the present study, ultraviolet cross-linking analyses of this region demonstrate HTC cell cytosolic mRNA-binding proteins ranging from 38 to 76 kDa, with a major complex migrating at approximately 50 kDa. RNA electrophoretic mobility shift analyses demonstrate high molecular weight multiprotein complexes that specifically interact with the 134-nt cyclic nucleotide-responsive sequence. The 50, 61, and 76 kDa and multiprotein complexes form with an A-rich sequence at the 3' end of the cyclic nucleotide-responsive region; a 38-kDa complex forms with a U-rich region at the 5' end of the 134 nt sequence. Mutation of the A-rich region prevents both the binding of the 50-, 61-, and 76-kDa proteins and formation of the multiprotein complexes, as well as cyclic nucleotide-regulated degradation of chimeric globin:PAI-1 transcripts in HTC cells. These data suggest that the proteins identified in this report play an important role in the cyclic nucleotide regulation of PAI-1 mRNA stability.
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PMID:Cyclic nucleotide regulation of PAI-1 mRNA stability. Identification of cytosolic proteins that interact with an a-rich sequence. 987 66

We have characterized the regulation of plasminogen activator inhibitor-1 (PAI-1) gene expression by phorbol 12-myristate 13-acetate (PMA), serum, and interleukin-1alpha (IL-1alpha) in the human hepatoma cell line HepG2. PMA, serum, and IL-1alpha induced a rapid and transient 28-fold (PMA), 9-fold (serum), and 23-fold (IL-1alpha) increase in PAI-1 mRNA, peaking after approximately 4 hours. These inductions of PAI-1 mRNA accumulation were reduced by pretreatment of the HepG2 cells with the protein tyrosine kinase inhibitor genistein. Conversely, stimulation of tyrosine phosphorylation by sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, caused an increase in PAI-1 mRNA levels. The effects of PMA, serum, and IL-1alpha on PAI-1 mRNA expression have been compared with their ability to modulate the expression of a chloramphenicol acetyltransferase (CAT) reporter plasmid, which was under control of the -489 to +75 region of the PAI-1 promoter, and stably transfected into HepG2 cells. This region of the PAI-1 promoter was previously found to contain a tetradecanoyl phorbol acetate-response element (TRE; between -58 and -50) necessary for PMA responsiveness and with a high affinity for c-Jun homodimers. Whereas incubation of these transfected HepG2 cells with PMA and serum showed an induction profile of CAT mRNA similar to that of PAI-1 mRNA, hardly any induction of CAT mRNA was found with IL-1alpha. In line with these findings, IL-1alpha poorly induced c-Jun homodimer binding to the PAI-1 TRE in gel mobility-shift assays. Pretreatment of HepG2 cells with the protein kinase C inhibitor Ro 31-8220 or the mitogen-activated protein kinase kinase (MAPKK)1,2 activity blocker PD98059 selectively suppressed the induction of PAI-1 (and CAT) expression by PMA, but not that by IL-1alpha. In contrast, the protein tyrosine kinase inhibitor herbimycin A blocked PAI-1 mRNA induction by IL-1 alpha only. We propose 2 separate PAI-1 inductory pathways for PMA and IL-1alpha in HepG2, both involving protein tyrosine kinase activation; the serum-induced signaling pathway may (partially) overlap with the PMA-activated protein kinase C/mitogen-activated protein kinase kinase pathway, leading to c-Jun homodimer binding to the PAI-1 TRE.
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PMID:On the role of c-Jun in the induction of PAI-1 gene expression by phorbol ester, serum, and IL-1alpha in HepG2 cells. 988 64

Protein C inhibitor is a member of the serpin family that inhibits a variety of serine proteases. Protein C inhibitor is present in numerous body fluids and is produced in the liver and by various epithelial cells. To determine if this epithelial serpin is present in skin, immunohistochemical studies were performed that showed strong staining for protein C inhibitor antigen in the epidermis. Protein C inhibitor mRNA was detected in the keratinocyte cell line HaCaT and the epidermoid carcinoma cell line A431 using reverse transcription-polymerase chain reaction suggesting that also in normal skin protein C inhibitor is derived from keratinocytes. Conditioned media from these cell lines were analyzed on immunoblots, which revealed a protein C inhibitor-antigen band that comigrated with protein C inhibitor derived from the hepatoma cell line HepG2. Using an enzyme-linked immunosorbent assay specific for total protein C inhibitor antigen the accumulation of protein C inhibitor in the cell culture supernatants of HaCaT keratinocytes was found to be 0.3 ng per h per 1 million cells. This is similar to the amount of plasminogen activator inhibitor-1 produced by these cells, which also produce tissue plasminogen activator and urokinase. Fluorescence-activated cell sorter analysis revealed similar expression of intracellular protein C inhibitor antigen in proliferating and confluent HaCaT cells. These findings demonstrate that protein C inhibitor antigen is present in the normal epidermis and that protein C inhibitor is constitutively expressed by keratinocytes in culture. Therefore, protein C inhibitor may provide protease inhibitory activity not only to internal, but also to the external surface of the body. Additionally, protein C inhibitor could contribute to the regulation of retinoid supply in the epidermis, as we have shown recently that retinoic acid binds specifically to protein C inhibitor.
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PMID:Protein C inhibitor is expressed in keratinocytes of human skin. 1041 15

The multifunctional cytokine interleukin-6 (IL-6) regulates growth and differentiation of many cell types and induces production of acute-phase proteins in hepatocytes. Here we report that IL-6 protects hepatoma cells from apoptosis induced by transforming growth factor-beta (TGF-beta), a well known apoptotic inducer in liver cells. Addition of IL-6 blocked TGF-beta-induced activation of caspase-3 while showing no effect on the induction of plasminogen activator inhibitor-1 and p15(INK4B) genes, indicating that IL-6 interferes with only a subset of TGF-beta activities. To further elucidate the mechanism of this anti-apoptotic effect of IL-6, we investigated which signaling pathway transduced by IL-6 is responsible for this effect. IL-6 stimulation of hepatoma cells induced a rapid tyrosine phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and its kinase activity followed by the activation of Akt. Inhibition of PI 3-kinase by wortmannin or LY294002 abolished the protection of IL-6 against TGF-beta-induced apoptosis. A dominant-negative Akt also abrogated this anti-apoptotic effect. Dominant-negative inhibition of STAT3, however, only weakly attenuated the IL-6-induced protection. Finally, inhibition of both STAT3 and PI 3-kinase by treating cells overexpressing the dominant-negative STAT3 with LY294002 completely blocked IL-6-induced survival signal. Thus, concomitant activation of the PI 3-kinase/Akt and the STAT3 pathways mediates the anti-apoptotic effect of IL-6 against TGF-beta, with the former likely playing a major role in this anti-apoptosis.
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PMID:Interleukin-6 inhibits transforming growth factor-beta-induced apoptosis through the phosphatidylinositol 3-kinase/Akt and signal transducers and activators of transcription 3 pathways. 1043 68

Plasminogen activator inhibitor (PAI)-1, a serine protease inhibitor, inactivates urokinase-type plasminogen activator (uPA) and regulates degradation of the extracellular matrix; whether it functions for or against tumor progression, however, has been the subject of controversy. To assess the role of PAI-1 in invasion and proliferation of hepatocellular carcinoma (HCC) cells, HLE cells were transfected with a vector capable of expressing an antisense PAI-1 transcript. Analysis of seven stably transfected clones (PAI-1-) showed reductions of 81% in PAI-1 mRNA by northern blot analysis and 63% in the cellular PAI-1 antigen level by enzyme-linked immunosorbent assay (ELISA). There was no change in the levels of secreted PAI-1 or PAI-2. The activity of cellular uPA increased by 54%, without change in the protein level or the secreted uPA activity evaluated by ELISA. Morphologically, PAI-1 antisense induced a spindle shape with narrower cytoplasmic processes in HLE cells. The forced inhibition of PAI-1 increased the invasion and the growth of PAI-1- cells by 75% and 82%, respectively. These results suggest that PAI-1 plays a role in inhibiting invasion and proliferation, and the balance between uPA and PAI-1 expression is important to assess the invasiveness of HCC cells.
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PMID:Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. 1047 Feb 87

It has become more and more clear in recent decades that the plasminogen activation system, which includes urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor (PAI)-1 and PAI-2, plays a very important role in the aggressiveness of cancer. Using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), the expression of these four components of the uPA system was analyzed in 19 cases of hepatocellular carcinoma (HCC) and 18 cases of the adjacent non-cancer tissues which all had chronic active hepatitis with liver fibrosis or liver cirrhosis. Four cases of normal liver tissues, as controls for immunohistochemical stains, were obtained from the hepatectomized liver of patients with metastatic cancer in the liver. The positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical stains in cancer tissues were 78.9, 68.4, 57.9 and 31.6%, respectively. Positive signals were mainly distributed in the cytoplasm of the cancer and in stromal cells. Moreover, the strong stains were chiefly located in the invasive front of the cancer cells. No specific stain was detected in four cases of normal liver tissues. In ELISA, there were significant differences between cancer and non-cancer tissues in concentration of uPA, uPAR and PAI-1 (P < 0.0003, 0.0024 and 0.01, respectively), but there was no significant difference in that of PAI-2 (P = 0.37). These results suggest that uPA, uPAR and PAI-1 are related to invasion of HCC.
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PMID:Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma. 1084 28

Incubation of HTC rat hepatoma cells with 8-bromo-cAMP results in a 3-fold increase in the rate of degradation of type-1 plasminogen activator inhibitor (PAI-1) mRNA. We have reported previously that the 3'-most 134 nt of the PAI-1 mRNA is able to confer cyclic nucleotide regulation of message stability onto a heterologous transcript. R-EMSA and UV cross-linking experiments have shown that this 134 nt cyclic nucleotide-responsive sequence (CRS) binds HTC cell cytoplasmic proteins ranging in size from 38 to 76 kDa. Mutations in the A-rich region of the CRS both eliminate cyclic nucleotide regulation of mRNA decay and abolish RN-protein complex formation, suggesting that these RNA-binding proteins may be important regulators of mRNA stability. By sequential R-EMSA and SDS-PAGE we have purified a protein from HTC cell polysomes that binds to the PAI-1 CRS. N-terminal sequence analysis and a search of protein data bases revealed identity with two human sequences of unknown function. We have expressed one of these sequences in E. coli and confirmed that the recombinant protein interacts specifically with the PAI-1 CRS. Mutation of the A-rich portion of the PAI-1 CRS reduces binding by the recombinant PAI-1 RNA-binding protein. The amino acid sequence of this protein includes an RGG box and two arginine-rich regions, but does not include other recognizable RNA binding motifs. Detailed analyses of nucleic acid and protein data bases demonstrate that blocks of this sequence are highly conserved in a number of metazoans, including Arabidopsis, Drosophila, birds, and mammals. Thus, we have described a novel RNA-binding protein that identifies a family of proteins with a previously undefined sequence motif. Our results suggest that this protein, PAI-RBP1, may play a role in regulation of mRNA stability.
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PMID:Identification and cDNA cloning of a novel RNA-binding protein that interacts with the cyclic nucleotide-responsive sequence in the Type-1 plasminogen activator inhibitor mRNA. 1100 48

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