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)

Our experiments with the hIR protein have been designed to address a very general question of transmembrane receptor structure and function: What are the roles and interactions of the various deduced structural domains of such molecules in the initiation of the response of cells to extracellular signals? All of the evidence to date supports the previous hypothesis based on biochemical data that the IR requires ligand-activated TPK functions to initiate the insulin response by cells (for review, see Kahn 1985). Thus, mutations that compromise hIR TPK activity (site-directed point mutations or deletions) result in a concomitant decrease in at least one aspect of insulin action (glucose uptake; Ellis et al. 1986a). Other studies utilizing microinjection of antibodies to inhibit the receptor kinase have extended this conclusion to include a critical role for the receptor kinase in insulin's ability to stimulate ribosomal protein S6 phosphorylation in CHO cells, glycogen synthetase in hepatoma cells, glucose uptake in adipocytes (Morgan and Roth 1987), and frog oocyte maturation (Morgan et al. 1986). Second, analyses of cell lines that express experimentally truncated hIR TPKs demonstrate that, when membrane-anchored, this TPK domain is in fact capable of autonomous hormone-independent IR function: Such cells exhibit a constitutively elevated, insulin-independent uptake of 2-deoxyglucose (Ellis et al. 1987). Finally, by substitution of a homologous TPK for that of hIR, we find that although such a hybrid is capable of insulin-dependent transmembrane signaling (phosphorylation of the hybrid beta-subunit on tyrosine residues), the hybrid IR.ros molecule does not function as an IR in such cells: It mediates neither short-term (uptake of 2-deoxyglucose) nor long-term (incorporation of [3H]thymidine) effects of insulin (L. Ellis et al., in prep.). Together, these results suggest that (1) the hIR TPK domain conveys a substrate specificity for the insulin response and (2) that a functional hIR extracellular domain alone is not sufficient for generation of the insulin response (e.g., ligand-induced aggregation, or simple delivery of insulin into the cell). With the linking of the extracellular and cytoplasmic domains of the hIR molecule has evolved a cellular mechanism for the control of hIR TPK activity; the result is that cells which express the IR are now insulin responsive, and the physiological responses associated with the hormone are ligand-activated. Thus, the uncontrolled state of autonomous TPK activity, with the associated constitutive physiological response (e.g., as exhibited by the spBam hIR mutant), is circumvented.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of receptor-mediated transmembrane communication. 347 60

Phorbol-12-myristate-13-acetate (PMA) induced a dose-dependent proliferation of human hepatocarcinoma cell line SMMC-7721. In the presence of 100 nmol/L PMA, the activity of alkaline phosphatase was decreased and gamma-glutamyltransferase increased in the cell, suggesting that PMA is a proliferative inducer of hepatocarcinoma cell. PMA (100 nmol/L) also lead to a cytosol to membrane translocation of protein kinase C (PKC) within 5 minutes and down regulation after 1 hour. The decline of PKC activity in cytosolic fraction was far faster than that of membranous fraction. After long-term treatment with PMA for 1-5 days, the activities of PKC in cytosolic or membranous fraction almost disappeared, but the tyrosine protein kinase in both subcellular fractions was increased, being most obviously on the third day of culture. The increase in cytosolic TPK was more than that of membranous TPK, further indicating that TPK is a marker of cell proliferation.
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PMID:[Effect of phorbol ester on protein kinase C and tyrosine protein kinase in human hepatocarcinoma cell line]. 790 36

To better understand the role of beta-catenin mutation in hepatocellular carcinoma (HCC), we correlated the gene mutation with hepatitis virus B (HBV) and hepatitis virus C (HCV) status and the clinicopathological features in 366 patients with resected primary unifocal HCC. beta-Catenin mutations were also analyzed in 55 patients with multifocal HCC (68 tumors). Of the whole series, 57 (13.1%) of 434 tumors examined had beta-catenin mutations, 34 occurred at the serine/threonine residues of the GSK-3beta region of beta-catenin. Outside the GSK-3beta phosphorylation site, codons 32 and 34 were two mutational hot spots (17 tumors). The non-HBV-related HCC that was predominantly HCV related had a higher frequency of mutation (P: < 0.00001) and more frequent mutations at codon 45 than HBV-related HCC. HBV-related HCC had a younger mean age (P: < 0.00001), and higher male-to-female ratio (P: < 0.003) and positive familial history of HCC (P: < 0.014). Among 366 unifocal HCCs selected for clinicopathological analysis, beta-catenin mutations were associated with grade I (P: = 0.005) and stage I and II HCC (P: < 0.0001), and a better 5-year survival rate (P: = 0. 00003). These findings suggest mechanisms for beta-catenin mutations differ between HBV-related and non-HBV-related HCCs, and that beta-catenin mutation is a favorable prognostic factor related to low stage. beta-Catenin mutation was associated with nuclear expression of the protein (P: < 0.00001), but we failed to detect point or large fragment deletion mutation in 39 HCCs with nuclear beta-catenin expression, presumably wild-type protein. HCCs expressing mutant nuclear beta-catenin had a better 5-year survival rate (P: < 0.007), suggesting that mutant and wild-type nuclear beta-catenin proteins are not functionally equivalent and deserve more studies for further clarification.
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PMID:Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. 1098 Jan 16

We examined the interplay between the insulin/IGF-1- and beta-catenin-regulated pathways, both of which are suspected to play a role in hepatocarcinogenesis. Insulin and IGF-1 stimulated the transcription of a Lef/Tcf-dependent luciferase reporter gene by 3-4-fold in HepG2 cells. This stimulation was mediated through the activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and the inhibition of glycogen synthase kinase-3beta (GSK-3beta) since the effects of insulin and IGF-1 were inhibited by dominant-negative mutants of PI 3-K or Akt and an uninhibitable GSK-3beta. Together with inhibiting GSK-3beta, insulin and IGF-1 increased the cytoplasmic levels of beta-catenin. The PI 3-K/Akt/GSK-3beta pathway was not the sole to mediate insulin and IGF-1 stimulation of Lef/Tcf-dependent transcription. The Ras signalling pathway was also required as (i) the stimulatory effects of insulin and IGF-1 were inhibited by dominant-negative Ras or the MEK1 inhibitor PD98059 and (ii) activated Ha-Ras or constitutively active MEK1 synergized with catalytically inactive GSK-3beta to stimulate Lef/Tcf-dependent transcription. This study provides the first evidence that insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades bifurcating downstream of PI 3-K and involving GSK-3beta inhibition and Ras activation. These findings demonstrate for the first time the ability of insulin and IGF-1 to activate the beta-catenin pathway in hepatoma cells and thereby provide new insights into the role of these factors in hepatocarcinogenesis.
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PMID:Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. 1131 52

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.
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PMID:Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphatase and phosphoenolypyruvate carboxykinase gene expression. 1133 36

The molecular details of hypoxia-induced cellular responses have been difficult to identify since there is as yet no known oxygen receptor. We used cDNA microarray technology to extend our studies pertaining to these molecular details in human hepatocellular carcinoma (Hep3B) cells that produce erythropoietin (Epo) in response to hypoxia. Of approximately 1200 genes in the array, those associated with integrin-linked kinase (ILK), fibronectin precursor and glycogen synthase kinase-3beta (GSK-3beta) were markedly stimulated after exposure of Hep3B cells to low oxygen (1%) for 6 h. Epo, HIF-1, and von Hippel-Lindau cDNAs were measured in parallel as markers of low oxygen responses in Hep3B cells. ILK is a serine, threonine protein kinase that interacts with the cytoplasmic domains of integrin beta1 and beta3. This interaction localizes ILK to focal adhesion plaques. ILK is stimulated by cell-fibronectin interaction as well as insulin. It is regulated in a phosphatidylinositol 3-kinase dependent manner and can phosphorylate protein kinase B (PKB/AKT) and GSK-3beta. As a result of these and other activities ILK has been shown to affect anchorage-independent cell survival, cell cycle progression and tumorigenesis in nude mice. ILK has also been implicated in the Wnt pathway and as a critical target in PTEN-dependent tumor therapies. To our knowledge this is the first report implicating the ILK pathway in low oxygen responses. Other genes identified as a result of the microarray analysis not previously known to change as a result of low oxygen treatment were elongation factor-1alpha, glycyl-tRNA synthetase, and laminin receptor protein-1. These findings were all corroborated by RT-PCR assays and in some instances Western blot analysis.
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PMID:Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. 1140 33

Experimental data support a role for FAK, an important component of the integrin signaling pathway, in insulin action. To test the hypothesis that FAK plays a regulatory role in hepatic insulin action, we overexpressed wild type (WT), a kinase inactive (KR), or a COOH-terminal focal adhesion targeting (FAT) sequence-truncated mutant of FAK in HepG2 hepatoma cells. In control untransfected (NON) and vector (CMV2)- and WT-transfected cells, insulin stimulated an expected 54 +/- 13, 37 +/- 4, and 47 +/- 12 increase in [U-(14)C]glucose incorporation into glycogen, respectively. This was entirely abolished in the presence of either KR (-1 +/- 7%) or FAT mutants (0 +/- 8%, n = 5, p < 0.05 for KR or FAT versus other groups), and this was associated with a significant attenuation of incremental insulin-stimulated glycogen synthase (GS) activity. Insulin-stimulated serine phosphorylation of Akt/protein kinase B was significantly impaired in mutant-transfected cells. Moreover, the ability of insulin to inactivate GS kinase-3beta (GSK-3beta), the regulatory enzyme immediately upstream of GS, by serine phosphorylation (308 +/- 16, 321 +/- 41, and 458 +/- 34 optical densitometric units (odu) in NON, CMV2, and WT, respectively, p < 0.02 for WT versus CMV2) was attenuated in the presence of either FAT (205 +/- 14, p < 0.01) or KR (189 +/- 4, p < 0.005) mutants. FAK co-immunoprecipitated with GSK-3beta, but only in cells overexpressing the KR (374 +/- 254 odu) and FAT (555 +/- 308) mutants was this association stimulated by insulin compared with NON (-209 +/- 92), CMV2 (-47 +/- 70), and WT (-39 +/- 31 odu). This suggests that FAK and GSK-3beta form both a constitutive association and a transient complex upon insulin stimulation, the dissociation of which requires normal function and localization of FAK. We conclude that FAK regulates the activity of Akt/protein kinase B and GSK-3beta and the association of GSK-3beta with FAK to influence insulin-stimulated glycogen synthesis in hepatocytes. Insulin action may be subject to regulation by the integrin signaling pathway, ensuring that these growth and differentiation-promoting pathways act in a coordinated and/or complementary manner.
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PMID:Focal adhesion kinase (FAK) regulates insulin-stimulated glycogen synthesis in hepatocytes. 1180 46

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells.
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PMID:P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells. 1243 47

It has been reported that upstream components of the insulin-like growth factor (IGF) signaling axis could be overexpressed during hepatocarcinogenesis in humans and rodents. However, the signal transduction pathways activated downstream have been poorly studied. Here, we examined whether glycogen synthase kinase-3beta (GSK-3beta) could be a target in human hepatoma cell lines and transgenic ASV mice with hepatic expression of the SV40 large T antigen. In HuH7, Mahlavu, and Hep3B cells, basal levels of GSK-3beta(Ser9) phosphorylation were strongly elevated, indicating that GSK-3beta was inhibited. GSK-3beta phosphorylation was insensitive to exogenous IGFs and was blocked with an IGF-1 receptor-neutralizing antibody in Mahlavu and Hep3B cells. By using LY294002 and ML-9, which act as phosphatidylinositol 3-kinase (PI3-K) and Akt inhibitors, respectively, we showed that GSK-3beta phosphorylation required PI3-K activation in both cell lines whereas downstream Akt activation was required only in Mahlavu cells. However, in the 2 cell lines, GSK-3beta(Ser9) phosphorylation was controlled by protein kinase C (PKC)zeta because it was blocked by an inhibitory PKCzeta peptide. The blockage of GSK-3beta phosphorylation markedly inhibited glycogen synthesis and decreased beta-catenin expression. In addition, the overexpression of a constitutively active GSK-3beta reduced AP-1-mediated gene transcription in Hep3B cells. Finally, we observed that reexpression of IGF-2 in tumoral livers from ASV mice was associated with a marked phosphorylation of GSK-3beta. In conclusion, our results identify GSK-3beta as a molecular target of the constitutive activation of the IGF axis in in vitro and in vivo models of hepatocarcinogenesis. Persistent phosphorylation of GSK-3beta could be critical for regulation of glycogen metabolism and cell growth in hepatoma cells.
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PMID:Dysregulation of glycogen synthase kinase-3beta signaling in hepatocellular carcinoma cells. 1244 79

The aim of this study is to investigate the potential correlation between the expression of phosphorylated glycogen synthase kinase-3beta (phospho-GSK-3beta) and beta-catenin, and the mutations of beta-catenin gene at the consensus GSK-3beta phosphorylation site. The reason for this approach is to gain a better understanding of the molecular mechanisms of hepatocarcinogenesis in Malaysia. The expression of phospho-GSK-3beta and beta-catenin by immunohistochemistry and the mutations of beta-catenin were studied in 23 hepatocellular carcinoma (HCC) and surrounding tissues. Overexpression of phospho-GSK-3beta and beta-catenin was found in 12/23 (52.2%) and 13/23 (56.5%) in HCC tissues, 6/23 (26.1%) and 9/23 (39.1%) in surrounding tissues, respectively. Overexpression of beta-catenin in HCC tissues compared to the surrounding liver tissue was found to be higher in HCC tissues (p=0.015). In addition, we found that the expression of phospho-GSK-3beta was related with the accumulation of beta-catenin in surrounding tissues (p<0.05). The expression of phospho-GSK-3beta and its association with the development of HCC is reported for the first time. In addition, this is the first report from Malaysia which shows that there are no mutations at the GSK-3beta consensus phosphorylation sites on beta-catenin gene in all 23 paired HCC and surrounding tissues. This result differed from HCC in geographical areas with high aflatoxin exposure.
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PMID:GSK-3beta phosphorylation and alteration of beta-catenin in hepatocellular carcinoma. 1296 93

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