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)

Although cooperative interactions between growth factors and integrins, cell surface receptors for extracellular matrices (ECM), have been reported, little is known about the interaction between hepatocyte growth factor (HGF) and integrin in hepatoma cells. We investigated the effects and mechanisms of integrin on the proliferation of hepatoma cells regulated by HGF. Human HepG2 hepatoma cells stably transfected with beta 1-integrin were treated with HGF and compared with parental and mock-transfected control cells. Cell proliferation and expression of cyclin-dependent kinase (Cdk) inhibitors and S-phase kinase-associated protein 2 (Skp2), were investigated. HGF dose-dependently suppressed the proliferation of parental and mock-transfected HepG2 cells. However, cells overexpressing beta 1-integrin exhibited increased proliferation in response to HGF. Although HGF increased p27 and decreased Skp2 expression in the parental and mock-transfected cells, the p27 and Skp2 levels in cells overexpressing beta 1-integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing beta 1-integrin showed increased Skp2 expression. Furthermore, HGF did not reduce the proliferation of HepG2 cells transfected with antisense p27 or sense Skp2. Thus, HGF suppresses HepG2 cell proliferation by directly increasing p27 expression and indirectly decreasing Skp2 expression, and beta 1-integrin modulates the responsiveness of hepatoma cells to HGF via a p27-dependent manner by increasing Skp2. In conclusion, these results strongly suggest that integrin-mediated signals from the ECM can modulate growth factor-mediated signals in hepatoma cells, and may contribute to the growth of hepatocellular carcinomas.
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PMID:Mechanism of beta 1-integrin-mediated hepatoma cell growth involves p27 and S-phase kinase-associated protein 2. 1288 71

The inactivation of the p16INK4A (p16) gene by promoter hypermethylation has been reported in many human cancers. We previously reported that aberrant p16 RNA transcripts are expressed in hepatocellular carcinoma (HCC) cell lines having hypermethylated p16 promoters. In this study, we investigated the functional roles of aberrant p16 RNA transcripts in HCC cells to elucidate molecular events underlying hepatocarcinogenesis. The aberrant p16 RNA transcripts encoded key peptides (amino acids 84-103) involved in binding with cyclin-dependent kinase (CDK) 4. GST-aberrant p16 fusion proteins were found to interact with endogenous CDK4 in vitro. Furthermore, overexpression of these aberrant p16 RNA transcripts resulted in decreased cell proliferation rate, enlargement of cell shape and reduced level of hyperphosphorylated forms of pRb. Overall, our results suggest that the aberrant p16 RNA transcripts have functions similar to those of wild type p16 in controlling cell cycle.
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PMID:Aberrant p16INK4A RNA transcripts expressed in hepatocellular carcinoma cell lines regulate pRb phosphorylation by binding with CDK4, resulting in delayed cell cycle progression. 1295 83

mRNA abundance for a number of genes is increased by amino acid limitation. From an array screening study in HepG2 human hepatoma cells, it was established that one set of genes affected by amino acid availability is the set associated with cell-cycle control. The present study describes the increased expression of both mRNA and protein for the cyclin-dependent kinase inhibitors p21 and p27 in response to deprivation of HepG2 cells for a single essential amino acid, histidine. The increase in p21 and p27 mRNA content depended on de novo protein synthesis and involved a post-transcriptional mRNA stabilization component. For p21, increase in mRNA by histidine depletion appeared to be independent of p53 transactivation, and the absolute level of p53 protein was unaffected by this treatment. Histidine limitation caused an increase in the phosphorylation of ERK1/ERK2 (extracellular-signal-regulated kinase), and inhibition of the ERK signal transduction pathway resulted in a reduction in the starvation-dependent increase in p21 mRNA. Blockade of the phosphoinositide 3-kinase and mTOR (mammalian target of rapamycin) pathways also blunted the increase in p21 mRNA content. These results document the amino acid-dependent control of the synthesis of specific cell-cycle regulators and help to explain the block at G1 phase after amino acid limitation.
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PMID:Induction of p21 and p27 expression by amino acid deprivation of HepG2 human hepatoma cells involves mRNA stabilization. 1471 82

Growth inhibition by transforming growth factor (TGF)-beta 1 has been attributed to the induction of cyclin-dependent kinase inhibitors, among which p21/Waf1 plays a major role in many biological contexts. In the present study, two new intracellular mediators for the induction of p21/Waf1 by TGF-beta 1 were identified in a human hepatocellular carcinoma cell line (JHH-5) expressing mutant-type p53. After addition of TGF-beta 1 to JHH-5 cells, a marked increase of the p21/Waf1 expression preceded the inhibition of DNA synthesis. Expression of IFN regulatory factor (IRF)-1, a known transacting factor for p21/Waf1 promoter, was elevated just before or in parallel with the increase of p21/Waf1. Transduction of antisense IRF-1 inhibited the increase in p21/Waf1 in JHH-5 cells treated with TGF-beta 1 and partially released the cells from the growth arrest by TGF-beta 1. Expression of S100C/A11, a member of the Ca(2+)-binding S100 protein family, also markedly increased after addition of TGF-beta 1. S100C/A11 protein was translocated to and accumulated in nuclei of TGF-beta 1-treated JHH-5 cells, where p21/Waf1 was concomitantly accumulated. When a recombinant S100C/A11 protein was introduced into nuclei of JHH-5 cells, DNA synthesis was markedly inhibited in a dose-dependent manner in the absence of TGF-beta 1. Prior transfection of p21/Waf1-targeted small interfering RNA efficiently blocked decrease of DNA synthesis in JHH-5 cells caused by TAT-S100C/A11 or TGF-beta 1 and markedly inhibited expression of p21/Waf1 protein in the cells. These results indicate that IRF-1 and S100C/A11 mediate growth inhibition by TGF-beta 1 via induction of p21/Waf1.
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PMID:Involvement of interferon regulatory factor 1 and S100C/A11 in growth inhibition by transforming growth factor beta 1 in human hepatocellular carcinoma cells. 1520 26

Oncostatin M regulates membrane traffic and stimulates apicalization of the cell surface in hepatoma cells in a protein kinase A-dependent manner. Here, we show that oncostatin M enhances the expression of the cyclin-dependent kinase (cdk)2 inhibitor p27(Kip1), which inhibits G(1)-S phase progression. Forced G(1)-S-phase transition effectively renders presynchronized cells insensitive to the apicalization-stimulating effect of oncostatin M. G(1)-S-phase transition prevents oncostatin M-mediated recruitment of protein kinase A to the centrosomal region and precludes the oncostatin M-mediated activation of a protein kinase A-dependent transport route to the apical surface, which exits the subapical compartment (SAC). This transport route has previously been shown to be crucial for apical plasma membrane biogenesis. Together, our data indicate that oncostatin M-stimulated apicalization of the cell surface is critically dependent on the ability of oncostatin M to control p27(Kip1)/cdk2-mediated G(1)-S-phase progression and suggest that the regulation of apical plasma membrane-directed traffic from SAC is coupled to centrosome-associated signaling pathways.
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PMID:Oncostatin M-stimulated apical plasma membrane biogenesis requires p27(Kip1)-regulated cell cycle dynamics. 1524 Aug 18

This study delineates the antiproliferative activities and in vivo efficacy of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] in human hepatocellular carcinoma cells. YC-1 inhibited the growth of HA22T and Hep3B cells in a concentration-dependent manner without significant cytotoxicity. YC-1 induced G(1) phase arrest in the cell cycle, as detected by an increase in the proportion of cells in the G(1) phase using FAC-Scan flow cytometric analysis. It was further shown that cGMP, p42/p44 mitogen-activated protein kinase, or AKT kinase-mediated signaling pathways did not contribute to the YC-1-induced effect. Of note, YC-1 induced a dramatic increase in the expression of cyclin-dependent kinase (CDK)-inhibitory protein, p21(CIP1/WAP1), and a modest increase in p27(KIP1). The association of p21(CIP1/WAP1) with CDK2 was markedly increased in cells responsive to YC-1. YC-1 did not modify the expression of cyclin D1, cyclin E, CDK2, or CDK4. In a corollary in vivo study, YC-1 induced dose-dependent inhibition of tumor growth in mice inoculated with HA22T cells. Immunohistochemical analysis revealed an inverse relationship between the staining of p21(CIP1/WAF) and the staining of Ki-67, a cell proliferation marker. Based on the results reported herein, we suggest that YC-1 induces cell cycle arrest and inhibits tumor growth both in vitro and in vivo via the up-regulation of p21(CIP1/WAP1) expression in HA22T cells. Because of this, YC-1 is a potential antitumor agent worthy of further investigation.
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PMID:YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] exhibits a novel antiproliferative effect and arrests the cell cycle in G0-G1 in human hepatocellular carcinoma cells. 1552 95

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24

After the transfection of alpha-1,3-fucosyltransferase (FucT)-VII cDNA into H7721 human hepatocarcinoma cells, the protein expression of some cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDIs) p16INK4 and p21waf1/Cip1 were unchanged. However, CDI p27Kip1 protein, both the total amount and the amount that bound to CDK2, but not its mRNA, was significantly reduced. The de-inhibited CDK2 stimulated the phosphorylation of retinoblastoma (Rb) protein and facilitated the G1/S transition and growth rate of the cells. The decrease of p27Kip1 protein, the increase of CDK2 activity and Rb phosphorylation, as well as the cell growth and percentage of S phase cells were correlated to the increased amount of cell surface sialyl Lewis X (SLe(x)) antigen in cells with different alpha-1,3-FucT-VII expression. The reduction in p27Kip1 and the difference in its expression among different transfected cells were blocked by the SLe(x) antibody KM93 in a dose-dependent manner, indicating that p27Kip1 expression was influenced by alpha-1,3-FucT-VII and its product SLe(x). The MEK/MAPK signaling pathway was more important than the PI-3K pathway in the regulation of p27Kip1 expression.
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PMID:alpha-1,3-Fucosyltransferase-VII stimulates the growth of hepatocarcinoma cells via the cyclin-dependent kinase inhibitor p27Kip1. 1566 88

Although a number of studies have shown that vitamins K1, K2 and K3 exerted antitumor effects on various types of rodent- and human-derived neoplastic cell lines, it has not been examined whether or not vitamin K5 also possesses antitumor activity. In the present study, we examined the antitumor effects of vitamin K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of vitamin K5 not only in vitro but also in vivo. Vitamin K5 was shown to suppress the proliferation of PLC/PRF/5 cells at a concentration of 30 microM. By a flow cytometric analysis, it was shown that although vitamin K5 did not induce apoptosis on PLC/PRF/5 cells, it did induce G1 arrest on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that vitamin K5 markedly suppressed the growth of HCC tumors. Although protein expression levels of cyclin D1 and p16INK4a cyclin-dependent kinase (Cdk) inhibitor in HCC tumors were not decreased by vitamin K5 treatment, those of Cdk4 were reduced significantly by the treatment. Taken collectively, vitamin K5 could induce potent antitumor effects on HCC not only in vitro but also in vivo, at least in part by inducing G1 arrest of cell cycle through downregulation of Cdk4 expression. The results demonstrated here indicate that vitamin K5 may be a useful agent for the treatment of patients with HCC.
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PMID:In vitro and in vivo antitumor effects of vitamin K5 on hepatocellular carcinoma. 1580 26

Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5 year survival new therapeutic approaches are mandatory. Several reports indicate that the epidermal growth factor receptor (EGFR) is expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. Cetuximab, a chimeric monoclonal IgG1 antibody directed against the EGFR, potently suppresses the growth of various cancers but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of cetuximab in human HCC cells alone and in combination with growth factor tyrosine-kinase inhibition (TKI) or HMG-CoA-reductase inhibiton or conventional cytostatics. Cetuximab inhibited growth of p53 wild-type HepG2 hepatocellular cancer cells in a time- and dose-dependent manner. Cetuximab treatment resulted in arresting the cell cycle in the G(1)/G(0)-phase due to an increase of expression of the cyclin-dependent kinase inhibitors p21(Waf1/CIP1) and p27(Kip1) and a decrease in cyclin D1 expression. Additionally, we observed a moderate increase in apoptosis as demonstrated by caspase-3 activation. Combining cetuximab with TKIs (erlotinib or AG1024) or the HMG-CoA-reductase inhibitor fluvastatin or doxorubicin resulted in synergistic antiproliferative effects. In contrast, p53 mutated Huh-7 hepatocellular cancer cells proved to be less sensitive towards cetuximab, but when combined with TKIs or fluvastatin or doxorubicin a pronounced reduction of cell growth was observed. To conclude, our study may provide a rationale for future clinical investigations of cetuximab combination therapy for growth control of hepatocellular cancer.
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PMID:EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. 1622 26


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