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)

The modulation of GnT-V activity by signaling molecules in PI-3-K/PKB pathway in human hepatocarcinoma cell line 7721 was studied. GnT-V activity was determined after the transfection of sense or antisense cDNA of PKB into the cells, as well as the addition of activators, specific inhibitors, and the antibodies to the enzyme assay system or culture medium. It was found that the basal activity of GnT-V was up regulated by the sense and down regulated by the antisense cDNA of PKB transfected into 7721 cells. GnT-V was activated by PIP2, PIP3 or GTPgamma[S] added to the assay system, and the activation of PIP2 or GTPgamma[S] was abolished by LY2940002, a specific inhibitor of PI-3-K, but the activation of PIP3 was not attenuated by LY2940002. In addition, GnT-V activity in cultured parental or H-ras transfected cells was inhibited by the antibody against PKB or PI-3-K. These findings demonstrated the involvement of PI-3-K/PKB signaling pathway in the regulation of GnT-V. Moreover, ET18-OCH3, an inhibitor of Raf translocation and PI-PLC enzyme, which produces the activator of PKC, as well as the antibodies against Raf-1 or MEK also inhibited GnT-V activity in the parental and H-ras transfected cells. The inhibitory rates, however, were less in the transfected cells than those in the parental cells. These results reveal that in parental and H-ras transfected 7721 cells, the basal activity of GnT-V is also regulated by the Ras/Raf-1/MEK/MAPK cascade in addition to PI-3-K/PKB signaling pathway. The significance of these two pathways in the regulation of GnT-V and their relations to the activation of PKC previously reported by our laboratory (Ju TZ et al., 1995 Glyconjugate J 12, 767-772) was discussed.
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PMID:Modulation of the basal activity of phosphatidylinositol-3-kinase/protein kinase B signaling pathway in human hepatocarcinoma cells. 1126 40

A property of signal transduction pathways that might explain their efficiency and specificity is the formation of signaling complexes. The recent demonstration that adaptor proteins can interact with many components of the extracellular signal-regulated kinases (ERKs) signaling cascade leads us to investigate whether such complexes may include the transmembrane receptor. The present work shows that in human hepatoma Hep3B cells, insulin receptor (IR) can be coimmunoprecipitated with other components of the ERKs cascade: insulin receptor substrate (IRS), Raf-1, and ERKs. Furthermore, these complexes formed near the cytoplasmic membrane even prior to insulin stimulation.
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PMID:Complexes formation between insulin receptor and extracellular signal-regulated kinases ERKs. 1140 18

Chronic hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The HCV capside core is a multifunctional protein with regulatory functions that affects transcription and cell growth in vitro and in vivo. Here, we show that both HCV genotype 1a and 3 core proteins activate MEK1 and Erk1/2 MAP kinases and that the costitutive expression of the HCV core results in a high basal activity of Raf1 and MAP/kinase/kinase, as determined by endogenous Raf1 in vitro kinase assay and immunodetection of hyperphosphorylated Erk1 and Erk2 even after a serum starvation. Moreover, the activation of both Erk1/2 and the downstream transcription factor Elk-1 in response to the mitogenic stimulus EGF is significantly prolonged. The sustained response to EGF in cells expressing the HCV core occurs despite a normal induction of the MAP phosphatases MKP regulatory feedback and is likely due to the costitutive activation of Raf-1 activity. The ability of HCV core proteins to directly activate the MAP kinase cascade and to prolong its activity in response to mitogenic stimuli may contribute to the neoplastic transformation of HCV infected liver cells.
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PMID:Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. 1142 Jun 71

Gene expression profiling with cDNA array allows simultaneous analysis of the gene expression pattern of a large number of genes and may enhance the investigation of the molecular mechanisms involved in the treatment of hepatocellular carcinoma with cisplatin. We used cDNA array technology to assess the gene expression profiles related to cell cycle regulation and apoptosis in human hepatoma Hep3B cells in response to cisplatin treatment. In Hep3B cells, apoptosis induced by cisplatin was p53-independent, and was associated with up-regulation of cell cycle regulators, pro-apoptotic genes, growth receptors, and genes involved in signal transduction. These included p33ING1, c-Abl, Bax, insulin-like growth factor binding protein 3, Siva, cyclin D1, RhoA, and Raf-1. Down-regulation of cell cycle regulator CDC2 was observed. Semi-quantitative reverse transcription-polymerase chain reaction and/or Western blot analysis performed on seven of these genes confirmed their upregulation of gene expression. Such global analysis of the cytotoxic response to chemotherapeutic drugs may yield insight into the mechanisms of drug action and allow rational design of more effective treatment strategies.
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PMID:Gene expression profiling by cDNA array in human hepatoma cell line in response to cisplatin treatment. 1199 Dec 55

Liver cirrhosis accompanies at least 70% of hepatocellular carcinomas world-wide. To evaluate the dysregulation of apoptosis and the MAPK pathway in hepatocarcinogenesis, we investigated the expression profiles of the genes involved in apoptosis and MAPK pathway in cirrhosis and hepatocellular carcinoma. A total of 94 tissue specimens (61 cirrhosis and 33 hepatocellular carcinoma) obtained from 67 patients were analyzed by microarray, quantitative PCR and Western blot experiments. Of 71 apoptosis-associated genes, c-raf-1 and S6 were up-regulated in 42.9% and 32.1% of 28 cirrhosis tissues, respectively, and both genes were well correlated in a five-cluster K-means analysis. For c-raf-1 and down stream genes in the MAPK pathway, c-raf-1, MEK, and MAPK were up-regulated in 40%, 80%, and 86.7% of 45 cirrhosis specimens, respectively, and in 50%, 63.6%, and 59.1% of 22 hepatocellular carcinoma specimens, respectively. Western blot analysis showed that activated Raf-1 was over-expressed in 91.2% (52/57) of cirrhosis and in 100% (30/30) of hepatocellular carcinoma. The expression level of Raf-1 in 14 of 26 paired samples (53.8%) was significantly higher in hepatocellular carcinoma than in cirrhosis ( [Formula: see text] -fold, [Formula: see text] ). These results suggest that the activation of Raf-1 plays an important role in the development of hepatocellular carcinoma.
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PMID:Over-expression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma. 1516 33

We have previously shown that Compound 5 (Cpd 5), an inhibitor of protein phosphatase Cdc25A, inhibits Hep3B human hepatoma cell growth. We now show that hepatocyte growth factor (HGF), a hepatocyte growth stimulant, can strongly enhance Cpd 5-induced growth inhibition in Hep3B cells, and this enhancement in cell growth inhibition is correlated with a much stronger ERK phosphorylation when compared to cells treated with Cpd 5 or HGF separately. We found that HGF/Cpd 5-induced ERK phosphorylation and cell growth inhibition were mediated by Akt (protein kinase B) pathway, since combination HGF/Cpd 5 treatment of Hep3B cells inhibited Akt phosphorylation at Ser-473 and its kinase activity, which led to the suppression of Raf-1 phosphorylation at Ser-259. The suppression of Raf-1 Ser-259 phosphorylation caused the induction of Raf-1 kinase activity, as well as hyper-ERK phosphorylation. Transient transfection of Hep3B cells with dominant negative Akt c-DNA further enhanced both Cpd 5- and HGF/Cpd 5-induced ERK phosphorylation, while over-expression of wild-type Akt c-DNA diminished their effects. In contrast, HGF antagonized the growth inhibitory actions of Cpd 5 on normal rat hepatocytes, thus showing a selective effect on tumor cells compared to normal cells. Our data suggest that Akt kinase negatively regulates MAPK activity at the Akt-Raf level. Suppression of Akt activity by either combination HGF/Cpd 5 treatment or by dominant negative Akt c-DNA transfection antagonizes the Akt inhibitory effect on Raf-1, resulting in an enhancement of Cpd 5-induced MAPK activation and cell growth inhibition.
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PMID:Hepatocyte growth factor enhances protein phosphatase Cdc25A inhibitor compound 5-induced hepatoma cell growth inhibition via Akt-mediated MAPK pathway. 1553 60

Development of radiation resistance is one of the major reasons that cancer cells do not respond to radiotherapy and the mechanism for resistance is still not clear. Two sublines of human hepatocellular carcinoma Hep G2 cells were established from cells that survived two different irradiation regimes, 2 Gy for 10 days or 10 Gy for 2 days, respectively. Using MTT assay, the radiation conditioned cells were found to be more resistant to gamma-irradiation and have a greater extent of potentially lethal damage repair (PLDR) for radiation than the parent cells. By Western blot analysis, the radiation-conditioned cells were found to overexpress Raf-1 which is known to regulate the radiation resistance of cells. Inhibition of Raf-1 expression by antisense oligonucleotides increased the radiation sensitivity of the radiation-conditioned cells while inhibitors of Ras (L744,832), PI3K (LY294002) and p38 (SB203580) had no effect. Moreover, antisense Raf-1 oligonucleotides also decreased the radiation induced PLDR capacity of the radiation conditioned cells. It is therefore suggested that Raf-1 may induce radiation resistance through an increase in radiation induced PLDR capacity in Hep G2 cells.
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PMID:The role of Raf-1 in radiation resistance of human hepatocellular carcinoma Hep G2 cells. 1554 62

Growth hormone (GH) plays an important role in growth and metabolism by signaling via at least three major pathways, including STATs, ERK1/2, and phosphatidylinositol 3-kinase/Akt. Physiological concentrations of insulin promote growth probably by modulating liver GH receptor (GHR) levels in vivo, but the possible effects of insulin on GH-induced post-GHR signaling have yet to be studied. We hypothesized that short-term insulin, similar to the fluctuations that occur following feeding, affects GH-induced post-GHR signaling. Our present studies suggest that, in rat H4IIE hepatoma cells, insulin (4 h or less) selectively enhanced GH-induced phosphorylation of MEK1/2 and ERK1/2, but not GH-induced activation of STAT5 and Akt. Although insulin pretreatment altered GH-induced formation of Shc.Grb2.SOS complex, it did not significantly affect GH-induced activation of other signaling intermediates upstream of MEK/ERK, including JAK2, Ras, and Raf-1. Immunofluorescent staining indicated that insulin pretreatment facilitated GH-induced cell membrane translocation of MEK1/2. Insulin pretreatment also increased the amount of MEK association with its scaffolding protein, KSR. In summary, short-term insulin treatment of cultured, liver-derived cells selectively sensitized GH-induced MEK/ERK phosphorylation independent of JAK2, Ras, and Raf-1, but likely resulted from increased cell membrane translocation of MEK1/2. These findings suggest that insulin may be necessary for sensitization of cells to GH-induced ERK1/2 activation and provides a potential cellular mechanism by which insulin promotes growth.
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PMID:Insulin enhances growth hormone induction of the MEK/ERK signaling pathway. 1627 59

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
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PMID:Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. 1647 53

Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.
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PMID:Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors. 1665 41


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