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 epidermal growth factor receptor (EGFR) is overexpressed in many epithelial tumors and plays an important role in the tumorigenesis of these tumors. Inhibitors of EGFR reduce the proliferation rate of cancers and are promising therapeutic agents of cancers. Recently, two studies have identified somatic mutations in the exons 18-21 of EGFR that were strongly correlated with robust clinical response to gefitinib treatment in patients with non-small cell lung cancer. To investigate whether EGFR mutation is involved in the tumorigenesis of hepatocellular carcinoma (HCC), we performed direct sequencing of exons 18-21 on 89 HCCs. No mutations causing amino acid changes or deletions were identified. The results indicate mutation of the kinase domain of EGFR does not play a significant role in the tumorigenesis of HCC and gefitinib is unlikely to be used as single-drug therapy for HCC.
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PMID:Absence of epidermal growth factor receptor exon 18-21 mutation in hepatocellular carcinoma. 1591 Nov 7

Recently, cryoconservable polyethylene glycol (PEG)-shielded and epidermal growth factor receptor (EGFR)-targeted polyplexes (EGF+ polyplexes) were engineered in our laboratory for tumor-directed transfer and expression of DNA. Here, we further analyzed specificity and kinetics of EGFR-mediated cellular uptake of these polyplexes. Similar to our previous results, EGF+ polyplexes significantly enhanced the transfection efficiency as compared to polyplexes without EGF (EGF- polyplexes) in HUH-7 hepatoma cells and Renca-EGFR renal carcinoma cells. EGF+ polyplexes rapidly associated with the cells within 30 min of exposure, and binding of EGF+ polyplexes to the cells after 4 h was significantly higher than that of EGF- polyplexes. In the presence of free EGF, both cell association and transfection efficiency of EGF+ polyplexes were markedly reduced indicating that these effects were primarily mediated via ligand receptor interaction. Fluorescence microscopy revealed that the cell-associated EGF+ polyplexes aggregated to micrometer sized clusters, resembling typical clustering of receptors upon ligand binding. In conclusion, EGFR-targeting enhances transfection efficiency due to accelerated and increased cell association followed by aggregation of the bound EGF+ polyplexes.
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PMID:Cryoconserved shielded and EGF receptor targeted DNA polyplexes: cellular mechanisms. 1593 38

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

Recent evidence indicates that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are involved in hepatocarcinogenesis. This study was designed to evaluate the possible interaction between the COX-2 and EGFR signaling pathways in human hepatocellular carcinoma (HCC) cells. Immunohistochemical analysis using serial sections of human HCC tissues revealed positive correlation between COX-2 and EGFR in HCC cells (P < 0.01). Overexpression of COX-2 in cultured HCC cells (Hep3B) or treatment with PGE(2) or the selective EP(1) receptor agonist, ONO-DI-004, increased EGFR phosphorylation and tumor cell invasion. The PGE(2)-induced EGFR phosphorylation and cell invasiveness were blocked by the EP(1) receptor siRNA or antagonist ONO-8711 and by two EGFR tyrosine kinase inhibitors, AG1478 and PD153035. The EP(1)-induced EGFR transactivation and cell invasion involves c-Src, in light of the presence of native binding complex of EP(1)/Src/EGFR and the inhibition of PGE(2)-induced EGFR phosphorylation and cell invasion by the Src siRNA and the Src inhibitor, PP2. Further, overexpression of COX-2 or treatment with PGE(2) also induced phosphorylation of c-Met, another receptor tyrosine kinase critical for HCC cell invasion. Moreover, activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells, whereas blocking PGE(2) synthesis or EP(1) attenuated EGFR phosphorylation induced by EGF, suggesting that the COX-2/PGE(2)/EP(1) pathway also modulate the activation of EGFR by its cognate ligand. These findings disclose a cross-talk between the COX-2/PGE(2)/EP(1) and EGFR/c-Met signaling pathways that coordinately regulate human HCC cell invasion.
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PMID:Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. 2617 17

We have shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) inhibits the development of intrahepatic metastases of hepatocellular carcinoma CBO140C12, and EGFR transactivation by tumor necrosis factor-alpha is a possible target of gefitinib. In the present study, we focused on the fibronectin (FN)-dependent signaling pathway to further elucidate the antimetastatic activity of gefitinib in CBO140C12 cells. We initially observed that FN induced activation of extracellular signal-regulated kinase (ERK), p38 and Akt, as well as cell proliferation and CBO140C12 cell invasion. These responses were mediated by EGFR tyrosine kinase, because gefitinib inhibited these effects of FN. FN-induced ERK, p38 and Akt activation was partly blocked by the Arg-Gly-Asp (RGD)-pseudo-peptide FC-336, anti-alphav integrin antibody RMV-7, the broad-spectrum matrix metalloprotease inhibitor GM6001 and the broad spectrum a disintegrin and metalloprotease (ADAM) inhibitor TAPI-1. But these inhibitors had no effect on EGF-induced signaling pathways, suggesting that integrins and ADAM may be upstream components of EGFR in these responses. These results suggest that FN-induced activation of ERK, p38, Akt, cell proliferation and invasion was mediated, at least in part, via integrins, ADAM and EGFR, and that this FN-induced signaling pathway might be involved in the antimetastatic activity of gefitinib.
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PMID:Activation of MEK/ERK and PI3K/Akt pathways by fibronectin requires integrin alphav-mediated ADAM activity in hepatocellular carcinoma: a novel functional target for gefitinib. 1644 27

Increased expression of epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, is associated with tumor progression in many carcinomas. Epidermal growth factor receptor inhibitors have shown promise in treating some of these tumors. Fibrolamellar hepatocellular carcinoma (FL-HCC) is an aggressive neoplasm that occurs in young patients with no history of cirrhosis. This study examines the expression and gene copy number of EGFR in FL-HCC. Formalin-fixed, paraffin-embedded FL-HCC (n = 13) sections were stained with a monoclonal antibody against EGFR. Fluorescence in situ hybridization analysis was performed using probes against EGFR gene and centromeric region of chromosome 7 (CEP 7). Epidermal growth factor receptor and CEP 7 signals were counted in 50 tumor nuclei per case as well as 300 normal hepatocyte nuclei. The EGFR to CEP 7 signal ratio was calculated for each case. Most (92%, 12/13) of FL-HCC showed strong and diffuse staining with anti-EGFR antibody. Fluorescence in situ hybridization was informative in 11 cases, 10 of which showed extra EGFR gene copy numbers (mean, 3.69; range, 3.13-5.0). Epidermal growth factor receptor was overexpressed in all these cases. The mean number of EGFR signals per cell in FL-HCC was double that of normal hepatocytes (3.69 versus 1.80); the mean EGFR/CEP 7 ratio in tumor cells was 1.05. In conclusion, EGFR is strongly overexpressed on the cell membrane in nearly all cases of FL-HCC. Similar gains of chromosome 7 are observed, indicating that the extra EGFR gene copies are due to polysomy rather than gene amplification. The strong expression of EGFR in FL-HCC tumors suggests that they may respond to treatment with EGFR antagonists.
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PMID:Epidermal growth factor receptor expression and gene copy number in fibrolamellar hepatocellular carcinoma. 1656 14

Hepatocellular carcinoma (HCC) is one of the most common tumor-related causes of death worldwide for which there is still no satisfactory treatment. We previously reported the antiangiogenic effect of gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been used successfully to treat lung cancer. In this study, we investigated the effects of gefitinib on tumor-induced angiogenesis by using HCC cell lines (HCC3, CBO12C3, and AD3) in vitro as well as in vivo. Oral administration of gefitinib inhibited angiogenesis induced by HCC3 and CBO12C3, but not by AD3 in the mouse dorsal air sac model. Production of both vascular endothelial growth factor (VEGF) and chemokine C-X-C motif ligand 1 (CXCL1) by EGF-stimulated HCC was more markedly inhibited by gefitinib in HCC3 and CBO12C3 cells than in AD3 cells. EGF stimulated the phosphorylation of EGFR, Akt, and extracellular signal-regulated kinase 1/2 (ERK1/2) in HCC3 and CBO12C3 cells, whereas EGF stimulated phosphorylation of EGFR and ERK1/2, but not Akt in AD3 cells. In fact, Akt was constitutively activated in the absence of EGF in AD3 cells. Gefitinib inhibited Akt phosphorylation in all three cell lines, but it was about five times less effective in AD3 cells. The concentration of PTEN in AD3 cells was about a half that in HCC3 and CBO12C3 cells. Transfection of HCC3 cells with PTEN small interfering RNA reduced their sensitivity to gefitinib in terms of its inhibitory effect on both Akt phosphorylation and the production of VEGF and CXCL1. In conclusion, effect of gefitinib on HCC-induced angiogenesis depends on its inhibition of the production of angiogenic factors, probably involving a PTEN/Akt signaling pathway.
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PMID:PTEN/Akt signaling through epidermal growth factor receptor is prerequisite for angiogenesis by hepatocellular carcinoma cells that is susceptible to inhibition by gefitinib. 1670 61

Hepatocellular carcinoma is a major cause of cancer-related deaths. Current treatments are not effective, and the identification of relevant pathways and novel therapeutic targets are much needed. Increasing evidences point to the activation of the epidermal growth factor receptor (EGFR) as an important mechanism in the development of hepatocarcinoma. We previously described that amphiregulin (AR), a ligand of the EGFR, is not expressed in healthy liver but is up-regulated during chronic liver injury, the background on which most liver tumors develop. Now, we have studied the expression and role of AR in human hepatocarcinoma. AR expression and function was studied in human liver tumors and cell lines. AR is expressed in human hepatocellular carcinoma tissues and cell lines and behaves as a mitogenic and antiapoptotic growth factor for hepatocarcinoma cells. We provide several lines of evidence, including AR silencing by small interfering RNAs and inhibition of amphiregulin by neutralizing antibodies, showing the existence of an AR-mediated autocrine loop that contributes to the transformed phenotype. Indeed, interference with endogenous AR production resulted in reduced constitutive EGFR signaling, inhibition of cell proliferation, anchorage-independent growth, and enhanced apoptosis. Moreover, knockdown of AR potentiated transforming growth factor-beta and doxorubicin-induced apoptosis. Conversely, overexpression of AR in SK-Hep1 cells enhanced their proliferation rate, anchorage-independent growth, drug resistance, and in vivo tumorigenic potential. These observations suggest that AR is involved in the acquisition of neoplastic traits in the liver and thus constitutes a novel therapeutic target in human hepatocarcinoma.
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PMID:Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. 1677 86

Our previous studies have shown that overexpression of beta1,4-galactosyltransferase1 (beta1,4GT1) leads to increased apoptosis induced by cycloheximide (CHX) in SMMC-7721 human hepatocarcinoma cells. However, the role of beta1,4GT1 in apoptosis remains unclear. Here we demonstrated that cell surface beta1,4GT1 inhibited the autophosphorylation of epidermal growth factor receptor (EGFR) especially at Try 1068. The phosphorylation of protein kinase B (PKB/Akt) and extracellular signal-regulated protein kinase1/2 (ERK1/2), which are downstream molecules of EGFR, were also reduced in cell surface beta1,4GT1-overexpressing cells. Furthermore, the translocations of Bad and Bax that are regulated by PKB/Akt and ERK1/2 were also increased in these cells. As a result, the release of cytochrome c from mitochondria to cytosol was increased and caspase-3 was activated. In contrast, RNAi-mediated knockdown of beta1,4GT1 increased the autophosphorylation of EGFR. These results demonstrated that cell surface beta1,4GT1 may negatively regulate cell survival possibly through inhibiting and modulating EGFR signaling pathway.
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PMID:Cell surface beta 1, 4-galactosyltransferase 1 promotes apoptosis by inhibiting epidermal growth factor receptor pathway. 1678 97

Exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produces hydronephrosis in developing mice, the etiology of which involves hyperplasia within the ureteric luminal epithelium. Dysregulation of epidermal growth factor receptor (EGFR), EGF, and transforming growth factor-alpha expression has been implicated as playing a role in TCDD-induced hydronephrosis. In this study, changes in the expression of genes encoding the EGFR and its cognate ligands in response to TCDD were evaluated within the developing ureter. C57BL/6 dams were injected ip with 30 mug/kg TCDD on gestational day (GD) 13 or 16 and fetal tissues removed on GD 17. Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator messenger RNA (mRNA) were expressed in control and treated fetal tissues at GD 14 and 17. Prototypical AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 were upregulated in TCDD-exposed fetal tissues, demonstrating AHR transcriptional activity at these developmental stages. Amphiregulin (AREG) and epiregulin, ligands for the EGFR, were induced at the transcriptional level in ureters of fetuses exposed to TCDD for 24 h. AREG mRNA was also induced by TCDD dose- and time-dependently in the mouse hepatoma cell line Hepa-1c1c7 (Hepa-1), mimicking the induction patterns of CYP1A1 mRNA. Other AHR ligands also induced AREG mRNA in Hepa-1 cells. Furthermore, variant Hepa-1 cells (TAOBP(r)c1 cells) virtually deficient in the AHR failed to display an increase in AREG mRNA in response to TCDD. Taken together, these data suggest that the AHR cross talks with the EGFR signaling pathway by directly inducing the expression of growth factors that are important for EGFR signaling in the developing mouse ureter.
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PMID:In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin induces amphiregulin gene expression in the developing mouse ureter. 1692 9


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