Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study is to investigate if the EGFR-Stat3 signal pathway contributes to the carcinogenesis of hepatoma in rats. Hepatoma was induced in rats by 3'Me-DAB as a model. EGFR, TGFalpha, Stat3, p-Stat3 in different stages of carcinogenesis were detected by immunohistochemistry and Western blot. In situ hybridization was applied to investigate the expression of Stat3 mRNA. The expressions of signal molecules were assessed by KS400 Image Analysis system. The data were statistically evaluated. EGFR, TGFalpha, Stat3 were highly expressed in the stages of liver necrosis and repairment. All hepatocellular carcinoma cases revealed elevated expression of EGFR, TGFalpha. Elevation of Stat3 mRNA and protein levels were identified, increase of activation of Stat3 was also observed. In HCC, there was positive correlation between p-Stat3 level and the expression of TGFalpha and PCNA. Increased expression of Bcl-2 (P < 0.05) coincided with elevated level of p-Stat3. Therefore, the EGFR-Stat3 signal pathway was related to the development of hepatoma in rats. TGFalpha-EGFR autocrine ring formation may lead to the activation of Stat3 and in turn, promote proliferation and regulate the transcription of genes regulating cell apoptosis and cell cycle.
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PMID:Roles of EGFR-Stat3 signal pathway in carcinogenesis of experimental hepatoma in rats. 1703 71

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Tumor specific cellular and humoral immunotherapy may be a viable approach for the treatment of HCC. This study investigated specific inhibitory and cytotoxic effects on hepatocellular carcinoma (HCC) induced by the peptide, designated HBc Delta-5L, using HBc carrier with multiple T cell and B cell sequence insertions. We developed the HBc Delta carrier containing insertions of multiple CTL and T helper (Th) epitopes, which were selected from HCC tumor associated antigens (TAAs) including alpha fetoprotein (AFP), melanoma antigen gene (MAGE) and telomerase reverse transcriptase (TERT) antigen, and ligands for EGFR and IGFR, designated HBc Delta-5L. LDH release assay and IFN-gamma ELISPOT assay were carried to determine whether HBc Delta-5L could induce specific cytotoxicity in peripheral blood mononuclear cells (PBMC) of HCC donors. The levels of antibodies and inhibitory effects of sera of immunized mice against HBc Delta-5L were also identified. LDH release assay revealed that PBMC from HCC donor group (n=8) stimulated with HBc Delta-5L could specifically kill target tumor cells and specific lysis was 62.7% (E:T=60:1). ELISPOT assay showed a significant increase in secretion of IFN-gamma from PBMC of HCC donor group in response to HBc Delta-5L. Further, high specific antibody titers were elicited in immunized mice and revealed 42% inhibition of cell growth. These results indicated that inhibitory and cytotoxic effects could be efficiently induced by HBc Delta-5L recombinant particles using HBc Delta as carrier and suggested that it could be important in design of immunotherapeutic approaches.
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PMID:Anti-tumor effects of immunotherapeutic peptide on the treatment of hepatocellular carcinoma with HBc carrier. 1754 80

Prostaglandins (PGs) such as PGE2 enhance proliferation in many cells, apparently through several distinct mechanisms, including transactivation of the epidermal growth factor (EGF) receptor (EGFR) as well as EGFR-independent pathways. In this study we found that in primary cultures of rat hepatocytes PGE2 did not induce phosphorylation of the EGFR, and the EGFR tyrosine kinase blockers gefitinib and AG1478 did not affect PGE2-stimulated phosphorylation of ERK1/2. In contrast, PGE2 elicited EGFR phosphorylation and EGFR tyrosine kinase inhibitor-sensitive ERK phosphorylation in MH1C1 hepatoma cells. These findings suggest that PGE2 elicits EGFR transactivation in MH1C1 cells but not in hepatocytes. Treatment of the hepatocytes with PGE2 at 3 h after plating amplified the stimulatory effect on DNA synthesis of EGF administered at 24 h and advanced and augmented the cyclin D1 expression in response to EGF in hepatocytes. The pretreatment of the hepatocytes with PGE2 resulted in an increase in the magnitude of EGF-stimulated Akt phosphorylation and ERK1/2 phosphorylation and kinase activity, including an extended duration of the responses, particularly of ERK, to EGF in PGE2-treated cells. Pertussis toxin abolished the ability of PGE2 to enhance the Akt and ERK responses to EGF. The results suggest that in hepatocytes, unlike MH1C1 hepatoma cells, PGE2 does not transactivate the EGFR, but instead acts in synergism with EGF by modulating mitogenic mechanisms downstream of the EGFR. These effects seem to be at least in part G(i) protein-mediated and include upregulation of signaling in the PI3K/Akt and the Ras/ERK pathways.
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PMID:Prostaglandin E2 upregulates EGF-stimulated signaling in mitogenic pathways involving Akt and ERK in hepatocytes. 1765 93

Hepatocellular carcinoma (HCC) is the main cause of death in cirrhotic patients and has become a major health problem in developed countries. Analysis of the somatic alterations and gene expression profiles in patients with HCC have provided important information the genes involved in liver carcinogenesis. Nevertheless, the most important molecular alterations in the initial stages of the disease are currently unknown. The application of high resolution technologies to other forms of cancer (genome analysis with oligo microarrays and SNP arrays) should lead to greater insight into the pathogenesis of this neoplasm. In the last few years, distinct signaling pathways involved in hepatocarcinogenesis have been identified. Among these, the Wnt, EGFR and PI3k/akt/mTOR pathways are constitutively altered in numerous studies, providing the molecular basis for the molecular treatment of this tumor. As in other neoplasms, the original tumor cell in HCC is controversial. The most widely accepted hypothesis suggests that numerous genomic alterations in the hepatocyte cells lead to a neoplastic phenotype. Alternatively, it has been postulated that at least a subgroup of tumors could be of stem cell origin. Both hypotheses agree on the existence of cancer stem cells, arising from the original tumor cell; these cancer stem cells would then perpetuate and disseminate the neoplasm. This review summarizes the most important information on the structural and functional alterations in HCC and describes some of the main signaling pathways implicated in liver cancer.
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PMID:[Cell biology and genetics in liver cancer]. 1766 21

The increasing number of patients with hepatocellular carcinoma (HCC) and the highly unfavourable prognosis of the disease are two important reasons why more effort needs to be devoted to investigating other therapies able to block or reduce tumor progression and cancer metastasis. The underlying cirrhosis on which HCC develops limits the use of common chemotherapies, mainly because of their toxicity. Recently, great attention has been paid to a family of molecules that inhibits the tyrosine kinase (TK) receptors, because of their relevant role in activating intracellular pathways responsible for several biological activities of the HCC cells. In particular, proliferation, invasion, survival, apoptosis, are regulated by Erk1/2 and Akt pathways, that can be considered for this reason as potential therapeutic targets. Therefore, the idea is to fight HCC by blocking the molecular mechanisms exploited by the cancer to develop and to metastasize. The epithelial growth factor and the vascular endothelial growth factor receptors (EGFR and VEGFR, respectively) have been identified as the major targets for these new therapies. In this review the biological role of both growth factors in HCC will be discussed, together with the use of anti-EGFR and anti-VEGFR. The preliminary results obtained in vitro or in "in vivo" experimental models have been very promising, whereas the few studies conducted in patients have been not comparably satisfactory. This could be because of the limited number of patients and of their advanced stage of HCC, nevertheless the possibilities of using this family of drugs should be further explored, together with aspects contributing to a better understanding of the molecular mechanisms driving HCC progression.
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PMID:Tyrosine kinase inhibitors: a potential approach to the treatment of hepatocellular carcinoma. 1804 82

Results published in 2007 improve treatments in digestive oncology. In esophageal cancer, efficacy of preoperative chemotherapy or radiochemotherapy is confirmed. In locally advanced esophageal cancer it has been proved that the definitive radiochemotherapy is an alternative at radiochemotherapy plus surgery. Two majors data have been presented for patients with metastatic colorectal cancer: monochemotherapy for the first line is back; molecular marker is necessary to optimize the use of anti EGFR antibody. Lastly, the first effective medical treatment of hepatocellular carcinoma has been presented.
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PMID:[News in digestive oncology]. 1823 May 77

Hepatocellular carcinoma (HCC) is a highly malignant cancer with poor prognosis. Inhibitors of EGFR and VEGFR for HCC treatment are currently under investigation. Gefitinib and vandetanib inhibit migration of HCC cells on Laminin-5 and Fibronectin, and invasion through matrigel. Both drugs inhibit p-EGFR after short time, while their efficacy on p-Erk1/2 and p-Akt is progressive and stable over time. PI3K/Akt and MEK/Erk1/2 inhibitors, inhibit migration and invasion as well as inducing de-phosphorylation of downstream effectors. Finally, both inhibitors, vandetanib and gefitinib down-regulated the secretion of matrix metalloproteases MMP-2 and MMP-9. All these biological effects seem to depend on the activity of gefitinib and vandetanib blocking activity towards p-EGFR mediated pathways.
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PMID:EGFR and VEGFR as potential target for biological therapies in HCC cells. 1824 88

We investigated whether EGFRvIII contributes to tumorigenicity and resistance to 5-FU in HCC cell lines. Our results show that several HCC cell lines have EGFRvIII expression. EGFRvIII-positive HCC cells grew more rapidly and had a lower sensitivity to 5-FU than EGFRvIII-negative HCC cells. For further analysis of the biological characteristics of EGFRvIII, an EGFRvIII or EGFR expression cassette was introduced into the HCC cell line, Huh-7. Compared with Huh-7 cells and Huh7-EGFR cells, Huh7-EGFRvIII not only exhibit significantly increase of cell growth in vitro and in vivo but also show enhanced migration in vitro. Furthermore, 5-FU has significantly lower inhibition effect on Huh7-EGFRvIII cells then on both Huh-7 and Huh7-EGFR cells in vitro and in vivo. Collectively, these results demonstrate that EGFRvIII plays a pivotal role in tumorigenicity and enhanced 5-FU resistance of HCC.
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PMID:Epidermal growth factor receptor vIII enhances tumorigenicity and resistance to 5-fluorouracil in human hepatocellular carcinoma. 1921 5

We describe a system that permits conditional mobilization of a Sleeping Beauty (SB) transposase allele by Cre recombinase to induce cancer specifically in a tissue of interest. To demonstrate its potential for developing tissue-specific models of cancer in mice, we limit SB transposition to the liver by placing Cre expression under the control of an albumin enhancer/promoter sequence and screen for hepatocellular carcinoma (HCC)-associated genes. From 8,060 nonredundant insertions cloned from 68 tumor nodules and comparative analysis with data from human HCC samples, we identify 19 loci strongly implicated in causing HCC. These encode genes, such as EGFR and MET, previously associated with HCC and others, such as UBE2H, that are potential new targets for treating this neoplasm. Our system, which could be modified to drive transposon-based insertional mutagenesis wherever tissue-specific Cre expression is possible, promises to enhance understanding of cancer genomes and identify new targets for therapeutic development.
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PMID:A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. 1947 87

N-acetylglucosaminyltransferase-V (GnT-V) has been reported to be closely associated with tumor migration, but the mechanism has been not currently clear. In this study we found that GnT-V activated EGFR signaling and promoted cell migration through receptor protein tyrosine phosphatase kappa (RPTPkappa). The overexpression of GnT-V gene in human hepatoma SMMC-7721 cell line not only induced the addition of beta1,6 GlcNAc branch to N-glycan of RPTPkappa but also decreased the protein level of RPTPkappa, which both contributed to the decreased phosphatase activity of RPTPkappa activating subsequently EGFR signaling. Moreover, we found that the knockdown of RPTPkappa and its addition of beta1,6 GlcNAc branch both promoted cell migration, which could be ascribed to the activation of EGFR signaling regulated by RPTPkappa. Therefore, our findings could provide an insight into the molecular mechanism of how GnT-V promoted cell migration, suggesting that RPTPkappa could be one of factors regulating the EGF-mediated migration signals.
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PMID:EGF-mediated migration signaling activated by N-acetylglucosaminyltransferase-V via receptor protein tyrosine phosphatase kappa. 1923 42


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