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)

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with increasing incidence worldwide. Most of patients with HCC are diagnosed at a late stage. Therefore, the prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Screening strategies including alpha-fetoprotein (AFP) and ultrasound every 6 months in patients with liver cirrhosis, the major risk factor for HCC development, have been recommended to detect HCC at earlier stages amenable to effective treatment strategies. AFP, however, is a marker with poor sensitivity and specificity and the ultrasound is highly dependent on the operator's experience. Apart from AFP, lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin and several other biomarkers (e.g., glypican-3, human hepatocyte growth factor, and insulin-like growth factor) have been proposed as markers for HCC detection. In addition, with recently employed techniques, such as gene-expressing microarrays and proteomics, it is to be expected that new HCC-specific markers will become available in the near future. For all such proposed markers, however, the clinical usefulness has to be carefully evaluated and validated.
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PMID:Serum markers of hepatocellular carcinoma. 1705 52

The insulin-like growth factor (IGF) system and type-I IGF receptor (IGF-IR) signaling are involved in protecting against chemotherapeutic drug-induced cell death in human hepatoma cells. Acetaminophen (AAP) hepatotoxicity is the leading cause of liver failure, and the prevention of AAP-induced cell death has been the focus of many studies. We determined whether IGF-I could protect against AAP-induced cell death in Chang liver cells and investigated the protective mechanism. Based on the results of MTS assays, LDH release assays, Hoechst 33342 cell staining, and DNA fragmentation experiments, AAP induced cell death in a dose-dependent manner. According to Western blot analysis, treatment with AAP increased the level of poly(ADP-ribose) polymerase (PARP) fragments in cells compared with that in control cells; however, caspase-3, a critical signaling molecule in apoptosis, was not activated after AAP overdose. Moreover, combined treatment with AAP and IGF-I inhibited PARP cleavage, which was consistent with the ability of IGF-I to restore the level of glutathione (GSH) and cell viability in GSH and MTS assays, respectively. We investigated whether the protective effect of IGF-I against AAP cytotoxicity is related to the extracellular signal-related kinase ERK1/2, which is generally activated by mitogenic and proliferative stimuli such as growth factors. Compared with AAP treatment alone, IGF-I and AAP co-treatment increased ERK1/2 phosphorylation but inhibited PARP cleavage. Thus ERK1/2 activation is instrumental in the protective effect of IGF-I against AAP-induced cell death in Chang liver cells.
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PMID:Chemoprotective effect of insulin-like growth factor I against acetaminophen-induced cell death in Chang liver cells via ERK1/2 activation. 1716 76

This is an extensive study in a defined initiation-promotion hepatocellular carcinoma model of hepatocarcinogenesis (in rats) in which many important marker enzymes and isoenzymes and 8-hydroxydeoxyguanosine formation have been studied together with two very important cellular proliferating genes, insulin-like growth factor II and c-raf.1, known for their role in hepatocellular cancer development. Experiments were carried out on hepatic tissues of male Sprague-Dawley rats. Variations in different enzyme/isoenzyme activities/contents/expression pattern and 8-hydroxydeoxyguanosine-positive cells were studied. Insulin-like growth factor II and c-raf.1 gene expressions were monitored. A direct shift with increase in size and numbers of lesions was found to occur in different experimental groups. In this study, glutathione peroxidase (1.14 and 1.46-fold) and reduced triphosphopyridine nucleotide (TPNH)-cytochrome-c-reductase (1.94 and 2.94-fold) activities, cytochrome b5 (1.57 and 3.28-fold) and P-450 contents (1.45 and 1.22-fold), glutathione content (1.27 and 1.45-fold) and superoxide dismutase and catalase (1.16 and 1.39-fold) activities in group A animals were found to be lower than those in initiation and promotion studies, respectively. 8-Hydroxydeoxyguanosine-positive nuclei count showed that oxidative damage of nuclear DNA enhanced with the progress of the disease. The insulin-like growth factor II expression was found to be predominant in hepatocellular carcinoma and in early preneoplastic lesions. Unlike insulin-like growth factor II, c-raf.1 expression was located in the late basophilic lesions associated with hepatocellular carcinoma. During the various stages of the development of hepatocellular carcinoma, the enzymes played a significant role in metabolizing carcinogens and thereby scavenging various toxic metabolites or free radicals produced. A sequence of cellular changes starting from the appearance of glycogen storage foci to basophilic foci leading to hepatocellular carcinoma via mixed cell foci varied the activity/content or expression pattern of the enzymes and isoenzymes and in 8-hydroxydeoxyguanosine formation. It has been established that c-raf.1-induced signaling pathways activated by insulin-like growth factor II is implicated in the late stage of development of cancer.
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PMID:Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats. 1755 10

Cell hydration changes play a key role in the regulation of cell function and critically affect insulin sensitivity of carbohydrate- and protein metabolism. Here, the modulation of gene expression profiles by hyperosmolarity and insulin was examined in H4IIE rat hepatoma cells by cDNA/oligonucleotiode array-, Northern- and Western blot analysis. Osmosensitive expression of the insulin-like growth factor binding protein Igfbp1, the multidrug resistance protein Mrp5 (Abcc5a) and cyclin D1 (Ccnd1) was established at the mRNA and protein level. Despite a hyperosmotic increase of cyclin D1 mRNA induction by insulin, the cyclin D1 protein expression was decreased by hyperosmolarity, suggesting a hyperosmotic interference with cyclin D1 mRNA translation. Hyperosmolarity at the mRNA level blunted the insulin response of betaine homocysteine-S-methyl transferase, the multidrug resistance proteins Mdr1a (Abcb1a) and 2 (Abcb4), the Igfbp 2 and 5, cyclin G1, dual specificity phosphatase Dusp1, signal transducers and activators of transcription Stat3 and 5, catalase and the bile salt export pump Bsep (Abcb11), whereas the insulin response was increased for Mrp5, cyclin D1 and the phosphoenolpyruvate carboxykinase. Insulin effects on the mRNA expression of the eukaryotic initiation factor 4E binding protein 4e-bp1, tubulin, gene 33, growth hormone receptor, keratin18, ornithine decarboxylase and heme oxygenase 1 were largely insensitive to hyperosmolarity. The data indicate that hyperosmolarity differentially modulates insulin sensitivity at the level of gene expression.
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PMID:Modulation of gene expression profiles by hyperosmolarity and insulin. 1776 65

The liver has enormous regenerative capacity. Restitution of the liver in response to different injuries involves proliferation of cells at different levels of liver lineage. Mature hepatocytes, which are normally dormant, could undergo rapid replication with a near infinite capacity to proliferate. When the replication of mature hepatocytes is inhibited, a reserve compartment of bipotential hepatic progenitor/stem cells is activated. The degree of activation appears to correlate with the degree of inflammation and stage of chronic liver disease. Deregulation of key regulatory signaling pathways such as transforming growth factor-beta, Wnt, hepatocyte growth factor, insulin-like growth factor, transforming growth factor-alpha and epidermal growth factor in this progenitor/stem cell population could give rise to HCC. Further understanding of these key signaling pathways and the molecular and genetic alterations associated with HCC could provide major advances in new therapeutic and diagnostic modalities.
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PMID:Hepatocellular stem cells. 1791 54

Several studies have examined the expression profiles of human hepatocellular carcinomas (HCCs) using high density microarray technology, but subtyping with potential mechanistic and therapeutic impact has not been achieved so far. Here we have analysed the expression pattern of human HCCs and HCC cell lines in comparison to normal liver. A characteristic of one group of HCCs and all HCC cell lines was overexpression of insulin-like growth factor (IGF)-II. Moreover, IGF-II expression was mutually exclusive to induction of several IFN-related genes. In vitro, treatment of HCC cells with IFNgamma leads to a strong reduction of IGF-II expression. Equally, specific reduction of IGF-II was achieved using RNAinterference in HCC cells. Therefore, IGF-II may represent an excellent target for IFNgamma-treatment and specific siRNA-mediated therapeutic intervention.
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PMID:[Insulin-like growth factor (IGF)-II in human hepatocarcinogenesis--a potential therapeutic target?]. 1803 99

5-Methoxy-2-{(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl}-3H-benzoimidazole (omeprazole), a benzoimidazole-derived gastric H(+)/K(+)-ATPase proton pump inhibitor (PPI) extensively prescribed for the treatment of gastroesophageal acid reflux disease, can stimulate the expression of CYP1A1 via activation of the human aryl hydrocarbon receptor (hAhR) in an apparent nonligand-binding manner. Here, we have examined the effect of nonclassical, i.e., nonligand binding, AhR activation by omeprazole upon human insulin-like growth factor binding protein (hIGFBP)-1, a secreted phosphoprotein involved in regulation of insulin-like growth factor-I/II bioavailability and mitogenic activity. Analysis of the proximal promoter of the hIGFBP-1 gene reveals the presence of an aryl hydrocarbon binding/dioxin response element (DRE). Quantitative mRNA analysis revealed hIGFBP-1 expression to be responsive to both ligand (TCDD) and nonligand (omeprazole) modes of hAhR activation in the human hepatocarcinoma HepG2 cell line. Furthermore, mutagenesis of the DRE renders the hIGFBP-1 promoter unresponsive to both compounds in HepG2 cells. Likewise, small interfering RNA-mediated hAhR ablation inhibits TCDD and omeprazole-dependent hIGFBP-1 induction, as determined by quantitative mRNA analysis. Cotreatment with cycloheximide further suggests a direct transcriptional role for hAhR at the hIGFBP-1 promoter. Omeprazole exposure prompted a significant increase in both hIGFBP-1 mRNA and secreted protein from HepG2 cells. In addition, we present in vitro evidence indicating that omeprazole at a concentration comparable with that found circulating in subjects undergoing PPI therapy can stimulate the expression of hIGFBP-1. These data demonstrate that activation of hAhR by pharmaceuticals such as omeprazole can alter IGFBP-1 expression and thus may influence IGFBP-1-dependent physiological processes.
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PMID:Omeprazole stimulates the induction of human insulin-like growth factor binding protein-1 through aryl hydrocarbon receptor activation. 1805 78

The ligand insulin-like growth factor (IGF)-II is highly overexpressed in human hepatocellular carcinoma (HCC) and promotes tumour cell growth. Thus, this signalling axis is a prime target for potential anti-cancer therapies. In this context, gene-specific siRNA against IGF-signalling components as well as IGF1R selective receptor tyrosine kinase (RTK)-inhibitors (tyrphostins) may therefore offer new therapeutic options since both small interfering RNAs (siRNA) and small inhibitory molecules significantly reduce IGFIR signalling in HCC cell lines. However, since highly specific inhibition by siRNA is currently not applicable in the treatment of cancer, selective RTK-inhibitors represent the most promising approach for future therapeutic strategies.
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PMID:[Insulin-like growth factor (IGF)-signalling pathway components are potential therapeutic targets in the treatment of human hepatocellular carcinoma]. 1831 25

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma (HCC). Especially the overexpression of the fetal growth factor IGF-II, IGF-I receptor (IGF-IR), and cytoplasmic downstream effectors such as insulin-receptor substrates (IRS) contribute to proliferation, anti-apoptosis, and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-II signaling during HCC development and progression. Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies, various experimental strategies have been developed, including neutralizing antibodies and selective receptor kinase inhibitors, with respect to the specific and efficient reduction of oncogenic IGF-II/IGF-IR-signaling.
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PMID:Reactivation of the insulin-like growth factor-II signaling pathway in human hepatocellular carcinoma. 1835 Jun

Research on insulin-like growth factor (IGF) system have shown it to be potent mitogen for hepatoma cells and made it an attractive therapeutic target. But little strategy has been reported to date on targeting and sequestrating IGF against hepatoma. This study is based on the capability of ligand oligopeptide (LOP) to recognize IGF receptor with high efficiency, which is over-expressed on some hepatoma cells. We have been hypothesizing that antibody to LOP would mimic the extracellular ligand-binding domain of IGF receptor and inhibit receptor signaling and cell proliferation. Gene encoding for LOP [E5 (EPFRSPDLALETYG)] of IGF receptor was inserted into HBc carrier for expression in Escherichia coli. The monoclonal antibody (mAb) specific LOP potently inhibited signal transduction mediated by the IGF-IR interaction with IGF-I. Furthermore, it exhibited 47% inhibitory rate of soft agar colony formation and also induced apoptosis. These results indicate an anti-hepatoma potential of the mAb to an LOP of IGF receptor could block the activation of receptor and downstream signaling pathways, and suppress the biological effects mediated by receptor.
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PMID:Inhibition of IGF receptor signaling and hepatoma cell growth by an antibody to ligand oligopeptide of receptor. 1836 77


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