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)

IGF-II and type I-IGF receptor (IGF-IR) gene expression is increased in primary liver tumors, and transgenic mice overexpressing IGF-II in the liver develop hepatocellular carcinoma (HCC) spontaneously, suggesting that alterations of IGF-IR signaling in vivo may play a role in the auto/paracrine control of hepatocarcinogenesis. We have addressed the contribution of PI-3'K/Akt signaling on the proliferation of HepG2 human hepatoma cells and on their protection against doxorubicin-induced apoptosis. Both basal HepG2 cell DNA replication and that stimulated by IGF-IR signaling were inhibited by the specific PI-3'K inhibitor Ly294002 (Ly). In the former case, PI-3'K signaling overcame cell cycle arrest in G1 via increased cyclin D1 protein and decreased p27kip1 gene expression. Doxorubicin treatment induced apoptosis in HepG2 cells and was concomitant with the proteolytic cleavage of Akt-1 and -2. Drug-induced apoptosis was reversed by IGF-I and this effect was (i) dependent on Akt-1 and -2 phosphorylation and (ii) accompanied by the inhibition of initiator caspase-9 activity, suggesting that IGF-IR signaling interferes with mitochondria-dependent apoptosis. Accordingly, Ly enhanced doxorubicin-induced apoptosis and suppressed its reversal by IGF-I. Altogether, the data emphasize the crucial role of PI-3'K/Akt signaling (i) in basal as well as IGF-IR-stimulated HepG2 cell proliferation and (ii) in controlling both doxorubicin-induced apoptosis (e.g., drug-induced cleavage of Akt) and its reversal by IGF-I (protection against apoptosis parallels the extent of Akt phosphorylation). They suggest that targeting Akt activity or downstream Akt effectors (e.g., GSK3-beta, FOXO transcription factors) may help define novel therapeutic strategies of increased efficacy in the treatment of HCC-bearing patients.
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PMID:Pleiotropic effects of PI-3' kinase/Akt signaling in human hepatoma cell proliferation and drug-induced apoptosis. 1738 42

CCAAT/enhancer-binding proteins (C/EBPs) are transcription factors consisting of six isoforms and play diverse physiological roles in vertebrates. In rainbow trout (Oncorhynchus mykiss), in addition to the reported C/EBPbeta1, we have isolated cDNA of four other isoforms, C/EBPalpha, C/EBPbeta2, C/EBPdelta1, C/EBPdelta2, from the liver. Comparison of the deduced amino acid sequence of rainbow trout C/EBPs with those of other vertebrates revealed that C/EBP isoforms are highly conserved. The profiles of tissue-specific expression of individual C/EBP isoform mRNA, determined by quantitative real-time (RT)-PCR showed distinct patterns. Furthermore, injection of bovine GH into yearling rainbow trout resulted in a significant increase of mRNA levels of C/EBPbeta1, C/EBPbeta2, and C/EBPdelta2 but not C/EBPalpha and C/EBPdelta1 in the liver. GH-dependent increase of mRNA levels of C/EBPbeta1, C/EBPbeta2, C/EBPdelta2, and IGF-II were also confirmed by treating rainbow trout hepatoma cells expressing a goldfish GH receptor with bGH. Together with our previous findings, the results presented in this paper strengthen our previous hypothesis that GH may regulate the expression of the IGF-II gene via mediating the expression of C/EBPbeta1, C/EBPbeta2, and C/EBPdelta2 mRNA.
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PMID:Molecular cloning and expression analysis of rainbow trout (Oncorhynchus mykiss) CCAAT/enhancer binding protein genes and their responses to induction by GH in vitro and in vivo. 1764 Dec 87

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

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

Glypican-3 (gpc3) is the gene responsible for Simpson-Golabi-Behmel overgrowth syndrome. Previously, we have shown that GPC3 is overexpressed in hepatocellular carcinoma (HCC). In this study, we demonstrated the mechanisms for GPC3-mediated oncogenesis. Firstly, GPC3 overexpression in NIH3T3 cells gave to cancer cell phenotypes including growing in serum-free medium and forming colonies in soft agar, or on the other way, GPC3 knockdown in HuH-7 cells decreased oncogenecity. We further demonstrated that GPC3 bound specifically through its N-terminal proline-rich region to both Insulin-like growth factor (IGF)-II and IGF-1R. GPC3 stimulated the phosphorylation of IGF-1R and the downstream signaling molecule extracellular signal-regulated kinase (ERK) in an IGF-II-dependent way. Also, GPC3 knockdown in HCC cells decreased the phosphorylation of both IGF-1R and ERK. Therefore, GPC3 confers oncogenecity through the interaction between IGF-II and its receptor, and the subsequent activation of the IGF-signaling pathway. This data are novel to the current understanding of the role of GPC3 in HCC and will be important in future developments of cancer therapy.
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PMID:Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway. 1841 66

One hundred and ninety-three Sprague-Dawley (SD) rats (average body weight 100-120g) were randomly divided into five groups (I-V). Groups I and II rats served as the negative and positive controls respectively and both received 0.1mg/kg Se from sodium selenite supplemented diets for the 18-week experimental period. Groups III-V rats were fed Se from SEM supplemented diets (0.3, 1 and 3mg/kg respectively). To induce hepatocarcinoma, groups II-V rats received diethylnitrosamine solution (100mg/L) at the dosage of 10mg/kg body weight in drinking water daily for 16 weeks, followed by sterilized water for a further 2 weeks. Group I rats received sterilized water throughout. At weeks 4, 8, 12 and 16 five rats in each group were sacrificed by cervical decapitation. At the termination of the study, at week 18, the surplus rats were sacrificed by cervical decapitation. Feed was withheld from the rats for 12 h before sampling. The following items including TNF-alpha, IGF-II, NO and T-NOS levels in plasma were tested using kit techniques. At the same time the expression of vascular endothelial growth factor (VEGF) in tumor tissue was analyzed by immunohistochemistry using the envision two-step methods with a kit. The results indicated that SEM could increase the levels of TNF-alpha in the early stages of hepatocarcinoma formation, however there was a decrease in the later stage of hepatocarcinogenesis. SEM could also significantly decrease the levels of IGF-II and NO, and inhibit the expression of VEGF in tumor tissue. SEM delayed the development of hepatocarcinoma in rats and that could be partially attributed to inhibition of angiogenesis.
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PMID:Effect of selenium-enriched malt on VEGF and several relevant angiogenic cytokines in diethylnitrosamine-induced hepatocarcinoma rats. 2012 81

Hepatocellular carcinoma is one of the most common malignant human tumors. Hepatocarcinogenesis is a multistep process with a multifactorial etiology. Chronic hepatitis B and hepatitis C virus infection, alcohol drinking and cirrhosis of any etiology are the major risk factors for hepatocellular carcinoma. Growth factors, their receptors and related proteins are involved in the process of malignant transformation. The IGF axis is involved in the proliferation and differentiation of normal, transformed and malignant hepatocytes. In the context of hepatocarcinogenesis, IGF-II has, in particular, been investigated thoroughly. Increased IGF-II bioavailability, protease activity of IGF-binding proteins and IGF-I receptor expression, decreased expression of IGF-II receptor and IGF-binding proteins are thought to contribute to hepatocellular carcinoma genesis. This review will first focus on the role of the IGF axis in hepatocarcinogenesis. In the second part it will emphasize circulating IGF-II levels in chronic liver disease and hepatocellular carcinoma, and diagnostic application of serum IGF-II level in both small and larger hepatocellular carcinoma.
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PMID:Insulin-like growth factor II in hepatocellular carcinoma. 2047 1

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide with poor prognosis. Based on high-throughput screening technology, we and others have identified factors and pathways that are pivotal for tumor progression including transcription factors and microtubule-interacting proteins. In addition, aberrant activation of the IGF signalling pathway is frequently observed in HCCs which is predominantly based on high level expression of its ligand IGF-II. Because protumorigenic effects of IGF-II such as proliferation, anti-apoptosis, and migration are transmitted through its receptor IGF-1R, selective inhibition of this tyrosine kinase by small molecule compounds might reduce IGF-II-driven tumor growth. Indeed, administration of IGF-1R-selective inhibitors reduces IGF-II-induced effects and was associated with a significant reduction of tumor growth in a xenograft transplantation model. In conclusion, the IGF-II/IGF-1R signalling pathway is critically involved in the regulation of tumor growth and tumor cell dissemination, representing a promising therapeutic target structure in the treatment of HCC.
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PMID:[Molecular mechanisms of progression in human hepatocarcinogenesis]. 2071 84

The insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor tyrosine kinase that mediates cell survival signaling and supports tumor progression in multiple tumor types. We identified a spectrum of inhibitory IGF-IR antibodies with diverse binding epitopes and ligand-blocking properties. By binding distinct inhibitory epitopes, two of these antibodies, BIIB4 and BIIB5, block both IGF-I and IGF-II binding to IGF-IR using competitive and allosteric mechanisms, respectively. Here, we explored the inhibitory effects of combining BIIB4 and BIIB5. In biochemical assays, the combination of BIIB4 and BIIB5 improved both the potency and extent of IGF-I and IGF-II blockade compared with either antibody alone. In tumor cells, the combination of BIIB4 and BIIB5 accelerated IGF-IR downregulation and more efficiently inhibited IGF-IR activation as well as downstream signaling, particularly AKT phosphorylation. In several carcinoma cell lines, the antibody combination more effectively inhibited ligand-driven cell growth than either BIIB4 or BIIB5 alone. Notably, the enhanced tumor growth-inhibitory activity of the BIIB4 and BIIB5 combination was much more pronounced at high ligand concentrations, where the individual antibodies exhibited substantially reduced activity. Compared with single antibodies, the BIIB4 and BIIB5 combination also significantly further enhanced the antitumor activity of the epidermal growth factor receptor inhibitor erlotinib and the mTOR inhibitor rapamycin. Moreover, in osteosarcoma and hepatocellular carcinoma xenograft models, the BIIB4 and BIIB5 combination significantly reduced tumor growth to a greater degree than each single antibody. Taken together, our results suggest that targeting multiple distinct inhibitory epitopes on IGF-IR may be a more effective strategy of affecting the IGF-IR pathway in cancer.
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PMID:Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response. 2080 83

Currently available evidence supports a role for the hepatitis B virus (HBV) x gene and protein in the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). HBx gene is often included, and remains functionally active, in the HBV DNA that is frequently integrated into cellular DNA during hepatocellular carcinogenesis. HBx protein promotes cell cycle progression, inactivates negative growth regulators, and binds to and inhibits the expression of p53 tumour suppressor gene and other tumour suppressor genes and senescence-related factors. However, the molecular mechanisms responsible for HBx protein-induced HCC remain uncertain. Only some of the more fully documented or more recently recognised mechanisms are reviewed. During recent years evidence has accumulated that HBx protein modulates transcription of methyl transferases, causing regional hypermethylation of DNA that results in silencing of tumour suppressor genes, or global hypomethylation that results in chromosomal instability, thereby playing a role in hepatocarcinogenesis. HBx protein has both anti-apoptotic and pro-apoptotic actions, apparently contradictory effects that have yet to be explained. Particularly important among the anti-apoptotic properties is inhibition of p53. Recent experimental observations suggest that HBx protein may increase the expression of TERT and telomerase activity, prolonging the life-span of hepatocytes and contributing to malignant transformation. The protein also interferes with nucleotide excision repair through both p53-dependent and p53- independent mechanisms. Carboxy-terminal truncated HBx protein loses its inhibitory effects on cell proliferation and pro-apoptotic properties, and it may enhance the protein's ability to transform oncogenes. Dysregulation of IGF-II enhances proliferation and anti-apoptotic effects of oncogenes, resulting in uncontrolled cell growth.
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PMID:Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. 2119 26


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