Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mRNA for the alpha1-acid glycoprotein (AAG) was expressed not only in hepatoma cells, but also in non-hepatic cancer cells. The expression of the AAG mRNA in HT-29 human colon carcinoma cells is induced by cytokines, IL-6, IL-1, and TNF-alpha, in a manner characteristic of the acute phase response, and the expression of AAG mRNA was up-regulated in differentiated HT-29 cells.
Mol Cells 2001 Apr 30
PMID:Induction of alpha1-acid glycoprotein mRNA by cytokines and differentiation in human colon carcinoma cell. 1135 96

The alpha1-acid glycoprotein (AAG) is a prototypical serum acute phase reactant in most mammalian species; it is synthesized mainly in liver parenchymal cells. Recently, we found that mRNAs of AAG were expressed in non-hepatic cancer cells, and the expression levels were regulated by the cytokines--IL-1, IL-6, and TNF-alpha. The functional role of AAG in non-hepatic cancer cells has not yet been established. In order to understand the functional role of the AAG expressed in HT-29 cells, the cancer cells were transfected with cloned cDNA for AAG, or exposed to antisense oligodeoxynucleotide (ODN) for AAG. The colony-forming capacity, invasion, and adhesion to laminin of these transformed cancer cells were measured. Overexpression of AAG by transfection, and inhibition of the AAG expression by antisense ODNs were identified by Western blot as well as nested reverse transcriptase-polymerase chain reaction (nested RT-PCR), respectively. Results showed that the overexpression of AAG by transfection reduced colony-forming capacities, invasion, and adhesion to laminin of the cancer cells; on the other hand, the antisense ODN for AAG elevated colony-forming capacities, invasion, and adhesion to laminin of the cancer cells. These results suggest that AAG, expressed in cancer cells inhibited proliferation, invasion, and metastasis of the cancer cells.
Mol Cells 2001 Jun 30
PMID:Effect of alpha1-acid glycoprotein expressed in cancer cells on malignant characteristics. 1145 24

The possible role of iron in facilitating the development of liver cancer is still debated. The aims of this study were to define the prevalence of the mutations 845G --> A and 187C --> G (C282Y and H63D) in the HFE gene associated with hereditary hemochromatosis in Italian patients with hepatocellular carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carcinoma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinoma. None of the patients had a phenotype compatible with homozygous hereditary hemochromatosis. Interaction between HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepatitis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule out gender influence on patients' iron status by using the case-only approach specifically designed to estimate departure from multiplicative risk ratios under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6%, P < 0.03). At univariate analysis, iron overload was significantly associated with both HFE mutations (P < 0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P < 0.05). By multivariate analysis, a trend for an increased risk of being positive for hepatitis virus markers (OR 2.9, CI 95% 0.9-9.5) and of having been alcohol abusers (OR 3, CI 95% 0.7-14) was observed in patients heterozygous for the HFE mutations. These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.
Blood Cells Mol Dis
PMID:Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma. 1150 61

Patients suffering from the metabolic disease hereditary tyrosinemia type I (HT1), caused by fumarylacetoacetate hydrolase deficiency, have a high risk of developing liver cancer. We report that a sub-apoptogenic dose of fumarylacetoacetate (FAA), the mutagenic metabolite accumulating in HT1, induces spindle disturbances and segregational defects in both rodent and human cells. Mitotic abnormalities, such as distorted spindles, lagging chromosomes, anaphase/telophase chromatin bridges, aberrant karyokinesis/cytokinesis and multinucleation were observed. Some mitotic asters displayed a large pericentriolar material cloud and/or altered distribution of the spindle pole-associated protein NuMA. FAA-treated cells developed micronuclei which were predominantly CREST-positive, suggesting chromosomal instability. The Golgi complex was rapidly disrupted by FAA, without evident microtubules/tubulin alterations, and a sustained activation of the extracellular signal-regulated protein kinase (ERK) was also observed. Primary skin fibroblasts derived from HT1 patients, not exogenously treated with FAA, showed similar mitotic-derived alterations and ERK activation. Biochemical data suggest that FAA causes ERK activation through a thiol-regulated and tyrosine kinase-dependent, but growth factor receptor- and protein kinase C-independent pathway. Pre-treatment with the MEK inhibitor PD98059 and the Ras farnesylation inhibitor B581 decreased the formation of CREST-positive micronuclei by approximately 75%, confirming the partial contribution of the Ras/ERK effector pathway to the induction of chromosomal instability by FAA. Replenishment of intracellular glutathione (GSH) with GSH monoethylester abolished ERK activation and reduced the chromosomal instability induced by FAA by 80%. Together these results confirm and extend the previously reported genetic instability occurring in cells from HT1 patients and allow us to speculate that this tumorigenic-related phenomenon may rely on the biochemical/cellular effects of FAA as a thiol-reacting and organelle/mitotic spindle-disturbing agent.
Hum Mol Genet 2001 Aug 15
PMID:Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability. 1153 83

Tumor suppressor p53 is known to inhibit transactivation by certain nuclear receptors, and overexpressed p53 is known to correlate with poor differentiation in liver cancer. Therefore, we investigated whether wild-type p53 might also affect the function of hepatocyte nuclear factor 4alpha1 (HNF4alpha1), an orphan receptor required for liver differentiation. Our results show that HNF4alpha1-mediated transactivation is repressed by p53 but that the mechanism of repression is not due to inhibition of HNF4alpha1 DNA binding. Rather, transfections with Gal4 fusion constructs indicate that the repression is via the ligand-binding domain of HNF4alpha1. Furthermore, we found that p53 in human embryonic kidney whole-cell extracts preferentially bound the ligand-binding domain of HNF4alpha1 and that the activation function 2 region was required for the binding. Competition for coactivator CREB binding protein could not entirely account for the repression but trichostatin A, an inhibitor of histone deacetylase activity, could reverse p53-mediated repression of HNF4alpha1. In contrast, p53-mediated repression of transcriptional activation of the same promoter by another transcriptional activator, CCAAT/enhancer-binding protein-alpha, could not be reversed by the addition of trichostatin A. These results suggest that p53, like other transcriptional repressors, inhibits transcription by multiple mechanisms, one of which involves interaction with the ligand-binding domain and recruitment of histone deacetylase activity.
Mol Endocrinol 2002 Feb
PMID:Repression of hepatocyte nuclear factor 4alpha tumor suppressor p53: involvement of the ligand-binding domain and histone deacetylase activity. 1181 10

Sex steroid hormones are thought, among several other risk factors, to play a role in liver malignancies. For example, from epidemiological studies in hepatocellular carcinoma (HCC), a clear disadvantage for male sex is evident. In addition, elevated levels of serum testosterone (T) and increased T to Estradiol (E(2)) ratio have been reported to predict an increased risk of HCC for male cirrhotic patients. On the other hand, palliative treatment of liver cancer patients with anti-hormones has been widely used in the past. However, the molecular mechanism(s) underlying sex steroid action on either normal or transformed liver cells, have not yet been fully clarified, nor endocrine discriminants have been satisfactorily assessed for an adequate characterization of liver cancer tissues. In this paper, we report studies on hormonal status of human liver tissues and cells, especially focusing on androgens, to better define endocrine end-points of interest for HCC. A consistent evidence from ex vivo or in vitro systems strongly suggests that high affinity binding sites of androgens are expressed at sufficient concentrations to induce a biological response in either normal or phenotipically transformed hepatocytes; in the latter, however, high heterogeneity and/or more scattering concentrations were encountered. Further, experimental data seem to suggest that lack of response to androgens may be due to a rapid metabolic conversion of steroids by neoplastic tissues and cells. Cancer hepatocytes privilege in fact 5beta more than 5alpha metabolic pathway of androgens. This may eventually lead biologically active androgens to be transformed into less active derivatives, as it occurs for T which is massively converted (>90% at 6 h) thus hindering the whole mechanism of action of androgens.
Mol Cell Endocrinol 2002 Jul 31
PMID:Altered androgen metabolism eventually leads hepatocellular carcinoma to an impaired hormone responsiveness. 1216 Oct 1

Hepatocellular carcinoma (HCC) is one of the most common malignancy in the world and it usually occurs in individuals with chronic liver disease. The neoplasm is predominant in the male gender, where it is characterized also by a worst prognosis than in females. The pathogenesis of HCC is obscure. Because of its striking male predominance, androgens have been investigated as potential factors able to induce or at least promote hepatic carcinogenesis; this hypothesis has been also supported by the ability of androgens of inducing liver neoplasms in experimental models. On the other hand, due to the fact that HCC occurs predominantly in male cirrhotics who present a characteristic hormone imbalance with a relative hyperestrogenic state, the potential role of estrogen in liver cancer has been studied as well. In this paper, the potential role of sex hormones in liver carcinogenesis has been reviewed.
Mol Cell Endocrinol 2002 Jul 31
PMID:Sex hormones and liver cancer. 1216 Oct 2

There is considerable evidence that reactive oxygen species (ROS) have a causative role in chronic hepatic injury and cancer development via direct and indirect mechanisms. Estrogens produce free oxygen radicals through redox cycling and affect cell proliferation, also in the liver. We are presently involved in evaluating the possible relationship between estrogens receptor expression, type of receptor, oxidative DNA damage and c-myc in chronic liver disease. The data on DNA adducts, c-myc mRNA and variant estrogen receptor in patients with HCV- or HBV-related chronic liver disease are suggesting that those positive for variant liver estrogen receptor present higher genomic oxidative damage, as reflected in 8-OHdG levels. We are also observing that patients with chronic hepatitis and cirrhosis, when positive for variant estrogen receptor, present higher c-myc m-RNA expression, a factor reportedly associated with increased genomic instability, augmented cytoproliferation and carcinogenesis. Our own and other author's data are shedding new light on estrogen pathophysiology, liver damage and hepatic cancer.
Mol Cell Endocrinol 2002 Jul 31
PMID:Estrogens receptors and oxidative damage in the liver. 1216 Oct 6

Boswellic acids are the compounds isolated from the gum resin of Boswellia serrata and have been used for the treatment of inflammatory diseases for many years in the countries of the east. Recently, a few studies showed that the acids may have anti-cancer effect on leukemia and brain tumours. We investigated the apoptotic and anti-proliferative effects of two types of boswellic acids, keto-beta-boswellic acid and acetyl-keto-beta-boswellic acid, on liver cancer Hep G2 cells. After treating the cells with the boswellic acids, cell proliferation, DNA synthesis, and apoptosis were analysed. The activities of caspase-3, -8 and -9 were assayed. To explore the apoptotic pathway, specific caspase inhibitors were employed. It was found that boswellic acids decreased cell viability and [3H]thymidine incorporation, checked the cells in the G1 phase, and increased percentage of sub-G1. Boswellic acids strongly induced apoptosis accompanied by activation of caspase-3, -8 and -9. The apoptosis was blocked completely by caspase-8 or caspase-3 inhibitor, but inhibited partly by caspase-9 inhibitor. However, these caspase inhibitors did not show any effect on the alternations of cell viability caused by boswellic acids. In conclusion, boswellic acids have anti-proliferation and anti-cancer effects on Hep G2 cells. The apoptotic effect is mediated by a pathway dependent on caspase-8 activation. The acids may be a promising drug for the chemoprevention of liver cancer.
Int J Mol Med 2002 Oct
PMID:Keto- and acetyl-keto-boswellic acids inhibit proliferation and induce apoptosis in Hep G2 cells via a caspase-8 dependent pathway. 1223 1

Farnesyltransferase inhibitors (FTIs) block the growth of tumor cells in vitro and in vivo with minimal toxicity toward normal cells. In general, inhibition of protein farnesylation results in G0/G1 cell cycle block, G2/M cell cycle arrest, or has no effect on cell cycle progression. One aspect of FTI biology that is poorly understood is the ability of these drugs to induce cancer cell growth arrest at the G2/M phase of cell cycle. In the present study, we investigated the effects of the farnesyltransferase inhibitor FTI-277 on two human liver cancer cell lines, HepG2 and Huh7. Treatment of these cells with FTI-277 inhibited Ras farnesylation in a dose-dependent manner. Both HepG2 and Huh7 cell growth was inhibited by FTI-277 and cells accumulated at the G2/M phase of the cell cycle. In HepG2 and Huh7 cells, FTI-277 induced an up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) without affecting the cellular levels of p53 and p21(Waf1). This event correlated with reduced activity of the cyclin-dependent kinase 2 and cyclin-dependent kinase 1. Moreover, increased expression of Bcl-2 protein was observed in HepG2 and Huh7 cells treated with FTI-277, and this was coincidental with reduced association between Raf-1 and Bcl-2. Finally, transient transfection of a dominant-negative Ras allele induced Bcl-2 expression and reduced Bcl-2/Raf-1 association demonstrating a requirement for Ras. Taken together, these findings show that increased expression of p27(Kip1) and Bcl-2 is concomitant with altered association between Ras, Raf-1 and Bcl-2 and suggest that this is responsible for the growth-inhibitory properties of FTI-277.
Mol Pharmacol 2003 Jan
PMID:Growth inhibition by the farnesyltransferase inhibitor FTI-277 involves Bcl-2 expression and defective association with Raf-1 in liver cancer cell lines. 1248 48


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