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 effects of several immunomodulatory peptides (recombinant, human) on the in vitro production of erythropoietin (Epo) were studied in cultures of the human hepatoma cell line Hep G2. A dose-dependent decrease of up to 60% in Epo production was induced by interleukin-1 beta, interleukin-1 alpha, and tumor necrosis factor-alpha (in that order of potency). In contrast, moderately increased Epo levels resulted with interleukin-6 or interferon-gamma treatment at high concentrations. Concomitant measurements of the production of alpha-fetoprotein indicated that the observed effects were specific for Epo. Hence, we suspect a modulating role of the immune system in the in vivo control of Epo production and postulate that interleukin-1 and tumor necrosis factor-alpha are involved in some of the cases of lowered blood Epo levels in association with renal diseases, chronic inflammation, and malignancies.
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PMID:Interleukin-1 and tumor necrosis factor-alpha inhibit erythropoietin production in vitro. 171 53

The human hepatoma cell line, Hep3B, synthesizes large quantities of erythropoietin (Epo) mRNA and protein in a regulated manner in response to hypoxia and cobaltous chloride (CoCl2). To further understand the regulation of Epo gene expression, we studied the effects of hypoxia and CoCl2 on the rate of Epo gene transcription. While Northern blot analyses showed that steady-state Epo mRNA levels increase more than 50-fold in response to hypoxia or CoCl2, nuclear run-off experiments demonstrated only a 10-fold increase in Epo gene transcription in response to these stimuli. In the presence of either actinomycin D (Act D) or cycloheximide, the stability of biologically functional Epo mRNA was much greater than that observed in the absence of these agents and much greater than that which has been reported in vivo. These findings suggest that the stability of Epo mRNA is modulated by the transcription and translation of rapidly turning over gene product(s). Thus, Epo mRNA levels are determined by both the rate of gene transcription and posttranscriptional events. These experiments demonstrate a potential pitfall in estimating mRNA half-lives based on Act D chase experiments alone.
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PMID:Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscriptional events. 198 93

Because the human hepatoma cell line Hep3B produces erythropoietin (Epo) in a regulated fashion, it can be used to investigate the cis-acting regulatory elements of the Epo gene. Comparison of primate and mouse sequences shows strong homology not only in the coding sequence but also within the 5' flanking region, the first intron, and the 3' flanking region. These portions of the Epo gene were inserted 5' and 3' to a reporter gene, human growth hormone (GH). 5A is a 1,192-base pair (bp) HindIII-Xbal fragment that extends from 378 bp 5' to the cap site through the first intron. To obviate the problem of false initiation of translation from the Epo ATG start codon, this site was changed to TAG by site-directed mutagenesis. 3A is a 255-bp Accl-BglII fragment that extends 67 bp upstream from the Epo termination codon and covers most of the 3' noncoding region of homology. The plasmid DNAs were transfected by electroporation into Hep3B cells with RSVCAT as an internal standard to correct for transfection efficiency. One aliquot of cells was exposed to 50 mumol/L CoCl2 or to 1% O2. At the end of the incubations, GH and Epo were measured in the cell media and the cell pellet was assayed for CAT. Production of GH was stimulated 1.7-fold by cobalt or hypoxia. Furthermore, addition of 3A to the GH gene, irrespective of orientation, stimulated GH production 2.6-fold with CoCl2 and 2.3-fold with hypoxia. Stable cell lines were produced by cotransfection of the above constructions, along with the selectable marker pSV-Neo. In two clones, exposure to hypoxia resulted in much more marked (16-fold) induction of GH. Stimulus of both GH and Epo production by hypoxia was partially abrogated by carbon monoxide. These results demonstrate the presence of promoter and enhancer elements within the human Epo gene that are appropriately responsive to hypoxia and cobalt.
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PMID:Regulatory elements of the erythropoietin gene. 198 94

A yearling Arabian-type filly with a history of poor growth, erythrocytosis, hypoglycemia, and high liver enzyme activities was admitted to the hospital for evaluation. Three days after admission, the filly collapsed, deteriorated rapidly despite treatment, and was euthanatized. A metastatic hepatocellular carcinoma with capsular rupture and hemoperitoneum were found at necropsy. Primary liver tumors are rare in horses, and hepatocellular carcinoma has been reported in only 1 other horse. The systemic manifestations of the tumor in this filly included weakness, weight loss, inappetence, erythrocytosis with tumor production of erythropoietin, persistent hypoglycemia with normal serum insulin concentrations, serum alpha-fetoprotein (normally present only during fetal life), and terminal massive hemoperitoneum, all features of the syndrome in man.
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PMID:Hepatocellular carcinoma associated with erythrocytosis and hypoglycemia in a yearling filly. 215 51

We have measured the serum erythropoietin concentrations in 14 patients with liver cirrhosis and in 14 patients with a hepatocellular carcinoma. Among these patients, 2 with liver cirrhosis (14.3%) and 7 with a hepatocellular carcinoma (50.0%) were found to have raised serum erythropoietin concentrations, ranging up to 40 mU/ml. Negative correlations were found between erythropoietin and the RBC, and the Hb and Ht in the cases with liver cirrhosis. In contrast, a positive correlation which was not significant was found only between the erythropoietin and the RBC in cases involving a hepatocellular carcinoma. This has suggested that the relationship between the erythropoietin and the RBC in cases of a hepatocellular carcinoma differs from the relationship seen under the usual physiological circumstances of those with liver cirrhosis.
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PMID:[A clinical study of serum erythropoietin concentrations in patients with liver cirrhosis and hepatocellular carcinomas]. 215 46

Knowledge of the endogenous blood level of erythropoietin (Epo) has gained recent interest in view of the advances in Epo replacement therapy in anemic patients. By radioimmunoassay, we have carried out comparative measurements of the serum Epo level in patients suffering from chronic enterocolitis or leukemia. In chronic enterocolitis, the Epo level showed an exponential increase with the degree of anemia (up to 250 U Epo/1 serum at 70 g hemoglobin/1 blood). Similarly anemic patients with leukemia and severe bone marrow insufficiency of erythropoiesis had much higher Epo levels (usually above 500 U/1). Our findings indicate that the level of Epo is not only dependent on the blood hemoglobin concentration but also on the type of anemia. In fact, additional in vitro studies showed that immunomodulatory peptides can significantly influence the production of Epo in the hepatoma cell culture HepG2.
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PMID:Immunoreactive erythropoietin in the anemia of non-renal chronic diseases. 216 83

Effects of agents affecting cytochrome P450 were studied on the production of erythropoietin (Epo) in cultures of the human hepatoma cell line HepG2. Epo was measured by radioimmunoassay of the culture media after 24 h of incubation. The addition of phenobarbital or 3-methylcholanthrene, which induce cytochrome P450, significantly enhanced the formation of Epo. Likewise, the thyroid hormones T3 and T4 stimulated the rate of the production of Epo. On the other hand, the formation of Epo was lowered following the addition of diethyldithiocarbamate or cysteamine chloride, which inhibit cytochrome P450. These findings support the idea that O2 sensitive hemoproteins of the microsomal mixed-functional oxidases play a role in the control of the synthesis of Epo.
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PMID:Role of cytochrome P450 in the control of the production of erythropoietin. 216 16

Erythrocytosis (polycythemia) is a well-described paraneoplastic phenomenon in patients with hepatocellular carcinoma, but its pathogenesis remains uncertain. Using a radioimmunoassay, we have measured serum erythropoietin concentrations in 65 southern African blacks with this tumor and 61 matched controls. Four patients had an increased hemoglobin concentration and packed cell volume, and the remainder had normal values. Twenty-three percent of the patients with hepatocellular carcinoma (15/65) were found to have raised serum erythropoietin concentrations, the values ranging up to 344 mu/ml. Only one of these patients had an increased hemoglobin concentration and packed cell volume. This apparent anomaly could be explained if the erythrocytosis that would normally result from high serum erythropoietin values had been counteracted by the inhibition of erythropoiesis which occurs in advanced malignant disease. Alternatively, the erythropoietin produced by the tumor might not always be biologically active. Three patients had increased hemoglobin values and packed cell volumes in the presence of normal serum erythropoietin concentrations. One of these patients was hypoxic as a result of multiple pulmonary metastases, and the others may also have been. There was no correlation between serum erythropoietin and alpha-fetoprotein concentrations in individual patients.
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PMID:Serum erythropoietin concentrations in patients with hepatocellular carcinoma. 242 57

The development of a cell culture system that produces erythropoietin (Epo) in a regulated manner has been the focus of much effort. We have screened multiple renal and hepatic cell lines (including MDCK, LLC-PK1, BHK, WRL 68, CLCL, A704, CRFK, A498, ACHN, TCMK-1, LLC-MK2, CaKi-2, HepG2, and Hep3B) for either constitutive or regulated expression of Epo. Only the human hepatoma cell lines, Hep3B and HepG2, made significant amounts of Epo as measured both by radioimmunoassay and in vitro bioassay (as much as 330 milliunits per 10(6) cells in 24 hr). The constitutive production of Epo increased dramatically as a function of cell density in both cell lines. At cell densities less than 3.3 X 10(5) cells per cm2, there was little constitutive release of Epo in the medium (less than 30 milliunits per 10(6) cells in 24 hr). With Hep3B cells grown at low cell densities, a mean 18-fold increase in Epo expression was seen in response to hypoxia and a 6-fold increase was observed in response to incubation in medium containing 50 microM cobalt(II) chloride. At similar low cell densities, Epo production in HepG2 cells could be enhanced an average of about 3-fold by stimulation with either hypoxia or cobalt(II) chloride. Upon such stimulation, both cell lines demonstrated markedly elevated levels of Epo mRNA. Hence, both Hep3B and HepG2 cell lines provide an excellent in vitro system in which to study the physiological regulation of Epo expression.
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PMID:The regulated expression of erythropoietin by two human hepatoma cell lines. 282 72

A case of hepatocellular carcinoma associated with polycythemia and chronic thyroiditis, is reported in a 76-year-old female. At autopsy, the liver tumor was shown to be co-existent with liver cirrhosis. A series of hematological studies including the determination of plasma erythropoietin levels, led to the conclusion that this patient's polycythemia was most likely due to an excessive production of erythropoietin by the liver tumor. Chronic thyroiditis, another combined disease, might be related to liver cirrhosis, if the formerly advocated "hepato-thyroidal syndrome" is accepted. The author reports on this patient, since prior to this case there has been no documented case report of hepatocellular carcinoma accompanying both polycythemia and chronic thyroiditis.
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PMID:Hepatocellular carcinoma associated with a rare combination of polycythemia and chronic thyroiditis. 283 79


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