UMLS:C0019204 - FACTA Search

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)

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II. The GH response to hypoglycaemia was impaired and plasma levels of both IGF-I and the GH-dependent IGF binding protein (IGFBP-3) were low. A recently described unextracted assay directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II) allows direct plasma estimation (plasma E-21) of larger molecular forms of IGF-II without interference from normal IGF-II and IGF binding proteins. Basal values were grossly elevated (23.7 and 23.8 nmol/l). Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4.25 +/- 0.21 mol/l (mean +/- SEM) before treatment, compared with 4.86 mmol/l +/- 0.17 following GH (P < 0.01)) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP-3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change in plasma glucose levels or insulin-like growth factors. Two courses of intrahepatic adriamycin restored elevated levels of E-21 to normal. Total IGF-II remained normal and IGF-I increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E-21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin. 752 21

[125I]IGF-I binding to chicken hepatoma cell (LMH) membranes was displaced by unlabelled IGF-I or IGF-II, but not by insulin. Cross-linking revealed specific binding sites of 128 and 28-31 kDa, which following solubilization could be separated by wheat germ agglutinin (WGA) chromatography. [125I]IGF-I binding to the WGA eluate (128 kDa) could be displaced by insulin although with a 30-fold lower potency than IGF-I. Binding to the WGA flow-through (28-31 kDa) was not inhibited by insulin. This suggested that IGF binding to LMH was due mainly to membrane bound IGFBP rather than to type 1 IGF receptors. A reverse proportion was observed in normal chicken liver. A predominant 28 kDa IGFBP was synthesized and secreted by LMH cells, together with an unusual 60 kDa IGF binding entity which only bound [125I]IGF-II (with weak affinity). This process was not affected by the presence or absence of glucose, dexamethasone, glucagon, insulin or IGF-I.
...
PMID:Preferential binding of insulin-like growth factors to a binding protein rather than to receptors on chicken hepatoma cell (LMH) membranes. 753 43

Human IGFBP-1 is phosphorylated by cells in culture and is present in both phosphorylated and nonphosphorylated forms in human fetal serum and amniotic fluid. We have found immunoprecipitable [32P]IGFBP-1 in the conditioned media of both Chinese hamster ovary (CHO) cells (stabley transfected and secreting human IGFBP-1) and human hepatoma (HepG2) cells metabolically labelled with [32P]orthophosphate. Phosphoamino acid analysis of this [32P]IGFBP-1 demonstrates that only serine residues are phosphorylated. Four phosphorylated isoforms of IGFBP-1 can be separated from one nonphosphorylated form by nondenaturing gel electrophoresis. Since we have shown that the nonphosphorylated form of IGFBP-1 has a lower affinity for IGF-I compared to phosphorylated forms and a greater potentiating effect of IGF-I actions, we determined which serine residues in human IGFBP-1 are phosphorylated. After metabolically labelling IGFBP-1 with 32P, the purified phosphoprotein was digested first with trypsin and then with endoproteinase Glu-C. By radiosequencing the resulting 32P-labelled phosphopeptides, we found 3 serine residues to be phosphorylated. Approximately 70% of incorporated 32P was attributed to Ser101, while Ser169 accounted for approximately 25% and Ser119 for 5%. To investigate the physiologic importance of Ser101, this residue (and the nonphosphorylated Ser98) were changed to alanine by site directed mutagenesis of a human IGFBP-1 expression vector, followed by transfection into CHO cells. The [Ala98,101]IGFBP-1 purified from the conditioned media of these cells had the following characteristics: 1) when labelled with [32P]orthophosphate, it contained 63% less radioactivity than wild type IGFBP-1; 2) when analyzed by nondenaturing gel electrophoresis, it contained none of the most rapidly migrating and most rapidly migrating and most highly phosphorylated isoform, more of the nonphosphorylated isoform, and more of the most slowly migrating phosphorylated isoform; and 3) its affinity for IGF-I was reduced 2.5-fold and was midway between wild type IGFBP-1 from transfected CHO cells and dephosphorylated IGFBP-1. We conclude that Ser101 represents the major site of phosphorylation of IGFBP-1 and that while phosphorylation of Ser101 increases affinity of IGFBP-1 for IGF-I, phosphorylation of Ser169 and/or Ser119 also contributes to the high affinity of fully phosphorylated IGFBP-1.
...
PMID:Human IGFBP-1 is phosphorylated on 3 serine residues: effects of site-directed mutagenesis of the major phosphoserine. 768 25

The insulin-like growth factor-binding proteins (IGFBPs) are a family of six proteins that modulate the biological activity of IGF-I and IGF-II and determine their bioavailability to tissues. One of the IGFBPs, IGFBP-1, is distinctive in the dynamic response of its levels in human plasma to metabolic changes. Parallel changes occur in IGFBP-1 mRNA and IGFBP-1 transcription in rat liver. Using the well differentiated H4-II-E rat hepatoma cell line as a model system, we demonstrated previously that IGFBP-1 transcription is positively regulated by dexamethasone and negatively regulated by insulin. We now examine the effect of the protein synthesis inhibitor, cycloheximide, on the hormonal regulation of IGFBP-1 gene expression. Preincubation of H4-II-E cells with 10.7 microM cycloheximide for 1.5 h did not prevent the induction of IGFBP-1 mRNA and IGFBP-1 transcription (determined in nuclear run-on assays) by dexamethasone. By contrast, cycloheximide treatment abolished the decrease in IGFBP-1 mRNA induced by insulin. Insulin rapidly decreased IGFBP-1 transcription in the absence of cycloheximide (> 50% inhibition in 20 min) and caused a similar decrease in cells pretreated with cycloheximide. Cycloheximide alone also decreased IGFBP-1 transcription. Similar results were observed with a second protein synthesis inhibitor, anisomycin, which also prevented the insulin-induced decrease in IGFBP-1 mRNA without abolishing the insulin-induced inhibition of IGFBP-1 transcription. These results suggest that although insulin decreases IGFBP-1 gene transcription in the presence of protein synthesis inhibitors, IGFBP-1 mRNA levels are maintained because of stabilization of the mRNA. Stabilization was demonstrated directly in actinomycin D-treated cells, where the t1/2 of IGFBP-1 mRNA increased from approximately 2 to approximately 20 h in the presence of cycloheximide; insulin did not affect IGFBP-1 mRNA turnover. Thus, cycloheximide-sensitive labile proteins contribute to the maintenance of basal IGFBP-1 promoter activity and the rapid turnover of IGFBP-1 mRNA, which determine the dynamic regulation of IGFBP-1 gene expression.
...
PMID:Cycloheximide stabilizes insulin-like growth factor-binding protein-1 (IGFBP-1) mRNA and inhibits IGFBP-1 transcription in H4-II-E rat hepatoma cells. 768 68

Recombinant insulin-like growth factor-II (IGF-II) and two structural analogues, des(1-6)IGF-II and [Arg6]-IGF-II, were produced to investigate the role of N-terminal residues in binding to IGF-binding proteins (IGFBPs) and hence the biological properties of the modified peptides. The growth factors were modelled on two previously characterized variants of IGF-I, des(1-3)IGF-I and [Arg3]-IGF-I, which both show substantially decreased binding to IGFBPs and were expressed as fusion proteins in Escherichia coli. The biological activities of the corresponding analogues of IGF-I and IGF-II were compared in rat L6 myoblasts and H35B hepatoma cells. In the L6-myoblast protein-synthesis assay, the IGF-II analogues, des(1-6)IGF-II and [Arg6]-IGF-II, were slightly more potent than IGF-II but about 10-fold less potent than IGF-I and 100-fold less potent than the respective IGF-I analogues, des(1-3)IGF-I and [Arg3]IGF-I. In H35 hepatoma cells the anabolic response measured was the inhibition of protein breakdown, and the potency order was insulin >>> [Arg3]-IGF-I > des(1-3)IGF-I > [Arg6]-IGF-II > des(1-6)IGF-II > IGF-I > IGF-II. Binding of the IGFs and their analogues to the type 1 IGF receptor in L6 myoblasts and to the insulin receptor in H35 hepatoma cells did not fully explain the observed anabolic potency differences. Moreover, binding of all four analogues to the IGFBPs secreted by L6 myoblasts and H35B hepatoma cells was greatly decreased compared with the parent IGF. We conclude that the observed anabolic response to each IGF was determined by their relative binding to the competing cell receptor and IGFBP binding sites present.
...
PMID:Insulin-like growth factor (IGF)-II binding to IGF-binding proteins and IGF receptors is modified by deletion of the N-terminal hexapeptide or substitution of arginine for glutamate-6 in IGF-II. 768 57

In the present study effects of estrogens (natural estradiol and synthetic ethinyl estradiol) on liver derived proteins (angiotensinogen, IGF-I) were investigated in vivo in ovariectomized rats and in vitro in a rat hepatoma cell line (Fe33). The aim of this study was to establish both an animal and an in vitro model for quantification of the hepatic activity of given estrogenic compounds, and to study underlying mechanisms as regards the question of direct or indirect mode of estrogen action. In ovariectomized rats subcutaneous (s.c.)-treatment for 11 days with either estradiol (E2) or ethinyl estradiol (EE) (dose range 0.1-3 micrograms/animal/day) induced a comparable dose-dependent increase in uterine weight indicating a similar estrogenic potency of the two estrogens. Equipotency was also found as regards the effects on IGF-I plasma levels which dose-dependently decreased by about 50% at the highest dose tested (3 micrograms/animal/day). The decrease in IGF-I serum levels was accompanied by a significant 40% decrease in liver IGF-I mRNA. In contrast angiotensinogen plasma levels were affected only by EE (60% increase for the 3 micrograms/animal/day dose) but not by E2. When rats, in addition to ovariectomy, were also hypophysectomized (substituted with human growth hormone and dexamethasone) angiotensinogen again increased by 80% upon administration of 3 micrograms/animal/day EE, whereas IGF-I remained unaffected by EE. In a rat hepatoma cell line (Fe33) which is stably transfected with an estrogen receptor expression plasmid, 10 nmol/l EE for 24 h caused a 2.4-fold increase in angiotensinogen mRNA level. We conclude from our studies that estrogen effects on angiotensinogen serum levels in the rat are direct effects via the hepatic estrogen receptor, whereas estrogen effects on IGF-I serum levels are indirect effects, the primary target of estrogen action being probably the pituitary. The changes in angiotensinogen serum levels in the rat model are comparable to the situation in humans indicating the rat model and the Fe33 model to be useful tools to study the hepatic activity of estrogenic compounds.
...
PMID:Estrogen action on hepatic synthesis of angiotensinogen and IGF-I: direct and indirect estrogen effects. 814 96

It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1-2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38-42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide.
...
PMID:Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats. 854 25

Current treatment for disseminated prostate cancer, whether progressive or hormone-resistant, do not improve survival. Insulin growth factors (IGFs) are potent stimulants of prostate epithelial cells growth, their presence having been demonstrated in high quantities in several tumours such as lung, hepatoma, pheochromocytoma, malignant glioma and breast cancer. Local management of growth factors production could improve the results of second line therapy in hormone-resistant prostate cancer. Levels of IGF-I were determined by radioimmunoassay (RIA) in normal (n = 5), hyperplastic (n = 5) and tumoral (n = 8) prostate tissue. Presence of IGF-I is confirmed in all tissues (9.62 +/- 5.81; 8.32 +/- 7.81 and 6.02 +/- 1.42 ng/mg protein, respectively) but no significant differences are displayed among the three groups.
...
PMID:[Insulin growth factor I (IGF-I) in normal, hyperplastic, and tumor prostatic tissue]. 876 97

Recently we demonstrated that rat glioma cells when transfected with a vector encoding antisense IGF-I c-DNA lost tumorigenicity and induced a tumor specific immune response involving CD8+ lymphocytes. Here we showed, using immunostaining flow cytometry analysis, that the transfected cell lines, rat C-6 glioma and rat LF hepatoma, expressed an increase level of MHC-class I, and even the amount of MHC-I was found to be higher in the transfected hepatoma, than in the transfected glioma cells. This increased expression of MHC-I could contribute to the final immune recognition of tumour immunogenicity.
...
PMID:[Immunotherapy of tumors expressing IGF-I]. 888 Dec 77

Our previous work has shown that, in the normal circulation, insulin-like growth factor-binding protein-1 (IGFBP-1) is present as a single highly phosphorylated species. In this study, we have purified this previously uncharacterized isoform of IGFBP-1 to determine its ligand-binding affinity and the potential significance of highly phosphorylated IGFBP-I. Immunoaffinity chromatography was used to isolate IGFBP-1 from normal human plasma and from human hepatoma (Hep G2) cell medium as an alternative source of the IGFBP-1 phosphoform in the circulation. The affinity of this highly phosphorylated IGFBP-1 was compared with that of nonphosphorylated IGFBP-1 and recombinant human (rh) IGFBP-3 by equilibrium binding to IGF-II and IGF-II. Anion exchange (IEX) HPLC, nondenaturing electrophoresis, alkaline phosphatase treatment, and ligand-binding studies indicated that the highly phosphorylated IGFBP-1 from HepG2 cells was comparable with IGFBP-1 from plasma. In binding to IGF-I, the plasma phosphoform of IGFBP-1 was found to have a higher affinity (2.3 +/- 1.1 x 10(10) M-1) than nonphosphorylated IGFBP-1 (2.5 +/- 1.7 x 10(9) M-1, P < 0.002). However, when binding to IGF-II, phosphorylation had no affect on the affinity of IGFBP-1 (3.6 +/- 2 x 10(9) M-1 vs. 1.8 +/- 3 x 10(9) M-1, P not significant). Therefore, in the circulation, IGF-I has a considerably higher affinity than IGF-II for IGFBP-1 (P < 0.02). The affinity of phosphorylated IGFBP-1 from plasma (2.3 +/- 1.1 x 10(10) M-1) also was significantly higher than the affinity of IGFBP-3 for IGF-I (5.6 +/- 4.2 x 10(9) M-1, P < 0.005). These data suggest that the highly phosphorylated IGFBP-1 in the normal circulation will preferentially bind IGF-I rather than IGF-II, whereas in pregnancy, the affinity of IGFBP-1 for IGF-I will be reduced because of the appearance of non- and lesser-phosphorylated forms. This lends support to the theory that changes in IGFBP-1 phosphorylation may influence the modulatory effects of IGFBP-1 on IGF bioavailability.
...
PMID:Purification and characterization of the insulin-like growth factor-binding protein-1 phosphoform found in normal plasma. 904 19

<< Previous 1 2 3 4 5 6 7 8 9 Next >>