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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of insulin-like growth factors (IGFs) and insulin on erythropoietin (EPO) production by human hepatoma cells (Hep G2). Compared with normoxia (20% O2), EPO production by Hep G2 cells during a 72-h incubation was stimulated fivefold by exposure to low oxygen tension (1% O2) and nearly threefold by exposure to cobalt chloride (100 microM). IGF-I caused a concentration-dependent attenuation of EPO formation under normoxic conditions and inhibited (maximally 50%) EPO production stimulated by either low oxygen tension or cobalt [half-maximal effect (ED50) approximately 5 nM]. The increase of EPO mRNA levels in response to hypoxia was significantly reduced by IGF-I. Similarly to IGF-I, IGF-II (ED50 approximately 8 nM) and insulin (ED50 approximately 80 nM) also inhibited EPO formation in Hep G2 cells. IGF-I (100 pM-100 nM) stimulated the incorporation of radiolabeled alanine as a measure for total protein synthesis, 3H-labeled thymidine incorporation into DNA, and glycogen synthesis at 20 and 1% O2 in a concentration-dependent fashion. IGF-I exhibited a high affinity for the IGF-I receptor (apparent Kd approximately 3 nM). Unlabeled insulin was greater than 100-fold less potent than IGF-I in competing for 125I-IGF-I binding (apparent Kd approximately 360 nM). Conversely, insulin bound to the insulin receptor with high affinity (apparent Kd approximately 0.3 nM), whereas IGF-I was less than 1% as potent in competing for 125I-insulin binding. In summary, IGFs and insulin exert a negative control function on oxygen-regulated EPO production in Hep G2 cells. The inhibitory effect of IGFs and insulin on EPO formation appears to be mediated via the IGF-I receptor.
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PMID:Insulin-like growth factors decrease oxygen-regulated erythropoietin production by human hepatoma cells (Hep G2). 132 19

Western blot technique was used to detect the expression of gene products of IGF-II and IGF-II receptor as well as CSF-1 receptor in hepatocellular carcinoma and its adjacent nontumours liver tissue. A fetal expression of IGF-II was noted in 33 KD. IGF-II receptor was expressed in 260 KD and 230 KD with mature and immature forms, and CSF-1 receptor in 180 KD, 139KD and 122KD with different forms. The close relationship between the synthesized regulation and overexpression of three gene protein products and hepatocarcinogenesis was discussed.
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PMID:[Expression of gene products of insulin-like-growth-factor II, insulin-like-growth-factor II receptor and colony-stimulating-factor-I receptor in human primary hepatocellular carcinoma and non-cancerous liver tissues]. 133 23

For colorectal carcinomas, the rate of tumor development is proportional to the fourth to sixth power of elapsed time, suggesting that four to six independent events are necessary. Although similar calculations have not been made for HBV-associated HCCs, it is likely that this is also the case for HCCs, since individuals with persistent HBV infection do not usually develop HCC until they are 45 or greater years old. As evidence for specific genetic and epigenetic changes in HCCs accumulate, the important players in multistep hepatocarcinogenesis are becoming clearer. However, even though Myc family oncogenes are clearly implicated in woodchuck HCC, similar integrations have not been found in human HCCs. Therefore, although rodent and human systems have many similarities, we must realize that important differences may also exist. Regarding tumor suppressor genes, the evidence for p53 alterations in HCC is strong. A growing body of evidence suggests further that alterations in the retinoblastoma gene and one or more tumor suppressor genes on chromosome 11 are also involved in HCC. HBV integrations may certainly play a role in the generation of chromosome aberrations leading to loss of tumor suppressor alleles, since chromosomes 11 and 17 are the most common integration sites. Finally, the role of X proteins as participants in malignant transformation has been demonstrated for certain immortalized, nontransformed hepatocytes. Altered autocrine mechanisms of cell growth control, possibly involving IGF-II, are clearly implicated in HCC. Paracrine mechanisms for the control of hepatocyte growth and differentiated functions may also be altered as a result of the synthesis and secretion of a complex array of interleukins, HGF, and basic and acidic FGFs by cells in the inflammatory and cirrhotic lesions of precancerous livers. Whether the order of molecular changes in the hepatocyte is important for malignant progression is presently not clear. What is clear, however, is that hepatocarcinogenesis involves alterations in the concerted action of protooncogenes, growth factor, and tumor suppressor genes. How these factors interact will provide a more complete understanding of the mechanism or mechanisms of hepatic oncogenesis.
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PMID:Cellular and molecular mechanisms of hepatocarcinogenesis. 143 79

We describe a modified RIA using a rabbit polyclonal antiserum directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II). For standardization, we purified big IGF-II from patients with nonislet cell tumor hypoglycemia (NICTH). Under the conditions of our assay there was no significant interference from IGF-binding proteins. The big IGF-II present in the serum of a patient with NICTH displaced [125I]E-(1-21) from antibody parallel to our big IGF-II standard. We found a progressive rise in E-21 immunoactivity (IA) during childhood, with somewhat higher values in girls than in boys. In normal adults the mean E-21 IA level was 138 +/- 49 (+/- SD) micrograms/L. Women with twin pregnancies had higher E-21 IA than women with single pregnancies (302 +/- 66 compared with 120 +/- 18 micrograms/L). We found a marked elevation of E-21 IA in patients with NICTH due to sarcomas (n = 3), hepatoma (n = 2), adrenal carcinoma (n = 1), and carcinoma of the lung (n = 1). No elevation of E-21 IA was present in the serum of a hypoglycemic patient with a hypernephroma or another patient with carcinoma of the lung. Marked elevation of E-21 IA was observed in the serum of patients with renal failure receiving chronic hemodialysis. We conclude that this assay will prove useful in the diagnosis of NICTH in patients who are not azotemic and the investigation of the role of the kidney in clearing products of pro-IGF-II processing.
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PMID:Measurement of derivatives of proinsulin-like growth factor-II in serum by a radioimmunoassay directed against the E-domain in normal subjects and patients with nonislet cell tumor hypoglycemia. 161 98

A comparative study on HBV status and ets-2, IGF-II, C-myc and N-ras expression in 12 pairs of human primary hepatocellular carcinoma (PHC) and adjacent non-tumorous tissues (NT) showed that integrated forms of HBV DNA were present in 91.5% PHC and 75% NT. No specific integration sites were detected. Three PHC and 4 NT were found to have free forms of HBV DNA, which were defective in 2 PHC and 3 NT, i. e., being able to replicate but not to be secreted into the blood. At least one of four oncogenes studied was overexpressed in the 12 pairs of samples. IGF-II was expressed as 5.0 and 2.0 Kb fetal transcripts in 3 pairs of samples and 1 NT. Six NT had more than one of the four oncogenes that was expressed higher than PHC. This was commonly encountered in tissues with free forms of HBV DNA. The relation between HBV status, expression of ets-2, IGF-II, C-myc and N-ras and carcinogenesis of PHC is discussed.
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PMID:[HBV status and expression of ets-2, IGF-II, C-myc and N-ras in human hepatocellular carcinoma and adjacent nontumorous tissues--a comparative study]. 165 92

Binding proteins for the insulin-like growth factors (IGFBP) are important modulators of the biological actions of IGF-I and IGF-II. Concentrations of one of these proteins, IGFBP-1, in human plasma and IGFBP-1 mRNA in rat liver are markedly altered in diabetes and fasting. We now examine the regulation of IGFBP-1 and IGFBP-I mRNA in H4-II-E cells, a rat cell line derived from the minimal deviation H35 Reuber hepatoma previously reported to synthesize IGFBP-1 as its predominant IGF-binding protein. Confluent H4-II-E cells in serum-free medium were incubated with different hormones for 48 h, and the conditioned medium was analyzed by ligand blotting. Dexamethasone (10(-6) M) increased levels of 30-kDa IGFBP-1 approximately 10-fold; stimulation was half-maximal at 6 x 10(-9) M dexamethasone. No stimulation was seen with progesterone, testosterone, IGF-I, or rat GH, whereas insulin gave a small inhibition. Immunoblot analysis using a monoclonal antibody to human IGFBP-1 confirmed that the 30-kDa IGFBP induced by dexamethasone was IGFBP-1. IGFBP-1 mRNA was increased to a similar extent (7-fold), as determined by Northern blot hybridization using human or rat IGFBP-1 cDNA probes. The stimulation of IGFBP-1 mRNA was observed within 3 h after the addition of dexamethasone; IGFBP-1 in the medium increased more slowly. After withdrawal of dexamethasone from stimulated cells, IGFBP-1 mRNA decreased by 80% after 48 h; IGFBP-1 decreased more slowly. The increased abundance of IGFBP-1 mRNA in dexamethasone-treated cells primarily reflected increased transcription rather than increased mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dexamethasone stimulates transcription of the insulin-like growth factor-binding protein-1 gene in H4-II-E rat hepatoma cells. 170 85

The insulin-like growth factors (IGF-I and IGF-II) are present in extracellular fluids bound to specific IGF-binding proteins (IGFBPs). We and others have reported varying biologic activity of different preparations of IGFBP-1 that appeared to have identical amino acid sequences and molecular sizes. This observation prompted us to determine whether IGFBP-1 undergoes posttranslational modifications. Immunoprecipitation was used to show that Chinese hamster ovary cells (transfected with a human IGFBP-1 cDNA construct) and human hepatoma (HepG2) cells secrete 32P-labeled IGFBP-1 following incubation with [32P]orthophosphate. Phospho amino acid analysis of 32P-labeled IGFBP-1 revealed only phosphoserine residues. A method was developed that could separate nonphosphorylated IGFBP-1 from four or five phosphorylated isoforms. Using this technique we demonstrated that human amniotic fluid and human fetal serum contain a large proportion of nonphosphorylated IGFBP-1, as well as phosphorylated forms. In contrast, HepG2 cells and human decidual cells secrete predominantly the phosphorylated isoforms. These observations suggest that IGFBP-1 is secreted as a phosphoprotein and is subsequently dephosphorylated in vivo. Binding studies showed that the phosphorylated IGFBP-1 secreted by HepG2 cells has a 6-fold higher affinity for IGF-I than it does after dephosphorylation. We conclude that IGFBP-1 is phosphorylated and that this phosphorylation is a physiologically important posttranslational modification.
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PMID:Phosphorylation of insulin-like growth factor (IGF)-binding protein 1 in cell culture and in vivo: effects on affinity for IGF-I. 171 65

The insulin-like growth factor-binding proteins (IGFBPs) are thought to determine the distribution of IGF-I and IGF-II between the blood and tissue compartments and to modulate their biological activities. A dynamic metabolic role for one of the IGFBPs, IGFBP-1, is suggested by the fact that plasma IGFBP-1 was increased after fasting and diabetes and rapidly decreased by refeeding or insulin treatment, respectively. IGFBP-1 mRNA also is increased in the livers of diabetic rats and decreased by insulin treatment. To understand the molecular basis for this regulation, we have examined the effects of insulin on IGFBP-1 and IGFBP-1 mRNA in the H4-II-E cell line derived from the well differentiated H35 rat hepatoma. IGFBP-1, identified by ligand blotting and immunoblotting, is the major IGFBP in H4-II-E cells. Incubation of H4-II-E cells with insulin for 24 h decreased IGFBP-1 in the culture medium by approximately 50%. Inhibition was observed at physiological concentrations of insulin (ED50, less than 0.5 nM), but not at higher concentrations of IGF-II. These results, together with the fact that H4-II-E cells do not possess IGF-I receptors with which insulin might cross-react, suggest that insulin acts via the insulin receptor. Insulin inhibited IGFBP-1 in the medium by 80% in the absence of glucose, suggesting that the inhibition is a direct effect of insulin; glucose exerted a smaller independent effect in the absence of insulin. Insulin decreased IGFBP-1 mRNA in H4-II-E cells by 50% within 1 h and by 90% after 2-12 h of incubation. Nuclear run-on transcription assays indicated a corresponding decrease in the rate of IGFBP-1 gene transcription. Pretreatment of H4-II-E cells with dexamethasone stimulated IGFBP-1 transcription and increased steady state IGFBP-1 mRNA; stimulation was abolished by insulin treatment, indicating that inhibition by insulin was dominant over induction by dexamethasone. Thus, insulin, acting through the insulin receptor, rapidly decreases the abundance of IGFBP-1 mRNA in H4-II-E cells. Regulation occurs at least in part at the level of gene transcription. We propose that regulation of IGFBP-1 synthesis is an important component of the regulation of IGFBP-1 by insulin in vivo.
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PMID:Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells. 171 86

We have previously demonstrated increased levels of insulin-like growth factor (IGF)-II mRNAs and protein with re-expression of a fetal pattern of transcripts in human hepatocarcinoma. In the present study, we have investigated IGF-II transcripts and protein in liver tissues from patients with hepatocarcinoma infected with hepatitis B virus, by using in situ hybridization and immunohistochemical techniques. The IGF-II transcripts and protein have been localized to the hepatocytes, be they normal or tumoral with a gradient for IGF-II expression from normal to dysplastic and tumoral tissues. Hepatitis B virus mRNAs and viral surface antigen have only been detected in some hepatocytes in the peritumoral tissues. Therefore, the results show expression of IGF-II in hepatocytes. The increase of IGF-II expression in tumor hepatocytes support the hypothesis that it might represent a marker of hepatocytes differentiation.
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PMID:Localization of insulin-like growth factor-II and hepatitis B virus mRNAs and proteins in human hepatocellular carcinomas. 184 56

We recently identified a 32 K mol wt insulin-like growth factor (IGF)-binding protein (BP) which is markedly increased in the serum of streptozotocin-diabetic rats and recognized by antiserum against the human amniotic fluid IGFBP (hIGFBP-1). In the present study we sought to confirm that this protein represents the rat homolog of IGFBP-1 (rIGFBP-1), and that rIGFBP-1 may, therefore, play an important role in the regulation of IGF bioactivity in experimental diabetes. Since the abundance of related hepatic mRNA is high in diabetic rats, we asked whether well differentiated H4EIIC3 rat hepatoma cells produce rIGFBP-1 and provide sufficient amounts of this protein for purification and further characterization. Specific IGF-binding activity in hepatoma conditioned medium was detected initially by incubation with 125I-labeled recombinant human IGF-II and precipitation with polyethylene glycol. Ligand blotting demonstrated a 32 K BP, identical in size to the major low mol wt IGFBP found in diabetic rat serum. Affinity labeling and immunoprecipitation confirmed that this BP is related to human IGFBP-1 and is distinct from the fetal rat IGFBP, rIGFBP-2. Incorporation of [35S]methionine into 32 K BPs confirmed synthesis by hepatoma cells. For purification of BPs, conditioned medium was collected in roller culture, and BPs were purified by ammonium sulfate precipitation, Sephadex G-75 chromatography, and reverse phase HPLC. Partial amino acid sequencing of purified protein demonstrated 68% identity with the human IGFBP-1 and distinguished this BP from previously characterized rat IGFBPs. Purified protein bound both IGF-I and IGF-II with high affinity. We conclude that the 32 K IGFBP produced by H4EIIC3 hepatoma cells in culture represents the rat form of IGFBP-1 (rIGFBP-1). Regulation of rIGFBP-1 may play an important role in the modulation of IGF bioactivity in experimental animals with metabolic disease. The availability of purified rIGFBP-1 and identification of a cell line that produces this BP will greatly facilitate future studies of IGFBP-1 in the rat model.
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PMID:Production of the rat type 1 insulin-like growth factor-binding protein by well differentiated H4EIIC3 hepatoma cells: identification, purification, and N-terminal amino acid analysis. 216 20


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