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)

T4-binding globulin (TBG), the principal carrier of thyroid hormone in serum, is a glycoprotein containing 20% carbohydrate. The importance of the carbohydrate moiety has been previously studied by enzymatic deglycosylation, which showed that deglycosylated TBG retains its original immunological an T4-binding properties. However, the structure and properties of TBG before glycosylation and the steps involved in carbohydrate addition have not been explored. In the present report, we used a human hepatoma cell line (Hep G2) which synthesizes and secretes TBG into the medium. This TBG binds T4 and possesses immunoreactivity and microheterogeneity identical to those of native TBG (nTBG) from serum. Cells were pulsed with [35S]methionine, [3H]mannose, and [3H]glucosamine in the absence or presence of 5 micrograms tunicamycin/ml medium. Materials from cells and media were immunoprecipitated with antibodies specific for nTBG and denatured TBG molecule. They were then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cells incubated with [35S]methionine contained two forms of labeled TBG, with apparent mol wt of 60K (TBG1) and 54K (TBG2). Medium contained only the TBG1 form, which is identical to nTBG in serum. In contrast, in the presence of tunicamycin, the predominant intracellular form of TBG had an apparent mol wt of 44K (TBG3). At no time was this material detected in the medium. [3H]Mannose and [3H]glucosamine labeled both TBG1 and TBG2, but not TBG3. TBG1 and TBG2 reacted with anti-nTBG serum, whereas TBG3 reacted only with anti-dentured TBG serum, specific for the unfolded TBG molecule. Intracellular TBG was rich (80-90%) in high mannose (seven to nine mannose residues) oligosaccharides and was relatively poor (10-20%) in complex-type species, resistant to endoglycosidase H. These results indicate that 1) the precursor nonglycosylated 44K TBG3 is glycosylated to produce TBG2 (54K) and TBG1 (60K); 2) TBG2 contains oligosaccharides rich in mannose and appears to be a major intracellular intermediate in the synthesis of TBG1; 3) only the endoglycosidase H-resistant TBG1 is secreted; and 4) prior glycosylation of TBG appears to be required for the molecule to assume its tertiary structure and, ultimately, for its secretion. However, once the peptide chain is folded, removal of the carbohydrate moieties does not alter the tertiary structure.
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PMID:The role of glycosylation in the molecular conformation and secretion of thyroxine-binding globulin. 308 30

To elucidate the recently advanced hypothesis that glutathione [L-gamma-glutamyl-L-cysteinyl glycine (GSH)] regulates deiodinating enzyme activities, accounting for the decreased conversion of T4 to T3 in the liver of fetal and starved animals, we investigated thyroid hormone metabolism in GSH-depleted neoplastic and normal hepatocytes. In monkey hepatocarcinoma cells, intracellular total GSH decreased below 10% of the control value (approximately 25 micrograms/mg protein) when cells were grown for 44 h in medium deficient in cystine and methionine or in cystine alone. The latter finding indicated that transsulfuration from methionine to cysteine was defective in these neoplastic cells. In primary cultured adult rat hepatocytes, on the other hand, the transsulfuration pathway was intact, and total GSH decreased below 10% of control (approximately 20 micrograms/mg protein) only in cells grown in cystine- and methionine-deficient medium. In both cell types, the oxidized GSH fraction remained constant (2-5% of total). Incubation with 125I-labeled T4 and T3, followed by chromatography, was used to evaluate 5-deiodination in hepatocarcinoma cells and both 5- and 5'-deiodination in normal hepatocytes. Deiodination was not decreased by GSH deficiency in either case, but was actually increased in hepatocarcinoma cells. This resulted from an increase in the Vmax of 5-deiodinase related to growth arrest. Diamide at 2 mM reversibly inhibited both 5'- and 5'-deiodination in rat hepatocytes, accompanied by decreased total GSH as well as increased GSH disulfide (27% of total). The data suggest that GSH is so abundant in the liver that hepatocytes can tolerate a greater than 90% decrease in intracellular concentration without any change in thyroid hormone deiodination and indicate that altered thyroid hormone metabolism in the fetus and in starvation cannot be accounted for by a decreased hepatic GSH concentration.
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PMID:Glutathione deficiency induced by cystine and/or methionine deprivation does not affect thyroid hormone deiodination in cultured rat hepatocytes and monkey hepatocarcinoma cells. 679 Feb 65

In this communication, we provide evidence that proliferation of transplantable Morris hepatoma 7777 might to some extent be regulated by triiodothyronine and/or a specific serum protein, the levels of which are correlated with levels of triiodothyronine. The protein has an estimated molecular weight of 80,000 and migrates as one band on polyacrylamide gel electrophoresis. In normal rats, this protein accounts for approximately 1% of the total serum protein. Both the circulating levels of the serum protein and proliferating of transplanted hepatoma cells were decreased in thyroidectomized rats. Elevated levels of the serum protein and increased cell proliferation were observed when animals had 70% of their lives removed prior to transplant, were given injections of triiodothyronine, or had a 10-day-old first transplant surgically removed. Some evidence is also provided suggesting that the synthesis of the serum protein is stimulated by thyroid hormone.
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PMID:Correlation of circulating levels of a serum protein with triiodothyronine levels and hepatoma growth. 705 45

The local growth rate of Morris Hepatoma 44 (generation time, 6 months) was inhibited by 66 to 87%, and host survival was prolonged by 36 to 78% after the induction of hypothyroidism within 2 weeks of tumor implantation by propylthiouracil (0.1% in Purina chow), 131I(1 mCi/100 g body weight i.p.), or surgical thyroidectomy. In additional experiments, we studied the effects of inducing hypothyroidism (131I) at different stages in the natural history of Morris Hepatoma 44 on local and metastatic growth as well as on host survival. Induction of hypothyroidism within 2 weeks of tumor implantation (Group I) reduced local tumor growth as well as the number and size of pulmonary metastases, and prolonged survival by 70 to 80%. Induction of hypothyroidism at 6 weeks postimplantation when tumors were palpable (Group II) inhibited local growth by 39%, reduced the number and size of pulmonary metastases by approximately 80%, and prolonged host survival by 35%. Initiation of 131I treatment at 11 weeks when microscopic pulmonary emboli were present in most animals (Group III) reduced local growth by 19% and the number and size of pulmonary metastases by 72 and 50%, respectively. In this case, survival was prolonged by 17%. We conclude from these results that the local and metastatic growth of Morris hepatoma 44 as well as host survival are thyroid hormone-dependent processes. The mechanisms responsible for these observations remain to be explained.
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PMID:Inhibition of local and metastatic hepatoma growth and prolongation of survival after induction of hypothyroidism. 724 60

"Spot 14" is a nuclear protein that is rapidly induced by thyroid hormone (T3) and dietary carbohydrate in liver. We used an antisense oligonucleotide to inhibit induction of spot 14 protein by T3 and glucose in primary cultures of rat hepatocytes to test the hypothesis that the protein could function in the regulation of lipid synthesis. Spot 14 protein was undetectable in hepatocytes maintained in 5.5 mM glucose without T3, and was induced within 4 h after addition of 27.5 mM glucose and 50 nM T3 to the culture medium, reaching a maximal level within 24 h. Accumulation of spot 14 protein was markedly inhibited in hepatocytes transfected with a spot 14 antisense oligonucleotide, but not in those treated with a control oligonucleotide. Transfection of the antisense, but not control, oligonucleotide also abrogated the increase in lipogenesis induced by T3 and glucose. Reduced triglyceride formation accounted for the diminished net lipid synthesis. In contrast to lipogenesis, glucose uptake was not significantly affected by the transfections. Antisense transfection inhibited the induction of both ATP-citrate lyase and fatty acid synthase immunoreactivities, as well as malic enzyme activity, indicating that the observed reduction in lipogenesis could be explained by diminished cellular content of lipogenic enzymes. Reduced malic enzyme activity in antisense-transfected hepatocytes was accompanied by lowered relative abundance of malic enzyme mRNA, suggesting that the antisense effects on lipogenic enzymes were mediated at the pretranslational level. The oligonucleotides did not significantly affect lipogenesis in a rat hepatoma cell line that does not express detectable spot 14 mRNA or protein. These data directly implicate the spot 14 protein in the transduction of hormonal and dietary signals for increased lipid metabolism in hepatocytes.
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PMID:Direct evidence for a role of the "spot 14" protein in the regulation of lipid synthesis. 762 69

Human GH (hGH) has been shown to stimulate hepatic low density lipoprotein (LDL) receptor expression in man in vivo. To further characterize this effect in vitro, we determined the expression of LDL receptors in cultured human hepatoma (HepG2) cells exposed to hGH. After incubation with hGH, stimulation of LDL receptors appeared at a concentration of 0.25 nM hGH. The presence of hGH receptors on HepG2 cells could be demonstrated by immunocytochemistry using a hGH receptor-specific monoclonal antibody. Binding studies, using 125I-labeled hGH, revealed high affinity binding with the appropriate somatogenic specificity. The LDL receptor induction was specific for hGH, as both bovine GH and recombinant human PRL were without effect. The LDL receptor stimulation occurred in parallel with increased levels of LDL receptor messenger RNA. Inclusion of dexamethasone and thyroid hormone in the incubation medium enhanced the LDL receptor stimulation by hGH. Although incubation with insulin-like growth factor-I (IGF-I) stimulated LDL receptor expression, the hGH-induced stimulation was unaltered after preincubation of cells with a monoclonal mouse anti-IGF-I antibody, suggesting that the release of IGF-I is not involved in LDL receptor stimulation by hGH. We conclude that hGH specifically induces the LDL receptor in cultured HepG2 cells at both the protein and the messenger RNA level, and that the induction is independent of IGF-I release.
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PMID:Growth hormone specifically stimulates the expression of low density lipoprotein receptors in human hepatoma cells. 764 83

The growth-regulating actions of IGFs are modulated by their binding proteins (IGFBPs). The serum concentration of IGFBP-1 is down-regulated by insulin, and in-vitro studies have demonstrated that IGFBP-1 secretion from various tissues and cells can be stimulated by theophylline, forskolin, oestrogen and progesterone. We have studied the effects and mechanisms of thyroid hormone action on IGFBP-1 gene expression and secretion by human hepatoma cells in vitro. Tri-iodothyronine dose-dependently enhanced IGFBP-1 secretion in serum-free HepG2 cell cultures after 24-48 h of exposure, as measured by a specific immunofluorometric assay. This was accompanied by an increase (+ 50%) in the amount of IGFBP-1 mRNA, which could be prevented by cycloheximide, a protein synthesis inhibitor. Cycloheximide transiently enhanced (+ 200%) the accumulation of IGFBP-1 mRNA at 3-12 h of incubation, when no effect of tri-iodothyronine was observed. It is concluded that thyroid hormone stimulates IGFBP-1 secretion slowly by enhancing IGFBP-1 gene expression by a protein mediator. The acute stimulation of IGFBP-1 gene transcription by cycloheximide associates this gene with a number of growth-related genes encoding growth- and tumour-associated peptides.
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PMID:Tri-iodothyronine and cycloheximide enhance insulin-like growth factor-binding protein-1 gene expression in human hepatoma cells. 768 Aug 63

We constructed a recombinant adenovirus carrying the firefly luciferase gene driven by the thymidine kinase promoter and controlled by the palindromic thyroid hormone/retinoic acid-responsive element. The same adenovirus vector without the hormone-responsive element was used as control. Regulation of the luciferase gene expression was tested in pituitary-derived GH cells and hepatoma-derived HepG2 cells infected with the recombinant adenoviruses. Administration of triiodothyronine to GH cells and all-trans-retinoic acid to HepG2 cells resulted in 8.0 +/- 0.3-fold and 4.6 +/- 0.5-fold induction of luciferase activity, respectively. No significant increase was observed with the control adenovirus. Hormonal regulation was also examined in adult mice. Mice depleted of thyroid hormone were injected intravenously with the recombinant adenoviruses and given 4 times the replacement dose of triiodothyronine or vehicle only for 4 days. Hormone administration resulted in 4.2-fold increase of luciferase activity in liver homogenates. No significant effect was observed in animals injected with the control adenovirus. This recombinant adenovirus provides a new experimental system in the study of thyroid hormone and retinoic acid action and offers the potential to regulate by physiological means the expression of genes transferred for the purpose of therapy.
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PMID:Expression of a thyroid hormone-responsive recombinant gene introduced into adult mice livers by replication-defective adenovirus can be regulated by endogenous thyroid hormone receptor. 792 32

To understand the role of thyroid hormone nuclear receptors (TRs) in hepatocarcinogenesis, we characterized the TRs in nine human hepatocarcinoma cell lines. The expression of TR proteins is receptor subtype- and cell type-dependent. TR alpha 1 protein expresses similarly at a low level in each of the nine cell lines. In contrast, TR beta 1 is overexpressed in hepatocarcinoma cells which are poorly differentiated. Furthermore, thyroid hormone was found to stimulate the proliferation of cells in which TR beta 1 is overexpressed. These results suggest that TR beta 1 is most likely involved in the differentiation and proliferation of hepatocarcinoma cells. Our studies have shed new light in the understanding of the role of TRs in liver carcinogenesis.
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PMID:Stimulation of proliferation by 3,3',5-triiodo-L-thyronine in poorly differentiated human hepatocarcinoma cells overexpressing beta 1 thyroid hormone receptor. 795 36

1. Hormonal regulation of apolipoprotein E (apoE) gene expression by insulin and thyroid hormone was studied in a human hepatoma cell line, HepG2. 2. Changes at the mRNA level, mRNA translation, in vivo synthesis and secretion were monitored. 3. Both insulin and triiodothyronine were found to have no significant effect on apoE mRNA levels. 4. Insulin treatment caused an inhibition of: (a) the in vitro translation of endogenous apoE mRNA in a HepG2 cell-free system (25%), and (b) the incorporation of radioactivity into newly-synthesized apoE in an in vivo pulse-chase labeling experiment (32%). 5. Interestingly, apoE secretion rate was found to be significantly reduced with insulin (84%) suggesting that a major portion of newly-synthesized apoE may be shunted into a degradative pathway. 6. Using a similar experimental approach, triiodothyronine showed no significant effect on the rate of apoE synthesis or translation (6-15% decrease), however a slight reduction (20%) in secretion rate was shown. 7. Overall, apoE gene expression does not appear to be influenced by triiodothyronine significantly but is modulated by insulin at the translational and post-translational level.
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PMID:Hormonal regulation of human apolipoprotein E gene expression in HepG2 cells. 834 6


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