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

Serum-free, hormonally defined media have been developed for optimal growth of a rat hepatoma cell line. The cells' hormonal requirements for growth are dramatically altered both qualitatively and quantitatively by whether they were plated onto tissue culture plastic or collagenous substrata. On collagenous substrata, the cells required insulin, glucagon, growth hormone, prolactin, and linoleic acid (bound to BSA), and zinc, copper, and selenium. For growth on tissue culture plastic, the cells required the above factors at higher concentrations plus several additional factors: transferrin, hydrocortisone, and triiodothyronine. To ascertain the relative influence of hormones versus substratum on the growth and differentiation of rat hepatoma cells, various parameters of growth and of liver-specific and housekeeping functions were compared in cells grown in serum-free, hormonally supplemented, or serum-supplemented medium and on either tissue culture plastic or type I collagen gels. The substratum was found to be the primary determinant of attachment and survival of the cells. Even in serum-free media, the cells showed attachment and survival efficiencies of 40-50% at low seeding densities and even higher efficiencies at high seeding densities when the cells were plated onto collagenous substrata. However, optimal attachment and survival efficiencies of the cells on collagenous substrata still required either serum or hormonal supplements. On tissue culture plastic, there was no survival of the cells at any seeding density without either serum or hormonal supplements added to the medium. A defined medium designed for cells plated on tissue culture plastic, containing increased levels of hormones plus additional factors over those in the defined medium designed for cells on collagenous substrata, was found to permit attachment and survival of the cells plated into serum-free medium and onto tissue culture plastic. Growth of the cells was influenced by both substrata and hormones. When plated onto collagen gel substrata as compared with tissue culture plastic, the cells required fewer hormones and growth factors in the serum-free, hormone-supplemented media to achieve optimal growth rates. Growth rates of the cells at low and high seeding densities were equivalent in the hormonally and serum-supplemented media as long as comparisons were made on the same substratum and the hormonally supplemented medium used was the one designed for that substratum. For a given medium, either serum or hormonally supplemented, the saturation densities were highest for tissue culture plastic as compared with collagen gels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of growth and differentiation of a rat hepatoma cell line by the synergistic interactions of hormones and collagenous substrata. 613 87

A subclone of the FU5-5 rat hepatoma cell line has been isolated which is inducible more than several hundred fold for the 20,000 dalton form of the major rat urinary protein alpha 2u-globulin. The basal relative synthetic rate (RSR) in growth medium containing 10% fetal calf serum was less than 2 X 10(-6) of total protein synthesis. Both dexamethasone and insulin were necessary for induction, and yielded a maximum induced RSR of 4-8 X 10(-3). Triiodothyronine (T3), dihydrotestosterone (DHT), rat growth hormone (GH), and estrogen, all of which have been shown to influence the induction of alpha 2u-globulin in the intact rat, were without effect on the cell line. A factor present in fetal calf serum was also necessary for maximum induction, since dexamethasone plus insulin in serum-free medium raised the RSR to only 3 X 10(-5); exogenous T3, GH, and DHT could not substitute for this serum factor. The kinetics of induction by dexamethasone were slow, with a lag of approximately 48 hr followed by a period of increasing RSR for 6-20 days. Removal of dexamethasone from induced cells led to an exponential decline in the RSR (t 1/2 15 hr). The concentrations of dexamethasone and insulin that could yield half maximum induction were 5 X 10(-8)M and 3 X 10(-11)M, respectively. Higher concentrations of insulin, although still in physiological range (10(-9)M), inhibited induction. At yet higher insulin levels, beyond the physiological range, alpha 2u-globulin synthesis returned to maximum values. The lack of DHT, T3, and GH requirement for alpha 2u-globulin induction in this cell line may mean that a regulatory aberrancy has occurred in this transformed cell line, or, alternatively, that these hormones act indirectly in the intact animal. This cell line should prove useful for the study of the molecular events associated with alpha 2u-globulin induction and for genetic approaches to the problem of multihormonal regulation of gene expression.
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PMID:Multihormonal induction of alpha 2u-globulin in an established rat hepatoma cell line. 618 49

The role of DNA methylation in the expression of the rat growth hormone (rGH) gene was assessed by using a hypomethylating agent, 5-azacytidine, and the iso-schizomeric restriction enzymes MspI and HpaII. 5-Azacytidine increased rGH mRNA 3-8-fold in GH3D6 cells, a subclone of rat pituitary tumor cell lines that expresses one-tenth to one-fifteenth the GH expressed by two other clones, GH3 and GC. The effect was also detected at the level of pre-mRNA. The effect was independent of glucocorticoids and thyroid hormones and was found to be inheritable. The DNA methylation pattern generated by the isoschizomeric restriction enzymes indicated that the HpaII sites in the rGH gene were mostly methylated in GH3D6 cells but mostly unmethylated in GC cells. After treatment with 5-azacytidine, about 22% of these HpaII sites in GH3D6 cells became unmethylated. Thus, DNA methylation correlates inversely with the expression of the rGH gene in these cell lines. However, three other observations indicate that factors in addition to DNA methylation control rGH expression. First, in GC cells, even though most of the HpaII sites are unmethylated, the gene is not fully expressed. Second, in rat hepatoma cells, which do not express GH at all, the GH gene is less methylated than that in GH3D6 cells. Third, within the sensitivities of the assay methods, 5-azacytidine has no effect on the GH gene when it is completely silent. Taken together, the findings indicate that DNA methylation modulates but does not control GH gene expression. It is tempting to speculate that DNA methylation can influence expression only when the gene is committed to express.
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PMID:The effects of 5-azacytidine on the expression of the rat growth hormone gene. Methylation modulates but does not control growth hormone gene activity. 620 70

At birth testicular androgens irreversibly program brain centers involved in hypothalamopituitary control of hepatic sex-dependent steroid and drug metabolism. This imprinting process results in activation of a hypothalamic "feminostatin"-a secreting center that is turned on just before puberty. Feminostatin inhibits pituitary secretion of "feminizing factor," a pituitary hormone that feminizes the basal type of metabolism characterizing the liver of hypophysectomized and gonadectomized rats. Consequently, female rats that are devoid of feminostatin will secrete feminizing factor from the pituitary, leading to a feminine type of hepatic metabolism. Male rats have an active feminostatin-secreting center, and inhibition of pituitary feminizing factor release results in an autonomous type of liver metabolism. Female rats show a relative androgen unresponsiveness and seem incapable of releasing feminostatin after treatment with natural androgens, possibly because of more efficient metabolism (breakdown) of androgen in the female than in the male rat brain. Frontal deafferentation at the retrochiasmatic and suprachiasmatic level resulted in a complete "feminization" of hepatic steroid metabolism in male rats. Such an effect was also seen when lesions involving mainly the anterior periventricular hypothalamic area and the suprachiasmatic nucleus were performed in male rats. No effects were seen in analogous lesions in female rats in any of the cases studied. These findings suggest that a region including the anterior hypothalamic periventricular area, the suprachiasmatic nucleus and adjacent areas is involved in the control of hepatic steroid metabolism. It is postulated that the neuronal cell bodies that produce feminostatin have their origins in this area of the hypothalamus or may send axons through this area to the basal hypothalamus and thus directly or indirectly influence the anterior pituitary gland. Regulation by the central nervous system of a "lactogenic" (prolactin, Prl) receptor, present in the female rat liver, was also studied. This receptor is present in very low concentration or absent in the male rat. Anterior hypothalamic deafferentation at the retrochiasmatic level in male rats increased the hepatic Prl receptor concentration to the female level 3-4 days following the operation. A transection rostral to the suprachiasmatic nucleus had no effect on the concentration of Prl receptors in male animals. Our results demonstrate that the number of Prl receptors is regulated by the hypothalamo-pituitary system. The receptor-inducing pituitary factor might be related to the feminizing factor. Experiments were carried out to elucidate the nature of the Prl receptor-inducing pituitary factor. Human growth hormone (hGH) continuously administered was shown to induce Prl receptors in livers from male and female hypophysectomized-gonadectomized rats. The prolactin receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and thyroidectomized male rats. The induced Prl receptors in male rats had similar characteristics as hepatic Prl receptors in female rats. Also the endogenous rat hormones, rPrl and rGH, were administered in minipumps. In the concentration used (10 mug/mul), rPrl had no effect whereas rGH increased Prl receptor levels to approximately 37% of the female control level. These results indicate that GH or a peptide related to GH may be involved in the regulation of hepatic Prl receptors. The hypothalamo-pituitary-liver axis represents a new concept in endocrine regulation of drug toxicity. The male rat liver has been shown to be more susceptible than the female rat liver to the hepatocarcinogenic action of certain drugs, and it is conceivable that sex differences in the metabolic activation of the drugs in the liver may explain the greater sensitivity of male rats to chemically induced hepatocellular carcinoma. Similar sex differences in liver cancer incidence have been reported in the human.
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PMID:Role of the hypothalamo-pituitary-liver axis in sex differences in susceptibility of the liver to toxic agents. 626 6

Immunoreactive serum levels of human chorionic gonadotrophin (HCG), its alpha- and beta- subunits (alpha-HCG and beta-HCG), calcitonin (CT), parathyroid hormone (PTH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and growth hormone (GH) were increased in 8 to 68% of 44 patients with hepatocellular carcinoma. With the exception of two patients, ACTH and PRL levels were only moderately increased, while alpha-HCG, GH, ACTH and PRL levels were not significantly different from the levels found in cirrhosis suggesting that metabolic effects due to impaired liver function may be responsible for their increase in liver cirrhosis and primary liver cell carcinoma. In contrast, HCG, beta-HCG, CT and PTH were associated with a higher incidence of elevated immunoreactive hormone levels than the other peptide hormones; higher concentrations were noted in tumor patients than with liver cirrhosis alone. Therefore, we suggest that metabolic effects due to cirrhosis may influence the serum levels and be more important than ectopic secretion by hepatocellular carcinoma.
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PMID:Peptide hormones in liver cirrhosis and hepatocellular carcinoma. 627 36

We have demonstrated recently that the local metastatic growth of Morris hepatoma 44 is thyroid dependent ( Mishkin , S., Morris, H. P., Yalovsky , M., and Murthy , P. V. N. Gastroenterology, 77; 547-555, 1979; Mishkin , S. Y., Pollack , R., Morris, H. P., Yalovsky , M., and Mishkin , S. Cancer Res., 41: 3040-3045, 1981) and that exogenous thyroxine (8 micrograms/kg/day) and prolactin (100 micrograms/day) significantly stimulated tumor growth, while growth hormone (100 micrograms/day) failed to do so ( Pollack , R., Mishkin , S. Y., Morris, H. P., and Mishkin , S. Hepatology, 2: 836-842, 1982). In the present study, thyroid ablation (hypothyroidism) and hypophysectomy inhibited tumor growth significantly. These effects were almost totally reversed by administration of exogenous thyroxine to hypothyroid rats. While prolactin or growth hormone or thyroxine alone failed to restore tumor growth in hypophysectomized animals, administration of all three hormones partially but significantly reversed the inhibition of tumor growth. The number and size of pulmonary metastases paralleled local growth in all the above-mentioned conditions. Plasma membrane lactogenic receptors, measured using human growth hormone, were decreased in hypothyroidism and hypophysectomy groups. Binding levels were restored in those groups in which tumor growth was stimulated. In summary, the local and metastatic growth of Morris hepatoma 44 is affected by anterior pituitary hormones. Plasma membrane lactogenic receptors may mediate these effects.
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PMID:Effects of hypophysectomy and hormone replacement on the local and metastatic growth of Morris hepatoma 44. 632 29

Rat liver hepatoma cells (HTC) which express liver-specific gene products were assayed for the expression of the rat growth hormone (rGH) gene, which is normally expressed in anterior pituitary somatotrophs. The combination of immunoprecipitation and two-dimensional gel electrophoresis provided a highly sensitive assay for rGH synthesis at levels as low as one part in 10(9) of cell protein synthesis (or four molecules of rGH per cell). No rGH expression was detected at this level. The lack of expression in HTC cells did not derive from a deletion of the rGH gene, as shown by Southern hybridization analysis of genomic DNA. Because the gene is expressed at greater than 30% of anterior pituitary protein synthesis, differentiation regulated rGH expression by over 10(8)-fold between the two cell types. Additionally, DNA-excess solution hybridization was used to measure the level of rGH mRNA sequences. A novel and general method for preparing single-strand probes from recombinant plasmids was developed. Hybridization analyses with a sensitivity of detection of 1 part in 10(8) failed to detect any rGH RNA sequences in either the nucleus or cytoplasm of HTC cells. It is concluded, therefore, that the restriction in rGH expression in the liver tumor cells is likely to occur at the level of the transcription of the gene, and that for all practical purposes, the rGH gene is completely shut off in the hepatoma cells.
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PMID:The level of expression of the rat growth hormone gene in liver tumor cells is at least eight orders of magnitude less than that in anterior pituitary cells. 662 33

Cultured human lymphocytes and rat hepatoma cells were labeled with [32P]orthophosphate and the insulin receptor subunits identified by immunoprecipitation and sodium dodecyl sulfate-gel electrophoreses. In both cell types the 95,000-dalton (beta) subunit of the insulin receptor was selectively phosphorylated. Phosphorylation was specifically stimulated by insulin in a dose-dependent fashion after 1 and 15 minutes of hormone treatment, whereas human growth hormone was without effect. This phosphorylation may be a very early event in insulin action.
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PMID:Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. 703

The hepatic expression of the alpha-2u-globulin gene family is controlled by a variety of hormones including steroids, growth hormone and insulin. The mechanisms by which these hormones affect alpha 2u-globulin expression are only partially understood. Recently we isolated and characterized clone RAP 01, an alpha 2u-globulin gene expressed in the liver. In preliminary experiments we noted that partial hepatectomy, a procedure which results in a sharp rise in the level of the oncoproteins c-Fos and c-Jun, also causes a transient induction of the messenger RNA corresponding to clone RAP 01. Using the DNAseI footprinting technique we were able to show that this clone contains a TPA (phorbol 12-myristate 13-acetate)-responsive element (TRE) in its first intron. This element (denoted as element X) is identical to the consensus AP-1 binding site (TGACTCAG) and is protected by rat liver nuclear extracts as well as by purified c-Jun. Gel retardation experiments show that an oligonucleotide containing the TRE consensus sequence competes for binding of liver nuclear proteins to element X and that antibodies directed against the M2 peptide of the mouse Fos protein or the PEP-2 peptide of Jun prevent the formation of specific complexes with the same element. Moreover, element X functions as a TRE in transfected BWTG3 hepatoma cells treated with TPA. Co-transfection with fos and jun expression vectors mimics the effects of TPA suggesting that AP-1 is in fact the mediator of the observed response. It is concluded that the first intron of RAP 01 contains a functional Fos-Jun element.
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PMID:A Fos-Jun element in the first intron of an alpha 2u-globulin gene. 750 7

Astrocytes have been identified as the primary source of brain angiotensinogen (Ao), but the regulation of the secretion of this protein from astrocytes is poorly defined. In this study, the rat C6 glioma cell line was used as an astrocyte model to investigate the regulation of Ao secretion. C6 cultures secreted Ao at a rate of 4.05 +/- 1.52 (mean +/- SD) ng of Ao/10(6) cells/24 h as determined by a direct radioimmunoassay. This rate was not significantly altered by the hormones thyroxine, estradiol, angiotensin II, growth hormone, and prostaglandins or by increased levels of intracellular cyclic AMP. Treatment with the synthetic glucocorticoid dexamethasone (DEX; 10(-6) M) reduced the rate of Ao secretion to 1.82 +/- 0.28 ng of Ao/10(6) cells/24 h. By comparison, the basal secretion rate for rat H4 hepatoma cells was 142.4 +/- 10.0 ng of Ao/10(6) cells/24 h, and this increased fourfold (572.4 +/- 173.1 ng/10(6) cells/24 h) in the presence of 10(-6) M DEX. Both these inhibitory (C6) and stimulatory (H4) actions of DEX were dose related. The inhibition observed in C6 cells was mimicked by RU28362, a pure glucocorticoid agonist, and reversed by the antagonist RU486, demonstrating that DEX was functioning as a true glucocorticoid. The action of DEX was also antagonized by the cyclic AMP analogue N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dBcAMP) (control, DEX, and DEX + dBcAMP, 3.58 +/- 0.73, 1.69 +/- 0.82, and 4.93 +/- 1.88 ng of Ao/10(6) cells/24 h, respectively, and by the beta-adrenergic agonist isoprenaline, which stimulates cyclic AMP production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A novel inhibitory role for glucocorticoids in the secretion of angiotensinogen by C6 glioma cells. 751 Jul 76


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