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 binding of ten steroids possessing antiglucocorticoid activity has been studied in rat skeletal muscle cytosol. The affinity of these steroids for both the androgen and the glucocorticoid receptors was determined by competition with radioactive R1881 (methyltrienolone, metribolone) and dexamethasone, respectively. The antiglucocorticoid activity of these compounds was assessed in rat hepatoma (HTC) cells by measuring their inhibitory effect on the glucocorticoid-induced tyrosine aminotransferase activity. This led to identification of five novel in vitro glucocorticoid antagonists. All the steroids tested bound to both the glucocorticoid and the androgen receptors in muscle. Four steroids had an affinity for the glucocorticoid receptor higher than for the androgen receptor. The assumption is made that the steroids tested also behave as antagonists when binding to the glucocorticoid receptor in muscle and behave as agonists when binding to the androgen receptor. On this basis, the data allow one to compute a potential anticatabolic (PAG) and a potential anabolic (PAA) index for each compound. These indices might be of predictive value to determine whether these steroids exert their anabolic action in muscle through the glucocorticoid receptor or through the androgen receptor. The data also make it unlikely that satellite cells are a preferential target for anabolic steroids in muscle.
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PMID:Binding of glucocorticoid antagonists to androgen and glucocorticoid hormone receptors in rat skeletal muscle. 348 22

We studied the effect of antiandrogen treatment on the Solt-Farber model of hepatocarcinogenesis in male Sprague-Dawley rats. The size and number of the liver tumors were reduced by various antiandrogen treatments (orchiectomy, an LH-RH analog, and chlormadinone acetate). In addition, the proportion of poorly differentiated carcinomas was decreased by the antiandrogen treatment, while that of well-differentiated trabecular or glandular carcinomas was increased. The bromodeoxyuridine labeling index of the tumor cells was significantly decreased after the antiandrogen treatment. The expression of rat androgen receptor mRNA in carcinoma tissue was increased when compared to control liver tissue, and was decreased after the antiandrogen treatment. Orchiectomy had the greatest inhibitory effect on carcinoma, although the effect of chemical orchiectomy using an LH-RH analog was almost similar to that of orchiectomy. These results suggest that the clinical application of antiandrogen therapy for human hepatocellular carcinoma might be possible in the future.
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PMID:Effect of antiandrogen treatment on chemical hepatocarcinogenesis in rats. 752 37

Seventy-eight patients in whom androgen or oestrogen receptors, or both, were assayed in hepatocellular carcinoma (HCC) and the surrounding liver were discharged from hospital after curative resection of the tumour. Intrahepatic recurrence was evaluated retrospectively after 28-128 months follow-up to determine the association with receptor status. Androgen and oestrogen receptors in HCC significantly influenced the intrahepatic recurrence rate. The recurrence-free 5-year survival rate was 55 per cent for patients who had androgen receptor-negative tumours, 24 per cent for oestrogen receptor-negative, 10 per cent for oestrogen receptor-positive and 0 for androgen receptor-positive (P = 0.0322). Recurrence-free 5-year survival in 57 patients who had both receptor assays was 75 per cent for patients who had androgen receptor-negative, oestrogen receptor-negative tumours, 50 per cent for androgen receptor-negative, oestrogen receptor-positive, but 0 for androgen receptor-positive, oestrogen receptor-positive and androgen receptor-positive, oestrogen receptor-negative (P = 0.0104). The presence or absence of androgen or oestrogen receptor in the liver, however, was not associated with intrahepatic recurrence (P = 0.7534). Thus, androgen receptors are strongly associated with intrahepatic recurrence of HCC, while oestrogen receptors are weakly associated. Receptor status in the normal liver was not related to intrahepatic recurrence.
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PMID:Androgen and oestrogen receptors in hepatocellular carcinoma and surrounding liver parenchyma: impact on intrahepatic recurrence after hepatic resection. 761 7

Hepatocellular carcinoma is the most commonly fatal malignant tumour worldwide. The role of androgen receptors, which have been found in hepatocellular carcinoma, is controversial. Sequence specific polymerase chain reaction (PCR) was used to quantify, for the first time, the expression of androgen receptor in four adult liver biopsy specimens (HL-A to HL-D), fetal liver, and Hep-G2 cells. The measurement of androgen receptor is expressed as a ratio (androgen receptor: beta-actin) of the value of androgen receptor to the value of a control gene, beta-actin. The value of the androgen receptor: beta-actin ratios for HL-A, HL-B, HL-C, HL-D, fetal liver, and Hep-G2 were 0.37, 0.86, 0.37, 0.44, 0.87, and 0.66 respectively. To verify sequence specific amplification of the androgen receptor, the PCR androgen receptor fragment was sequenced. The resultant sequence data for both strands of the double stranded PCR androgen receptor fragment had 100% similarity with the published androgen receptor mRNA sequence (complete codons).
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PMID:Measurement of androgen receptor expression in adult liver, fetal liver, and Hep-G2 cells by the polymerase chain reaction. 820 May 66

We investigated the cell clonality of 12 cases of female solitary hepatocellular carcinoma (HCC) that were associated with hepatitis virus infection. The clonal origin of HCC could be assessed by the method based on restriction fragment length polymorphism (RFLP) of X-chromosome-linked androgen receptor gene (AR) and phosphoglycerate kinase (PGK) gene, taking advantage of random inactivation of one of two X-chromosomes by methylation in females. We extracted DNA samples from both fresh and paraffin-embedded specimens of the same lesion as a source of DNA sample for polymerase chain reaction (PCR). Consequently, it was possible to use methylation-sensitive restriction enzymes and PCR to study differential methylation patterns among alleles of these genes for both DNA samples. The RFLPs of AR gene and PGK gene were found in eight of 12 cases and five of 12 cases, respectively. There were two cases which had no RFLPs in either AR gene or PGK gene. All cases of HCC which had RFLP in either AR gene or PGK gene demonstrated monoclonal origin of the tumor regardless of their histologic patterns.
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PMID:[Clonal analysis of hepatocellular carcinoma]. 867 65

Heterogeneity in the growth response to androgen and androgen receptor (AR) status in an AR-positive human hepatocellular carcinoma (HCC) line, KYN-1, was investigated in the present study. Seven sublines were obtained from KYN-1 by the limited dilution method. Four of them had no detectable amounts of AR and did not show any growth response to dihydrotestosterone (DHT) at the concentration up to 1000 nM, while the other three had varying amounts of both cytosolic and nucleosolic AR that were 5- to 7-fold higher than that of the parent cell. In the parent cell, the addition of DHT caused a modest but significant increase in the cell number (21%) in a 14-day culture. Such effect was increased by 2- to 7-fold in two AR-positive sublines. In addition, the sensitivity of the response in these two sublines was increased by up to 24-fold. The one remaining AR-positive subline did not show any growth response to DHT, although the behavior of its AR in sucrose gradient ultracentrifugation and Western blotting was the same as that of the other two sublines. These data clearly show that sublines derived from an established human HCC line have a broad heterogeneity in the growth response of HCC to androgen as well as in AR status and could be classified into three groups on the basis of the growth responsiveness to androgen and the AR expression.
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PMID:Heterogeneity in androgen receptor levels and growth response to dihydrotestosterone in sublines derived from human hepatocellular carcinoma line (KYN-1). 906 78

Giant cell tumor of tendon sheath (GCTTS) is a common soft tissue tumor. Immunophenotypical evidence suggests it is of synovial cell origin. There is controversy regarding the underlying nature of this lesion, specifically whether it is a neoplastic or nonneoplastic (ie, reactive or hyperplastic) process. Karyotypic abnormalities have been identified in GCTTS and interpreted as evidence of neoplasia, although the finding of similar karyotypic abnormalities in unequivocally nonneoplastic proliferations raises questions about using such findings to define a neoplasm. In an attempt to resolve this uncertainty, a polymerase chain reaction (PCR)-based assay for methylation of the X-linked human androgen receptor gene (HUMARA) was used to assess whether GCTTS is a clonal or polyclonal proliferation. DNA was isolated from formalin-fixed, paraffin-embedded tissue blocks from eight cases of digital GCTTS in female subjects; two cases of hepatocellular carcinoma (HCC) were used as clonal controls. Seven of eight cases of GCTTS were informative, and each showed a polyclonal proliferation, whereas both cases of HCC were clonal. Our results indicate that GCTTS is a nonneoplastic proliferation, if one accepts that a population of cells forming a tumorous mass must show clonality to be classified as a neoplasm. Our results emphasize that simple karyotypic abnormalities do not define a neoplasm. It remains to be determined whether GCTTS is a reactive or hyperplastic process.
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PMID:Giant cell tumor of tendon sheath is a polyclonal cellular proliferation. 922 50

The role of the large regenerative nodule (RN) in hepatocarcinogenesis is not clear, although the incidence of hepatocellular carcinoma (HCC) is high in cirrhotic liver. This study was aimed at clarifying the preneoplastic nature of large RN without atypia. We analyzed the clonality of HCCs and large RNs, ranging in size from 0.6 to 1.2 cm, of cirrhotic liver by X-linked human androgen receptor (HUMARA) gene assay, using the principle of random X chromosome methylation and inactivation in females. Eleven cases of HCC and five cases of large RN without atypia from ten female patients were selected. All HCCs, large RNs and paired non-tumorous tissue from adjacent liver were selectively microdissected from deparaffinized hematoxylin and eosin stained slides. Genomic DNA was isolated and digested with Hha I. Polymerase chain reaction (PCR) amplification of the HUMARA gene was performed using a PCR mixture containing [alpha-32P]-dCTP. The PCR products were separated by gel electrophoresis and analysed by autoradiography. HUMARA was informative in nine out of ten female patients. In the informative 10 HCCs from nine patients, 9 HCCs were monoclonal and one case was polyclonal. The HCC case that showed polyclonality contained many inflammatory cells in the tumor. All of the large RNs were polyclonal. No allelic loss of chromosome 18q was present in the large RNs in constrast to the 3 out of 7 HCCs, which showed allelic deletion in chromosome 18q. We conclude that all or most of the cells composing the large RNs without atypia are polyclonal and the size of a nodule may not be important in hepatocarcinogenesis. This clonality assay may be informative for the differentiation between regenerative and preneoplastic nodules in cirrhotic liver.
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PMID:Clonality of large regenerative nodules in liver cirrhosis. 938 17

Dehydroepiandrosterone sulfotransferase (Std) catalyzes sulfonation of androgenic steroids and certain aromatic procarcinogens. In rats, this enzyme is selectively expressed in the liver, and its expression is strongly repressed by androgens. DNase I footprinting and electrophoretic mobility shift analyses revealed two hepatocyte nuclear factor-1 (HNF1), three CCAAT/enhancer-binding protein (C/EBP), and one consensus palindromic thyroid hormone response elements within the first 215 base pairs (bp) of the promoter sequence of rat Std. This promoter is normally inactive in fibroblast-derived NIH 3T3 cells. However, overexpression of HNF1 and C/EBP resulted in synergistic activation of the Std promoter in this cell type, indicating essential roles of these two trans-regulators in liver-selective expression of the rat Std gene. On the other hand, point mutations at any one of five cis elements proximal to the -215 bp region markedly reduced reporter gene expression, suggesting that all of these sites are important for overall promoter function. Androgenic repression of the Std gene in rat liver can be recapitulated in androgen receptor (AR)-negative HepG2 hepatoma cells after cotransfection with an AR expression plasmid. Functional assay of a nested set of 5'-deleted promoters mapped the negative androgen response region between positions -235 and -310. Antibody supershift and oligonucleotide competition identified three OCT-1 and two C/EBP elements between bp -231 and -292. An additional OCT-1 site was found to overlap with a C/EBP element at the -262/-252 position. Mutational inactivation of any one of five cis elements within the -231/-292 region abolished negative androgen response. However, none of these cis elements showed DNase I protection by recombinant AR in footprinting assay, suggesting the absence of a direct AR-DNA interaction. Thus, these studies on rat Std promoter function indicate that (i) HNF1 and C/EBP are responsible for liver specificity of the rat Std gene; (ii) androgenic repression of the gene requires the presence of all of the OCT-1 and C/EBP elements between positions -231 and -292; and (iii) AR may exert its negative regulatory effect indirectly through transcriptional interference of OCT-1 and C/EBP rather than through a direct DNA-AR interaction.
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PMID:Tissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoter. 970 24

Recent reports have raised new concerns that chemicals in our environment may disrupt normal reproduction and development through inhibition of androgen receptor function. This heightened concern has also increased our need for methods that allow us to characterize chemical interaction with the androgen receptor. In this report we describe an androgen receptor assay that utilizes the HepG2 human hepatoma cell line transiently transfected with the human androgen receptor and an androgen-responsive reporter. We used this assay to characterize the interaction with the androgen receptor of several steroidal and nonsteroidal chemicals, including isomers of DDT and methoxychlor. Chemicals were tested either in the absence (for determining agonist activity) or presence of 10(-7) M dihydrotestosterone (for determining antagonist activity). Testosterone and dihydrotestosterone were equally potent agonists in this assay. Estradiol and progesterone displayed partial agonist/antagonist activity. Flutamide was a complete agonist, whereas its hydroxylated metabolite, hydroxyflutamide, only partially antagonized and displayed some agonist activity at 10(-6) M and above. o,p'-DDT, o,p'-DDE, o,p'-DDD, p,p'-DDT, p,p'-DDE, and p, p'-DDD all behaved as antagonists at concentrations above 10(-6) M. p,p'-DDE also showed some agonist activity at 10(-5) M. Methoxychlor was only weakly antagonistic while its hydroxylated metabolite, HPTE, was approximately 10-fold more potent. Our results demonstrate that the HepG2 assay is a sensitive and specific method for detecting chemical interaction with the androgen receptor. This reporter gene assay, which we have used to characterize interaction with both the estrogen and androgen receptors, coupled with more extensive in vivo studies, should be useful for determining the role of multiple steroid receptors in the mechanism of action of endocrine active chemicals.
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PMID:Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells. 970 96


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