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)

The male hybrid B6C3F1 mouse exhibits a 30% spontaneous hepatoma incidence, and both males and females of this strain are sensitive to chemical induction of liver tumors. The Ha-ras, Ki-ras, and myc oncogenes have been implicated in a variety of solid tumors. Specifically, Ha- and, less frequently Ki-ras have been reported to be activated in B6C3F1 mouse liver tumors, and such activated oncogenes frequently contain a particular point mutation. In light of indications that the transforming capacity of some oncogenes is directly related to the level of the gene product, we hypothesized that transcriptional control of Ha-ras, Ki-ras, and myc is compromised in B6C3F1 mouse liver tumors. A positive correlation has been established between gene expression and hypomethylation. Therefore, the methylation states of these genes were examined in spontaneous liver tumors and in tumors induced by two diverse hepatocarcinogens: phenobarbital and chloroform. Ha-ras was found to be hypomethylated in all tumors examined, whereas Ki-ras was sometimes hypomethylated; such hypomethylation might play a role in the promotion stage of carcinogenesis. The methylation state of myc was unaltered, although this gene appeared to be amplified in tumors. These results suggest that a component of the mechanism by which these oncogenes are activated in B6C3F1 mouse liver tumors involves loss of stringent control of expression, via hypomethylation of the ras oncogenes and, possibly, amplification of myc. These results support the assertion that tumors induced by different classes of carcinogens or arising spontaneously share common biochemical pathways of oncogene activation during tumorigenesis.
 ...
PMID:Hypomethylation of ras oncogenes in chemically induced and spontaneous B6C3F1 mouse liver tumors. 165 50

We previously reported that only one of the three mouse multidrug-resistance (mdr) genes, mdr3, is activated in hepatocellular carcinomas (HCCs). The present study examined the expression of mdr family members during mouse liver regeneration after partial hepatectomy to determine whether the regeneration that occurs during hepatic tumorigenesis is responsible for mdr3 elevation in HCC. We demonstrated that in both C3H/HeN and B6C3/F1 mice strains, the levels of both mdr2 and mdr3 mRNAs coordinately increased five- to sevenfold 24 h after partial hepatectomy, whereas the levels of mdr1 mRNA were not statistically different from those in the controls. Forty-eight hours after partial hepatectomy, mdr mRNA levels decreased and in most cases returned to normal levels after 72 h. These results indicate that mdr3 induction during hepatocarcinogenesis is not due to liver regeneration alone.
 ...
PMID:Coordinate activation of multidrug-resistance (P-glycoprotein) genes mdr2 and mdr3 during mouse liver regeneration. 168 Mar 39

The early stages of the carcinogenic process induced by aflatoxin B1 (AFB1) in rat liver during 24 weeks of feeding and the resulting tumours have been studied with respect to cytokeratin (CK) expression. A previously uncharacterized monoclonal antibody, MRCTU/J1, has been shown to recognize rat CK18 and together with antibodies against human CK8, 18 and 19, has been used to examine the possible lineage of tumour cells and also to identify the altered foci that might be most relevant to tumorigenesis. Results suggested that AFB1-induced transformation in liver may occur in more than one cell type, since tumours with the normal hepatocyte CK pattern and those with bile duct or oval cell CK phenotype were identified. Additionally, hepatocytes with a bile duct CK phenotype appeared during the early stages of carcinogenesis. The in vivo pattern of CK expression also appeared to be maintained in one normal and one hepatoma-derived cell line. Overexpression of CKs (particularly of CK19) was a much more selective marker for altered foci, compared to gamma-glutamyltranspeptidase, and was more consistently expressed at high levels in tumours, suggesting that it might be a more reliable way of identifying those cells involved in the transformation process.
 ...
PMID:Cytokeratin expression during AFB1-induced carcinogenesis. 169 54

The benzofurane derivative benzbromarone (BBR) previously has led to liver tumor formation after long-term treatment of rats, but no indications of genotoxicity were detected. The present studies were designed to elucidate the mechanism(s) possibly involved in liver tumor formation by BBR. Female Wistar rats were used. Phenobarbital (PB) served as a positive control. (1) Short-term treatment (7 days) with daily doses of 2 to 100 mg/kg BBR led to adaptive responses in the liver, i.e., growth (increases in DNA, RNA, and protein) and induction of monooxygenases. These changes were also observed after feeding BBR for 8, 33, 77, and 102 weeks at doses of 2, 10, and 50 mg/kg/day but tended to weaken with time. Similar effects were obtained with PB fed at 2, 10, or 50 mg/kg/day. However, unlike PB, BBR did not enhance the expression of cytochrome P450-PB as demonstrated by immunostaining of histological liver sections. (2) BBR feeding for 102 weeks, but not for 77 weeks, produced some neoplastic liver nodules and at 50 mg/kg produced one hepatocellular carcinoma (HCC). Thus, BBR was tumorigenic in the present study, but was clearly weaker than PB which had induced liver nodules and HCCs at 77 weeks and even more markedly at 102 weeks. (3) To check for tumor-initiating activity 100 mg/kg BBR was given 14 hr after a two-thirds hepatectomy followed by promotion with PB (50 mg/kg) for 15 weeks. No phenotypically altered liver foci were detected. (4) To test for tumor-promoting activity rats received a single dose of N-nitrosomorpholine (250 mg/kg), and subsequently BBR or PB at doses of 2, 10, and 50 mg/kg/day. While PB markedly enhanced the development of neoplastic nodules and HCCs, BBR had only a weak enhancing effect on the induction of HCC, which was not dose related. gamma-glutamyl transpeptidase-positive foci dramatically increased in PB-treated animals, in contrast they showed no response after 2 and 10 mg/kg BBR and even decreased after 50 mg/kg BBR. (5) With PB changes in liver growth, monooxygenase activity, foci expansion, and tumor promotion all correlating with tumorigenesis in a quantitative manner, apparent no-observed-effect-levels are somewhat below 2 mg/kg (or 10 mg/kg for liver enlargement). (6) These studies suggest that BBR belongs to a group of nongenotoxic, growth-stimulating drugs with tumorigenic potential in rat liver. Its effects on the liver are different from those of PB, but seemed to resemble those of peroxisome proliferators, a hypothesis studied in the subsequent papers.
 ...
PMID:Toxicological studies on a benzofurane derivative. I. A comparative study with phenobarbital on rat liver. 170 30

Hepatocellular carcinoma has one of the poorest 5 year survival rates of any human cancer. Preventive measures offer the best possibility of ameliorating this disease and chemoprotective agents are being developed for this purpose. The dithiolethiones, including oltipraz and the unsubstituted molecule 1,2-dithiole-3-thione, have been shown to be potent inhibitors of aflatoxin-induced hepatic tumorigenesis in rats. However, subsequent evaluation of dithiolethiones or other chemoprotective agents in human clinical trials will require the development of intermediate, non-invasive biomarkers to evaluate the efficacy of these interventions. In this study, levels of molecular dosimetry biomarkers for determining genotoxic damage caused by aflatoxin B1 have been measured in a chronic exposure model with male F344 rats wherein half the animals were fed a diet supplemented with 0.03% 1,2-dithiole-3-thione to lower their risk for tumors and the other half were fed unsupplemented AIN-76A diet and were at high risk for tumor development. Levels of hepatic aflatoxin-DNA adducts, serum aflatoxin-albumin adducts and excreted aflatoxin-N7-guanine adducts in urine were determined following multiple administrations of 250 micrograms aflatoxin B1/kg body wt on days 0-4 and 7-11 to assess the use of the serum and urinary biomarkers as indices of chemoprotective efficacy. In the rats fed 1,2-dithiole-3-thione, the overall diminutions in the levels of hepatic DNA adducts, urinary aflatoxin-N7-guanine and serum aflatoxin-albumin adducts over the 2 week exposure period were 76, 62 and 66% respectively. This parallelism in reductions of levels of biomarkers relative to target organ DNA adduct burden suggests that these biomarkers are predictive short-term, non-invasive measures for assessing the efficacy of chemoprotective interventions in experimental studies and can be applied to human clinical trials directed at populations at high risk for aflatoxin exposure and primary hepatocellular carcinoma.
 ...
PMID:Molecular dosimetry of urinary aflatoxin-N7-guanine and serum aflatoxin-albumin adducts predicts chemoprotection by 1,2-dithiole-3-thione in rats. 173 61

Although epidemiologic studies have clearly demonstrated the importance of the hepatitis B virus in the genesis of hepatocellular carcinoma, the molecular basis for this tumorigenic effect is still under debate. Studies of woodchucks infected with a virus closely related to the human hepatitis B virus suggest that integration of the viral DNA in the host genome often plays a direct role by activating myc cellular oncogenes through insertional mutagenesis. A similar mechanism involving other cell genes has been found less frequently in human hepatocellular carcinomas. The human hepatitis B virus may contribute to tumorigenesis in a more indirect fashion, by inducing preneoplastic liver lesions which gradually become malignant.
 ...
PMID:[Hepatitis B and primary cancer of the liver: recent data on the role of B virus in oncogenesis]. 185 Jan 21

One of insulin's least studied actions is its ability to induce DNA synthesis and cell division. In rat H4IIE hepatoma cells insulin, acting through its own receptor, stimulates cell division. However, little is known about the molecular mechanisms involved in this effect. The proto-oncogene c-myc is a cellular gene which when expressed at abnormal levels is often associated with the process of tumorigenesis. Expression of the normal cellular myc gene may be necessary for growth factor-induced cell cycling. In the present work, insulin was shown to regulate cellular accumulation and transcription of the c-myc gene in rat hepatoma cells. The control of c-myc by insulin was complex, with an initial-induced decrease in c-myc transcription to 50% of control values at 15 and 30 min. This was followed by an increase in transcription of about 3-fold by 60-120 min. Similar to the initial inhibitory effect of insulin, the protein synthesis inhibitors cycloheximide or anisomycin decreased c-myc transcription. However, there was no secondary induction of c-myc transcription by protein synthesis inhibitors. The effects of both insulin and protein synthesis inhibitors were shown to be through alterations in intragenic pausing of transcription of the sense mRNA, not through changes initiation of transcription.
 ...
PMID:Inhibition and stimulation of c-myc gene transcription by insulin in rat hepatoma cells. Insulin alters the intragenic pausing of c-myc transcription. 191 37

Hepatitis B virus (HBV) DNA frequently integrates into the genome of human primary liver cancer cells, but the significance of this integration in liver carcinogenesis is still unclear. Here we report the cloning of a single HBV integration site in a human hepatocellular carcinoma at an early stage of development, and of its germline counterpart. The normal locus was found to be transcribed into two polyadenylated messenger RNA species of 1.8 and 2.7 kilobases. We have isolated a complementary DNA clone from a normal adult human liver cDNA library which has an open reading frame with a coding capacity for a protein of 432 amino acids and relative molecular mass 48,536. The strong homology of the C-terminal half of the protein to the A-type cyclins of clam and Drosophila identifies it as a human cyclin A. The cyclin A gene has several exons, and the HBV integration occurs within an intron. As cyclins are important in the control of cell division, the disruption of a cyclin A gene by viral insertion might contribute to tumorigenesis.
 ...
PMID:Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. 196 22

Hepatitis B virus (HBV) is regarded as the main aetiologic factor in the development of human hepatocellular carcinoma (HCC), one of the most frequent fatal malignancies worldwide. Detection of integrated HBV sequences in the cellular DNA of almost all HCCs studied, and the recent finding that the integrated HBV open reading frame (orf) X encodes a transactivating activity, supports the notion that integrated HBV DNA could contribute to liver carcinogenesis by activation of cellular genes in trans. But not all HCCs seem to harbour a functional orf X. We report here that 3'-truncated preS2/S sequences in integrated HBV DNA of liver cell carcinomas encode a so far unidentified transcriptional trans-activation activity. This activity is also produced by an artificially 3'-truncated preS2/S gene of the wild-type HBV genome. Besides the simian virus 40 promoter of the reporter plasmid pSV2CAT, the promoter of the human c-myc oncogene can also be activated. These results, taken together with the fact that preS/S is the only HBV gene found to be integrated in almost every HBV-related HCC analysed so far, indicate that trans-activation by integrated preS2/S sequences is a possible mechanism for HBV-associated oncogenesis.
 ...
PMID:The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. 215 38

The recent finding of c-myc activation by insertion of woodchuck hepatitis virus DNA in two independent hepatocellular carcinoma has given support to the hypothesis that integration of hepatitis B viruses into the host genome, observed in most human and woodchuck liver tumours, might contribute to oncogenesis. We report here high frequency of woodchuck hepatitis virus DNA integrations in two newly identified N-myc genes: N-myc1, the homologue of known mammalian N-myc genes, and N-myc2, an intronless 'complementary DNA gene' or 'retroposon' that has retained extensive coding and transforming homology with N-myc. N-myc2 is totally silent in normal liver, but is overexpressed without genetic rearrangements in most liver tumours. Moreover, viral integrations occur within either N-myc1 or N-myc2 in about 20% of the tumours, giving rise to chimaeric messenger RNAs in which the 3' untranslated region of N-myc was replaced by woodchuck hepatitis virus sequences encompassing the viral enhancer. Insertion sites were clustered in a short sequence of the third exon that coincides with a retroviral integration hotspot within the murine N-myc gene, recently described in T-cell lymphomas induced by murine leukaemia virus. Thus, comparable mechanisms, leading to deregulated expression of N-myc genes, may operate in the development of tumours induced either by hepatitis virus or by nonacute retroviruses in rodents. Activation of myc genes by insertion of hepadnavirus DNA now emerges as a common event in the genesis of woodchuck hepatocellular carcinoma.
 ...
PMID:Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. 216 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>