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)

Somatic alterations of the c-Ha-ras gene were examined in 21 Japanese patients with hepatocellular carcinoma. Restriction endonuclease analysis by double digestion with MspI and HpaII revealed that DNAs from two of 21 hepatocellular carcinoma tissues were affected by nucleotide substitution at the twelfth amino acid coding sequence of the c-Ha-ras gene. DNAs from cirrhotic noncancerous liver tissue, but not leukocytes, of one of these patients possessed the mutation, whereas DNAs from noncirrhotic liver tissue and leukocytes of the other patient did not. In one of the nine patients harboring heterozygosity for c-Ha-ras-related BamHI-fragments, the loss of one allele was demonstrated as a somatic change not only in DNA from the tumor tissue but also in DNA from the cirrhotic nontumorous tissue. In two of the 19 patients comparatively examined for digestion patterns of c-Ha-ras locus with HpaII and MspI, extensive methylation was observed as a somatic modification in both DNAs from the tumor and the cirrhotic nontumorous tissues. These results thus indicate that the genetic lesions affecting the c-Ha-ras gene do occur in human hepatocellular carcinoma and probably serve as one of the multiple steps in the process of hepatic carcinogenesis.
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PMID:Point mutation, allelic loss and increased methylation of c-Ha-ras gene in human hepatocellular carcinoma. 184 46

Oxidative metabolism (OM) of paracetamol was studied in 19 patients with hepatocellular carcinoma (HCC), 39 with chronic hepatitis B virus infection (CHBV) and 26 healthy controls. Paracetamol (1.5 g) was given and the subsequent 24 h urine collection assayed for paracetamol and its metabolites by HPLC. HCC patients showed greatly increased OM, as reflected by the combined fractional recoveries of mercapturic acid and cysteine conjugates (22%), in comparison with controls (7%) and CHBV patients (10%). As the cytochrome P-450 dependent OM of xenobiotics has been implicated in carcinogenesis, it is interesting that two CHBV patients also had increased OM.
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PMID:Increased oxidative metabolism of paracetamol in patients with hepatocellular carcinoma. 185 Oct 52

The Ah receptor is a soluble protein complex that mediates carcinogenesis by a wide range of environmental pollutants, including polycyclic aromatic hydrocarbons, heterocyclic amines, and polychlorinated aromatic compounds. The best understood activity of the receptor concerns its role in the induction of cytochrome P450IA1. We undertook a somatic cell genetic analysis of P450IA1 induction using the mouse hepatoma cell line, Hepa-1. Clones of Hepa-1 were isolated that are defective in induction of P450IA1. Evidence was obtained that the clones are mutational in origin. Cell fusion experiments demonstrated that a few of the mutants are dominant, while the majority are recessive. The dominant mutants were shown to synthesize a repressor of P450IA1 transcription. The recessive mutants were assigned to 4 complementation groups (probably corresponding to 4 different genes). Complementation group A corresponds to the P450IA1 structural gene. Mutations in the B, C and D genes all affect functioning of the Ah receptor. A 'reverse selection procedure', whereby cells that express P450IA1 inducibility can be selected from a majority population of cells lacking inducibility, was developed. The reverse selection procedure was used to isolate transfectants of representative recessive mutants in which the mutational defects are complemented by exogenously applied genomic DNA. A human DNA-derived transfectant of a C- mutant was used to clone the human C gene. The C gene is not the ligand-binding subunit of the Ah receptor but is a protein that is required for translocation of Ah receptor-ligand complexes from cytoplasm to nucleus. In analogous experiments the dominant gene from one of the dominant mutants was transfected into wild-type Hepa-1 cells. Success in transfecting the dominant gene should provide the means for cloning it.
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PMID:Genetic and molecular analysis of the Ah receptor and of Cyp1a1 gene expression. 185 44

We studied the copper concentrations in the non-cancerous and cancerous liver tissues of LEC rats with hereditary hepatitis and spontaneous hepatoma by atomic absorption spectrophotometry. Copper concentration in the non-cancerous livers of 29-month-old male LEC rats was comparable to that in the livers of LEC rats aged 2, 3 and 8 months whose hepatic copper concentrations were more than 40 times those of normal LEA rats. Copper concentration in spontaneously developed hepatocellular carcinomas of the 29-month-old male LEC rats was lower than that in the surrounding non-cancerous liver tissues, but was still more than 39 times that of 8-month-old male LEA rats. These findings suggest that in LEC rats an abnormal copper metabolism may be maintained during the process of hepatic carcinogenesis.
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PMID:Abnormal copper accumulation in non-cancerous and cancerous liver tissues of LEC rats developing hereditary hepatitis and spontaneous hepatoma. 190 94

PCBs are compounds whose physical/chemical properties led to their wide spread commercial use. The persistence and stability of PCBs have resulted in a world wide distribution. PCDFs, ones of PCB derivatives, are primary causal agents of mass food poisoning, called Yusho in Japan and Yu-Cheng in Taiwan. Several epidemiologic studies on the carcinogenicity of PCBs in both occupational exposure and accidental intoxication suggest that PCBs might be a potent carcinogen in liver and lung. Many investigators reported that PCBs induced hepatocellular carcinoma in rat and mice. Although either mutagenic or genotoxic effects of PCBs are not definite, their tumor promoting effects have been repeatedly demonstrated in the liver. The effects of PCBs as tumor promoter in the lung have also been reported. PCB congeners that efficaciously promote carcinogenesis increase cytochrome P-450-dependent monooxygenases, which are abundant both in bronchiolar Clara cells and in hepatocytes. PCB congeners which are inducers of P-450 may be active as tumor promoter by inhibiting intercellular communication and/or by stimulating cell proliferation. Furan derivatives like PCDFs have high affinity to bronchiolar Clara cells and hepatocytes. PCDFs induce necrosis and epoxide formation to their target cells, which might result in carcinogenesis of liver and lung.
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PMID:[Carcinogenic effects of polychlorinated biphenyls (PCBs) and their derivatives, including carcinogenicity to the lung]. 191 96

The LEC rat is a mutant inbred strain isolated from Long-Evans rats, which spontaneously develops hepatitis and hepatoma with high frequency. In this study, copper profiles of LEC rats, including copper concentration in the liver and concentrations of copper and ceruloplasmin in the serum, were investigated. It was found that copper accumulated in the liver of LEC rats immediately prior to the onset of hepatitis with a concentration of more than 50 times that of normal LEA rats, and serum concentrations of copper and ceruloplasmin decreased markedly, which resembled biochemically characteristic features of human Wilson's disease. Administration of d-penicillamine (100 mg/Kg/day p. o), a chelating agent, reduced the hepatic copper level and completely inhibited the development of hepatitis in LEC rats. Copper also accumulated in both cancerous and non-cancerous liver tissues of three 29-month old male LEC rats which had spontaneously developed hepatocellular carcinomas. These findings suggest that the hepatitis in LEC rats is caused by copper toxicity, and that the abnormal copper metabolism may be involved in hepatic carcinogenesis in the LEC rats. Therefore, it is considered that the LEC rat will provide a promising animal model for not only elucidating the pathogenesis of Wilson's disease and developing treatment strategies of the disease, but also for studying the role of copper in hepatic carcinogenesis.
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PMID:[Abnormal hepatic copper accumulation and its significance in LEC rats developing spontaneous hepatitis and hepatoma]. 195 41

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.
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PMID:Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. 196 22

The initiating potential of the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), for rat hepatocarcinogenesis was investigated using the development of hyperplastic nodules and/or glutathione S-transferase placental form (GST-P)-positive liver foci as the end point. Five week old male F344 rats were given either basal diet, or diets containing 0.5% DCA or 0.5% LCA for 3 weeks in conjunction with partial hepatectomy performed midway, followed by a selection regimen consisting of 2 weeks feeding of 0.02% 2-acetylaminofluorene diet and a single gastric intubation of carbon tetrachloride. The animals were then placed on either basal diet or a diet containing 0.05% phenobarbital (PB) for 52 weeks. Significantly higher numbers of hyperplastic liver nodules developed in the DCA-treated rats irrespective of PB promotion as compared with the respective control groups. No such increase was evident in the LCA-treated rats. In contrast, both DCA and LCA treatments enhanced the development of GST-P-positive liver foci with or without subsequent PB promotion. Only one hepatocellular carcinoma was diagnosed in a control group animal. The present data indicate that a short period of feeding of DCA and LCA in the initiation stage in conjunction with partial hepatectomy results in enhanced development of preneoplastic liver lesions under selection pressure conditions with or without subsequent PB promotion. They thus confirm and extend our previous finding of enhanced gamma-glutamyltranspeptidase-positive liver foci development in a short-term assay of DCA and LCA, and suggest that these secondary bile acids either possess possible initiating activity or some other priming effect for rat hepatocarcinogenesis.
Carcinogenesis 1990 Aug
PMID:Enhanced preneoplastic liver lesion development under 'selection pressure' conditions after administration of deoxycholic or lithocholic acid in the initiation phase in rats. 197 29

The peptide pyroGlu-Gln-Gly-Ser-Asn, recently isolated from mouse liver, inhibited DNA synthesis and proliferation in vitro of MH1C1 cells, a rat clonal strain derived from a Morris transplantable hepatoma. Both the biological peptide isolated from mouse liver and the synthetic homolog showed bell-shaped dose-response curves. Maximal inhibition (approximately 50%) was observed at two separate dose ranges: one at 10(-7)-10(-10) M, and one at 10(-14)-10(-15) M.
Carcinogenesis 1991 Feb
PMID:The peptide pyroGlu-Gln-Gly-Ser-Asn, isolated from mouse liver, inhibits growth of rat hepatoma cells in vitro. 199 86

The C57BL/6 x C3H F1 (hereafter called B6C3F1) mouse is an important animal model for long-term carcinogenesis studies. Maintained under normal laboratory conditions, these mice develop various types of spontaneous tumors during their lifetime. Activated Ha-ras genes have been detected in 66% of spontaneous hepatocellular tumors in the B6C3F1 mouse [Reynolds et al., Science (Washington DC), 237:1309, 1988]. In this study 49 spontaneous non-liver tumors were investigated for oncogene activation by DNA transfection techniques. Of the 49 tumor DNAs analyzed, only 5 yielded multiple foci in the NIH 3T3 focus assay: 2 of 10 pulmonary adenocarcinomas; 0 of 25 lymphomas; 2 of 2 Harderian gland adenomas; 0 of 1 adenocarcinoma of the small intestine; 1 of 6 malignant skin tumors; 0 of 4 hemangiosarcomas; and 0 of 1 lung metastasis of a hepatocellular carcinoma. DNA from six lymphomas which were negative in the NIH 3T3 focus assay were further analyzed for transforming genes by the nude mouse tumorigenicity assay. One of the five lymphomas tested positive with this assay. Southern blot analysis identified five activated ras genes: H-ras in two Harderian gland adenomas; K-ras in one pulmonary adenocarcinoma and in one s.c. adenocarcinoma; and N-ras in one lymphoma. The mutations involved were CG to AT and AT to TA in codon 61 of the Ha-ras genes, GC to AT or TA in codon 12 of the K-ras genes, and a GC to AT mutation in codon 12 of the N-ras gene. Transformant DNA from a pulmonary adenocarcinoma which yielded multiple foci in the transfection assay did not hybridize to DNA probes specific for the K-, H-, and N-ras, raf, neu, and met genes. Thirteen additional tumor DNAs yielded a single focus in the NIH 3T3 transfection assay. The transformant DNAs retransmitted in a second cycle transfection assay. Rearranged and/or amplified raf genes were detected in six of the transformant DNAs. At present we do not know whether these activated raf genes were present in the original tumor DNA. The other seven transformant DNAs did not hybridize with any of the above mentioned specific DNA probes utilized in Southern blot analysis. Unlike liver tumors, the activation of ras protooncogenes is not a frequent event in the development of spontaneous non-liver tumors of the B6C3F1 mouse. The results from this study should aid in understanding the neoplastic development associated with exposure to chemical carcinogens in the B6C3F1 mouse.
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PMID:Activation of protooncogenes in spontaneously occurring non-liver tumors from C57BL/6 x C3H F1 mice. 199 58


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