UMLS:C0019204 - FACTA Search

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

We have cloned and sequenced the murine AHD4 cDNA encoding the 'Class 3' cytosolic aldehyde dehydrogenase (ALDH-3c). The cDNA is 1722 bp in length, excluding the poly(A+) tail, and has 5' and 3' nontranslated regions of 174 bp and 186 bp, respectively. AHD4 encodes a protein of 453 amino acids, including the first methionine (M(r) = 50,466). The murine AHD4 protein is 91% and 80% similar to the rat and human ALDH3c proteins, respectively, 64% identical to the rat microsomal ALDH3 protein, and < 28% similar to ALDH 'Class 1' and 'Class 2' proteins. Surprisingly, in contrast to the rat gene that is expressed in both cell cultures and the intact liver, the murine Ahd-4 gene is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) or benzo[a]pyrene in cell cultures but not in liver of the intact adult or newborn mouse. Southern hybridization analysis of mouse DNA probed with the full-length cDNA reveals that the Ahd-4 gene is likely to span less than a total of 15 kb, and was mapped to chromosome (Chr) 11 between the Mgat-1 and Shbg loci by analysis of two multilocus crosses. AHD4 mRNA levels are strikingly elevated in the untreated mouse hepatoma Hepa-1c1c7 mutant line c37 lacking CYP1A1 (aryl hydrocarbon hydroxylase) activity and in the untreated 14CoS/14CoS mouse cell line having a homozygous deletion of about 1.2 cM on Chr 7. Our data suggest that the Ahd-4 gene in murine cell cultures is regulated by three distinct mechanisms: Ah receptor-mediated induction by TCDD or benzo[a]pyrene, CYP1A1 metabolism-dependent repression, and Chr 7-mediated putative derepression.
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PMID:Mouse dioxin-inducible cytosolic aldehyde dehydrogenase-3: AHD4 cDNA sequence, genetic mapping, and differences in mRNA levels. 814 69

We have cloned and sequenced the mouse AHD3 cDNA, which codes for the Class 3 microsomal aldehyde dehydrogenase (ALDH3m). The cDNA is 2,997 bp in length excluding the poly(A)+ tail, and has 5' and 3' non-translated regions of 113 bp and 1,429 bp, respectively. The deduced amino acid sequence consists of 484 amino acids, including the first methionine (Mr = 53,942), and contains a hydrophobic segment at the carboxyl terminus which is the putative membrane anchor. The mouse AHD3 protein was found to be: 95% similar to the rat microsomal ALDH3m protein, 65% identical to the mouse, rat and human cytosolic ALDH3c protein, and <28% similar to the rat Class 1 and Class 2 ALDH and methylmalonate-semialdehyde dehydrogenase proteins. Southern hybridization analysis of mouse cDNA probed with the full-length AHD3 cDNA revealed that the Ahd3 gene likely spans less than a total of 25 kb. The mouse Ahd3 gene is very tightly linked to the Ahd4 gene on chromosome 11. Mouse AHD3 mRNA levels are increased by dioxin in mouse Hepa-1c1c7 hepatoma wild-type (wt) cells but not in the Ah receptor nuclear translocator (ARNT)-defective (c4) mutant line, indicating that the induction process is mediated by the Ah (aromatic hydrocarbon) dioxin-binding receptor. AHD3 mRNA levels are also inducible by clofibrate in both the wt and c4 lines. AHD3 mRNA levels are not elevated in the CYP1A1 metabolism-deficient c37 mutant line or as part of the oxidative stress response found in the untreated 14CoS/14CoS mouse cell line. These data indicate that, although inducible by dioxin, the Ahd3 gene does not qualify as a member of the aromatic hydrocarbon [Ah] gene battery.
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PMID:Mouse microsomal Class 3 aldehyde dehydrogenase: AHD3 cDNA sequence, inducibility by dioxin and clofibrate, and genetic mapping. 863 52

Phthalate esters such as di(2-ethylhexyl)phthalate (DEHP) either promote or inhibit rat liver tumorigenesis depending on the carcinogenesis protocol. In this study, we examined the expression of two histochemical markers, the tumor associated isozyme of aldehyde dehydrogenase (ALDH-3) and the oncoprotein p21 Ras, in the livers of male F344 rats. The rats were initiated with DEN and further treated with either DEHP (a known inhibitor of hepatocarcinogenesis), phenobarbital (PB, a known promoter of hepatocarcinogenesis), or a combination of DEHP and PB. The studies were designed to examine the expression of these markers in both normal appearing liver and hepatic hyperplastic and neoplastic lesions and to correlate the early expression of the markers at 26 weeks in the normal appearing liver to later tumor incidence at 52 weeks. The expression of each marker was detected by immunohistochemical methods on formalin-fixed paraffin embedded sections of normal appearing liver or liver lesions. We found that ALDH-3 and p21 expression were significantly enhanced in rats receiving PB after DEN initiation at 26 weeks and that the incidence of hepatocellular carcinomas was likewise increased compared to control or DEN only treated animals. DEN initiation followed by a combination of PB and either 0.1 or 0.5% DEHP significantly reduced ALDH-3 but not p21 Ras expression at 26 weeks compared to DEN plus PB only. These treatment regimens also reduced the incidence of hepatocellular carcinomas at 52 weeks. DEN followed by any of the three doses of DEHP without PB resulted in ALDH-3 expression similar to DEN alone. However, p21 Ras expression was significantly increased after these treatments. For all treatment groups, both the early (26 weeks) expression of p21 Ras and ALDH-3 correlated with hepatocellular carcinoma incidence at 52 weeks. However, the correlation between hepatocellular carcinoma and ALDH-3 expression was better than p21 Ras or the other markers we have studied. We concluded that ALDH-3 expression is significantly downregulated after DEHP treatment, and that expression of the isozyme correlated with later hepatocarcinoma incidence and may indicate a significant relationship between ALDH-3 expression and hepatocarcinogenesis during DEHP treatment.
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PMID:Hepatocyte expression of tumor associated aldehyde dehydrogenase (ALDH-3) and p21 Ras following diethylnitrosamine (DEN) initiation and chronic exposure to di(2-ethylhexyl)phthalate (DHEP). 876 21

In this paper, we describe a clinicopathological study of primary hepatocellular carcinoma (HCC) associated with alcoholic liver disease without hepatitis virus infection. In 180 HCC patients who were admitted to Asahikawa Medical College Hospital from 1987 to 1995, 10 patients (6%) had HCC associated with pure alcoholic liver disease (Al-HCC), whereas the HCC in 165 patients was associated with chronic viral liver diseases, in 2 with primary biliary cirrhosis, in 1 each with coexistence of the hepatitis C virus infection and hemochromatosis, and in 2 with cirrhosis of unknown origin. In the Al-HCC group, all patients were male. The diagnosis of HCC was obtained at the age of 54 to 67 years old, and the duration of ethanol intake was 33 to 40 years. Four cases had a history of temperance. As an underlying liver disease, liver fibrosis was found in three cases and liver cirrhosis in seven cases. HCC was diagnosed histologically in all cases. Serum alpha-fetoprotein and PIVKA-II were positive in patients with advanced HCC. In cases with small HCC, the tumor was resected surgically in three cases and percutaneous ethanol injection was performed in two cases. In four cases with small HCC, the patients were alive without tumor recurrence during the observation period. In advanced HCC, transcatheter arterial chemolipiodolization was performed. In the analysis of genetic polymorphism of ALDH 2, all Al-HCC had ALDH 2(1)/2(1).
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PMID:Hepatocellular carcinoma associated with alcoholic liver disease: a clinicopathological study and genetic polymorphism of aldehyde dehydrogenase 2. 898 42

The metabolism of acetaldehyde (ACA), benzaldehyde (BA), propionaldehyde (PA) and valeraldehyde (VA) has been studied in two hepatoma cell lines, the rat HTC and mouse Hepa 1c1c7 cells. The cytotoxicity of the four aldehydes to these two cell lines has been compared. The end-points for evaluating cytotoxicity were 1) total macromolecular content (TMC) of confluent cultures, and 2) colony forming ability of dividing cells. These two assay systems had different sensitivities for the toxicity of aldehydes, probably due to different numbers of target cells. The activities of aldehyde dehydrogenases (NAD- and NADP-dependent, ALDH), alcohol dehydrogenase and aldehyde reductase were markedly greater in the HTC cell line compared to the Hepa 1c1c7 cell line, especially with BA as substrate. The cytotoxicities of aldehydes were generally stronger in the HTC cell line than in the Hepa 1c1c7 cell line; with the CF test. Particularly, BA was highly toxic to the HTC cells, which possessed the highest ALDH levels. Moreover, the treatment with (diethylamino)benzaldehyde, an ALDH inhibitor, completely abolished the toxicity of BA. Taken together, all these findings suggest that several cell lines expressing different aldehyde metabolizing activities could be used especially in the pre-screening phase to distinguish the metabolism-dependent cytotoxic effects from the metabolism independent effects.
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PMID:Comparative evaluation of cytotoxicity and metabolism of four aldehydes in two hepatoma cell lines. 929 76

Tumor-associated aldehyde dehydrogenase (T-ALDH) is strongly expressed in hepatocellular carcinoma (HCC) but undetectable in normal liver. In the present study, this enzyme from human HCC, HCC T-ALDH, was purified and the partial amino acid sequences (384 residues) determined by direct protein sequencing matched the amino acid sequence (453 residues) deduced from cloned HCC T-ALDH cDNAs with an open reading frame. The coding sequences of HCC T-ALDH cDNA, human stomach ALDH3A1 cDNA [Hsu et al., J. Biol. Chem. 267 (1992) 3030-3037] and human squamous cell carcinoma (SCC) T-ALDH cDNA (Schuuring et al., GenBank I.D. M74542) matched one another except for discrepancies at four positions, with consequent P12R, I27F and S134A substitutions. R and A were found in HCC and SCC T-ALDHs, whereas P and S were present in stomach ALDH3A1. To confirm that these discrepancies would have general occurrence, coding sequences of HCC T-ALDH cDNAs from six patients and stomach ALDH3A1 cDNAs from two individuals were examined and all were found to encode ALDH3A1 having R, I and A at protein positions 12, 27 and 134, respectively, indicating HCC T-ALDH to be variant ALDH3A1 which is common in human stomach tissues.
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PMID:Primary structure of human hepatocellular carcinoma-associated aldehyde dehydrogenase. 1101 24

In normal liver aldehyde dehydrogenase 3 (ALDH3) is poorly expressed. In hepatoma cells, its expression increases in direct correlation with the degree of deviation and increased ALDH3 activity is one cause of resistance to the toxicity of drugs and lipid peroxidation aldehydes. Hepatoma cells with high ALDH3 content are more resistant to the cytotoxic effect of aldehydes than those with low ALDH3, and inhibition of the enzyme with aldehydes, specific inhibitors or antisense oligonucleotides (AS-ODN), decreases cell growth. It remains open how ALDH3 influences cell growth or cell phenotype. Recently, we have shown that enrichment of a highly deviated rat hepatoma cell line, JM2, with arachidonic acid, a natural ligand of peroxisome proliferator activated receptors (PPARs), inhibits growth, partially restores ALDH2 and ALDH3 to their normal levels and induces PPAR expression. In the present study we address the effect of clofibrate, a hypolipidemic drug and synthetic PPAR ligand on ALDH gene expression. We show that treatment of JM2 cells with clofibrate inhibits cell growth, induces PPARgamma and decreases ALDH3 expression. To determine the relationship between PPARgamma and ALDH3 expression, we exposed JM2 cells to AS-ODN against PPARgamma. AS-ODN reduced PPARgamma content and prevented the inhibitory effect of clofibrate on cell proliferation and ALDH3 expression. Since these results indicate that ALDH3 expression is under PPAR control, we examined the 5' flanking sequence of the ALDH3 gene, but were unable to find any sequence similar to any known peroxisome proliferator response element. We thus believe that the effect of PPARgamma on ALDH3 occurs via other transcription factors, whose identity remain to be determined. The results indicate that PPARgamma plays a key role in regulation of growth and differentiation of hepatoma cells, and that ALDH3 collaborates in modulating cell proliferation and in determining some aspects of the hepatoma phenotype, i.e. resistance to drugs and to lipid peroxidation products.
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PMID:Aldehyde dehydrogenase 3 expression is decreased by clofibrate via PPAR gamma induction in JM2 rat hepatoma cell line. 1260 86

Hepatocellualr carcinoma is one of the most malignancy, and the pathogenesis has not been clarified yet. The individual variation in the capacity of xenobiotic metabolizing and DNA repair was the genetic susceptibility to malignancies. Studies on polymorphisms of metabolic enzymes (CYP, NAT, GST, EH, ALDH) and DNA repair genes (XRCC1,hOGG1,XPD), and susceptibility to hepatocellular carcinoma are reviewed in this paper.
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PMID:[Study on polymorphisms in metabolic enzyme genes, DNA repair genes and individual susceptibility to hepatocellular carcinoma]. 1729 Jul 73

In a poisonous incident in Kamisu, Japan, it is understood that diphenylarsinic acid (DPAA) was a critical contaminant of ground water. Most patients showed dysfunction of the central nervous system. To understand the overall mechanism of DPAA toxicity and to gain some insight into the application of a remedy specific for intoxication, the molecular target must be clarified. As an approach, a high throughput analysis of cell proteins in cultured human hepatocarcinoma HpG2 exposed to DPAA was performed by two-dimensional electrophoresis (2-DE). Four proteins, which were up- and down-regulated by exposure of cultured HepG2 cells to DPAA, were identified. They were chaperonin containing TCP-1 (CCT) beta subunit, aldehyde dehydrogenase 1 (ALDH1), ribosomal protein P0 and glutaminase C (GAC). Of these, GAC was the only protein that was down-regulated by DPAA exposure, and cellular expression levels were reduced by DPAA in a concentration- and time-dependent manner. Decrease in cellular GAC levels was accompanied by decreased activity of the enzyme, phosphate-activated glutaminase (PAG). Decreased expression of GAC by DPAA was also observed in human cervical carcinoma HeLa and neuroblastoma SH-SY5Y cells. By contrast, no significant changes in GAC protein expression were observed when cells were incubated with arsenite [iAs (III)] and trivalent dimethylarsinous acid [DMA (III)]. In the central nervous system, GAC plays a role in the production of the neurotransmitter glutamic acid. Selective inhibition of GAC expression by DPAA may be a cause of dysfunction of glutamatergic neuronal transmission and the resultant neurological impairments.
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PMID:Down-regulation of glutaminase C in human hepatocarcinoma cell by diphenylarsinic acid, a degradation product of chemical warfare agents. 1732 58

Recent efforts in our study of cancer stem cells (CSC) in hepatocellular carcinoma (HCC) have led to the identification of CD133 as a prominent HCC CSC marker. Findings were based on experiments done on cell lines and xenograft tumors where expression of CD133 was detected at levels as high as 65%. Based on the CSC theory, CSCs are believed to represent only a minority number of the tumor mass. This is indicative that our previously characterized CD133(+) HCC CSC population is still heterogeneous, consisting of perhaps subsets of cells with differing tumorigenic potential. We hypothesized that it is possible to further enrich the CSC population by means of additional differentially expressed markers. Using a two-dimensional PAGE approach, we compared protein profiles between CD133(+) and CD133(-) subpopulations isolated from Huh7 and PLC8024 and identified aldehyde dehydrogenase 1A1 as one of the proteins that are preferentially expressed in the CD133(+) subfraction. Analysis of the expression of several different ALDH isoforms and ALDH enzymatic activity in liver cell lines found ALDH to be positively correlated with CD133 expression. Dual-color flow cytometry analysis found the majority of ALDH(+) to be CD133(+), yet not all CD133(+) HCC cells were ALDH(+). Subsequent studies on purified subpopulations found CD133(+)ALDH(+) cells to be significantly more tumorigenic than their CD133(-)ALDH(+) or CD133(-)ALDH(-) counterparts, both in vitro and in vivo. These data, combined with those from our previous work, reveal the existence of a hierarchical organization in HCC bearing tumorigenic potential in the order of CD133(+)ALDH(+) > CD133(+)ALDH(-) > CD133(-)ALDH(-). ALDH, expressed along CD133, can more specifically characterize the tumorigenic liver CSC population.
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PMID:Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. 1864 79

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