UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prepubertal breast is more susceptible than the mature breast to the carcinogenic effects of ionizing radiation, and potentially to cigarette smoke and alkylating chemotherapeutics. Mammary epithelial cells (MECs) from sexually immature (3-week (wk)-old) Fischer 344 rats were more sensitive than mature (8-wk-old) rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea (NMU). The work reported here was undertaken to better define this age-specific susceptibility of the mammary gland to NMU. Using the alkaline comet assay, it was found that MECs from immature but not mature rats displayed an increase in single-strand DNA breaks or alkali-labile lesions 2 h following NMU treatment. Hoechst staining indicated apoptosis was not responsible for the increase. Inhibition of methylguanine methyltransferase (MGMT) did not affect immature MECs but caused mature MECs to recapitulate the immature response to NMU. Direct measurement of MGMT activity revealed that immature MECs are significantly deficient in MGMT activity relative to mature MECs. MECs had the lowest MGMT activity of all organs tested. Immature kidneys, which preferentially developed nephroblastomas after NMU treatment, also displayed significantly lower MGMT activity than mature kidneys. These results suggest that age-related differences in MGMT activity may play a significant role in age-differential susceptibility to rat mammary gland and kidney carcinogenesis, and argue the importance of extending these studies to humans. They also provide a mechanistic basis for studying, as potentially initiating events in breast cancer, exposures of prepubertal girls to alkylating agents, to which humans are exposed in cigarette smoke, the diet, and as chemotherapy.
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PMID:Methylguanine methyltransferase activity deficiency in immature rat mammary epithelial cells parallels increased carcinogenic susceptibility. 1608 75

Arsenic contaminates ground water worldwide. Methylation is an important reaction in the biotransformation of arsenic. We set out to study the pharmacogenetics of human arsenic methyltransferase (AS3MT, previously CYT19). After cloning the human AS3MT cDNA, we annotated the human gene and resequenced its 5'-flanking region, exons, and splice junctions using 60 DNA samples from African-American (AA) and 60 samples from Caucasian-American (CA) subjects. We observed 26 single nucleotide polymorphisms (SNPs), including 3 non-synonymous cSNPs, as well as a variable number of tandem repeats in exon 1 within an area encoding the cDNA 5'-untranslated region. The nonsynonymous cSNPs included T860C (M287T) with frequencies of 10.8 and 10% in AA and CA subjects, respectively, as well as C517T (A173W) in one AA and C917T (T306I) in one CA sample. Haplotype analysis showed that Ile(306) was linked to Thr(287), so this double variant allozyme was also studied functionally. After expression in COS-1 cells and correction for transfection efficiency, the Trp(173) allozyme displayed 31%, Thr(287) 350%, Ile(306) 4.8%, and Thr(287)/Ile(306) 6.2% of the activity of the wild type (WT) allozyme, with 20, 190, 4.4, and 7.9% of the level of WT immunoreactive protein, respectively. Apparent K(m) values for S-adenosyl-l-methionine were 4.6, 3.1, and 11 mum for WT, Trp(173), and Thr(287) allozymes, with K(m) values for sodium arsenite with the same allozymes of 11.8, 8.9, and 4.5mum. The Ile(306) and Thr(287)/Ile(306) allozymes expressed too little activity for inclusion in the substrate kinetic studies. Expression of reporter gene constructs for the 5'-flanking region and the variable number of tandem repeats in the 5'-untranslated region demonstrated cell line-dependent variation in reporter gene expression, with shorter repeats associated with increased transcription in HepG2 cells. These results raise the possibility that inherited variation in AS3MT may contribute to variation in arsenic metabolism and, perhaps, arsenic-dependent carcinogenesis in humans.
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PMID:Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies. 1640 88

We previously reported that upregulation of SMYD3, a histone H3 lysine-4-specific methyltransferase, plays a key role in the proliferation of colorectal carcinoma (CRC) and hepatocellular carcinoma (HCC). In the present study, we reveal that SMYD3 expression is also elevated in the great majority of breast cancer tissues. Similarly to CRC and HCC, silencing of SMYD3 by small interfering RNA to this gene resulted in the inhibited growth of breast cancer cells, suggesting that increased SMYD3 expression is also essential for the proliferation of breast cancer cells. Moreover, we show here that SMYD3 could promote breast carcinogenesis by directly regulating expression of the proto-oncogene WNT10B. These data imply that augmented SMYD3 expression plays a crucial role in breast carcinogenesis, and that inhibition of SMYD3 should be a novel therapeutic strategy for treatment of breast cancer.
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PMID:Enhanced SMYD3 expression is essential for the growth of breast cancer cells. 1644 21

Several studies have suggested that hypermethylation and hypomethylation of CpG islands within the promoters and 5' exons of tumor-related genes are closely associated with carcinogenesis. However, large-scale analysis of candidate genes has been hampered by the lack of a high throughput approach for analyzing methylation patterns. Using methylation-specific oligonucleotide (MSO) chips, we evaluated the methylation patterns of eight samples of fresh frozen glioblastoma tissue. The MSO chip used contained DNA probes with the CpG sites of p16 (p16INK4A, CDKN2A), MGMT (O6-Methylguanine-DNA-methyltransferase), APC (adenomatous polyposis coil), RASSF1A (human RAS effect homolog), which are usually hypermethylated in cancer cells and MAGE (melanoma antigen), which is usually hypomethylated in cancer cells. We selected CpG sites for analysis; 28 CpG sites (263 bp) for p16, 26 CpG sites (249 bp) for MGMT, 16 CpG sites (195 bp) for APC, 22 CpG sites (262 bp) for RASSF1A and 18 CpG sites (235 bp) for MAGE. We then constructed primer sets not including CpG sites. Bisulfite modification of genomic DNA, methylation specific PCR, hybridization and image scan with data analysis and sequencing of the bisulfite modified DNA were carried out. Of the eight glioblastomas, hypermethylation of the 5'-CpG sites of the MGMT were found in two, RASSF1A were found in five, and p16 and APC genes were not found in any cases and hypomethylation of that of the MAGE was found in eight cases. These results obtained from the oligo DNA chip study were correlated well with the sequencing data of bisulfite modified genomic DNA except in regard to the RASSF1A and MAGE genes. The devised MSO DNA chip is a useful tool for studies on methylation.
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PMID:Oligonucleotide DNA chips are useful adjuncts in epigenetic studies of glioblastomas. 1708 Jul 17

DNA-methyltransferase-3B (DNMT3b) plays an important role in the generation of aberrant methylation in carcinogenesis. DNMT3b SNP has been associated with susceptibility to lung, head, neck, and breast cancer, but its association with the development of colon cancer has not been reported. We investigated the relationship between the 39179GT polymorphism in the DNMT3b gene, which is involved in de novo methylation and is associated with the risk of adenocarcinoma of the colon in Koreans. The DNMT3b 39179GT genotypes were determined by a PCR-RFLP method in 248 adenocarcinomas of colon cancer patients and in 248 healthy controls matched as to age and sex. When stratified by sex and age, a significantly reduced risk of the combined GT and GG genotypes was observed in younger patients (<59, adjusted OR = 0.255, 95% CI = 0.133-0.489) and in male patients (adjusted OR = 0.383, 95% CI = 0.225-0.652). The DNMT3b 39179GT polymorphism may be a genetic determinant of adenocarcinoma of the colon, especially in younger Korean men.
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PMID:DNMT3b 39179GT polymorphism and the risk of adenocarcinoma of the colon in Koreans. 1731 76

Histone methyltransferase (HMT) enzymes that methylate the lysine of histones are involved in chromatin-mediated gene expression. Previously, we reported that a novel polymorphism of SUV39H2, the HMT that is required for the methylation of H3-K9, was associated with an increased risk of lung cancer in Koreans. The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is also a member of a histone/protein-methyltransferase superfamily, and the inactivation of RIZ in many cancers was detected as frameshift mutations, hypermethylation and missense mutations. In this study, we show the association of RIZ polymorphisms with the risk of lung cancer. In a hospital-based study of 335 lung cancer patients and 335 age- and gender-matched healthy controls, 120 polymorphisms of RIZ were screened. Of the 120 genotyped single nucleotide polymorphisms (SNPs), 42 SNPs were selected for the statistical analysis based on their frequency (>5%) and linkage disequilibrium [LD; only a representative SNP was analyzed if there were absolute LDs (r2 = 1)]; this resulted in three LD blocks. The +92337G>A and +95701C>A polymorphisms showed a statistically significant association with the reduced risk of lung adenocarcinomas after correcting the P values for multiple testing [for carrying one variant allele versus none, adjusted odds ratio (aOR) = 0.55 (95% CI = 0.38-0.78), corrected P = 0.04; aOR = 0.54 (95% CI = 0.38-0.77), corrected P = 0.02, respectively]. One haplotype (Ht5) in LD block 3 of RIZ was significantly associated with the reduced risk of lung adenocarcinomas (aOR = 0.28, 95% CI = 0.13-0.58) as well as overall lung cancer (aOR = 0.50, 95% CI = 0.30-0.82). This study suggested that RIZ polymorphisms may be important predictive markers for lung cancer susceptibility.
Carcinogenesis 2007 Sep
PMID:Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer. 1769 62

Chronic exposure to arsenic involves a biotransformation process leading to the excretion of methylated metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the parental inorganic species (As(III) and As(V)). Inter-individual variations in arsenic biotransformation have been reported and polymorphisms affecting the genes involved in arsenic biotransformation have been considered as one of the plausible explanations for this variation. Coding and flanking regions of the human arsenic methyltransferase (AS3MT) gene have been analysed in 50 Chilean men exposed to arsenic. Nine polymorphisms were found, including one non-synonymous SNP at exon 9 (Met(287)Thr) with an allele frequency of 0.14. Other four changes occurred at potentially regulatory regions: a variable number of tandem repeats (VNTR) at the 5'-untranslated region (UTR5'), a G/C substitution at the promoter region, a GC/AT substitution inside the VNTR, and a G/A substitution at the 3'-untranslated region (UTR3'). The rest of polymorphisms were located in non-coding regions: a T/G substitution in intron 1, a CTC deletion in intron 2 and a TTT and ATT insertions in intron 5. In addition, the individual urinary arsenic profiles were analysed. Our results indicate that genetic polymorphisms in AS3MT contribute to inter-individual variation in arsenic biotransformation and, therefore, may contribute to inter-individual variations in risk of arsenic toxicity and arsenic carcinogenesis. Individuals with the Met(287)Thr polymorphism displayed increased arsenic methylation and might be at increased risk for toxic and genotoxic effects of arsenic exposure if, as the classical arsenic metabolic pathway indicates, methylation enhances toxicity.
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PMID:Role of the Met(287)Thr polymorphism in the AS3MT gene on the metabolic arsenic profile. 1785 Aug 29

Three of the most plausible biological theories of arsenic carcinogenesis are protein binding, oxidative stress and altered DNA methylation. This review presents the role of trivalent arsenicals binding to proteins in arsenic carcinogenesis. Using vacuum filtration based receptor dissociation binding techniques, the lifetimes of unidentate (<1s), bidentate (1-2min) and tridentate (1-2h) arsenite containing peptide binding complexes were estimated. According to our experimental data some of the protein targets to which arsenite may bind in vivo include tubulin, poly(ADP-ribose)polymerase (PARP-1), thioredoxin reductase, estrogen receptor-alpha, arsenic(+3)methyltransferase and Keap-1. Arsenite binding to tubulin can lead to several of the genetic effects observed after arsenic exposures (aneuploidy, polyploidy and mitotic arrests). Among many other possible arsenite binding sites are rat hemoglobin, the DNA repair enzyme xeroderma pigmentosum protein A (XPA), and other C2H2, C3H and C4 zinc finger proteins including members of the steroid receptor superfamily (e.g. glucocorticoid receptor). Macromolecules to which arsenite does not bind to include calf thymus DNA, mixed Type II-A histones and bovine H3/H4 histone. Although all six tested arsenicals released iron from ferritin, radioactive arsenite did not bind to the protein horse ferritin.
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PMID:The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. 1816 70

Histone methylation is crucial for transcriptional regulation and chromatin remodeling. It has been suggested that the SET domain containing protein RE-IIBP (interleukin-5 [IL-5] response element II binding protein) may perform a function in the carcinogenesis of certain tumor types, including myeloma. However, the pathogenic role of RE-IIBP in these diseases remains to be clearly elucidated. In this study, we have conducted an investigation into the relationship between the histone-methylating activity of RE-IIBP and transcriptional regulation. Here, we report that RE-IIBP is up-regulated in the blood cells of leukemia patients, and we characterized the histone H3 lysine 27 (H3-K27) methyltransferase activity of RE-IIBP. Point mutant analysis revealed that SET domain cysteine 483 and arginine 477 are critical residues for the histone methyltransferase (HMTase) activity of RE-IIBP. RE-IIBP also represses basal transcription via histone deacetylase (HDAC) recruitment, which may be mediated by H3-K27 methylation. In the chromatin immunoprecipitation assays, we showed that RE-IIBP overexpression induces histone H3-K27 methylation, HDAC recruitment, and histone H3 hypoacetylation on the IL-5 promoter and represses expression. Conversely, short hairpin RNA-mediated knockdown of RE-IIBP reduces histone H3-K27 methylation and HDAC occupancy around the IL-5 promoter. These data illustrate the important regulatory role of RE-IIBP in transcriptional regulation, thereby pointing to the important role of HMTase activity in carcinogenesis.
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PMID:Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. 1817 12

The etiology of esophageal squamous cell carcinoma (ESCC) has been shown to be multifactorial, including genetic, epigenetic, and environmental factors, such as tobacco smoking. A variable number of tandem repeats (VNTR) polymorphism in the promoter region of SMYD3, a recently characterized histone lysine methyltransferase gene that is implicated in cell proliferation and carcinogenesis, has been shown to be functional, but its association with cancer risk has not been well established because of apparently discrepant results in different populations. In this case-control study, we genotyped 567 patients with newly diagnosed ESCC and 567 healthy controls and found an increased ESCC risk (odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.05-1.91) associated with the common SMYD3 VNTR genotype. Stratification analysis revealed that the increased risk was limited to smokers (OR = 1.99; 95% CI = 1.27-3.12). Furthermore, compared with the reference group of non-smokers carrying the homozygous or heterozygous genotype, ORs (95% CI) of the wild genotype for non-smokers, smokers who smoked <25, and >or=25 pack-years were 1.03 (0.70-1.53), 2.80 (1.66-4.70), and 4.76 (2.67-8.46), respectively (P < 0.001 for trend test), suggesting an interaction between this genetic polymorphism and smoking status. These findings provide additional evidence that the common VNTR polymorphism in the promoter region of SMYD3 gene may be a susceptibility factor for human cancers such as ESCC by interacting with tobacco carcinogens.
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PMID:Association of the variable number of tandem repeats polymorphism in the promoter region of the SMYD3 gene with risk of esophageal squamous cell carcinoma in relation to tobacco smoking. 1829 91

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