Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.
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PMID:MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. 1497 4

The incidence of colon cancer is high in many developed nations, especially New Zealand. Molecular understanding of the nature of colon cancer shows a disease whose well-characterized morphological progression is paralleled at the cellular level by increased numbers of gene or chromosome mutations, loss of heterozygosity, changed methylation patterns, and genomic instability. In the present study, we consider whether an imbalance of factors that affect DNA methylation patterns might explain at least part of the high colon cancer incidence in New Zealand. Folate is the major micronutrient whose intake impacts methylation, particularly through interaction with choline and methionine. Folate is generally somewhat deficient in the New Zealand diet, with the voluntary addition of folate to white flour not producing desired levels. Selenium affects methylation status in several ways and is recognized as being low in New Zealand soils and, therefore, diet. Zinc is also low in the diets of some New Zealand population groups, which can lead to hypomethylation. Several of the components of fruits and vegetables affect methylation patterns, and the average New Zealand intake, at two to three servings per day, is considerably below recommended amounts. Low dietary fiber, high tobacco use, and increasing rates of obesity are also likely New Zealand risk factors that may impact on methylation status. Dietary supplementation is not as common in New Zealand as in countries such as the United States, but may provide a way to raise the levels of nutrients and phytochemicals affecting methylation status, thereby enhancing colon cancer protection.
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PMID:Epigenetic events and protection from colon cancer in New Zealand. 1519 45

Protein myristoylation is a co-translational process, catalyzed by N-myristoyltransferase (NMT) that occurs after the initiating methionine is removed by methionine aminopeptidase (MetAP). The enzymes NMT and MetAP play a major role in the process of myristoylation of oncoproteins including the c-src family. In this study, we examined the levels of expression of MetAP2, NMT, and NMT inhibitor protein 71 (NIP71) in human colon cancer cell lines (HCCLs). We examined the influence of cell density on the expression of the above proteins in HT29 cells. Western blot analysis of MetAP2 and NMT demonstrated higher levels of protein expression in low density of HT29 while low expression in high density was observed. In addition, we observed that NIP71 and pp60(c-src) expressions were dependent on the cell density of HT29. This is the first study demonstrating the expression of MetAP2, NMT, pp60(c-src), and NIP71 in HCCLs.
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PMID:Expression of methionine aminopeptidase 2, N-myristoyltransferase, and N-myristoyltransferase inhibitor protein 71 in HT29. 1533 65

The past two decades have provided a vast amount of literature related to the primary prevention of colorectal cancer. Large international variation in colorectal cancer incidence and mortality rates and the prominent increases in the incidence of colorectal cancer in groups that migrated from low- to high-incidence areas provided important evidence that lifestyle factors influence the development of this malignancy. Moreover, there is convincing evidence from epidemiological and experimental studies that dietary intake is an important etiological factor in colorectal neoplasia. Although the precise mechanisms have not been clarified, several lifestyle factors are likely to have a major impact on colorectal cancer development. Physical inactivity and to a lesser extent, excess body weight, are consistent risk factors for colon cancer. Exposure to tobacco products early in life is associated with a higher risk of developing colorectal neoplasia. Diet and nutritional factors are also clearly important. Diets high in red and processed meat increase risk. Excess alcohol consumption, probably in combination with a diet low in some micronutrients such as folate and methionine, appear to increase risk. There is also recent evidence supporting a protective effect of calcium and vitamin D in the etiology of colorectal neoplasia. The relationship between intake of dietary fiber and risk of colon cancer has been studied for three decades but the results are still inconclusive. However, some micronutrients or phytochemicals in fiber-rich foods may be important; folic acid is one such micronutrient that has been shown to protect against the development of colorectal neoplasia and is currently being studied in intervention trials of adenoma recurrence. The overwhelming evidence indicates that primary prevention of colon cancer is feasible. Continued focus on primary prevention of colorectal cancer, in combination with efforts aimed at screening and surveillance, will be vital in attaining the greatest possible progress against this complex, yet highly preventable disease.
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PMID:Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. 1564 91

Previously, we showed that selenomethionine (Se-Met) inhibits growth of colon cancer cells via suppressing COX-2 expression at both mRNA and protein level. However, the molecular mechanism by which Se-Met suppresses COX-2 expression remains to be elucidated. To this end, we transiently transfected HCA-7 cells with different COX-2 promoter constructs followed by Se-Met treatment (90 microM) for 12 h. The results suggested the role of nuclear factor-kappa B (NF-kappaB) in transcriptional regulation of COX-2. We also observed complete inhibition of DNA binding activity of NF-kappaB in Se-Met (90 microM) treated HCA-7 cells as shown by electrophoretic mobility shift assay (EMSA). Supershift assays with anti-p65 antibody identified p65 subunit in the protein complex. We further demonstrate dose-dependent inhibition of nuclear translocation of NF-kappaB/p65 in Se-Met treated HCA-7 cells, which could explain the observed reduction in DNA binding of NF-kappaB/p65. These results suggest that Se-Met regulates COX-2 at transcriptional level by modulating the activity of NF-kappaB transcription factor.
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PMID:Selenomethionine regulates cyclooxygenase-2 (COX-2) expression through nuclear factor-kappa B (NF-kappaB) in colon cancer cells. 1565 49

Folate is an essential co-factor in the remethylation of homocysteine to methionine, thereby ensuring the supply of S-adenosylmethionine, the methyl group donor for most biological methylations, including that of DNA. Aberrant patterns and dysregulation of DNA methylation are consistent events in carcinogenesis and hence, DNA methylation is considered to be mechanistically related to the development of cancer. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered to be a leading mechanism by which folate deficiency enhances carcinogenesis. Although diets deficient in methyl group donors (choline, folate, methionine and vitamin B12) have been consistently observed to induce DNA hypomethylation, the effect of an isolated folate deficiency on DNA methylation remains highly controversial and unresolved. Whether or not isolated folate deficiency can modulate DNA methylation is an important issue because it would establish a mechanistic link between folate deficiency and cancer. We examined the effects of isolated folate deficiency on methionine cycle intermediates, genomic and site-specific DNA methylation and DNA methyltransferase in an in vitro model of folate deficiency, using untransformed NIH/3T3 and CHO-K1 cells, and human HCT116 and Caco-2 colon cancer cells. Our data demonstrate that the effect of folate deficiency on the methionine cycle pathway and DNA methylation in these cells is highly complex and appears to depend on the cell type and stage of transformation, and may be gene and site-specific. The direction of changes of methionine cycle intermediates in response to folate deficiency is not uniformly consistent with the known biochemical effect of folate on the methionine cycle pathway. Moreover, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways.
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PMID:Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. 1569 36

In the present studies, several hypotheses were tested to explain previously reported differential effects of soy and casein on colon cancer biomarkers like cell proliferation, fecal fat, fecal bile acid, alkaline phosphatase, and magnesium excretion in rats. In Study 1, the effect of methionine, a limiting amino acid in soy protein and an amino acid that is thought to have a marked effect on colonic cell proliferation, was tested. It was concluded that methionine up to 1% in the diet had no effect on cell proliferation, using the 3H-thymidine assay. The same study revealed that fecal alkaline phosphatase excretion is a good marker for colonic epithelial damage and fecal magnesium excretion is not. In Study 2, the hypothesis was tested that soy fractions enriched with isoflavones and saponins may increase fat excretion and so influence colonic cell proliferation in rats. It was indeed shown that soy protein isolate and an ethanolic extract from soy protein isolate slightly increased fecal fat excretion (up to 1.7-fold). However, fecal water bile acid and free fatty acid concentrations were decreased after feeding soy protein-based diets compared with casein, and no difference in fecal alkaline phosphatase excretion was observed. In Study 3, the lytic potential of soy saponins and the interaction between saponins and some lytic bile acids were tested in vitro. Data suggest a protective effect from soy saponins by reducing lytic activity of cholic acid. The overall conclusion is that soy protein compared with casein influences several colon cancer risk parameters, indicating a more protective rather than a stimulating effect on colon cancer risk.
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PMID:Possible mechanisms behind the differential effects of soy protein and casein feedings on colon cancer biomarkers in the rat. 1574 28

It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer.
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PMID:MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling. 1578 35

The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.
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PMID:Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer. 1582 74

Both Ki-ras mutation and hepatocyte growth factor (HGF) receptor Met overexpression occur at high frequency in colon cancer. This study investigates the transcriptional changes induced by Ki-ras oncogene and HGF/Met signaling activation in colon cancer cell lines in vitro and in vivo. The model system used in these studies included the DLD-1 colon cancer cell line with a mutated Ki-ras allele, and the DKO-4 cell line generated from DLD-1, with its mutant Ki-ras allele inactivated by targeted disruption. These cell lines were transduced with cDNAs of full-length Met receptor. Microarray transcriptional profiling was conducted on cell lines stimulated with HGF, as well as on tumor xenograft tissues. Overlapping genes between in vitro and in vivo microarray data sets were selected as a subset of HGF/Met and Ki-ras oncogene-regulated targets. Using the Online Predicted Human Interaction Database, novel HGF/Met and Ki-ras regulated proteins with putative functional linkage were identified. Novel proteins identified included histone acetyltransferase 1, phosphoribosyl pyrophosphate synthetase 2, chaperonin containing TCP1, subunit 8, CSE1 chromosome segregation 1-like (yeast)/cellular apoptosis susceptibility (mammals), CCR4-NOT transcription complex, subunit 8, and cyclin H. Transcript levels for these Met-signaling targets were correlated with Met expression levels, and were significantly elevated in both primary and metastatic human colorectal cancer samples compared to normal colorectal mucosa. These genes represent novel Met and/or Ki-ras transcriptionally coregulated genes with a high degree of validation in human colorectal cancers.
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PMID:Transcriptional targets of hepatocyte growth factor signaling and Ki-ras oncogene activation in colorectal cancer. 1615 56


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