Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ala(222)Val single nucleotide polymorphism (SNP) in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in one-carbon metabolism, has been associated with colorectal cancer risk. Many enzymes are involved in one-carbon metabolism, and SNPs in the corresponding genes may play a role in colorectal carcinogenesis. We examined 24 nonsynonymous SNPs in 13 genes involved in the one-carbon metabolism pathway in relation to the risk of colorectal cancer in a case-control study nested in the Nurses' Health Study and the Health Professionals Follow-up Study cohorts. Among 376 men and women with colorectal cancer and 849 controls, a reduced risk of colorectal cancer was observed for Val/Val versus Ala carriers of MTHFR Ala(222)Val [odds ratio (OR), 0.66; 95% confidence interval (CI), 0.43-1.00]. An increased risk was suggested for the variant carrier genotypes versus homozygous wild-type for betaine hydroxymethyltransferase Arg(239)Gln (OR, 1.40; 95% CI, 1.07-1.83) and two linked SNPs in methionine synthase reductase, Ser(284)Thr (OR, 1.85; 95% CI, 1.05-3.27) and Arg(415)Cys (OR, 2.03; 95% CI, 1.15-3.56). The other SNPs were not associated with colorectal cancer risk. Also, none of the SNPs were associated with risk in subgroups of dietary methyl status or were jointly associated with colorectal cancer risk in combination with another SNP, except possibly SNPs in methionine synthase and transcobalamin II. However, these analyses of gene-diet interactions were limited in statistical power. Our results corroborate previous findings for MTHFR Ala(222)Val and suggest that other genes involved in one-carbon metabolism, particularly those that affect DNA methylation, may be associated with colorectal cancer risk.
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PMID:Nonsynonymous polymorphisms in genes in the one-carbon metabolism pathway and associations with colorectal cancer. 1716 63

The adenomatous polyposis coli (APC) tumor suppressor is inactivated by mutation in most colorectal tumors. APC is a component of the Wnt signaling pathway and is best known for its ability to downregulate beta-catenin and consequent effects on transcriptional regulation. Previous work demonstrated that APC accelerates apoptosis-associated caspase activity independently of transcription, and suggested novel tumor suppressor functions of APC. In this work, we have mapped the APC apoptosis-accelerating region to amino acids (aa) 1-760 by testing a series of non-overlapping APC segments. Interestingly, this segment corresponds to a stable group II caspase cleavage product of APC released during apoptosis that includes the amino-terminal aa1-777. Mutation of the APC aspartic acid residue at position 777 to an alanine completely abolished in vitro cleavage of APC by a recombinant group II caspase and rendered the full-length protein unable to accelerate apoptosis in vitro. A truncated APC protein associated with familial and sporadic colorectal cancer, also unable to accelerate apoptosis in vitro and in vivo, is resistant to group II caspase cleavage. These results demonstrate that cleavage of APC and the subsequent release of an amino-terminal segment are necessary for the transcription-independent mechanism of APC-mediated apoptosis.
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PMID:Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis. 1729 57

Mat-8 was fused with a Myc-tag or green fluorescent protein at its carboxyl terminus, and then expressed in Chinese hamster ovary K1 cells. Determination of the cellular localization of the tagged proteins suggested that they were localized on the intracellular membrane, being not only detected around the nuclear envelope but also partly overlapping with markers for endosomes and Golgi bodies. However, Mat-8 with the Myc-tag was detected on the plasma membrane as well as the intracellular membrane, when it was expressed in colorectal cancer cells. The membrane fraction of the cancer cells was solubilized and immuno-precipitated with an antibody for the Myc-tag. Western-blotting analysis demonstrated that the Na+/K+-ATPase alpha subunit was present in the precipitate. Furthermore, the immuno-precipitate obtained with an antibody for the Na+/K+-ATPase alpha subunit reacted with that for the Myc-tag. These results suggested that Mat-8 could be associated with Na+/K+-ATPase similar to other FXYD family members. The Gly41-->Arg mutation in the transmembrane region of Mat-8 inhibited its association with the Na+/K+-ATPase alpha subunit and localization on the plasma membrane, whereas the Cys44-->Ala or Cys49-->Ala substitution did not. Thus the conserved Gly41 residue in the transmembrane domain could be indispensable for localization of Mat-8 on the cell surface.
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PMID:Interaction of Mat-8 (FXYD-3) with Na+/K+-ATPase in colorectal cancer cells. 1740 96

Inflammatory bowl disease predisposes to cancer of the colorectum, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the risk; hence genetic variations that modify the inflammatory response may alter the risk of colorectal cancer (CRC). The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with colorectal cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We studied 355 adenocarcinoma cases and 753 control persons, nested within the prospective "Diet, Cancer and Health" study. None of the polymorphisms were associated with risk of colorectal cancer. A statistically significant interaction between PPARgamma2 Pro(12)Ala and alcohol was found, where alcohol use was associated with a 22% increased risk of CRC per 10g alcohol/day among carriers of the variant allele but not among homozygous wild type allele carriers (P for interaction=0.02). Moreover, an interaction between DLG5 R30Q and NSAID use was found (P for interaction=0.02). Our results do not suggest that inborn variations in the inflammatory response play any major role in risk of colorectal cancer.
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PMID:Prospective study of interaction between alcohol, NSAID use and polymorphisms in genes involved in the inflammatory response in relation to risk of colorectal cancer. 1754 13

Although a number of studies have shown that vitamin K possesses antitumor activities on various neoplastic cell lines, there are few reports demonstrating in vivo antitumor effects of vitamin K, and the antitumor effect on colorectal cancer (CRC) remains to be examined. Therefore, antitumor effects of vitamin K on CRC were examined both in vitro and in vivo. Vitamins K2, K3 and K5 suppressed the proliferation of colon 26 cells in a dose-dependent manner, while vitamin K1 did not. On flow cytometry, induction of apoptosis by vitamins K2, K3 and K5 was suggested by population in sub-G1 phase of the cell cycle. Hoechst 33342 staining and a two-color flow cytometric assay using fluorescein isothiocyanate-conjugated annexin V and propidium iodide confirmed that vitamins K2, K3 and K5 induced apoptotic death of colon 26 cells. Enzymatic activity of caspase-3 in colon 26 cells was significantly up-regulated by vitamins K2, K3 and K5. The pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, substantially prevented vitamin K-mediated apoptosis. In vivo study using syngeneic mice with subcutaneously established colon 26 tumors demonstrated that intravenous administration of vitamins K2, K3 and K5 significantly suppressed the tumor growth. The number of apoptotic tumor cells was significantly larger in the vitamin K-treated groups than in the control group. These results suggest that vitamins K2, K3 and K5 exerted effective antitumor effects on CRC in vitro and in vivo by inducing caspase-dependent apoptotic death of tumor cells, suggesting that these K vitamins may be promising agents for the treatment of patients with CRC.
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PMID:Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. 1761 88

The c-myb gene is the progenitor of the v-myb oncogene, which causes avian myelomonocytic leukemia. Dysregulated c-myb gene expression is linked to the development of myeloid leukemia in mice and is predictive of poor prognosis in human colorectal cancer. Among the variety of post-translational modifications controlling the c-Myb protein, phosphorylation was shown to affect the transactivation activity and the rate of protein degradation. In this work we show that phosphorylation of c-Myb in response to stress led to rapid protein degradation, which occurred via a proteasome-dependent pathway. The kinases principally involved in this response were p38MAPK delta and, to a lesser extent, p38MAPK gamma. To assess whether c-Myb degradation was driven by changes in the overall level of phosphorylation or rather by phosphorylation at specific sites we systematically mutated potential sites of phosphorylation fulfilling the consensus for recognition by MAPKs (Ser/Thr-Pro). Among the point mutants examined, residues located downstream to the transactivation domain appeared to be essential for c-Myb stability. Particularly, mutation of Thr(354), Thr(486), Ser(556) and Thr(572) to Alanine conferred resistance to stress-induced degradation. The implications of c-Myb downregulation during inflammatory responses are discussed.
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PMID:p38MAPK delta controls c-Myb degradation in response to stress. 1800 38

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.
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PMID:DNA repair single-nucleotide polymorphisms in colorectal cancer and their role as modifiers of the effect of cigarette smoking and alcohol in the Singapore Chinese Health Study. 1800 25

Selenium (Se), a dietary trace metal essential for human health, is incorporated into selenoproteins as selenocysteine. Selenoprotein P (SePP), the major plasma selenoprotein, has both transport and antioxidant functions. In humans, it exists in plasma as two isoforms of approximately 50 and 60 kDa. This study investigated the effect of polymorphisms in the SEPP-1 gene, Se supplementation, and disease status on the proportions of SePP plasma isoforms. SePP was isolated from plasma from healthy volunteers, before and after a 6-week supplementation with 100 microg sodium selenite, and from colon cancer patients and controls. SePP isoform distribution was analysed by Western blot. In healthy volunteers, the relative abundance of each isoform depended on two SEPP-1 polymorphisms: rs3877899, predicted to cause an Ala-to-Thr amino acid change at position 234, and rs7579, located in the 3'-untranslated region of SEPP-1 mRNA. The difference between genotypes disappeared after Se supplementation. A genotype-dependent reduction was seen in the proportion of the 60-kDa isoform in patients with colorectal cancer compared with controls. We conclude that functional polymorphisms in the SEPP-1 gene influence the proportion of SePP isoforms in plasma. An elevated proportion of the 60-kDa isoform of SePP may increase selenoprotein synthesis and reduce colorectal cancer risk.
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PMID:Relative abundance of selenoprotein P isoforms in human plasma depends on genotype, se intake, and cancer status. 1945 53

Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (> or = 6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32-43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02-14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/ Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.
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PMID:Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer. 1993 46

Animal and in vitrostudies support a role for polyunsaturated fatty acids (PUFAs) in colon carcinogenesis; however, the epidemiological evidence is inconclusive. Recently, we investigated their role within the Singapore Chinese Health Study, a population-based cohort of Singapore Chinese men and women. We reported that a high intake of marine n-3 PUFAs was associated with an increased risk of colorectal cancer (CRC). Oxidation of PUFAs incorporated into cell membranes generates lipid hydroperoxides, which can be mutagenic. In this report, we investigated whether single nucleotide polymorphisms (SNPs) in DNA repair genes modified the effect of PUFAs on CRC risk using a nested case-control study within the Singapore Chinese Health Study. We genotyped 1,181 controls and 311 cases (180 colon and 131 rectal cancer) for SNPs in the XRCC1 (Arg194Trp, Arg399Gln), OGG1 (Ser326Cys), PARP (Val762Ala, Lys940Arg), and XPD (Asp312Asn, Lys751Gln) genes. We observed that the PARP Val762Ala SNP modified the association between marine n-3 PUFA and rectal cancer risk, with no evidence of interaction among colon cancer (heterogeneity test p=0.003). Our results suggest a positive association between high intake of marine n-3 PUFA and rectal cancer risk among carriers of at least one PARP codon 762 Ala allele (odds ratio=1.7, 95% confidence interval=1.1-2.7).
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PMID:Polyunsaturated fatty acids, DNA repair single nucleotide polymorphisms and colorectal cancer in the Singapore Chinese Health Study. 2055 12


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