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)

Protein microspheres have been used in the fields of biomedical imaging and drug delivery, but surface modification for cell targeting has been problematic. We have for the first time used an electrostatic adhesion approach to adhere arginine-glutamic acid-aspartic acid (RGD) containing peptides to the surface of protein microspheres for the purpose of targeting these vesicles to tumor cells. RGD sequences are recognized by integrin membrane receptors, which are overexpressed in various tumors. We have succeeded in modifying the surface of serum albumin core-shell microspheres, which have a fluorescent nonaqueous core by using several polylysine peptides containing the RGD sequence. Fluorescence microscopy reveals that these modified microspheres are selectively bound and taken up by HT29 human colon cancer cells in vitro.
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PMID:Tumor targeting by surface-modified protein microspheres. 1653 92

Colon cancer in humans is influenced by both genetic and dietary risk factors. The majority of colon cancers have somatic mutations in the APC (adenomatous polyposis coli) tumour-suppressor gene. Dietary arginine enhances the risk of APC-dependent colon carcinogenesis in mouse models by a mechanism involving NOS2 (nitric oxide synthase 2), as elimination of NOS2 alleles suppresses this phenotype. DFMO (difluoromethylornithine), a specific inhibitor of polyamine synthesis, also inhibits dietary arginine-induced colon carcinogenesis in C57BL/6J-Apc(Min)/J mice. The primary consequence of dietary arginine is to increase the adenoma grade in these mice. Either loss of NOS2 alleles or inhibition of polyamine synthesis suppresses the arginine-induced increase in adenoma grade. In addition to promoting intestinal carcinogenesis, polyamines can also reduce the efficacy of certain intestinal cancer chemopreventive agents. The NSAID (non-steroidal anti-inflammatory drug) sulindac is a potent inhibitor of intestinal carcinogenesis in the C57BL/6J-Apc(Min)/J mouse model and is used to treat humans with FAP (familial adenomatous polyposis). Dietary putrescine reduces the ability of sulindac to suppress intestinal tumorigenesis in the mouse model. These data suggest that reducing polyamine metabolism and dietary polyamine levels may enhance strategies for colon cancer chemoprevention.
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PMID:Impact of dietary amino acids and polyamines on intestinal carcinogenesis and chemoprevention in mouse models. 1737 Dec 70

The extravasation of cancer cells is a key step of the metastatic cascade. Polymorphisms in genes encoding adhesion molecules can facilitate metastasis by increasing the strength of interaction between tumor and endothelial cells as well as impacting other properties of cancer cells. We investigated the Ser128Arg (a561c at the nucleotide level) polymorphism in the E-selectin gene in patients with metastatic colon cancer and its functional significance. Genotyping for a561c polymorphism was performed on 172 cancer patients and on an age-matched control population. The colon cancer group was divided into groups with (M(+)) and without observable metastasis (M(-)). For in vitro functional assays, Huvec transfected cells expressing wild-type (WT) or the S128R variant of E-selectin were established to study in vitro binding ability and signal transduction processes of T84 colon cancer cell line. Our results demonstrated that the Arginine(128) allele was more prevalent in the M(+) group than in the M(-) group or normal controls (p < 0.005; odds ratio, 1.56; 95% confidence interval (CI) 1.16-1.92; p < 0.001, odds ratio = 1.65; CI = 1.24-1.99, respectively). In vitro, S128R E-selectin transfected Huvec cells, supported increased adhesion as well as increased cellular signaling of T84 cancer cells compared to WT E-selectin and mock-transfected Huvec cells. These findings suggest that the E-selectin S128R polymorphism can functionally affect tumor-endothelial interactions as well as motility and signaling properties of neoplastic cells that may modulate the metastatic phenotype.
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PMID:Role of S128R polymorphism of E-selectin in colon metastasis formation. 1737 5

A short peptide, corresponding to the nuclear localization signal of the human immunodeficiency virus-1 Tat protein, Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg, was modified by adding a cysteine residue at the COOH terminus. The peptide was mixed with a reporter plasmid, and then with cationic lipids, to form a tripartite complex, DNA/peptide/lipid (DPL). Various cell lines were treated with the DPL complex and compared for transfection efficiency with those of the conventional DNA/lipid (DL) complex. With the simple inclusion of the peptide, the DPL complex showed much enhanced transfection. Meanwhile, the plasmid DNA mixed only with the peptide exhibited some improvement but with much lower transfection than the DPL complex. When the DPL complex was formed with various cationic lipids, the DOSPA/DOPE exhibited superior transfection efficiency than the other cationic lipids tested at the optimal ratio of 1:3:5 (w:w:w) in many cell types. At the optimal ratio of the DPL components, transfection efficiency was routinely shown to be approximately 10-fold higher for reporter gene expression than that of the conventional DL complex. Furthermore, when subcutaneous tumors of a colon cancer cell line (SW480) were treated intratumorally with antisense oligos, k-ras-RiAS, delivered as a DPL complex, tumor growth was markedly suppressed. This study shows that the DPL complex, which is easy to formulate by ordered mixing, can be employed for a much enhanced cellular uptake of a transgene both in vitro and in vivo.
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PMID:Marked transfection enhancement by the DPL (DNA/peptide/lipid) complex. 1778 72

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

Evidence is accumulating supporting gender-related differences in the development of colonic carcinomas. Sex steroid hormone receptors are expressed in the colon and interact with epidermal growth factor receptor (EGFR), a gene widely expressed in colonic tissue. Increased EGFR expression is linked with poor prognosis in colon cancer. Within the EGFR gene there are two functional polymorphisms of interest: a polymorphism located at codon 497 (HER-1 R497K) and a dinucleotide (CA)(n) repeat polymorphism located within intron 1. These germ-line polymorphisms of EGFR were analyzed in genomic DNA from 318 metastatic colon cancer patients, 177 males and 141 females, collected from 1992 to 2003. Gender-related survival differences were associated with the HER-1 R497K polymorphism (P(interaction) = 0.003). Females with the HER-1 497 Arg/Arg variant had better overall survival (OS) when compared with the Lys/Lys and/or Lys/Arg variants. In males the opposite was true. The EGFR dinucleotide (CA)(n) repeat also trended with a gender-related OS difference (P(interaction) = 0.11). Females with both short <20 (CA)(n) repeat alleles had better OS than those with any long >or=20 (CA)(n) repeats. In males the opposite was true. Combination analysis of the two polymorphisms taken together also revealed the same gender-related survival difference (P(interaction) = 0.002). These associations were observed using multivariable analysis. The two polymorphisms were not in linkage disequilibrium and are independent of one another. This study supports the role of functional EGFR polymorphisms as independent prognostic markers in metastatic colon cancer. As a prognostic factor, these variants had opposite prognostic implications based on gender.
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PMID:Gender-related survival differences associated with EGFR polymorphisms in metastatic colon cancer. 1841 74

SLC3A2, a member of the solute carrier family, was identified by proteomics methods as a component of a transporter capable of exporting the diamine putrescine in the Chinese hamster ovary (CHO) cells selected for resistance to growth inhibition by high exogenous concentrations of putrescine. Putrescine transport was increased in inverted plasma membrane vesicles prepared from cells resistant to growth inhibition by putrescine compared with transport in inverted vesicles prepared from non-selected cells. Knockdown of SLC3A2 in human cells, using short hairpin RNA, caused an increase in putrescine uptake and a decrease in arginine uptake activity. SLC3A2 knockdown cells accumulated higher polyamine levels and grew faster than control cells. The growth of SLC3A2 knockdown cells was inhibited by high concentrations of putrescine. Knockdown of SLC3A2 reduced export of polyamines from cells. Expression of SLC3A2 was suppressed in human HCT116 colon cancer cells, which have an activated K-RAS, compared with their isogenic clone, Hkh2 cells, which lack an activated K-RAS allele. Spermidine/spermine N(1)-acetyltransferase (SAT1) was co-immunoprecipitated by an anti-SLC3A2 antibody as was SLC3A2 with an anti-SAT1 antibody. SLC3A2 and SAT1 colocalized on the plasma membrane. These data provide the first molecular characterization of a polyamine exporter in animal cells and indicate that the diamine putrescine is exported by an arginine transporter containing SLC3A2, whose expression is negatively regulated by K-RAS. The interaction between SLC3A2 and SAT1 suggests that these proteins may facilitate excretion of acetylated polyamines.
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PMID:Identification and characterization of a diamine exporter in colon epithelial cells. 1866 May 1

Increased extracellular pressure stimulates beta1-integrin-dependent cancer cell adhesion. We asked whether pressure-induced adhesion is mediated by changes in beta1-integrin binding affinity or avidity and whether these changes are phosphorylation dependent. We evaluated integrin affinity and clustering in human SW620 colon cancer cells by measuring differences in binding between soluble Arg-Gly-Asp (RGD)-Fc ligands and RGD-Fc-F(ab')2 multimeric complexes under ambient and 15-mmHg increased pressures. Phosphorylation of beta1-integrin S785 and T788/9 residues in SW620 and primary malignant colonocytes was assessed in parallel. We further used GD25-beta1-integrin-null murine fibroblasts stably transfected with either wild-type beta1A-integrin, S785A, TT788/9AA, or T788D mutants to investigate the role of beta1-integrin site-specific phosphorylation. SW620 binding of RGD-Fc-F(ab')2 multimeric complexes, but not soluble RGD-Fc ligands, was sensitive to integrin clustering. RGD-Fc ligand binding was significantly increased under elevated pressure, suggesting that pressure modulates beta1-integrin affinity. Pressure stimulated both beta1-integrin S785 and T788/9 phosphorylation. GD25-beta1A-integrin wild-type and S785A cells displayed an increase in adhesion to fibronectin under elevated pressure, an effect absent in beta1-integrin-null and TT788/9AA cells. T788D substitution significantly elevated basal cell adhesion but displayed no further increase under pressure. These results suggest pressure-induced cell adhesion is mediated by beta1-integrin T788/9 phosphorylation-dependent changes in integrin binding affinity.
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PMID:Increased extracellular pressure enhances cancer cell integrin-binding affinity through phosphorylation of beta1-integrin at threonine 788/789. 1900 62

The methylation of arginine has been implicated in many cellular processes, such as regulation of transcription, mRNA splicing, RNA metabolism and transport. The enzymes responsible for this modification are the protein arginine methyltransferases. The most abundant methyltransferase in human cells is protein arginine methyltransferase 1. Methylation processes appear to interfere in the emergence of several diseases, including cancer. During our study, we examined the expression pattern of protein arginine methyltransferase 1 gene in colon cancer patients. The emerging results showed that the expression of one of the gene variants is associated with statistical significant probability to clinical and histological parameters, such as nodal status and stage. This is a first attempt to acquire an insight on the possible relation of the expression pattern of protein arginine methyltransferase 1 and colon cancer progression.
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PMID:The PRMT1 gene expression pattern in colon cancer. 1907 53

Oral supplementations of L-arginine and L-lysine show tumor inhibition abilities. The splenic sympathetic nerve is involved in central modulation of cellular immunity and suppresses splenic natural killer cell activity in rats. An intravenous administration of a mixture of 10 mM L-arginine and L-lysine decreased splenic sympathetic nerve activity (splenic-SNA). We examined the effect of L-arginine and L-lysine mixtures on splenic-SNA in urethane-anesthetized rats by administration of 1 ml mixtures of 2 mM, 10 mM, and 50 mM L-arginine and L-lysine. We also studied the effect of the above mixtures on human colon cancer cell proliferation in athymic nude mice. An increase in splenic-SNA and tumor volume (2 mM), no effect (10 mM), and a decrease in both values (50 mM) were seen. Bivariate correlation analysis revealed a positive correlation between changes in splenic-SNA and tumor volume, indicating the tumor suppressing ability of weakened splenic-SNA.
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PMID:Effects of L-arginine and L-lysine mixtures on splenic sympathetic nerve activity and tumor proliferation. 1923 19


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