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)

Leptin may play an important role in colorectal cancer because of its role in energy balance, insulin and inflammation. We evaluated the LEP rs2167270 (19 G > A) and rs7799039 (-2548 G > A) polymorphisms and the leptin receptor, LEPR rs6588147 (located in intron 2), polymorphism with risk of developing colon cancer in a study of 1,567 cases and 1,965 controls. We evaluated the effects of the polymorphisms with body mass index (BMI), recent use of aspirin/NSAIDs and genetic variations in genes related to insulin signaling pathways including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), and insulin-related substrates 1 and 2 (IRS1, IRS2) and the vitamin D receptor (VDR). We observed a slight reduction in colon cancer risk with the AA LEP rs2167270 genotype (OR 0.79 95% CI 0.64, 0.98) and although not reaching statistical significance, with the combined GG LEP rs2167270 and GG LEPR rs6588147 (OR 0.70, 95% CI 0.49, 1.02) genotypes. BMI did not interact with any of these polymorphisms to alter colon cancer risk. However, recent aspirin/NSAID use significantly interacted with both LEP polymorphisms. Likewise, variants of IGF1 and IRS2 interacted with the LEP rs2167270 polymorphism. VDR polymorphisms interacted with all LEP and LEPR polymorphisms. These data support an association between LEP and colon cancer. They also suggest that the mechanisms linking leptin to colon cancer may be independent of energy balance.
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PMID:Leptin and leptin receptor genotypes and colon cancer: gene-gene and gene-lifestyle interactions. 1805 35

Studies suggest that polymorphisms of the vitamin D receptor (VDR) gene may influence colorectal cancer risk. In this study, we examine the association of the CDX2 VDR polymorphism (rs11568820) located in the 5'-untranslated region of the gene, and VDR haplotypes, including this polymorphism, with colon and rectal cancer using data from two large case-control studies of colon (N = 1,574 cases and 1,970 controls) and rectal (n = 791 cases and 999 controls) cancer. The frequency of the A allele of the CDX2 polymorphism was 19% among non-Hispanic white, 21% among Hispanic, 76% among African American, and 47% among Asian controls. The CDX2 polymorphism was not independently associated with either colon or rectal cancer, nor did it modify associations of dietary calcium, vitamin D, or fat with colon or rectal cancer. However, the bLFA haplotype which occurred in 6.5% of non-Hispanic white participants and 41.2% of African American participants was associated with an increased risk of colon cancer, and an odds ratio of 2.4 [95% confidence intervals (CI), 2.45 (1.38-4.38)]. The BSfG haplotype was associated with a 1.61 (95% CI, 1.05-2.49) increased risk of rectal but not colon cancer, whereas the BSFA haplotype was associated with a significantly reduced risk of rectal (odds ratio, 0.71; 95% CI, 0.52-0.97) but not colon cancer. These data suggest that haplotype analysis that encompasses different domains of the VDR gene might further our understanding of associations between the VDR gene and colon and rectal cancer.
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PMID:CDX2 VDR polymorphism and colorectal cancer. 1808 83

The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates calcium. 1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain omega3/omega6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.
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PMID:Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. 1829 Jul 15

Aberrant activation of the Wnt/beta-catenin signaling pathway is a hallmark of colon cancer. We show that the Wnt antagonist DICKKOPF-4 (DKK-4) gene is repressed by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) in human colon cancer cells. This effect correlated with the inhibition of the DKK-4 promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3 induces early and transient binding of the vitamin D receptor (VDR) and the SMRT corepressor to the region adjacent to the transcription start site of DKK-4. Additionally, we demonstrate that the DKK-4 gene is a new downstream target of TCF/beta-catenin. Remarkably, expression of DKK-4 messenger RNA (mRNA) was not detected in a series of 29 human normal (N) colon biopsies but expression was upregulated in all the matched tumour (T) tissues. An inverse correlation existed between the expression of DKK-4 and VDR RNA in the Ts. Ectopic DKK-4 expression increased the migration and invasion properties of colon cancer cells and conditioned media (CM) from DKK-4-expressing cells enhanced the capacity to migrate and form capillary-like tubules of human primary microvascular endothelial cells. In conclusion, DKK-4 is upregulated in colon cancer and is associated with the acquisition of malignant properties by neoplastic cells. DKK-4 downregulation is a novel effect of 1,25(OH)2D3 that may contribute to its anticancer action.
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PMID:DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. 1840 52

Histone deacetylase 3 (HDAC3) is overexpressed in approximately half of all colon adenocarcinomas. We took an RNAi approach to determine how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APC(Min) tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both positive and negative effects observed. However, long-term knockdown of HDAC3 suppressed beta-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
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PMID:HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. 1878 8

Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.
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PMID:Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor. 1894 Jun 64

Variation in genes associated with serum levels of proteins may be useful for examining specific disease pathways. Using data from a large study of colon cancer, we examine genetic variants in insulin, inflammation, estrogen, metabolizing enzymes, and energy homeostasis genes to explore associations with microsatellite instability (MSI), CpG Island methylator phenotype (CIMP), mutations of p53 in exons 5 through 8, and mutations in codons 12 and 13 of Ki-ras. Insulin-related genes were associated with CIMP-positive and MSI tumors, with the strongest associations among aspirin users. The Fok1 vitamin D receptor (VDR) polymorphism was associated with CIMP-positive/Ki-ras-mutated tumors; the Poly A and CDX2 VDR polymorphisms were associated only with Ki-ras-mutated tumors. NAT2 was associated with CIMP-positive/Ki-ras-mutated tumors but not with MSI tumors. The TCF7L2 rs7903146 polymorphism was associated with p53 mutated tumors. Most associations varied by recent aspirin/NSAID use: IL6 rs1800796 and rs1800795 polymorphisms were associated inversely with tumor mutations in the presence of aspirin/NSAIDs; POMC significantly reduced risk of Ki-ras-mutated tumors when aspirin/NSAIDs were not used; the TCF7L2 rs7903146 was associated with reduced risk of Ki-ras-mutated tumors in the presence of aspirin and increased risk in the absence of aspirin. These data, although exploratory, identify specific tumor subsets that may be associated with specific exposures/polymorphism combinations. The important modifying effects of aspirin/NSAIDs on associations with genetic polymorphisms reinforce the underlying role of inflammation in the etiology of colon cancer.
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PMID:Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. 1899 63

The active vitamin D metabolite 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) inhibits proliferation and promotes differentiation of colon cancer cells through the activation of vitamin D receptor (VDR), a transcription factor of the nuclear receptor superfamily. Additionally, 1,25(OH)(2)D(3) has several nongenomic effects of uncertain relevance. We show that 1,25(OH)(2)D(3) induces a transcription-independent Ca(2+) influx and activation of RhoA-Rho-associated coiled kinase (ROCK). This requires VDR and is followed by activation of the p38 mitogen-activated protein kinase (p38MAPK) and mitogen- and stress-activated kinase 1 (MSK1). As shown by the use of chemical inhibitors, dominant-negative mutants and small interfering RNA, RhoA-ROCK, and p38MAPK-MSK1 activation is necessary for the induction of CDH1/E-cadherin, CYP24, and other genes and of an adhesive phenotype by 1,25(OH)(2)D(3). RhoA-ROCK and MSK1 are also required for the inhibition of Wnt-beta-catenin pathway and cell proliferation. Thus, the action of 1,25(OH)(2)D(3) on colon carcinoma cells depends on the dual action of VDR as a transcription factor and a nongenomic activator of RhoA-ROCK and p38MAPK-MSK1.
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PMID:RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. 1901 18

Colorectal cancer is a major health problem worldwide. Aberrant activation of the Wingless-type mouse mammary tumour virus integration site family (Wnt)/beta-catenin signalling pathway due to mutation of adenomatous polyposis coli (APC), beta-catenin (CTNNB1) or AXIN genes is the most common and initial alteration in sporadic colorectal tumours. Numerous epidemiological and experimental studies have indicated a protective action of vitamin D against colorectal cancer. Previous work has demonstrated that the most active vitamin D metabolite, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits beta-catenin transcriptional activity by promoting vitamin D receptor (VDR) binding to beta-catenin and the induction of E-cadherin expression. Recently, 1,25(OH)2D3 has been shown to distinctly regulate two genes encoding the extracellular Wnt inhibitors DICKKOPF-1 and DICKKOPF-4 (DKK-1, DKK-4). By an indirect transcriptional mechanism, 1,25(OH)2D3 increases the expression of DKK-1 RNA and protein, which acts as a tumour suppressor in human colon cancer cells harbouring endogenous mutations in the Wnt/beta-catenin pathway. In contrast, 1,25(OH)2D3 represses DKK-4 transcription by inducing direct VDR binding to its promoter. Unexpectedly, DKK-4 is a target of the Wnt/beta-catenin pathway and is up-regulated in colorectal tumours, and it has been shown to increase cell migration and invasion and to promote a proangiogenic phenotype. Together, these results show that 1,25(OH)2D3 exerts a complex set of regulatory actions leading to the inhibition of the Wnt/beta-catenin pathway in colon cancer cells that is in line with its protective effect against this neoplasia.
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PMID:Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. 1903 86

Postmenopausal hormone replacement therapy lowers colon cancer incidence. In humans, the mechanism is unknown, but animal models suggest that it may involve activation of the vitamin D receptor (VDR) pathway. The aims of our study were to determine whether estrogen intervention affects global gene expression in rectal mucosal biopsies and whether vitamin D-related genes are affected. Estradiol was given to raise serum estradiol to premenopausal levels in 10 postmenopausal women under close nutritional control. Primary end points were expression of VDR, CYP24A1, CYP27B1, and E-cadherin in rectal mucosa by reverse transcription-PCR and examining response to estradiol by genome-wide arrays. Responses in gene expression in rectal biopsies to estrogen were determined in each subject individually and compared with a human estrogen response gene array database and a custom array in vitro-generated database. Cluster analysis showed that subjects maintained their overall gene expression profile and that interindividual differences were greater than intraindividual differences after intervention. Eight of 10 subjects showed significant enrichment in estrogen-responsive genes. Gene array group analysis showed activation of the VDR pathway and down-regulation of inflammatory and immune signaling pathways. Reverse transcription-PCR analysis showed significant up-regulation of VDR and E-cadherin, a downstream target of vitamin D action. These data suggest that the chemopreventive action of hormone replacement therapy on colon neoplasia results, at least in part, from changes in vitamin D activity. Evaluation of gene arrays is useful in chemopreventive intervention studies in small groups of subjects.
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PMID:Chemoprevention of colorectal neoplasia by estrogen: potential role of vitamin D activity. 1913 17


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