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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of colonic neoplasias contain mutations in either the adenomatous polyposis coli or the beta-catenin (beta-cat) gene, both of which result in elevated levels of cytoplasmic beta-cat. The oncogenic activity of beta-cat has been explored in vivo and in vitro with conflicting results. We tested the hypothesis that beta-cat is capable of immortalizing and transforming cultured epithelial cells that represent the precursors to colon cancer. A truncated form of beta-cat (deltaN89) was stably expressed in murine colonic epithelial cells that were conditionally immortalized by temperature-sensitive T antigen expression and contained a mutant ApcMin allele [Immorto-Min colonic epithelium (IMCE)]. IMCE cells, grown under nonpermissive conditions, were immortalized by expression of the truncated beta-cat protein as determined by sustained growth in culture and escape from senescence as measured by endogenous beta-galactosidase activity. IMCE neo cells at nonpermissive conditions underwent extensive apoptosis, an effect that was blocked by the expression of deltaN89 beta-catenin. IMCE beta-cat cells had significantly lower p19 and p53 protein levels compared to IMCE neo cells, suggesting that alterations in these two key genes may mediate the effects of beta-cat on both cellular senescence and apoptosis. IMCE beta-cat cells were also transformed as determined by growth in the absence of serum, anchorage-independent growth, and sustained tumor growth in nude mice. Stable beta-cat-expressing populations could not be generated in conditionally immortalized colonic epithelia cells with a wild-type Apc background. These studies demonstrated the immortalizing activity of stabilized beta-cat for the first time and extend the transforming ability of mutated beta-cat to a cell line representing a precursor to colorectal cancer.
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PMID:Stabilized beta-catenin immortalizes colonic epithelial cells. 1128 Jul 72

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 fatty acids (n-3 PUFAs) reduce the risk of colon cancer. Docosahexaenoic acid (DHA), a long chain polyunsaturated fatty acid (PUFAs) is a major constituent of nutrients rich in n-3 PUFAs. There are studies to indicate that colon tumor inhibition by n-3 PUFA-rich diets is, in part, mediated through modulation of signaling pathways that alter gene expression which are involved in colon tumor growth. In the present study using CaCo-2 colon cancer cell lines we examined the effects of DHA on the genetic precursors of human colon cancer at the transcription level using DNA oligonucleotide arrays. Our results indicated that DHA inhibits the growth of CaCo-2 cells and induces apoptosis. For gene expression analysis using DNA microarrays, total RNA extracted from DHA treated CaCo-2 cells was converted to cDNA, labeled with Cy5-dCTP (DHA-treated) and Cy3-dCTP (untreated cells) and used as probes for hybridization in human chip spotted with 3,800 oligonucleotides consisting of 156 functional categories. The expression profiles of genes indicated a reprogramming pattern of previously known and unknown genes and transcription factors that provided clues to the possible functional mechanism of DHA. An average of (ratios from triplicate experiments) 504 out of 3,800 genes expressed after 48 h of DHA treatment. Altered expression on the transcription factors includes down regulation of nine members of the RNA II polymerases, transcription co-repressor associated protein and enhancer binding proteins such as AP2, in addition to changes in the expression of zinc finger group of transcription factors. Activation of cytochrome c which triggers caspases was associated with the elevated expression of pro-apoptotic caspases 10, 13, 8, 5 and 9 in DHA treated cells. Activation of cyclin-dependent kinase inhibitors such as p21 (waf1/cip1), p27, p57, p19 and growth arrest specific proteins by more than 2-fold is consistent with the induction of apoptosis and inactivation of antiapototic Bcl-2 family of genes. Inactivation of prostaglandin family of genes, lipoxygenases and altered expression of peroxisome proliferators (PPARalpha and gamma) by DHA seem to indicate a lipid peroxidation-induced apoptosis in addition to effect reflected on the modification of cell cycle regulatory genes. These findings support the conclusion that a genomewide expression profiling of human colon cancer precursor genes and transcription factors provides a set of novel regulatory mechanism(s) to determine the chemopreventive efficacy of DHA and thus to prevent the inflammation and neoplasia.
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PMID:Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. 1171 97

p19(ARF) is a tumor suppressor that is frequently deleted in human cancer. It lies at chromosome 9p21 and shares exons 2 and 3 with p16(ink4a), which is also inactivated by these cancer-associated deletions. The "canonical pathway" by which p19(ARF) is thought to suppress tumorigenesis through activation of the p53 tumor suppressor. In response to hyperproliferative signals, such as expression of oncogenes, p19(ARF) is induced and binds to the MDM2 ubiquitin ligase, sequestering it in the nucleolus to allow the accumulation of p53. However, p19(ARF) also has MDM2 and p53 independent functions. In human colon cancer, p19(ARF) is only rarely deleted, but it is more frequently silenced by DNA promoter methylation. Here we show that inactivation of p19(ARF) in mice increases the number of cycling cells in the crypts of the colonic epithelium. Moreover, inactivation of p19(ARF) exacerbated the ulceration of the colonic epithelium caused by dextran sodium sulfate (DSS). These effects were similar to those observed in mice lacking myeloid translocation gene-related-1 (Mtgr1), and mice lacking both of these genes showed an even greater sensitivity to DSS. Surprisingly, inactivation of p19(ARF) restored the loss of the secretory lineage in mice deficient in Mtgr1, suggesting an additional role for p19(ARF) in the small intestinal epithelium.
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PMID:Inactivation of the p19(ARF) tumor suppressor affects intestinal epithelial cell proliferation and integrity. 1844 38

Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19(Arf), Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors.
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PMID:Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model. 1977 66

The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19(Arf), Trp53 and p21(Cdkn1a). In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19(Arf), Trp53, p21(Cdkn1a) and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.
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PMID:Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling. 2089 Mar 2

The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable therapeutic index for cancer therapy. In human colon cancer cell peritoneal xenografts, MTOB treatment decreased tumor burden and induced tumor cell apoptosis. To verify the potential utility of CtBP as a therapeutic target in human cancer, the expression of CtBP and its negative regulator ARF was studied in a series of resected human colon adenocarcinomas. CtBP and ARF levels were inversely-correlated, with elevated CtBP levels (compared with adjacent normal tissue) observed in greater than 60% of specimens, with ARF absent in nearly all specimens exhibiting elevated CtBP levels. Targeting CtBP may represent a useful therapeutic strategy in human malignancies.
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PMID:Therapeutic targeting of C-terminal binding protein in human cancer. 2093 May 8

Colorectal cancer is the second most common malignancy in the Western world including the United Sates. In recent years there is a strong upward trend in colon cancer risk in Japan mainly due to Americanization of Japanese food habits. Several epidemiological studies point to a strong association between nutrient composition of the diet and cancer of the colon. The role of types of dietary fat, especially saturated fats of animal origin, n-6- and n-3-rich polyunsaturated fatty acids (PUFAs) in the etiology of colorectal cancer has become increasingly apparent. Epidemiological studies indicate a positive association between the dietary intake of saturated fat and/or animal fat and colon cancer risk and an inverse relationship between the intake of fish and fish oil rich in n-3 PUFAs and colon cancer development. Although the evidence from case-control studies and international correlational studies is not totally consistent, these inconsistencies may have arisen, at least in part, from methodological limitations. Animal, model studies have unequivocally provided evidence that the colon tumor-promoting effect of dietary fat depends on its fatty acid composition and that high dietary n-3 PUFAs lacks colon tumor-promoting effect, as compared to diets high in n-6 PUFAs or saturated fats. Diets rich in n-3 PUFAs inhibit colon carcinogenesis through the modulation of colonicras-p21, cyclooxygenase-2, and inducible nitric oxide synthase activities and apoptosis. Gene expression analysis using DNA microarrays indicates that n-3 fatty acid, docosahexaenoic acid activates cyclin-dependent kinase inhibitors such as p21, p27, p57 and p19 and inactivates antiapoptotic Bcl-2 family of genes, and prostagland in family of genes. These results suggest that decreasing the intake of n-6 PUFAs and saturated fats and increasing that of n-3 PUFAs, particularly eicosapentaenoic acid and docosahexaenoic acid has the potential to be a major component of colon cancer control.
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PMID:Types and amount of dietary fat and colon cancer risk: Prevention by omega-3 fatty acid-rich diets. 2143 90

SUMO conjugation emerges as an important mechanism in regulating protein localization, stability and activity. SUMOylation is a dynamic process and can be reversed by a family of sentrin/SUMO-specific proteases (SENPs). However, the biological roles of SENPs in cellular processes are largely unknown. Here, we show that SENP1, a member of SENP family, is overexpressed in most of colon cancer tissues. Silencing of SENP1 expression inhibits cell growth with G(1) arrest in vitro and in nude mice and colony formation in colon cancer cell line DLD-1, suggesting that SENP1 is essential for cell growth in the colon cancer cell line. Accordingly, silencing of SENP1 results in upregulation of CDK inhibitors such as p16, p19, p21 and p27. These results suggest that SENP1 might play a role in cell cycle regulation of colon cancer cells.
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PMID:SUMO-specific protease 1 regulates the in vitro and in vivo growth of colon cancer cells with the upregulated expression of CDK inhibitors. 2166 91