Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonsteroidal anti-inflammatory drugs (NSAIDs) lower the incidence of and mortality from colon cancer. Although there is much evidence from epidemiological and laboratory studies that NSAIDs have antitumor activity and reduce the incidence of colon cancer, the mechanism of action remains unknown. In this paper, we present the effect of indomethacin on growth inhibition, induction of apoptosis, and alterations in the expression of several genes involved in Wnt signaling in HT-29 colon cancer cells. We have shown that indomethacin reduces the proliferation rate of HT-29 colon cancer cells and induces apoptosis. Concentrations of indomethacin from 10(-4) to 10(-3) M strongly inhibited the growth of HT-29 cells. The inhibition of growth, as well as induction of apoptosis was dose and time dependent. The treatment of cells with 4 x 10(-4) M indomethacin caused strong inhibition of cell growth (about 70%), enhanced expression of APC, decreased expression of beta-catenin and induced expression of E-cadherin proteins. Expression of beta-catenin was not markedly reduced instead, beta-catenin was translocated from the nucleus and cytoplasm to the plasma membrane. These results were confirmed by real-time RT-PCR analysis on mRNA level. At a concentration of 4 x 10(-4) M indomethacin there was increased expression of APC gene (10.9-fold induction; DeltaDeltaCt = 3.43) and E-cadherin gene (3.5-fold induction; DeltaDeltaCt = 1.79). These results suggest the antiproliferative effect of indomethacin may contribute to enhanced cell adhesion through increased expression of E-cadherin and translocation of beta-catenin from the nucleus to the cell membrane.
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PMID:Effect of indomethacin on E-cadherin and beta-catenin expression in HT-29 colon cancer cells. 1596 97

Mutations in the canonical Wnt signaling pathway leading to its activation are known to cause the majority of intestinal tumors. However, few genes targeted by this pathway have been demonstrated to affect tumor development in vivo. Here we show that Tiam1, a selective Rac GTPase activator, is a Wnt-responsive gene expressed in the base of intestinal crypts and up-regulated in mouse intestinal tumors and human colon adenomas. Moreover, by comparing tumor development in APC mutant Min (multiple intestinal neoplasia) mice expressing or lacking Tiam1, we found that Tiam1 deficiency significantly reduces the formation and growth of polyps in vivo. However, invasion of malignant intestinal tumors is enhanced by a lack of Tiam1. In line with this, knock-down of Tiam1 reduced the growth potential of human colorectal cancer cells and their ability to form E-cadherin-based adhesions, a prerequisite for local invasion of tumor cells. Our data indicate a novel cross-talk between Tiam1-Rac and canonical Wnt-signaling pathways that influences intestinal tumor formation and progression.
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PMID:The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. 1624 75

The Min/+ mouse is a model for APC-dependent colorectal cancer (CRC). We showed that tumorigenesis in this animal was associated with decreased E-cadherin adhesion and increased epidermal growth factor receptor (Egfr) activity in the non-tumor intestinal mucosa. Here, we tested whether these abnormalities correlated with changes in the actin cytoskeleton due to increased Rho-ROCK signaling. We treated Apc+/+ (WT) littermate small intestine with EGTA, an inhibitor of E-cadherin, and with LPA, an RhoA activator; both induced effects on adhesion and kinase activity that mimicked the Min/+ phenotype. GTP-bound Rho was increased in Min/+ enterocytes relative to WT. Since RhoA activity is associated with actomyosin contractility, markers of this signaling cascade were assessed including phosphorylated myosin light chain (MLC), cofilin, Pyk2, Src, and MAPK kinases. The increased actomyosin contractility characterizing Min/+ intestinal tissue was suppressed by the ROCK inhibitor, Y27632, but was inducible in the WT by EGTA or LPA. Finally, ultrastructural imaging revealed changes consistent with actomyosin contractility in Min/+ enterocytes. Thus, the positive regulation of E-cadherin adhesion provided by Apc+ in vivo allows proper negative regulation of Egfr, Src, Pyk2, and MAPK, as well as RhoA activities.
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PMID:Deficient E-cadherin adhesion in C57BL/6J-Min/+ mice is associated with increased tyrosine kinase activity and RhoA-dependent actomyosin contractility. 1636 33

The development and progression of gastric cancer involves a number of genetic and epigenetic alterations of tumor suppressor and tumor-related genes. The majority of differentiated carcinomas arise from intestinal metaplastic mucosa and exhibit structurally altered tumor suppressor genes, typified by p53, which is inactivated via the classic two-hit mechanism, i.e. loss of heterozygosity (LOH) and mutation of the remaining allele. LOH at certain chromosomal loci accumulates during tumor progression. Approximately 20% of differentiated carcinomas show evidence of mutator pathway tumorigenesis due to hMLH1 inactivation via hypermethylation of promoter CpG islands, and exhibit high-frequency microsatellite instability. In contrast, undifferentiated carcinomas rarely exhibit structurally altered tumor suppressor genes. For instance, while methylation of E-cadherin is often observed in undifferentiated carcinomas, mutation of this gene is generally associated with the progression from differentiated to undifferentiated carcinomas. Hypermethylation of tumor suppressor and tumor-related genes, including APC, CHFR, DAP-kinase, DCC, E-cadherin, GSTP1, hMLH1, p16, PTEN, RASSF1A, RUNX3, and TSLC1, can be detected in both differentiated and undifferentiated carcinomas at varying frequencies. However, the significance of the hypermethylation varies according to the analyzed genomic region, and hypermethylation of these genes can also be present in non-neoplastic gastric epithelia. Promoter demethylation of specific genes, such as MAGE and synuclein Y, can occur during the progressive stages of both histological types, and is associated with patient prognosis. Thus, while the molecular pathways of gastric carcinogenesis are dependent on histological background, specific genetic alterations can still be used for risk assessment, diagnosis, and prognosis.
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PMID:Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. 1648 17

The aim of this study was to clarify the association between the epigenetic instability phenotype and the chromosomal instability phenotype in primary hepatocellular carcinoma (HCC). Sixty primary HCC tumors were examined. Methylation status for nine CpG islands (the p16, COX2, GSTP1, RASSF1A, E-cadherin, and APC gene promoters, and the MINT 1, 25, and 31 clones) was evaluated by methylation-specific polymerase chain reaction. Chromosomal structural alterations of these 60 HCC tumors were characterized in our previous study by using whole genomic array-based comparative genomic hybridization. We found that the epigenetic instability phenotype and the chromosomal instability phenotype are not mutually exclusive in hepatocarcinogenesis and that they do not show a simple cause-and-effect relationship. Hepatitis virus infection in the background liver was significantly associated with these instability phenotypes. Furthermore, we identified an epigenetic instability-dependent HCC that shows frequent epigenetic aberrations without chromosomal instability. It was noteworthy that epigenetic instability-positive and -negative HCCs displayed distinctive combinations of chromosomal structural alterations. In summary, by combined analyses of genetic and epigenetic aberration profiles in HCC, we obtained a comprehensive view of genomic alterations in hepatocarcinogenesis. Our results have clinical relevance because epigenetic instability-dependent HCCs may respond well to methylation inhibitory therapies.
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PMID:Epigenetic instability and chromosomal instability in hepatocellular carcinoma. 1656 10

The Wnt signaling pathway controls cell proliferation and body patterning throughout development. A surprising number of cytoplasmic Wnt regulators (e.g., beta-catenin, Bcl-9/Lgs, APC, Axin) also appear, often transiently, in the nucleus. beta-Catenin is an integral component of E-cadherin complexes at intercellular adherens junctions, but also recruits chromatin remodeling complexes to activate transcription in the nucleus. The APC tumor suppressor is a part of the cytoplasmic beta-catenin destruction complex, yet also counteracts beta-catenin transactivation and histone H3K4 methylation at Wnt target genes. Furthermore, APC coordinates the cyclic exchange of Wnt coregulator complexes at the DNA. These opposing roles of APC and beta-catenin enable a rapid coordination of gene expression and cytoskeletal organization throughout the cell in response to signaling.
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PMID:Wnt signaling: is the party in the nucleus? 1675 Nov 78

Alterations in the cadherin-catenin expression and activation of the Wnt signaling have been related to the pathology of ovarian carcinomas. Here, we evaluated the immunoreactivity of cadherins (E-, P-, and N-cadherin and cadherin-11) and catenins (alpha-, beta-, and gamma-catenin and p120) in 86 ovarian tumors. We found significant differences in the expression of all cadherins and catenins among the distinct histologic tumor types. Clear cell tumors were rarely N-cadherin- and P-cadherin-positive and showed reduced membranous expression in all the catenins; Serous carcinomas were frequently N-cadherin- and P-cadherin-positive, mucinous tumors strongly expressed E-cadherin and the catenins in the membrane, and endometrioid tumors characteristically expressed nucleocytoplasmic beta-catenin in most of the cases. We next studied whether allelic losses in the chromosomal regions containing various cadherin genes (16q22) or APC gene (5q21) occurred in ovarian tumors and observed a high frequency of loss of heterozygosity in 16q22 (78%) and 5q21 (33%) regions, but there were no differences among the tumor types analyzed. Finally, we also assessed the molecular alterations responsible for beta-catenin nuclear accumulation in endometrioid tumors by screening for mutations in AXIN1, AXIN2, APC, and KRAS genes. Mutations in KRAS were observed in 2 of 19 tumors, but no mutations were detected in AXIN1, AXIN2, or APC genes. Only beta-catenin gene mutations were associated with nuclear beta-catenin staining in these tumors. In conclusion, different cadherin-catenin expression patterns are associated with distinct histologic types. Oncogenic Wnt signaling plays a role only in endometrioid tumors, where beta-catenin mutations seem to be the main cause of its aberrant expression.
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PMID:Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas. 1686 67

The effects of 2-chloro-2'-deoxyadenosine, beta-D-arabinofuranosyl-2-fluoroadenine, and 5-aza-2'-deoxycytidine on promoter methylation of the selected tumor suppressor genes (i.e., ERalpha, BRCA1, E-cadherin, PTEN, and APC) were estimated using methylation-sensitive restriction analysis (MSRA) in K562 cells (human erythroleukemic cell line) and MCF-7 cells (human breast cancer cell line). In both cell lines all tested drugs completely reduced methylation of PTEN and APC promoters. The results indicate that the tested nucleoside analogues, which are known inhibitors of DNA synthesis, also are implicated in indirect (or direct in the case of 5-aza-dCyd) regulation of post-replicative DNA modifications (i.e., DNA methylation).
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PMID:Alteration of DNA methylation status in K562 and MCF-7 cancer cell lines by nucleoside analogues. 1706 59

Epigenetic abnormalities including the aberrant DNA hypermethylation of the promoter CpG islands play a key role in the mechanism of gene inactivation in cell carcinogenesis. To identify the genes associated with aberrant DNA hypermethylation in endometrial carcinogenesis, we studied the hypermethylation of the promoter regions of five genes: hMLH1, APC, E-cadherin, RAR-beta and p16. The frequencies of aberrant hypermethylation were 40.4% (21/52) in hMLH1, 22% (11/50) in APC, 14% (7/50) in E-cadherin, and 2.3% (1/44) in RAR-beta in endometrial cancer specimens. No aberrant DNA methylation was found in p16. In atypical endometrial hyperplasia, the frequencies of aberrant methylation were 14.3% (2/14) in hMLH1 and 7.3% (1/14) in APC, whereas normal endometrial cells showed no aberrant hypermethylation of any of the five genes. The high frequencies of the aberrant DNA hypermethylation of hMLH1, APC and E-cadherin suggest that the methylation of the DNA mismatch repair and Wnt signal-related genes may be associated with endometrial carcinogenesis.
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PMID:Relationship of the aberrant DNA hypermethylation of cancer-related genes with carcinogenesis of endometrial cancer. 1708 36

AKR/J mice are resistant to the tumorigenic properties of the colon carcinogen, azoxymethane (AOM). Following AOM exposure, limited numbers of preneoplastic lesions, referred to as aberrant crypt foci (ACF), are formed in the colon, and their progression to tumors rarely occurs. To determine whether genetic resistance can be overcome by exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% deoxycholic acid (DCA). DCA exposure was begun 1 wk prior to or 1 wk after tumor initiation with AOM. Mice placed on the DCA diet prior to AOM treatment developed a significantly higher multiplicity of ACF compared to AOM-exposed mice fed a control diet (15.50 +/- 0.96 vs. 6.17 +/- 0.48, respectively; P < 0.05). When DCA exposure was begun after AOM treatment (post-initiation), ACF formation was further enhanced (34.00 +/- 1.22). Interestingly, increased numbers of ACF were associated with the presence of nuclear beta-catenin, assessed by immunohistochemistry. While approximately 33% of ACF from mice exposed to DCA prior to AOM treatment contained positive nuclear beta-catenin staining, approximately 77% of ACF from mice fed DCA after AOM were positive. Accumulation of nuclear beta-catenin was not associated with a loss of E-cadherin from the plasma membrane, although loss of APC staining was a consistent feature of most AOM-induced ACF, regardless of DCA exposure. These results demonstrate that exposure to DCA, an important digestive component, is sufficient to sensitize the resistant AKR/J colon to formation of high-grade dysplasia, and that nuclear translocation of beta-catenin may play an important role in this process.
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PMID:Deoxycholic acid promotes the growth of colonic aberrant crypt foci. 1709 74


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