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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this review, we discuss the developments of fluorescence in situ hybridization (FISH) and place them in the context of their applications in cancer research. These methods are not only very useful for the causal analysis of the development and spread of certain tumors, they are also efficient tools for tumor diagnosis. Although a review of all of the literature in this field is not possible here, many of the major contributions are summarized along with recent work from our laboratory. Our group contributes to the goal of functional identification of tumor growth antagonizing genes. FISH and molecular analyses have shown that the short arm of human chromosome 3 is frequently deleted in kidney, lung, breast, uterus, testis and ovary carcinomas. Deletion-mapping studies have outlined several separate deletion prone regions in different tumors, namely 3pter-p25, p22-p21.3, p21.1-p14 and p14-p12, which may contain putative tumor suppressor genes (TSGs). Candidate suppressor genes isolated from frequently deleted regions need to be assayed for possible tumor-antagonizing ability by functional tests. We have developed a functional test system, the microcell hybrid (MCH) based "elimination test" (Et). The Et is based on the introduction of a single human chromosome into tumor cells of human or murine origin, via microcell fusion. The MCHs were analyzed by FISH painting and PCR for the elimination or retention of specific human chromosome 3 (chr. 3) regions after one or several passages in severe combined immunedeficient (SCID) mice. We have defined a common eliminated region (CER) on chr. 3p21.3. CER is approximately 1 megabase (Mb) in size. We have covered this region with PACs (bacteriophage PI based artificial chromosome) and used FISH mapping for localization and ordering PACs and cosmids on the chromosome 3 and high-resolution free chromatin/DNA fiber FISH to orient the PAC contig, to measure the lengths of PACs, and to establish their order. Activation of cellular oncogene by chromosomal tanslocation, which brings an oncogene under the influence of a highly active chromosome region, appears to play a pivotal role in the genesis of certain hematopoetic and lymphoid tumors. We have detected specific chromosomal translocations by FISH painting in mouse plamacytoma (MPC), human Burkitt lymphoma (BL) other B-cell derived tumors. We have showed in a murine sarcoma derived line (SEWA) that FISH can be also be used for detection of amplified oncogene (c-myc) and the linked locus (pvt-1). We have also applied the FISH technique for visualization of integrated and episomal Epstein-Barr virus (EBV) genomes and EBV transcripts in EBV-carrying B-cell derived human cell lines.
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PMID:Fluorescence in situ hybridization (FISH) in the molecular cytogenetics of cancer. 1207 27

Alterations of the Wnt/beta-catenin signaling pathway are known to occur in mutations of the component genes such as APC, Axin, and beta-catenin, and play a pathogenetic role in tumorigenesis. Activated Wnt signaling stabilizes beta-catenin, which associates with T cell factor, resulting in transactivation of the downstream target genes including c-myc and cyclin D1. To investigate the involvement of Wnt/beta-catenin signaling pathway in thyroid tumorigenesis, we analyzed its activation and localization in 5 human thyroid cancer cell lines and 132 thyroid tumor tissue samples. Dislocalization of beta-catenin was observed in all cell lines. Constitutive activation of T cell factor in two of four thyroid cancer cell lines was observed using reporter gene assay. Furthermore, high expression levels of c-Myc and cyclin D1 were observed in cell lines that showed cytoplasmic or nuclear accumulation of beta-catenin. In 132 paraffin-embedded thyroid carcinoma tissue samples, cytoplasmic beta-catenin was immunohistochemically observed in 52 out of 78 (67%) papillary thyroid cancers, but only in 3 of 34 (9%) follicular adenomas and 5 of 20 (25%) follicular cancers. Cytoplasmic localization of beta-catenin significantly correlated with overexpression of cyclin D1 in papillary carcinomas. Our results suggest that aberrant activation of Wnt/beta-catenin signaling is strongly involved in thyroid tumorigenesis.
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PMID:Aberrant localization of beta-catenin correlates with overexpression of its target gene in human papillary thyroid cancer. 1210 63

The development of intestinal cancer involves complex genetic and epigenetic alterations in the intestinal mucosa. The principal signaling pathway responsible for the initiation of tumor formation, the APC-beta-catenin-TCF4 pathway, regulates both cell proliferation and colonic cell differentiation, but many other intrinsic and extrinsic signals also modulate these cell maturation pathways. The challenge is to understand how signaling and cell maturation are also modulated by nutritional agents. Through gene expression profiling, we have gained insight into the mechanisms by which short chain fatty acids regulate these pathways and the differences in response of gene programs, and of the specific regulation of the c-myc gene, to physiological regulators of intestinal cell maturation, such as butyrate, compared with pharmacological regulators such as the nonsteroidal antiinflammatory drug sulindac. Moreover, we used a combination of gene expression profiling of the response of cells in culture to sulindac and the response of the human mucosa in subjects treated with sulindac for 1 month, coupled with a mouse genetic model approach, to identify the cyclin dependent kinase inhibitor p21(WAF1/Cip1) as an important suppressor of Apc-initiated intestinal tumor formation and a necessary component for tumor inhibition by sulindac. Finally, the mucous barrier, secreted by intestinal goblet cells, is the interface between the luminal contents and the intestinal mucosa. We generated a mouse genetic model with a targeted inactivation of the Muc2 gene that encodes the major intestinal mucin. These mice have no recognizable goblet cells due to the failure of cells to synthesize and store mucin. This leads to perturbations in intestinal crypt architecture, increased cellular proliferation and rates of cell migration, decreased apoptosis and development of adenomas and adenocarcinomas in the small and large intestine and the rectum.
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PMID:Short chain fatty acids and colon cancer. 1246 28

Germline mutations in APC tumor suppressor gene are responsible for familial adenomatous polyposis (FAP). A major role of these genetic changes is the constitutive activation of beta-catenin-Tcf-4 mediated transcription of nuclear target genes, but other cellular functions can be misregulated. To assess how different APC mutations can drive the early steps of colonic tumorigenesis, we studied the effect of 10 different germline-truncating alterations on the phenotype of the corresponding adenomas. A significant reduction of apoptosis, uncoupled with an increased c-myc and cyclin-D1 expression, was seen with a frameshift mutation on codon 1383, in the 20-aa repeats of the beta-catenin degradation domain, independent of a somatic alteration on the wild-type allele. The decreased apoptotic level was associated with a higher incidence of cancerization. No other APC mutation was linked with a similar effect, even in presence of a somatic allelic loss. These findings suggest that mutations in critical sites of the beta-catenin degradation domain of APC gene can convey a selective advantage to the colonic neoplastic clones by altering the apoptotic surveillance rather than enhancing the beta-catenin-Tcf-4 transcription of growth-promoting genes.
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PMID:Germline APC mutation on the beta-catenin binding site is associated with a decreased apoptotic level in colorectal adenomas. 1252 14

Peroxisome proliferator activated receptors (PPARs) are a family of related receptors implicated in a diverse array of biological processes. There are 3 main isotypes of PPARs known as PPARalpha, PPARbeta and PPARgamma and each is organized into domains associated with a function such as ligand binding, activation and DNA binding. PPARs are activated by ligands, which can be both endogenous such as fatty acids or their derivatives, or synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene transcription. The different isotypes differ in their expression patterns, lending clues on their function. PPARalpha is expressed mainly in liver whereas PPARgamma is expressed in fat and in some macrophages. Activation of PPARalpha in rodent liver is associated with peroxisome proliferation and with suppression of apoptosis and induction of cell proliferation. The mechanism by which activation of PPARalpha regulates apoptosis and proliferation is unclear but is likely to involve target gene transcription. Similarly, PPARgamma is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. However, it has been implicated in the regulation of cell cycle and cell proliferation in colon cancer models. Less in known concerning PPARbeta but it was identified as a downstream target gene for APC/beta-catenin/T cell factor-4 tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-myc and cyclin D1. Marked species and tissue differences in the expression of PPARs complicate the extrapolation of pre-clinical data to humans. For example, PPARalpha ligands such as the hypolipidaemic fibrates have been used extensively in the clinic over the past 20 years to treat cardiovascular disease and side effects of clinical fibrate use are rare, despite the observation that these compounds are rodent carcinogens. Similarly, adverse clinical responses have been seen with PPARgamma ligands that were not predicted by pre-clinical models. Here, we consider the response to PPAR ligands seen in pre-clinical models of efficacy and safety in the context of human health and disease.
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PMID:Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease. 1262 71

Heterocyclic amines are potent mutagens and carcinogens formed in cooked protein rich foods. In this study, we screened liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) in CDF1 mice for beta-catenin and APC mutations and other genetic alterations shown to occur in human hepatocellular carcinomas (HCC), including mutations in the p53 and H-ras genes, c-myc amplification and E-cadherin promoter methylation. SSCP followed by direct DNA sequencing revealed mutations in exon 2 of the beta-catenin gene in 2 of 16 liver tumors (12.5%). Promoter methylation of the E-cadherin gene was detected in one liver tumor induced by MeIQ. There were no mutations in the mutation cluster region of the APC gene, in exons 5-8 of the p53 gene, or in codons 12, 13 and 61 of the H-ras gene, nor c-myc amplification in any of liver tumors induced by MeIQ. These data indicate that except for the occasional disruption of the Wnt pathway through beta-catenin mutations, the genetic pathways involved in the development of HCC differ significantly between human liver cancer and tumors induced in mice by MeIQ, but do not rule out the possibility that heterocyclic amines constitute a carcinogenic risk factor in humans.
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PMID:Beta-catenin mutations in liver tumors induced by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in CDF1 mice. 1289 27

Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. We investigated its function during apoptosis induced by MG132 in three hepatocellular carcinoma (HCC) cell lines, endowed (HepG2 and HuH-6) or not (HA22T/VGH) with activating mutations of beta-catenin. Induction of apoptosis was associated with cell growth inhibition, accumulation of the cells at the G(2)/M phases of the cell cycle, as well as with fragmentation of beta-catenin (but not of alpha- or gamma-catenin) in all the cell lines. The cleavage of beta-catenin was inhibited by the caspase inhibitors Z-VAD-fmk and Z-DEVD-fmk. Fragmented beta-catenin was found in the nuclei of the treated cells. Analyses through the reporter plasmid pTOPflash showed that MG132 significantly reduces Tcf transcriptional activity in the cells. This was associated with a decrease in the mRNA expression of survivin and c-myc, which are target genes of the APC/beta-catenin/Tcf signaling. Nevertheless, Z-VAD-fmk or Z-DEVD-fmk did not reverse the MG132 effects on Tcf transcriptional activity, suggesting that the compound may affect this activity also by other mechanisms. Overall, the present study supports the therapeutic potential of the proteasome inhibitors in HCC.
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PMID:Induction of apoptosis by the proteasome inhibitor MG132 in human HCC cells: Possible correlation with specific caspase-dependent cleavage of beta-catenin and inhibition of beta-catenin-mediated transactivation. 1506 80

The wingless-type (Wnt) signalling transduction pathway is essentially a network of a number of separate but interacting pathways. Specific Wnt ligands bind to their target 'frizzled' membrane receptor and interfere with the multi-protein destruction complex, resulting in downstream activation of gene transcription by beta-catenin. Simplistically, the multi-protein destruction complex involves Axin and APC serving as scaffolds binding both beta-catenin and GSK3, to facilitate phosphorylation of beta-catenin by GSK-3beta. Phosphorylated beta-catenin is degraded in proteasomes by the ubiquination machinery. Unphosphorylated beta-catenin accumulates and associates with nuclear transcription factors leading to the eventual transcription and expression of target genes such as c-myc, c-jun, Fra and cyclin D1. There are several regulatory mechanisms for the down-regulation of the Wnt/beta-catenin signal, perhaps reflecting the pivotal nature of the pathway and the detrimental consequences of inappropriate activation. There has been intense investigation into the role of Wnt genes in human cancer. Although no documentation is made of any mutation or amplification of genes encoding Wnt ligands or receptors linked to human cancer to date, several components of the Wnt pathway have been implicated in carcinogenesis, especially APC and beta-catenin.
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PMID:The significance of the Wnt pathway in the pathology of human cancers. 1520 47

The aim of this study is to assess the effects of DNA methylation and histone acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methylation-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.
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PMID:Epigenetic modification regulates both expression of tumor-associated genes and cell cycle progressing in human colon cancer cell lines: Colo-320 and SW1116. 1522 15

Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT-PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited beta-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/beta-catenin pathway.
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PMID:HOXB13 is downregulated in colorectal cancer to confer TCF4-mediated transactivation. 1592 69


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