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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

Mutational activation of beta-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated beta-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either beta-catenin or cyclin D1 may be activated by various pathways independently of beta-catenin mutations. In this study, we investigated beta-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3beta (GSK3 beta) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of beta-catenin, a sign of beta-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The beta-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear beta-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic beta-catenin staining showed beta-catenin mutations indicated that beta-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the beta-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3 beta and ERK1/2, although GSK3 beta was frequently over-expressed in the tumors. These results indicate that, although beta-catenin and cyclin D1 activation are well correlated, the Akt/GSK3 beta and ras/ERK1/2 pathways may not play a major role in the beta-catenin/cyclin D1 activation.
Carcinogenesis 2003 Mar
PMID:Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. 1266 2

We described previously the isolation and characterization of two non-tumorigenic revertants from the HeLa cervical carcinoma cell line, and demonstrated that loss of the transformed phenotype in these cells was the result of dominant somatic mutations. The goal of the present study was to use cDNA microarrays to identify candidate tumor suppressors among the set of genes whose increased expression correlated with loss of tumorigenicity in both revertants. Among the genes with significantly increased expression levels in both HA and HF revertants we identified Insulin Growth Factor Binding Protein-3 (IGFBP-3) and the Dickkopf-1 (DKK-1) genes. Both of these genes encode secreted proteins implicated in the modulation cell growth and differentiation, and IGFBP-3 was shown previously to have tumor suppressing activity. To test the hypothesis that increased expression of IGFBP-3 or the DKK-1 genes could have contributed to the suppression of tumorigenicity in the revertants, we expressed IGFBP-3 or DKK-1 in HeLa cells, and assessed their effects on anchorage dependent and independent growth, and tumor formation in athymic nude mice. Ectopic expression of IGFBP-3 or DKK-1 resulted in significantly decreased growth in soft agar. HeLa cells expressing ectopic IGFBP-3 or DKK-1 showed statistically significant differences in the kinetics of tumor formation. In any tumors that arose in animals injected with the IGFBP-3 expressing cells, there was a complete loss of IGFBP-3 activity, as measured by binding to IGF-1 and IGF-2 proteins. All tumors that arose after injection of cells expressing DKK-1, invariably showed almost a complete loss of ectopic DKK-1 expression. The observations that loss of DKK-1 expression or IGFBP-3 activity was required for tumorigenicity suggested that both proteins encode putative tumor suppressor genes. We also show that while DKK-1 expression does not affect cell growth in vitro, the protein does sensitize cells to apoptosis. We also demonstrated that effect of DKK-1 was not due to inhibition of beta-catenin/TCF4-regulated transcription. Taken together, our results indicate that somatic cell genetics combining with gene expression profiling may be a useful approach for the identification of functional suppressors of malignant cell growth.
Carcinogenesis 2004 Jan
PMID:A functional genomics approach for the identification of putative tumor suppressor genes: Dickkopf-1 as suppressor of HeLa cell transformation. 1455 16

In order to understand the role of mismatch repair (MMR) gene in colorectal carcinogenesis,microsatellite instability (MSI) status of 16 microsatellite loci of 62 adenomas from 59 patients, including sporadic and familial adeonmatous polyposis (FAP) adenomas were detected by microdissection-PCR-SSLP, and protein expressions of beta-catenin, P53, and BAX, etc. were assayed by immunohistochemistry. Results were as following: (1)The overall MSI alteration rate of the 16 loci was 14.4%. Different adenomas from the same patient showed different microsatellite alterations at the same loci; (2)All of the five FAP patients were MSI-L, three of which showed MSI at the locus of hMSH3; (3)The membrane expression rate of beta-catenin in adenomas and accompanied carcinomas was 42.9% and 11.4%, respectively (P<0.001); (4)Microsatellite alterations of the microsatellite loci of TP53, D5S346, TCF4(A)(9), TGFbetaRII(GT)(3) and TGFbetaRII(A)(10) were associated with the changes of their protein expressions. It could be concluded the following: (1)Microsatellite instability existed even in the early stage (adenomas) of colorectal tumorigenesis. The alterations of chromosome 1p, APC genes, and the TGFbeta signal transduction pathway could also be deduced; (2)In the progression of adenoma to carcinoma, the staining of beta-catenin would be transferred from membrane to cytoplasm and then nucleus, and the cytoplasm stain was stronger in carcinoma than that in adenomas. The abnormality of the signal transduction pathway of APC-beta-catenin-TCF4 could be concluded.
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PMID:[Microsatellite instability and relative gene expressions in sporadic and familial adenomatous polyposis adenomas]. 1562 58

An unselected series of 310 colorectal carcinomas, stratified according to microsatellite instability (MSI) and DNA ploidy, was examined for mutations and/or promoter hypermethylation of five components of the WNT signaling cascade [APC, CTNNB1 (encoding beta-catenin), AXIN2, TCF4, and WISP3] and three genes indirectly affecting this pathway [CDH1 (encoding E-cadherin), PTEN, and TP53]. APC and TP53 mutations were each present more often in microsatellite-stable (MSS) tumors than in those with MSI (P < .001 for both). We confirmed that the aneuploid MSS tumors frequently contained TP53 mutations (P < .001), whereas tumors with APC mutations and/or promoter hypermethylation revealed no associations to ploidy. Mutations in APC upstream of codons 1020 to 1169, encoding the beta-catenin binding site, were found in 15/144 mutated tumors and these patients seemed to have poor clinical outcome (P = .096). Frameshift mutations in AXIN2, PTEN, TCF4, and WISP3 were found in 20%, 17%, 46%, and 28% of the MSI tumors, respectively. More than half of the tumors with heterozygote mutations in AXIN2 were concurrently mutated in APC. The present study showed that more than 90% of all samples had alteration in one or more of the genes investigated, adding further evidence to the vital importance of activated WNT signaling in colorectal carcinogenesis.
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PMID:Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. 1580 15

Wnt signaling induces the nuclear accumulation of beta-catenin and transcription of specific target genes via the DNA-binding proteins TCF/Lef. Although all known beta-catenin target genes encode proteins, genome-wide RNA profiling studies indicate that many transcripts do not have this capability. Transcription factor-binding sites associated with these noncoding transcripts can be identified using unbiased techniques such as serial analysis of chromatin occupancy (SACO). We used this method to identify a beta-catenin-regulated antisense RNA expressed in HCT116 colorectal carcinoma cells, a cellular model of activated beta-catenin signaling. Genomic signature tags designating putative beta-catenin-binding sites mapped to the 3'-untranslated region (3'-UTR) of the E2F4 gene. We showed that both beta-catenin and TCF4 bind to the E2F4 3'-UTR site in vivo, inducing expression of an E2F4 antisense transcript. LiCl, which mimics Wnt signaling, also induced expression of the E2F4 antisense transcript and decreased E2F4 protein levels. This effect was blocked by a cDNA expressing the E2F4 3'-UTR sense strand. The antisense-mediated decrease in E2F4 protein was reflected by reduced E2F4 association with specific target genes, including CCNA2, CDC2, PCNA, and Rad54. We propose that Wnt/beta-catenin signaling may contribute to colorectal carcinogenesis by reducing the level of the E2F4 cell cycle repressor via an antisense mechanism.
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PMID:An antisense transcript induced by Wnt/beta-catenin signaling decreases E2F4. 1712 28

Calcium homeostasis of the endoplasmic reticulum (ER) is involved in intracellular signaling pathways and is implicated in major cell functions such as cell growth, differentiation, protein synthesis and apoptosis. The accumulation of calcium in the ER is performed by specific sarco/endoplasmic reticulum calcium transport ATPases (SERCA iso-enzymes). The expression of biochemically distinct SERCA isoforms is cell type dependent and developmentally regulated. This review summarizes pertinent data about the modulation of the expression of SERCA enzymes during the differentiation of normal and tumor cells. These data support the implication of SERCA pumps and especially SERCA3 in the differentiation program of cancer and leukemia cells. During the multi-step process of colon carcinogenesis, the decrease of SERCA3 expression seems to be linked to enhanced APC/ss-catenin/TCF4 signaling and deficient Sp1-like factor-dependent transcription.
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PMID:[Expression of SERCA pumps during cell differentiation and tumorigenesis: application to colonic carcinogenesis]. 1712 48

Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), accelerate the growth of gastrointestinal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide and Ggly activate different G proteins of the Rho family of small GTPases. For example, Gamide signals Rac/Cdc42 to activate p21-activated kinase 1 while Ggly signals Rho to activate Rho-activated kinase. p21-activated kinase 1 and Rho-activated kinase induce changes in phosphorylation or expression, respectively, of proteins of the Bcl-2 family, which then affect the caspase cascade with consequent inhibition of apoptosis. In addition, interaction of p21-activated kinase 1 with beta-catenin results in phosphorylation of beta-catenin, which enhances its translocation in to the nucleus, activation of TCF4-dependent transcription, and proliferation and migration. The central role of the beta-catenin pathway in carcinogenesis suggests that specific inhibitors of p21-activated kinase 1 may in the future provide novel therapies for gastrointestinal malignancies.
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PMID:Rho GTPases and p21-activated kinase in the regulation of proliferation and apoptosis by gastrins. 1856 85

The proteasome is a multiprotein complex that regulates the stability of hundreds of cellular proteins and thus, it is implicated in virtually all cellular functions. Most of the time, to be recognized and processed by the proteasome, a protein has to be linked to a chain of ubiquitin molecules. Cell proliferation, apoptosis, angiogenesis and motility, processes with particular importance for carcinogenesis are regulated by the ubiquitin-proteasome system (UPS). In colorectal epithelium, UPS plays a role in the regulation of the Wnt/beta-catenin/APC/TCF4 signaling which regulates proliferation of colorectal epithelial cells in the bottom of the crypts and the inhibition of this proliferation as cells move towards colon villi tips. In most colorectal cancers APC (Adenomatous Polyposis Coli) disabling mutations interfere with the ability of the proteasome to degrade beta-catenin leading to uninhibited cell proliferation. Other key molecules in colorectal carcinogenesis such as p53, Smad4 and components of the k-ras pathways are also regulated by the UPS. In this review I discuss the role of UPS in colorectal carcinogenesis and colorectal cancer prognosis and aspects of its inhibition for therapeutic purposes.
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PMID:The ubiquitin-proteasome system in colorectal cancer. 1861 33

Mutations in components of the Wnt signaling pathway initiate colorectal carcinogenesis by deregulating the beta-catenin transcriptional coactivator. beta-Catenin activation of one target in particular, the c-Myc proto-oncogene, is required for colon cancer pathogenesis. beta-Catenin is known to regulate c-Myc expression via sequences upstream of the transcription start site. Here, we report that a more robust beta-catenin binding region localizes 1.4 kb downstream from the c-Myc transcriptional stop site. This site was discovered using a genome-wide method for identifying transcription factor binding sites termed serial analysis of chromatin occupancy. Chromatin immunoprecipitation-scanning assays demonstrate that the 5' enhancer and the 3' binding element are the only beta-catenin and TCF4 binding regions across the c-Myc locus. When placed downstream of a simian virus 40-driven promoter-luciferase construct, the 3' element activated luciferase transcription when introduced into HCT116 cells. c-Myc transcription is negligible in quiescent HCT116 cells but is induced when cells reenter the cell cycle after the addition of mitogens. Using these cells, we found that beta-catenin and TCF4 occupancy at the 3' enhancer precede occupancy at the 5' enhancer. Association of c-Jun, beta-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription. Our findings indicate that a downstream enhancer element provides the principal regulation of c-Myc expression.
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PMID:A genome-wide screen for beta-catenin binding sites identifies a downstream enhancer element that controls c-Myc gene expression. 1885 87


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