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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wnt family of secreted proteins coordinate cell fate decision-making in a broad range of developmental and homeostatic contexts. Corruption of Wnt signal transduction pathways frequently results in degenerative diseases and cancer. We have used an iterative genome-wide screening strategy that employs multiple nonredundant RNAi reagents to identify mammalian genes that participate in Wnt/beta-catenin pathway response. Among the genes that were assigned high confidence scores are two members of the TCF/LEF family of DNA-binding proteins that control the transcriptional output of the pathway. Surprisingly, we found that the presumed cancer-promoting gene TCF7L2 functions instead as a transcriptional repressor that restricts colorectal cancer (CRC) cell growth. Mutations in TCF7L2 identified from cancer genome sequencing efforts abolish its ability to function as a transcriptional regulator and result in increased CRC cell growth. We describe a growth-promoting transcriptional program that is likely activated in CRC tumors with compromised TCF7L2 function. Taken together, the results from our screen and studies focused on members of the TCF/LEF gene family refine our understanding of how aberrant Wnt pathway activation sustains CRC growth.
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PMID:A genome-wide RNAi screen for Wnt/beta-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer. 1862 8

Proline oxidase (POX), a flavoenzyme localized at the inner mitochondrial membrane, catalyzes the first step of proline degradation by converting proline to pyrroline-5-carboxylate (P5C). POX is markedly elevated during p53-induced apoptosis and generates proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, to induce apoptosis through both mitochondrial and death receptor pathways. These previous studies also showed suppression of the mitogen-activated protein kinase pathway leading us to broaden our exploration of proliferative signaling. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found that three pathways which cross talk with each other were downregulated by POX: the cyclooxygenase-2 (COX-2) pathway, the epidermal growth factor receptor (EGFR) pathway and the Wnt/beta-catenin pathway. First, POX markedly reduced COX-2 expression, suppressed the production of prostaglandin E2 (PGE(2)) and importantly, the growth inhibition by POX was partially reversed by treatment with PGE(2.) Phosphorylation of EGFR was decreased with POX expression and the addition of EGF partially reversed the POX-dependent downregulation of COX-2. Wnt/beta-catenin signaling was decreased by POX in that phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) was decreased on the one hand and phosphorylation of beta-catenin was increased on the other. There changes led to decreased accumulation of beta-catenin and decreased beta-catenin/TCF/LEF-mediated transcription. Our newly described POX-mediated suppression of proliferative signaling together with the previously reported induction of apoptosis suggested that POX could function as a tumor suppressor. Indeed, in human colorectal tissue samples, immunohistochemically-monitored POX was dramatically decreased in tumors compared with normal counterparts. Thus, POX metabolism of substrate proline affects multiple signaling pathways, modulating both apoptosis and tumor growth, and could be an attractive target to metabolically control the cancer phenotypes.
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PMID:Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. 1879 9

Aberrant Wnt/beta-catenin signaling has recently been implicated in tumorigenesis. On the basis of our screening program targeting inhibition of TCF/beta-catenin transcriptional activity, a plant extract of Eleutherine palmifolia was selected as a hit sample. Activity-guided fractionations led to the isolation of 15 naphthalene derivatives (1-15), including 4 new glucosides, eleutherinosides B-E (1-4), and 10 of the 15 compounds showed strong activities with high viability among 293T cells. Our data showed that 2 and 9 inhibited the transcription of TCF/beta-catenin in SW480 colon cancer cells in a dose-dependent manner. These two compounds also showed selective cytotoxicity against three colorectal cancer cell lines. In addition, treatment with 9 led to a significant decrease in the level of nuclear beta-catenin protein, suggesting this reduction to have resulted in the inhibitory effect of 9 on the transcription of TCF/beta-catenin.
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PMID:New Wnt/beta-catenin signaling inhibitors isolated from Eleutherine palmifolia. 1906 97

Pygopus is a core component of the beta-catenin/TCF (T-cell factor) transcriptional activation complex required for the expression of canonical Wnt target genes. Recent evidence suggests that Pygopus could interpret histone methylation associated with target genes and it was shown to be required for histone acetylation. The involvement of a specific acetyltransferase, however, was not determined. In this report, we demonstrate that Pygopus can interact with the HAT (histone acetyltransferase) CBP [CREB (cAMP-responsive-element-binding protein)-binding protein]. The interaction is via the NHD (N-terminal homology domain) of Pygopus, which binds to two regions in the vicinity of the HAT domain of CBP. Transfected and endogenous hPygo2 (human Pygopus2) and CBP proteins co-immunoprecipitate in HEK-293 (human embryonic kidney 293) cells and both proteins co-localize in SW480 colorectal cancer cells. The interaction with CBP also enhances both DNA-tethered and TCF/LEF1 (lymphoid enhancing factor 1)-dependent transcriptional activity of Pygopus. Furthermore, immunoprecipitated Pygopus protein complexes displayed CBP-dependent histone acetyltransferase activity. Our data support a model in which the NHD region of Pygopus is required to augment TCF/beta-catenin-mediated transcriptional activation by a mechanism that includes both transcriptional activation and histone acetylation resulting from the recruitment of the CBP histone acetyltransferase.
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PMID:The transcriptional activity of Pygopus is enhanced by its interaction with cAMP-response-element-binding protein (CREB)-binding protein. 1955 49

We and others previously cloned and characterized vertebrate WNT11 orthologs, which are involved in gastrulation, neurulation, cardiogenesis, nephrogenesis, and chondrogenesis during fetal development. WNT11 orthologs activate both canonical and non-canonical WNT signaling cascades depending on the expression profile of WNT receptors, such as Frizzled family members, LRP6, ROR2, and RYK. Human WNT11 is expressed in breast cancer, gastric cancer, esophageal cancer, colorectal cancer, neuroblastoma, Ewing sarcoma, and prostate cancer. Canonical WNT signals and GATA family members are involved in WNT11 transcription during embryogenesis of model animals; however, precise mechanisms of WNT11 expression remain unclear. Here, refined integrative genomic analyses of WNT11 are carried out to elucidate the mechanisms of WNT11 transcription. The WNT11 gene was found to encode two isoforms by using alternative first exons. WNT11 isoform A (NM_004626.2 RefSeq) consists of exons 2, 3, 4, 5 and 6, whereas WNT11 isoform B consists of exons 1, 2, 3, 4, 5 and 6. We identified double TCF/LEF-binding sites within the proximal promoter regions -48-bp position from the TSS of human WNT11 isoform B and -43-bp position from the TSS of human WNT11 isoform A), and also double GATA-binding sites within intron 2 of human WNT11 gene (+933-bp and +5001-bp positions from TSS of human WNT11 isoform A). Double TCF/LEF- and double GATA-binding sites within the regulatory regions of human WNT11 gene were conserved in other mammalian WNT11 orthologs. These facts indicate that canonical WNT signals and GATA family members directly upregulate WNT11 transcription. Canonical WNT-induced WNT11 activates non-canonical WNT signaling cascades to induce cellular movement, and also activates the Ca2+-MAP3K7-NLK signaling cascade to break the canonical WNT signaling. Canonical WNT-to-WNT11 signaling loop is involved in cellular migration during embryogenesis as well as tumor invasion during carcinogenesis.
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PMID:Integrative genomic analyses of WNT11: transcriptional mechanisms based on canonical WNT signals and GATA transcription factors signaling. 1957 97

The L1 cell adhesion molecule (L1CAM) has been identified as a target gene of beta-catenin-TCF signaling in colorectal cancer (CRC) and associated with aggressive tumor behavior such as invasion and metastasis. We investigated the methylation status at the L1CAM gene promoter and/or L1CAM mRNA/protein expression in 4 CRC cell lines and 71 primary CRCs. Aberrant L1CAM expression was immuno histochemically observed in 31 (43.7%) of 71 cases, and correlated with advanced stage and presence of lymph node and distant metastases (P<0.05). Treatment with a demethylating agent induced L1CAM mRNA/protein expression in two cell lines lacking L1CAM expression. Bisulfite-modified genome sequencing suggested that DNA methylation status at core promoter and putative TCF-binding sites within the L1CAM promoter was correlated with L1CAM mRNA/protein expression in 4 CRC cell lines. Using the crypt isolation followed by bisulfite-modified genome sequencing and methylation-specific PCR methods, we confirmed that the DNA hypomethylation at core promoter and putative TCF-binding sites was well correlated with the aberrant L1CAM protein expression in primary CRC samples. These results suggest that DNA hypomethylation at the L1CAM CpG islands might induce L1CAM aberrant expression and contribute to the acquisition of aggressive tumor behavior in CRC.
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PMID:DNA hypomethylation at the CpG island is involved in aberrant expression of the L1 cell adhesion molecule gene in colorectal cancer. 1963 67

Wnt signalling maintains the undifferentiated state of intestinal crypt/progenitor cells through the TCF4/beta-catenin-activating transcriptional complex. In colorectal cancer, activating mutations in Wnt pathway components lead to inappropriate activation of the TCF4/beta-catenin transcriptional programme and tumourigenesis. The mechanisms by which TCF4/beta-catenin activate key target genes are not well understood. Using a proteomics approach, we identified Tnik, a member of the germinal centre kinase family as a Tcf4 interactor in the proliferative crypts of mouse small intestine. Tnik is recruited to promoters of Wnt target genes in mouse crypts and in Ls174T colorectal cancer cells in a beta-catenin-dependent manner. Depletion of TNIK and expression of TNIK kinase mutants abrogated TCF-LEF transcription, highlighting the essential function of the kinase activity in Wnt target gene activation. In vitro binding and kinase assays show that TNIK directly binds both TCF4 and beta-catenin and phosphorylates TCF4. siRNA depletion of TNIK followed by expression array analysis showed that TNIK is an essential, specific activator of Wnt transcriptional programme. This kinase may present an attractive candidate for drug targeting in colorectal cancer.
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PMID:The kinase TNIK is an essential activator of Wnt target genes. 1981 3

Aberrant MYC gene expression by the Wnt/beta-catenin pathway is implicated in colorectal carcinogenesis. Wnt/beta-catenin signaling stimulates association of the beta-catenin coactivator complex with two Wnt responsive enhancers (WREs) located in close proximity to MYC gene boundaries. Each enhancer directly binds members of the TCF/Lef family of transcription factors that, in turn, recruit beta-catenin. In a previous report, we showed that the downstream MYC enhancer (MYC 3' WRE) cooperated with the upstream enhancer (MYC 5' WRE) to activate expression of a heterologous reporter gene in response to Wnt/beta-catenin and mitogen signaling. Here we use chromatin conformation capture (3C) to show that the MYC 5' and 3' WREs are juxtaposed at the genomic MYC locus during active transcription. This MYC 5'3' chromatin loop is present in HCT116 human colorectal cancer cells that contain high levels of nuclear beta-catenin and is absent in HEK293 cells that contain trace amounts of nuclear beta-catenin. Depletion of functional beta-catenin/TCF complexes blocks formation of the MYC 5'3 chromatin loop. Furthermore, we find that the chromatin loop is absent in quiescent cells, but is rapidly and transiently induced by serum mitogens in a beta-catenin-dependent manner. Thus, we propose that a distinct chromatin architecture coordinated by beta-catenin/TCF-bound WREs accompanies transcriptional activation of MYC gene expression.
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PMID:A beta-catenin/TCF-coordinated chromatin loop at MYC integrates 5' and 3' Wnt responsive enhancers. 1996 99

A central point of regulation in the Wnt/beta-catenin signalling pathway is the formation of the beta-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of beta-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/beta-catenin pathway. These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH(2)-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes.
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PMID:MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway. 2012 90

Activating beta-catenin mutations with aberrant cytoplasmic and nuclear protein accumulation are hallmarks of adamantinomatous craniopharyngiomas (adaCP). These tumours tend to be associated with unfavourable and occasionally disastrous sequelae, as they invade adjacent brain structures such as the hypothalamus. The peculiar digitate growth pattern does not always allow gross surgical removal often leading to recurrence. The tips of invading adaCP epithelium harbour cell clusters with nuclear beta-catenin accumulations, suggesting an influence of beta-catenin-dependent signal transduction on the tumour migratory capacity. This hypothesis was tested by suppressing beta-catenin expression in six primary human adaCP cell cultures using small interfering RNA (siRNA) directed against the beta-catenin gene (CTNNB1). Tumour cell migration was significantly reduced in Boyden chamber and wound-healing experiments following siRNA treatment. We further showed that fascin, a target gene of beta-catenin TCF signalling in colorectal cancer cells and a key component of filopodia, is also involved in this process. beta-Catenin accumulating tumour cells co-express fascin and fascin mRNA levels can be significantly down-regulated in adaCP cultures treated with CTNNB1 siRNA. Furthermore, migration experiments showed a significantly lower cell motility of adaCP tumour cells in vitro when transfected with fascin siRNA. This suggests that activated Wnt-signalling serves as a promoter of the epithelial migration machinery by regulating target molecules such as fascin in adaCP tumour cells.
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PMID:Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling. 2013 Oct 60


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