561 research outputs found

    Differential gene expression profile reveals deregulation of pregnancy specific β1 glycoprotein 9 early during colorectal carcinogenesis

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    BACKGROUND: APC (Adenomatous polyposis coli) plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process. METHODS: To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines. RESULTS: Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific β-1 glycoprotein 9 (PSG9) (p < 0.006). PSG9 is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18) of FAP adenomas and 75% (45/60) of sporadic colorectal cancer cases tested. CONCLUSION: Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease

    Positive Feedback Regulation between Phospholipase D and Wnt Signaling Promotes Wnt-Driven Anchorage-Independent Growth of Colorectal Cancer Cells

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    Aberrant activation of the canonical Wnt/β-catenin pathway occurs in almost all colorectal cancers and contributes to their growth, invasion and survival. Phopholipase D (PLD) has been implicated in progression of colorectal carcinoma However, an understanding of the targets and regulation of this important pathway remains incomplete and besides, relationship between Wnt signaling and PLD is not known.Here, we demonstrate that PLD isozymes, PLD1 and PLD2 are direct targets and positive feedback regulators of the Wnt/β-catenin signaling. Wnt3a and Wnt mimetics significantly enhanced the expression of PLDs at a transcriptional level in HCT116 colorectal cancer cells, whereas silencing of β-catenin gene expression or utilization of a dominant negative form of T cell factor-4 (TCF-4) inhibited expression of PLDs. Moreover, both PLD1 and PLD2 were highly induced in colon, liver and stomach tissues of mice after injection of LiCl, a Wnt mimetic. Wnt3a stimulated formation of the β-catenin/TCF complexes to two functional TCF-4-binding elements within the PLD2 promoter as assessed by chromatin immunoprecipitation assay. Suppressing PLD using gene silencing or selective inhibitor blocked the ability of β-catenin to transcriptionally activate PLD and other Wnt target genes by preventing formation of the β-catenin/TCF-4 complex, whereas tactics to elevate intracellular levels of phosphatidic acid, the product of PLD activity, enhanced these effects. Here we show that PLD is necessary for Wnt3a-driven invasion and anchorage-independent growth of colon cancer cells.PLD isozyme acts as a novel transcriptional target and positive feedback regulator of Wnt signaling, and then promotes Wnt-driven anchorage-independent growth of colorectal cancer cells. We propose that therapeutic interventions targeting PLD may confer a clinical benefit in Wnt/β-catenin-driven malignancies

    Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi

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    We present a study of ten B-meson decays to a D(*), a proton-antiproton pair, and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs. Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B- -> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi- pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first observations. The branching fractions for 3- and 5-body decays are suppressed compared to 4-body decays. Kinematic distributions for 3-body decays show non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4) MeV/c2, respectively, where the first (second) errors are statistical (systematic). For 5-body decays, mass projections are similar to phase space expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0

    Search for the standard model Higgs boson at LEP

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