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AuthorRipka, Stefaniedc.contributor.author
Date of accession2016-03-14T13:41:21Zdc.date.accessioned
Available in OPARU since2016-03-14T13:41:21Zdc.date.available
Year of creation2007dc.date.created
AbstractPreviously, we have identified the transcription factor CUTL1 as important mediator of tumor invasion and target of TGFb. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multi-gene family. The aim of this study was to investigate the role of WNT5A as a novel target of CUTL1 in pancreatic cancer. CUTL1 and WNT5A were stably overexpressed as well as transiently and stably knocked-down by RNA interference. Effects on proliferation, migration and invasiveness were investigated by thymidine incorporation, Boyden chamber experiments and time-lapse microscopy. Expression of WNT5A in pancreatic cancer tissues was analyzed by real-time PCR and immunohistochemistry. We also analyzed the effect of CUTL1 and WNT5A on TRAIL-induced apoptosis using knock-down by RNAi and quantified apoptosis by FACS, TUNEL-assays, PARP-cleavage and caspase-3/7/8 activity assays. We found that CUTL1 transcriptionally upregulated WNT5A on RNA, protein and promoter level. WNT5A significantly enhanced migration, proliferation and invasiveness, mediating the pro-invasive effects of CUTL1 to a major extent. WNT5A effects were accompanied by a marked modulation of marker genes associated with epithelial-mesenchymal-transition (EMT). Using real-time PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias (PanIN lesions) and in invasive pancreatic adenocarcinomas, as compared to normal pancreas tissues. Furthermore CUTL1 and WNT5A are playing a significant role in modulating resistance to apoptosis in pancreatic cancer. Knock-down of CUTL1 and WNT5A resulted in significantly enhanced TRAIL-induced apoptosis, associated with increased PARP-cleavage and acitivity of the caspases 3, 7 and 8. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.dc.description.abstract
Languagededc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseStandard (Fassung vom 03.05.2003)dc.rights
Link to license texthttps://oparu.uni-ulm.de/xmlui/license_v1dc.rights.uri
KeywordCUTL1dc.subject
KeywordWNT5Adc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHApoptosisdc.subject.mesh
MeSHPancreatic neoplasmsdc.subject.mesh
MeSHRepressor proteinsdc.subject.mesh
MeSHWnt proteinsdc.subject.mesh
TitleFunktionelle Analyse des Glykoproteins WNT5A als Zielgen des Transkriptionsfaktors CUTL1 im Pankreaskarzinomdc.title
Resource typeDissertationdc.type
DOIhttp://dx.doi.org/10.18725/OPARU-829dc.identifier.doi
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-vts-59357dc.identifier.urn
GNDInvasion <Biologie>dc.subject.gnd
GNDZellmigrationdc.subject.gnd
FacultyMedizinische Fakultätuulm.affiliationGeneral
Date of activation2007-06-21T13:56:38Zuulm.freischaltungVTS
Peer reviewneinuulm.peerReview
Shelfmark print versionZ: J-H 11.542 ; W: W-H 9.749uulm.shelfmark
DCMI TypeTextuulm.typeDCMI
VTS ID5935uulm.vtsID
CategoryPublikationenuulm.category
Bibliographyuulmuulm.bibliographie


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