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dc.contributor.authorSano, Makoto
dc.contributor.authorDriscoll, David R.
dc.contributor.authorDe Jesus-Monge, Wilfredo E.
dc.contributor.authorQuattrochi, Brian J.
dc.contributor.authorAppleman, Victoria A.
dc.contributor.authorOu, Jianhong
dc.contributor.authorZhu, Lihua (Julie)
dc.contributor.authorLewis, Brian C.
dc.date2022-08-11T08:09:46.000
dc.date.accessioned2022-08-23T16:42:52Z
dc.date.available2022-08-23T16:42:52Z
dc.date.issued2016-11-28
dc.date.submitted2017-03-27
dc.identifier.citationNeoplasia. 2016 Dec;18(12):785-794. doi: 10.1016/j.neo.2016.11.004. Epub 2016 Nov 25. <a href="https://doi.org/10.1016/j.neo.2016.11.004">Link to article on publisher's site</a>
dc.identifier.issn1476-5586 (Linking)
dc.identifier.doi10.1016/j.neo.2016.11.004
dc.identifier.pmid27889647
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40179
dc.description<p>Full author list omitted for brevity. For full list of authors see article.</p>
dc.description.abstractPancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding beta-cateninS37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-beta-cateninS37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active beta-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the beta-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/beta-catenin signaling pathway in pancreatic cancer cells. Nuclear beta-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear beta-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a beta-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/beta-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27889647&dopt=Abstract">Link to Article in PubMed</a>
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCancer Biology
dc.titleActivation of WNT/beta-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61
dc.typeJournal Article
dc.source.journaltitleNeoplasia (New York, N.Y.)
dc.source.volume18
dc.source.issue12
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3983&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2978
dc.identifier.contextkey9928028
refterms.dateFOA2022-08-23T16:42:52Z
html.description.abstract<p>Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding beta-cateninS37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-beta-cateninS37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P < .05). Ectopic expression of active beta-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the beta-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/beta-catenin signaling pathway in pancreatic cancer cells. Nuclear beta-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear beta-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P < .01). Knockdown of CYR61 in a beta-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/beta-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.</p>
dc.identifier.submissionpathoapubs/2978
dc.contributor.departmentCancer Center
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Molecular, Cell and Cancer Biology
dc.source.pages785-794


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