Carcinogenesis Advance Access published online on January 16, 2007
Carcinogenesis, doi:10.1093/carcin/bgl255
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WNT5A – target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer
1 Dept. of Internal Medicine I, University of Ulm, 89081 Ulm, Germany
2 Dept. of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
3 Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom
4 Division of Gastroenterology and Endocrinology, Department of Internal Medicine, Philipps-University, 35043 Marburg, Germany
# Correspondence address: Dr. Patrick Michl, Department of Internal Medicine, Division of Gastroenterology, University of Marburg, Baldinger Strasse, 35043 Marburg, Germany. Phone: +49 6421 286 1714, Fax: +49 6421 286 8922, E-mail: michlp{at}med.uni-marburg.de
Previously, we have identified the transcription factor CUTL1 as important mediator of tumor invasion and target of TGF-beta. 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 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. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.
Key Words: CUTL1 • WNT5A • migration • invasion • pancreatic cancer
* equal contribution
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