TY - JOUR
T1 - WNT5A - Target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer
AU - Ripka, S.
AU - König, A.
AU - Buchholz, M.
AU - Wagner, M.
AU - Sipos, B.
AU - Klöppel, G.
AU - Downward, J.
AU - Gress, T. M.
AU - Michl, P.
N1 - Funding Information:
We thank Dr A.Nepveu for providing various expression and luciferase constructs and Ms Susanne Braun and Ms Beate Knobel for expert technical advice and assistance. This work was supported by grants of the Deutsche Forschungsgemeinschaft to P.M. (MI 710/3-1) and to T.M.G. (SFB 518 project B1) and partially of the Deutsche Krebshilfe to T.M.G. (PancNet 106840).
PY - 2007/6
Y1 - 2007/6
N2 - Previously, we have identified the transcription factor CUTL1 as an important mediator of tumor invasion and target of tumor growth factor-beta. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multigene 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 over-expressed 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 polymerase chain reaction (RT-PCR) and immunohistochemistry. We found that CUTL1 transcriptionally up-regulated 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. Using RT-PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas, as compared with normal pancreas tissues. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.
AB - Previously, we have identified the transcription factor CUTL1 as an important mediator of tumor invasion and target of tumor growth factor-beta. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multigene 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 over-expressed 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 polymerase chain reaction (RT-PCR) and immunohistochemistry. We found that CUTL1 transcriptionally up-regulated 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. Using RT-PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas, as compared with normal pancreas tissues. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.
UR - http://www.scopus.com/inward/record.url?scp=34447326176&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgl255
DO - 10.1093/carcin/bgl255
M3 - Article
C2 - 17227781
AN - SCOPUS:34447326176
SN - 0143-3334
VL - 28
SP - 1178
EP - 1187
JO - Carcinogenesis
JF - Carcinogenesis
IS - 6
ER -
