WNT5A is a potent modulator of tumor cell proliferation and invasion overexpressed in pancreatic cancer

WNT5A is a secreted member of the Wnt multi-gene family which has been implicated in modulation of tumor progression in melanoma and lymphoma cells. Recently, we identified WNT5A as downstream target of the pro-invasive transcription factor CUTL1 downstream TGFbeta. To investigate the effect of WNT5A on proliferation and invasion, we used PANC1 pancreatic carcinoma cells stably overexpressing WNT5A as well as cells with a transient knock-down of WNT5A by RNA interference. We observed a significantly increased cell proliferation in WNT5A expressing cells, as assessed by cell counting, thymidine incorporation and FACS analysis. To study the effect of WNT5A on migration and invasion, we used the highly motile HT1080 fibrosarcoma cell line as well as PANC1 cells. WNT5A significantly increased migration and invasion of both cell lines, as analyzed by modified Boyden chamber assays and video time-lapse microscopy. Furthermore, WNT5A led to upregulation of marker genes associated with epithelial-mesenchymal-transition (EMT) such as vimentin, which was accompanied by a downregulation of epithelial markers such as E-cadherin and cytokeratin 8/18. By immunohistochemistry, we found that WNT5A is highly overexpressed in a series of pancreatic adenocarcinomas, as compared to normal pancreas tissues. These data identify WNT5A as a new important enhancer of invasiveness and tumor progression in pancreatic cancers.

Keywords: CUTL1, EMT, WNT5A, invasion, migration, proliferation