Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

Abstract

Oral squamous cell carcinoma (OSCC) constitutes 90% of all cancers in the oral cavity, and the prognosis for patients diagnosed with OSCC is still poor. The identification of novel therapeutic targets and prognostic markers for OSCC is therefore essential. Previous studies of OSCC revealed an increased expression of WNT5A in the tumor tissue. However, no functional studies of WNT5A-induced effects in OSCC have been performed. Two different OSCC cell lines were used for analysis of WNT5A expression by Western blot, whereas WNT5A-induced responses were analyzed by measuring calcium (Ca²⁺) signaling, PKC activation, migration and invasion. Despite the lack of WNT5A expression, both cell lines responded to recombinant WNT5A (rWNT5A) with activation of the non-canonical WNT/Ca²⁺ /PKC pathway. This effect was ascertained to be mediated by WNT5A by use of the WNT5A antagonist, Box5. To investigate how WNT5A affects tumor progression, rWNT5A-induced alterations in BrdU absorbance (reflecting the number of tumor cells) were analyzed. rWNT5A had no effect on BrdU absorbance but instead promoted tumor cell migration and invasion. These results were confirmed by the use of the WNT5A-mimicking peptide Foxy5, while the rWNT5A-induced migration was blocked by secreted Frizzled-related protein 1 (SFRP1), protein kinase C inhibitors or the intracellular Ca²⁺ chelator, MAPT. These novel data clearly show that WNT5A activates the non-canonical WNT/Ca²⁺ /PKC pathway and increases migration and invasion of OSCC cells. This may indicate how an increased WNT5A expression in the tumor tissue is likely to promote progression of OSCC.