Identifying key mediators of
cancer invasion and
metastasis is crucial to the development of new and more effective
therapies. We previously identified
FILamin A Interacting
Protein 1-Like (FILIP1L) as an important inhibitor of cell migration and invasion. FILIP1L expression was inversely correlated with the invasive potential of ovarian
tumors. In our study, we established an orthotopic
ovarian cancer model, wherein FILIP1L expression can be regulated in vivo. Using this model, we observed that expression of FILIP1L in
ovarian cancer cells inhibited spontaneous lung
metastasis. Experimental lung
metastases (established via tail vein injection of
cancer cells) as well as the extravasation step of
metastasis were not inhibited by FILIP1L, suggesting that FILIP1L inhibits the earlier steps of
metastasis such as invasion and intravasation. FILIP1L inhibited
matrix metalloproteinase (
MMP)-dependent invasion in vivo. MMP3, -7 and -9 were transcriptionally downregulated, and MMP9
protein expression and activity were inhibited in FILIP1L-expressing
tumors. Importantly, overexpression of MMP9 compensated for the anti-invasive activity of FILIP1L. Furthermore, our studies suggest that FILIP1L regulates invasion and
metastasis by inhibiting components of the WNT signaling pathway. FILIP1L expression reduced the induction of WNT target genes such as MMP3, -7 and -9, and β-
catenin-directed transcriptional activity, suggesting inhibition of the canonical WNT pathway. Nuclear β-
catenin, an
indicator of an active canonical WNT pathway, was reduced in FILIP1L-expressing
tumors. Overall, these findings suggest that FILIP1L reduces β-
catenin levels, which may lead to the transcriptional downregulation of WNT target genes such as
MMPs, resulting in inhibition of
metastasis. Modulation of FILIP1L expression has the potential to be a target for
cancer therapy.