Abstract 3904: Potential role of WNT7A in ovarian cancer

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Most ovarian cancers are of epithelial origin, arising from a single layer of simple epithelial cells that covers the surface of the ovary. Epithelial ovarian cancer (EOC) remains the most common cause of death from a gynecological malignancy. The high mortality related to EOC is thought to be because of the advanced stage of the disease at presentation. Therefore, the early stage of detection and diagnosis as well as staging of ovarian cancer ultimately lead patients to the chance for a complete cure and long-term survival. The WNT system is known to play an important role in the regulation of developmental events where they govern cellular proliferation and differentiation. While WNT signaling plays a key role in the embryonic development of the ovary as well as normal follicular development and ovarian function, abnormal activation the WNT/CTNNB1 signaling pathway has been associated with ovarian tumorigenesis. It is likely that the WNT signaling pathway is involved in ovarian cancer development via multiple, diverse mechanisms such as gene mutations and changes in pathway components such as extracellular inhibitors and intranuclear transcription cofactors. However, the ligand partners associated with WNT signaling have not been examined in ovarian cancers. WNT7A is exclusively expressed in the luminal epithelium in reproductive tracts, whereas role of WNT7A in the normal ovary has not been reported, because WNT7A is not detected in the normal ovarian surface epithelium. Therefore, the objective is to study the functional role of WNT7A in ovarian cancer, especially to investigate WNT7A regulation of known metastatic inducing factors. First, we found that WNT7A was widely expressed in highly metastatic epithelial ovarian cancer cell lines (SKOV3.ip1). WNT7A was very low or almost undetectable in the ovarian biopsies taken from normal tissues, moderately expressed in the benign, but exclusively increased in the malignant ovarian tumors. Further, PLAU, MMP7, MMP9 and CDH1 were highly expressed in the same malignancy cases. To determine whether WNT7A activates the CTNNB1-TCF/LEF signal transduction pathway in ovarian tumors, SKOV3 cells, which do not express WNT7A, were transfected with the TOP-FLASH reporter, then treated with WNT7A conditioned media. The activity of the TOP-FLASH reporter in the SKOV3 cells was significantly stimulated by WNT7A conditioned media. WNT7A siRNA treatment reduced WNT7A mRNA to 27% (P<0.05). Down-regulation of WNT7A led to significant reduction in the mRNA levels of MMP7 (64%), MMP9 (47%) and CDH1 (72%) in the SKOV3.ip1 cells. While immunoreactive CTNNB1 was observed in the cytoplasmic and membrane of the SKOV3.ip1 and SKOV3 cells, nuclear CTNNB1 was only limited in the SKOV3.ip1 cells, but not in the SKOV3 cells. Further, WNT7A increased directional cell migration and attachment. Therefore, these results suggest that WNT7A is active as a secreted protein and a critical regulator of ovarian tumorigenesis as a metastatic factor of EOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3904.