Abstract 3058: WNT7A regulates ovarian tumorigenesis through the canonical WNT signaling pathway
Authors: Hayashi Kanako , Yoshioka Shin , Ran Sophia , Maclean James A. 
Published: June 2012

Abstract
The WNT system is known to play an important role in the regulation of developmental events where it governs cellular proliferation and differentiation. WNT signaling plays a key role in the normal 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 including gene mutations and changes in pathway components such as extracellular inhibitors and nuclear transcription cofactors. To date, the ligand partners associated with WNT signaling have not been examined in ovarian cancers. The present study investigated the potential role of WNT7A in the ovarian carcinomas including its functional mechanisms. Although WNT7A has not been detected in normal ovary, we found that WNT7A became abundantly expressed in 40-60 % of serous high grade ovarian malignant tumors, and 20-30 % of mucinous and clear cell adenocarcinomas, but not in the endometrioid carcinomas. To determine whether WNT7A activates the canonical CTNNB1-TCF/LEF pathway in ovarian tumors, epithelial ovarian cancer cells, which do not express WNT7A, were transfected with the TOP-FLASH reporter, then overexpressed WNT7A. The activity of the TOP-FLASH reporter was significantly stimulated by cells transiently transfected with WNT7A, and its activity was increased by transfected with frizzled receptor 5 (FZD5). Further, WNT inhibitors and antagonists (DKKs and SFRPs) blocked the activity of the TOP-FLASH reporter in the epithelial ovarian cancer cells. Overexpression of WNT7A stimulated the expression of MMP7 in SKOV3 and HEY cells compared to control. MMP7 promoter activity was conferred by 237 bp 5’-flanking sequence which contains 2-TCF binding sites, and its activity stimulated by WNT7A was not observed by mutation of this flanking sites. These results indicate that epithelial ovarian cancer cells have an intact CTNNB1-TCF/LEF signaling pathway that could be activated by WNT7A, and regulate its target genes. Further, overexpression of WNT7A stimulates HOXA11, which is one of critical inducers of morphological differentiation in the epithelial ovarian carcinomas. Stable overexpression of WNT7A in SKOV3 cells increased cell adhesion and migration. The directional cell migration decreased by 60% in WNT7A knocked down SKOV3.ip1 cells, which are highly expressed WNT7A, using siRNA. In vivo xenograft experiment revealed that WNT7A knockdown inhibited tumor development. Therefore, these results suggest that WNT7A is a critical regulator of ovarian tumorigenesis and progression via the canonical WNT/CTNNB pathway. Supported by ACS-IL 139038.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3058. doi:10.1158/1538-7445.AM2011-3058