Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells

Abstract

In the endometrium, hormonal effects on epithelial cells are often elicited through stromal hormone receptors via unknown paracrine mechanisms. Several lines of evidence support the hypothesis that Wnts participate in stromal-epithelial cell communication. Wnt7a is expressed in the luminal epithelium, whereas the extracellular modulator of Wnt signaling, secreted frizzled-related protein 4 (SFRP4), is localized to the stroma. Studies have reported that SFRP4 expression is significantly decreased in endometrial carcinoma and that both SFRP4 and Wnt7a genes are differentially regulated in response to estrogenic stimuli. Aberrant Wnt7a signaling irrevocably causes organ defects and infertility and contributes to the onset of disease. However, specific frizzled receptors (Fzd) that bind Wnt7a and the particular signal transduction pathway each Wnt7a-Fzd pair activates have not been identified. Additionally, the function of SFRP4 in the endometrium has not been addressed. We show here that Wnt7a coimmunoprecipitates with Fzd5, Fzd10, and SFRP4 in Ishikawa cells. Wnt7a binding to Fzd5 was shown to activate B-catenin/canonical Wnt signaling and increase cellular proliferation. Conversely, Wnt7a signaling mediated by Fzd10 induced a noncanonical c-Jun NH 2 -terminal kinase -responsive pathway. SFRP4 suppresses activation of Wnt7a signaling in both an autocrine and paracrine manner. Stable overexpression of SFRP4 and treatment with recombinant SFRP4 protein inhibited endometrial cancer cell growth in vitro. These findings support a mechanism by which the nature of the Wnt7a signal in the endometrium is dependent on the Fzd repertoire of the cell and can be regulated by SFRP4.

The Embryonic Transcription Cofactor LBH Is a Direct Target of the Wnt Signaling Pathway in Epithelial Development and in Aggressive Basal Subtype Breast Cancers

“…To our knowledge, this is the first evidence that Wnt7a can inhibit canonical Wnt signaling. One possible mechanism for the observed inhibitory effect could be that Wnt7a activates the noncanonical planar cell polarity (PCP) pathway in tissue culture cells (12,40). However, given our developmental genetics studies and the fact that Wnt7a and Wnt5a, which can also activate the PCP pathway (58,61), exerted different effects on Wnt3-induced gene expression, we propose that the inhibitory effect of Wnt7a on canonical Wnt3a signaling in tissue culture cells could be mediated by a poorly understood noncanonical pathway involving Lmx1b (37).…”

Secreted Frizzled-Related Protein 4

“…40 The ability for sFRP4 to antagonize both the canonical ␤-catenin and noncanonical c-JNK pathways is in accordance with a previous study, which reported that sFRP4 antagonized Wnt7a signaling via both the canonical ␤-catenin and noncanonical c-JNK pathways in endometrial cancer cells. 41 Therefore, sFRP4 exhibits a multilevel effect on ␤-catenin. It directly antagonizes the canonical Wnt/␤-catenin pathway and also the noncanonical Wnt/planar cell polarity pathway.…”

Secreted frizzled related proteins: Implications in cancers

“…Both canonical and non-canonical Wnt signalling pathways have been shown to be activated by Wnt7a, and SFRP4 was shown to antagonize Wnt7a mediated signalling and inhibit proliferation of endometrial cancer cells [89]. Wnt7a is expressed in the luminal epithelium, with SFRP4 localised to the stroma and there was an interaction seen between them by immunoprecipitation, which could possibly explain SFRP4 mediated inhibition in Wnt7a signalling activation.…”