Abstract
Although Wnt signaling has been shown to be important for embryonic morphogenesis and cancer pathogenesis of several tissues, its role in prostatic development and tumorigenesis is not well understood. Here we show that Wnt signaling regulated prostatic epithelial branching morphogenesis and luminal epithelial cell differentiation in developing rat prostate organ cultures. Specifically, Wnt signaling regulated the proliferation of prostate epithelial progenitor cells. Assessment of the expression levels of a Wnt pathway transcriptional target gene, Axin2, showed that the Wnt pathway was activated in the developing prostate, but was down-regulated in the adult. Castration resulted in an upregulation of Axin2 whereas androgen replacement resulted in a down regulation of Axin2. Such dynamic changes of Wnt activity was also confirmed in a BAT-gal transgenic mouse line in which β-galactosidase reporter is expressed under the control of β-catenin/T cell factor responsive elements. Furthermore, we evaluated the role of Wnt signaling in prostate tumorigenesis. Axin2 expression was found upregulated in the majority of human prostate cancer cell lines examined. Moreover, addition of a Wnt pathway inhibitor, Dickkopf 1 (DKK1), into the culture medium significantly inhibited prostate cancer cell growth and migration. These findings suggest that Wnt signaling regulates prostatic epithelial ductal branching morphogenesis by influencing cell proliferation, and highlights a role for Wnt pathway activation in prostatic cancer progression.
Highlights
The Wnt signaling pathway is crucial in a variety of biological process including neural patterning, planar polarity, stem cell maintenance and cell differentiation [1]
The complexity of signaling arises in part from the multitude of components in this pathway including for example 19 human Wnt ligands, 1 Wnt inhibitory factor (WIF), 5 secreted frizzled related proteins (SFRPs) that can sequester Wnt ligands from binding to their cognate receptors, 2 low density lipoprotein receptor-related proteins (LRP5/6) and 4 Dickkopf (Dkk) proteins that modulate the activity of frizzled receptors [1,2]
To examine whether Wnt signaling plays a role in prostatic epithelial branching morphogenesis, we treated organ cultures of postnatal day 2 (P2) rat ventral prostates with a Wnt ligand, Wnt3a, or a potent Wnt signaling inhibitor, Dickkopf 1 (DKK1) [12]
Summary
The Wnt signaling pathway is crucial in a variety of biological process including neural patterning, planar polarity, stem cell maintenance and cell differentiation [1]. This has been demonstrated in a number of systems, via genetic and biochemical approaches. In absence of Wnt ligand binding, b-catenin is targeted to degradation via its interaction with the adenomatosis polyposis coli (APC) protein and the Wnt signaling is minimally activated. The Wnt signaling downstream program is poorly understood, and a very useful downstream gene specific for this pathway is Axin 2, which upon transcription and translation, acts as a negative feedback regulator of the Wnt siginaling pathway, by helping direct b-catenin for degradation in the proteasome [3,4]. Stabilization of b-catenin protein and elevation of Axin transcript are considered indicators of Wnt pathway activation [4]
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