Abstract
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.
Highlights
Expression of receptor 2 (Ror2) leads to increased tumorigenicity in renal cell carcinoma (RCC)
We have shown previously that Ror2 expression is associated with cellular migration and invasion phenotypes in renal carcinoma cells, growth of RCC is facilitated by -catenin transcription-mediated canonical signals [22]
Enrichment for genes in the Wnt receptor canonical signaling pathway (GO:0016055, p ϭ 2.6 ϫ 10Ϫ4) was observed (Fig. 1C). These results suggest that the role of Ror2 as a Wnt receptor in RCC tumors may not be limited to non-canonical Wnt pathways
Summary
Expression of Ror leads to increased tumorigenicity in RCC. Results: Ror expression stabilizes an increased pool of soluble -catenin, which enhances the response to Wnt stimulation. We provide evidence that Ror expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of -catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased -catenin pool associated with Ror expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror effect on -catenin signaling These results highlight a new role for Ror in conveying a tonic signal to stabilize soluble -catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC
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