Abstract
The role of pleiotrophin and its receptors RPTPβ/ζ and Syndecan-3 during tumor metastasis remains unknown. RPTPβ/ζ knockdown initiates EMT, promotes pleiotrophin-mediated migration and attachment through Syndecan-3 and induces in vivo metastasis. RPTPβ/ζ plays a suppressor-like role in prostate cancer metastasis. Boosting RPTPβ/ζ or attenuating Syndecan-3 signaling pathways may lead to more effective therapeutic strategies in treating prostate cancer metastasis. Pleiotrophin is a growth factor that induces carcinogenesis. Despite the fact that many published reports focused on the role of pleiotrophin and its receptors, receptor protein tyrosine phosphatase (RPTPβ/ζ), and syndecan-3 during tumor development, no information is available regarding their function in tumor metastasis. To investigate the mechanism through which pleiotrophin regulates tumor metastasis, we used two different prostate carcinoma cell lines, DU145 and PC3, in which the expression of RPTPβ/ζ or syndecan-3 was down-regulated by the RNAi technology. The loss of RPTPβ/ζ expression initiated epithelial-to-mesenchymal transition (EMT) and increased the ability of the cells to migrate and invade. Importantly, the loss of RPTPβ/ζ expression increased metastasis in nude mice in an experimental metastasis assay. We also demonstrate that RPTPβ/ζ counterbalanced the pleiotrophin-mediated syndecan-3 pathway. While the inhibition of syndecan-3 expression inhibited the pleiotrophin-mediated cell migration and attachment through the Src and Fak pathway, the inhibition of RPTPβ/ζ expression increased pleiotrophin-mediated migration and attachment through an interaction with Src and the subsequent activation of a signal transduction pathway involving Fak, Pten, and Erk1/2. Taken together, these results suggest that the loss of RPTPβ/ζ may contribute to the metastasis of prostate cancer cells by inducing EMT and promoting pleiotrophin activity through the syndecan-3 pathway.
Highlights
The role of pleiotrophin and its receptors RPTP/ and Syndecan-3 during tumor metastasis remains unknown
The mice that were injected with DU145-RM6 cells developed lung metastasis, but not those injected with DU145 or DU145-NC2 cells. This is the first demonstration that RPTP/ knockdown increases the intrinsic ability of prostate cancer cells to metastasize in vivo. These results suggest that RPTP/ may act as a tumor suppressor for prostate cancer metastasis
The present study demonstrates a role for pleiotrophin receptors, RPTP/ and syndecan-3, in prostate cancer metastasis and shed light on the molecular mechanism involved
Summary
The role of pleiotrophin and its receptors RPTP/ and Syndecan-3 during tumor metastasis remains unknown. To investigate the mechanism through which pleiotrophin regulates tumor metastasis, we used two different prostate carcinoma cell lines, DU145 and PC3, in which the expression of RPTP/ or syndecan-3 was down-regulated by the RNAi technology. While the inhibition of syndecan-3 expression inhibited the pleiotrophin-mediated cell migration and attachment through the Src and Fak pathway, the inhibition of RPTP/ expression increased pleiotrophin-mediated migration and attachment through an interaction with Src and the subsequent activation of a signal transduction pathway involving Fak, Pten, and Erk1/2 Taken together, these results suggest that the loss of RPTP/ may contribute to the metastasis of prostate cancer cells by inducing EMT and promoting pleiotrophin activity through the syndecan-3 pathway. In the present study, using RNAi technology, we stably transformed prostate carcinoma cells to down-regulate RPTP/ or syndecan-3 expression and investigated the in vivo and in vitro molecular mechanism through which pleiotrophin regulates tumor metastasis
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