The metastasis suppressor CD82/KAI1 represses the TGF-β and Wnt signalings inducing epithelial-to-mesenchymal transition linked to invasiveness of prostate cancer cells.

Background: The epithelial-to-mesenchymal transition (EMT) is closely associated with cancer invasion and metastasis. Since the transforming growth factor β (TGF-β) and Wnt signals induce EMT in various epithelial cell types, we examined whether and how the CD82/KAI1 metastasis suppressor affects the TGF-β and Wnt signal-dependent EMT in human prostate cancer cells.

Methods: The invasiveness of cancer cells was evaluated by examining their ability to pass through the basement membrane matrigel. The subcellular localizations of Smad4 and β-catenin proteins were respectively examined by confocal microscopy following immunofluorescence antibody staining and immunoblotting analysis following subcellular fractionation. The transcriptional activities of the TGF-β -responsive TRE and Wnt-responsive Tcf/Lef promoters were determined by a luciferase reporter assay following transfection of the recombinant reporter vector into the cell.

Results: TGF-β and Wnt3a treatments of human prostate cancer cells without CD82 expression resulted in not only increased invasiveness but also EMT involving the development of motile structures, downregulation of E-cadherin, and upregulation of the mesenchymal proteins. However, in the cells with high levels of CD82, the TGF-β and Wnt3a stimulations neither elevated invasiveness nor induced EMT. Furthermore, the TGF-β signaling events occurring in the CD82-deficient cells, such as phosphorylation of Smad2, nuclear translocation of Smad4, and transactivation of the TRE promoter, did not take place in the high CD82-expressing cells. Further, high CD82 expression interfered with the Wnt signal-dependent alterations in the phosphorylation pattern of glycogen synthase kinase 3β (GSK-3β) in prostate cancer cells, which allowed GSK-3β to continue phosphorylating β-catenin, thereby attenuating the Wnt signaling effects on the nuclear translocation of β-catenin and subsequent transactivation of the Tcf/Lef promoter.

Conclusions: The results of the present study suggest that CD82/KAI1 functions in suppressing TGF-β - and Wnt-induced EMT in prostate cancer cells by inhibiting the TGF-β /Smad and Wnt/β-catenin pathways. Therefore, loss or decrease of CD82 expression is likely to render prostate cancer cells prone to respond to the TGF-β and Wnt signals with EMT, resulting in the development of a motile and invasive mesenchymal phenotype related to the initiation of the metastatic cascade.