The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition

The WIF1 gene promoter was hypermethylated and its expression down-regulated in the majority (7 of 8) of PCa cell lines. Restoration of WIF1 expression in PC-3 cells resulted in a decreased cell motility and invasiveness via up-regulation of epithelial markers (E-cadherin, Keratin-8 and-18), down-regulation of mesenchymal markers (N-cadherin, Fibronectin and Vimentin) and decreased activity of MMP-2 and -9. PC3 cells transfected with WIF1 consistently demonstrated reduced expression of Epithelial-to-Mesenchymal Transition (EMT) transcription factors, Slug and Twist, and a change in morphology from mesenchymal to epithelial. Moreover, WIF1 expression significantly reduced tumor growth by approximately 63% in a xenograft mouse model. This was accompanied by an increased expression of E-cadherin and Keratin-18 and a decreased expression of vimentin in tumor tissues.These data suggest that WIF1 regulates tumor invasion through EMT process and thus, may play an important role in controlling metastatic disease in PCa patients. Blocking Wnt signaling in PCa by WIF1 may represent a novel strategy in the future to reduce metastatic disease burden in PCa patients.Prostate cancer (PCa) is the second most frequent cause of cancer-related mortality in men in the United States [1,2]. Although a significant portion of PCa is curable either by surgery or by radiotherapy when detected early [1,2], advanced PCa with metastases still presents a difficult therapeutic problem. Specifically, bone metastasis is the major cause of mortality in patients with PCa. Therefore, understanding the processes that promote metastasis of PCa could be useful in designing effective therapies for advanced PCa with bone metastasis.The wingless-type (Wnt) pathway plays a central role in the development of many tissues and organisms. Aberrant activation of the Wnt pathway contributes to the progression of several major human cancers, including PCa [3,4]. The best-studied Wnt signaling pathway is the Wnt/β-