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

Abstract

BackgroundAberrations in the Wnt pathway have been reported to be involved in the metastasis of prostate cancer (PCa) to bone. We investigated the effect and underlying mechanism of a naturally-occurring Wnt inhibitor, WIF1, on the growth and cellular invasiveness of a bone metastatic PCa cell line, PC3.ResultsThe 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.ConclusionThese 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.

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

“…Other in vivo studies have also evaluated the growth-inhibitory role of WIF1 in melanoma, lung, bladder, renal and prostate cancers (Kim et al, 2007;Lin et al, 2007;Kawakami et al, 2009;Tang et al, 2009;Yee et al, 2010). Most of these studies used tumor cells stably expressing the WIF1 transgene to show that WIF1 overexpression significantly attenuates tumor growth in mouse models.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…Ectopic expression of WIF1 in PC3 cells resulted in a dramatic increase in the protein levels of E-cadherin and cytokeratin-8 and a decrease in Ncadherin, vimentin, and fibronectin, suggesting that WIF1 expression caused a reversal of EMT (61). The mRNA expression and the protein levels of Slug and Twist were also decreased by WIF1 expression (61). It is conceivable that the WIF1-induced reversal of EMT is associated with inhibition of Wnt signaling, again highlighting the important role of Wnt signaling in the MET.…”

“…Similarly, silencing of FZD4 was shown to induce the phenotypic transition and activate b1-integrin and E-cadherin expression (59). Wnt inhibitory factor 1 (WIF1), a Wnt inhibitor that exists in vivo, can also modulate Wnt signaling by binding to Wnt ligands (60), and expression of WIF1 was found to be downregulated in numerous cancers (61,62). Ectopic expression of WIF1 in PC3 cells resulted in a dramatic increase in the protein levels of E-cadherin and cytokeratin-8 and a decrease in Ncadherin, vimentin, and fibronectin, suggesting that WIF1 expression caused a reversal of EMT (61).…”

“…Wnt inhibitory factor 1 (WIF1), a Wnt inhibitor that exists in vivo, can also modulate Wnt signaling by binding to Wnt ligands (60), and expression of WIF1 was found to be downregulated in numerous cancers (61,62). Ectopic expression of WIF1 in PC3 cells resulted in a dramatic increase in the protein levels of E-cadherin and cytokeratin-8 and a decrease in Ncadherin, vimentin, and fibronectin, suggesting that WIF1 expression caused a reversal of EMT (61). The mRNA expression and the protein levels of Slug and Twist were also decreased by WIF1 expression (61).…”

Enhanced antitumor effect of cisplatin in human NSCLC cells by tumor suppressor LKB1

“…The invasion index was quantified to correct cell motility. 22 The invasion and migration rates were calculated in terms of the number of treated cells relative to that of untreated cells.…”