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

David S Yee,Yi Guo,Anne R Simoneau,Xiaolin Zi,Xuesen Li,Zhongbo Liu,Bang H Hoang,Samia Ghaffar,Jun Xie,Peter Mcqueen,Yaxiong Tang,Dash Atreya

doi:10.1186/1476-4598-9-162

David S Yee, Yi Guo + Show 10 more

Open Access

https://doi.org/10.1186/1476-4598-9-162

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Journal: Molecular Cancer	Publication Date: Jun 23, 2010
Citations: 165	License type: cc-by

Affiliation: University of California, Irvine

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.

Highlights

Prostate cancer (PCa) is the second most frequent cause of cancer-related mortality in men in the United States [1,2]
We show here that Wnt inhibitory factor 1 (WIF1) mRNA expression is absent in the majority of prostate cancer (PCa) cell lines, as well as in normal prostate epithelial cells (Figure 1A &1B)
Treatment of PC-3 cells with 1 μM 5-azacytidine for 72 hours induced the re-expression of WIF1 mRNA (Figure 1D). These results suggest that the absence of WIF1 mRNA expression in the majority of PCa cell lines is due to WIF1 promoter hypermethylation

Summary

Introduction

Prostate cancer (PCa) is the second most frequent cause of cancer-related mortality in men in the United States [1,2]. Aberrant activation of the Wnt pathway contributes to the progression of several major human cancers, including PCa [3,4]. An exhaustive list of Wnt target genes has been posted in "The Wnt homepage" website, which includes cell cycle regulators, metalloproteinase (MMP), CD44, Met, Jagged, vascular endothelial growth factor, etc. This list indicates that the Wnt pathway participates in cell proliferation, and cell invasion, metastasis and angiogenesis through regulation of Wnt target gene expression in a context-dependent fashion. Aberrations 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

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