Wilt inhibitory factor-1 (WIF-1) is a secreted protein that antagonizes Wilt signaling. We recently demonstrated the importance of aberrant activation of the Wilt signaling pathway in various cancers including malignant pleural mesothelioma. In this study, we revealed downregulated WIF-1 expression in cell lines and primary tissue when compared to normal mesothelial cell lines and adjacent pleura, respectively. We observed hypemethylation in four of four mesothelioma cell lines, but not in two normal mesothelial cell lines. In primary tissue samples, we observed methylation in three paired tumor specimens compared to their adjacent normal pleura and methylation in eight of nine unpaired tumor tissue samples. Taken together, our studies suggest that WIF-1 silencing due to its promoter hypermethylation is all important mechanism underlying the constitutively activated Wilt signaling in mesothelioma. New therapies toward inhibition of the Wilt pathway through WIF-1 might be promising for the future treatment of malignant mesothelioma. (c) 2006 Elsevier Inc. All rights reserved.