Wnt inhibitory factor-1, a Wnt antagonist, is silenced by promoter hypermethylation in malignant pleural mesothelioma.
Wnt inhibitory factor-1 (WIF-1) is a secreted protein that antagonizes Wnt signaling. We recently demonstrated the importance of aberrant activation of the Wnt 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 hypermethylation 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 an important mechanism underlying the constitutively activated Wnt signaling in mesothelioma. New therapies toward inhibition of the Wnt pathway through WIF-1 might be promising for the future treatment of malignant mesothelioma.
Batra
Sonny
S
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Shi
Yihui
Y
Kuchenbecker
Kristopher M
KM
He
Biao
B
Reguart
Noemi
N
Mikami
Iwao
I
You
Liang
L
Xu
Zhidong
Z
Lin
Yu-Ching
YC
Clément
Geneviève
G
Jablons
David M
DM
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D020868:Gene Silencing; D006801:Humans; D008654:Mesothelioma / Q000235:genetics*; D010997:Pleural Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins