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F13. Wnt Inhibitory Factor-1 is silenced by promoter methylation in human lung cancer
Julien Mazieres, Biao He, Zhidong Xu, Liang You, David Jablons; San Francisco, CA

Objectives: Aberrant activation of the Wingless-type (Wnt) signaling pathway is associated with a variety of human cancers and we recently reported the importance of aberrant Wnt signaling in lung cancer. On the other hand, inhibition of Wnt signaling suppresses growth in numerous cell types. Wnt Inhibitory Factor-1 (WIF-1) is a secreted antagonist that can bind Wnt in the extracellular space and inhibit Wnt signaling. Recently, down-regulation of WIF-1 has been reported in several human cancers. To discover the mechanism of WIF-1 silencing in lung cancer, we examined the methylation status in the CpG islands of WIF-1 promoter region. Methods: Human lung cancer cell lines and fresh human lung cancer tissues were used. Methylation specific PCR and sequencing analysis after bisulfite treatment were used to examine methylation status. Semi-quantitative RT-PCR and Western blotting were used to analyze WIF-1 expression. Results: We demonstrate frequent CpG islands hypermethylation in the functional WIF-1 promoter region. This silencing correlates with its transcriptional silencing in human lung cancer cell lines. Moreover, treatment with DAC (5-aza-2'-deoxycytidine) restores WIF-1 expression. We then studied WIF-1 expression in 18 freshly resected lung cancers and show a downregulation in 15 of them (83%). This silencing also correlates with WIF-1 promoter methylation. Conclusions: Our results suggest that methylation-silencing of WIF-1 is a common and likely important mechanism of aberrant activation of the Wnt signaling pathway in lung cancer pathogenesis raising its therapeutic interest.

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