Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. Aberrant activation of WNT signaling is implicated in lung carcinogenesis. EMX2, a human homologue of the Drosophila empty spiracles gene is a homeodomain-containing transcription factor. The function of EMX2 has been linked to the WNT signaling pathway during embryonic patterning in mice. However, little is known about the role of EMX2 in human tumorigenesis. In this study, we found that EMX2 was dramatically downregulated in lung cancer tissue samples and this downregulation was associated with methylation of the EMX2 promoter. Restoration of EMX2 expression in lung cancer cells lacking endogenous EMX2 expression suppressed cell proliferation and invasive phenotypes, inhibited canonical WNT signaling, and sensitized lung cancer cells to the treatment of the chemo cytotoxic drug cisplatin. On the other hand, knockdown of EMX2 expression in lung cancer cells expressing endogenous EMX2 promoted cell proliferation, invasive phenotypes and canonical WNT signaling. Taken together, our study suggests that EMX2 may have important roles as a novel suppressor in human lung cancer.

Silencing of Wnt antagonists with aberrant activation of Wnt signaling is a common phenomenon in various human cancers. Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space. In this study, we tried to illuminate the impact of WIF-1 gene expression in melanoma with WIF-1 silencing by in vitro and in vivo studies. We restored the expression of WIF-1 by nonviral gene transfer with a pcDNA3.1 vector. We demonstrated inhibition of melanoma cell growth after WIF-1 restoration in colony formation and proliferation assays in vitro. In addition, the inhibitory effect was related to downregulation of Wnt signaling, which was demonstrated at both the transcriptional and translational levels. Furthermore, by using a xenograft mouse model, we confirmed the effect of WIF-1 expression in suppressing tumor growth by inhibition of Wnt signaling in vivo. Our results suggest the potential for further application of WIF-1 gene therapy in melanoma with WIF-1 silencing.

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Constitutive activation of the Wnt pathway as a result of APC, AXIN1 or CTNNB1 mutations has been found in most colorectal cancers. For a long time, this aberrant Wnt activation has been thought to be independent of upstream signals. However, recent studies indicate that upstream signals retain their ability to regulate the Wnt pathway even in the presence of downstream mutations. Wnt‐2 is well known for its overexpression in colorectal cancer. Galectin‐3 (Gal‐3), a multifunctional carbohydrate binding protein implicated in a variety of biological functions, has recently been reported to interact with β‐catenin. In this study, we investigated roles of Wnt‐2 and Gal‐3 in the regulation of canonical Wnt/β‐catenin signaling. We found that siRNA silencing of either Wnt‐2 or Gal‐3 expression inhibited TCF‐reporter activity, decreased cytosolic β‐catenin level and induced apoptosis in human colorectal cancer cells containing downstream mutations. More interestingly, we showed that inhibition of both Wnt‐2 and Gal‐3 had synergistic effects on suppressing canonical Wnt signaling and inducing apoptosis, suggesting that aberrant canonical Wnt/β‐catenin signaling in colorectal cancer can be regulated at multiple levels. The combined inhibition of Wnt‐2 and Gal‐3 may be of superior therapeutic advantage to inhibition by either one of them, giving rise to a potential development of novel drugs for the targeted treatment of colorectal cancer. © 2007 Wiley‐Liss, Inc.