Abstract
Abstract Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through the activation of β-catenin/TCF complex. Although genes up-regulated by Wnt/β-catenin signaling has been well studied, the down-regulated genes are poorly understood. To clarify the comprehensive changes regulated by the signaling in colorectal cancer cells, we explored a global gene expression of CRC cells transfected with β-catenin siRNAs or dominant negative form of TCF7L2 (dnTCF7L2). Consequently, a set of genes that were negatively regulated by β-catenin/TCF were identified. Among the genes, three members of interferon-induced proteins with tetratricopeptide repeats (IFIT) family (IFIT1, IFIT2, and IFIT3) expression were significantly increased by the inhibition of β-catenin/TCF. Comparison of gene expression data from normal colonic mucosa and the tumor tissues showed that the expression of IFIT1 and IFIT2 in the tumors was significantly lower than that in normal tissues. To elucidate the mechanism of IFITs expression regulated by β-catenin/TCF, we performed a reporter assay using plasmid containing 1.2-kb of 5’-flanking region of the IFIT2 gene. As a result, the reporter activity was significantly enhanced by either transduction of β-catenin or dnTCF7L2, suggesting that blockage of β-catenin/TCF stimulated IFITs through the promoter. In addition, we found that overexpression of IFIT2 increased apoptosis and decreased cell proliferation in SW480 and HCT116 cells. These results imply that Wnt signaling may promote anti-apoptotic effect in cancer cells through the suppression of IFIT2. Our findings suggest that analysis of down-regulated genes in response to activated Wnt/β-catenin signaling provides a better understanding of human colorectal carcinogenesis. Citation Format: Tomoyuki Ohsugi, Kiyoshi Yamaguchi, Chi Zhu, Tsuneo Ikenoue, Yoichi Furukawa. Wnt signaling induces anti-apoptotic effect in colorectal cancer cells through the suppression of IFITs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 373. doi:10.1158/1538-7445.AM2017-373
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