Abstract
Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the β-catenin/TCF7L2 complex. Although genes up-regulated by Wnt/β-catenin signaling have been intensively studied, the roles of down-regulated genes are poorly understood. In this study, we explored a global gene expression of colorectal cancer cells transfected with β-catenin siRNAs or a dominant negative form of TCF7L2 (dnTCF7L2), and identified a set of genes down-regulated by Wnt/β-catenin signaling. Among the genes, we focused here on IFIT2, a gene encoding interferon-induced protein with tetratricopeptide repeats. A reporter assay using plasmids containing a 5’-flanking region of the gene showed that the reporter activity was enhanced by either transduction of β-catenin siRNA or dnTCF7L2, suggesting that the region is involved in the transcriptional regulation as a downstream of the β-catenin/TCF7L2 complex. Consistent with this result, expression of IFIT2 was significantly lower in colorectal cancer tissues than that in normal tissues. Exogenous IFIT2 expression decreased cell proliferation and increased apoptosis of colorectal cancer cells. These data suggested that the down-regulation of IFIT2 by Wnt/β-catenin signaling may play a vital role in human colorectal carcinogenesis through the suppression of apoptosis.
Highlights
Wnt signaling pathway is associated with maintenance of organogenesis, growth, and homeostasis through the regulation of differentiation, proliferation, and cell fate of epithelial cells [1]
We identified IFIT1 and IFIT2 as genes down-regulated by Wnt signaling in colorectal cancer (CRC) cells, and clarified that inhibition of IFIT2 may play a role in the proliferation and anti-apoptotic properties of CRC cells
We discovered that IFIT1 and IFIT2 are negatively regulated by Wnt signaling in CRC cells and that suppressed expression of IFIT2 may confer prosurvival properties to cancer cells
Summary
Wnt signaling pathway is associated with maintenance of organogenesis, growth, and homeostasis through the regulation of differentiation, proliferation, and cell fate of epithelial cells [1]. In the absence of Wnt signaling, a multi-molecular complex comprising of β-catenin, APC, Axin, and GSK-3β phosphorylates β-catenin, leading to its degradation in a proteasome-dependent pathway [3]. Upon the binding of Wnt ligands to Frizzled receptors and low density lipoprotein receptor-related protein, Dishevelled proteins are activated and inhibit the activity of GSK-3β [4]. Degradation of β-catenin is suppressed, and the accumulated β-catenin is translocated into the nucleus, where it binds to transcription factors such as T-cell factor/lymphoid enhancer factor (TCF/LEF). The TCF/LEF family is activated and transactivates the expression of their target genes. In 93% of colorectal tumors, Wnt/β-catenin signaling is deregulated mainly due to the inactivation of APC or activating mutations of CTNNB1 [5], which results in the elevated expression of target genes of the β-catenin/TCF complex
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
