DDX3, a subunit of CK1 epsilon, phosphorylates Dvl2 to promote beta-catenin activation. Overexpression of the Dvl2 protein results in potent activation of beta-catenin/TCF signaling in colorectal cancer. Therefore, we hypothesized that DDX3 might promote tumor invasion via the CK1 epsilon/Dvl2 axis due to beta-catenin/TCF activation. Western blotting showed that beta-catenin expression was decreased by DDX3 knockdown and increased by DDX3 overexpression in colorectal cancer cells. The TCF promoter activity and invasion capability were concomitantly increased and decreased by DDX3 manipulation in these cells. The invasion capability in colon cancer cells and xenograft lung tumor nodules induced by a DDX3-overexpressing T84 stable clone in tail-vein injection model were nearly suppressed by inhibitors of CK1 epsilon (PF4800567) and beta-catenin/TCF signaling (XAV939). Among colorectal cancer patients, DDX3 expression was positively correlated with the expression of pDvl2 and nuclear beta-catenin in tumor tissues. The expression of pDvl2 occurred more frequently in high-nuclear than in low-nuclear beta-catenin tumors. A prognostic significance of DDX3, pDvl2, and nuclear beta-catenin on overall survival and relapse free survival was observed in this study population. We therefore suggest CK1 epsilon or beta-catenin/ TCF signaling as potential targets for improving tumor regression and outcomes in colorectal cancer, particularly tumors with high-DDX3/high-nuclear beta-catenin or high-DDX3/high-pDvl2/high-nuclear beta-catenin expression.